ORCID Profile
0000-0003-4058-0372
Current Organisations
Baker IDI Heart and Diabetes Institute
,
The Alfred Hospital
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Publisher: Elsevier BV
Date: 04-1997
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
Publisher: American Society for Clinical Investigation
Date: 23-03-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1999
DOI: 10.1097/00004872-199917080-00012
Abstract: Two hypotheses concerning mechanisms of weight gain and of blood pressure elevation in obesity were tested. The first hypothesis is that in human obesity sympathetic nervous system underactivity is present, as a metabolic basis for the obesity. The second hypothesis, attributable to Landsberg, is that sympathetic nervous activation occurs with chronic overeating, elevating blood pressure. These are not mutually exclusive hypotheses, since obesity is a heterogeneous disorder. Whole body and regional sympathetic nervous system activity, in the kidneys and heart, was measured at rest using noradrenaline isotope dilution methodology in a total of 86 research voluteers in four different subject groups, in lean and in obese people who either did, or did not, have high blood pressure. In the lean hypertensive patients, noradrenaline spillover for the whole body, and from the heart and kidneys was substantially higher than in the healthy lean volunteers. In normotensive obesity, the whole body noradrenaline spillover rate was normal, mean renal noradrenaline spillover was elevated (twice normal), and cardiac noradrenaline spillover reduced by approximately 50%. In obesity-related hypertension, there was elevation of renal noradrenaline spillover, comparable to that present in normotensive obese in iduals but not accompanied by suppression of cardiac noradrenaline spillover, which was more than double that of normotensive obese in iduals (P<0.05), and 25% higher than in healthy volunteers. There was a parallel elevation of heart rate in hypertensive obese in iduals. The sympathetic underactivity hypothesis of obesity causation now looks untenable, as based on measures of noradrenaline spillover, sympathetic nervous system activity was normal for the whole body and increased for the kidneys the low sympathetic activity in the heart would have only a trifling impact on total energy balance. The increase in renal sympathetic activity in obesity may possibly be a necessary cause for the development of hypertension in obese in iduals, although clearly not a sufficient cause, being present in both normotensive and hypertensive obese in iduals. The discriminating feature of obesity-related hypertension was an absence of the suppression of the cardiac sympathetic outflow seen in normotensive obese in iduals. Sympathetic nervous changes in obesity-related hypertension conformed rather closely to those expected from the Landsberg hypothesis.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-04-2009
DOI: 10.1161/CIRCULATIONAHA.108.843219
Abstract: Background— Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Methods and Results— Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL=−2.6±0.4 placebo=−2.1±0.3mmol/L P =0.018). rHDL increased plasma insulin (at 4 hours rHDL=3.4±10.0 placebo= −19.2±7.4 pmol/L P =0.034) and also the homeostasis model assessment β-cell function index (at 4 hours rHDL=18.9±5.9 placebo=8.6±4.4% P =0.025). Acetyl-CoA carboxylase β phosphorylation in skeletal muscle biopsies was increased by 1.7±0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177±12% and 144±18%, respectively P .05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n=5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. Conclusions— rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2003
DOI: 10.1097/00008571-200307000-00002
Abstract: Although the widespread introduction of beta-adrenoceptor antagonists into the management of congestive heart failure (CHF) has led to significant improvements in morbidity and mortality, it is also apparent that clinical responses to this therapy vary substantially. With the recognition that functionally significant genetic polymorphisms of the beta2-adrenoceptor exist with clinically relevant allelic frequency, we hypothesized that beta2-adrenoceptor genotype may affect the response to carvedilol. The clinical response, influence on left ventricular function and beta2-adrenoceptor (beta2AR) genotype was determined in 80 patients treated with carvedilol. A clinically significant improvement in left ventricular function (good responder) was defined as an absolute improvement of 10% in the left ventricular ejection fraction or 5% in the fractional shortening. Consistent with studies performed in vitro on the influence of beta2AR genotype and receptor desensitization, subjects who were homozygous for the allele encoding the Gln27 polymorphism displayed a significantly lower proportion of good responders than patients who were homozygous or heterozygous for the Glu27 polymorphism (26% versus 63%, P=0.003). These data demonstrate a significant influence of beta2AR genotype in the response to carvedilol in CHF patients. Accordingly, determination of beta2AR status may be of value in the tailoring of in idual therapy in patients with CHF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-11-2004
DOI: 10.1161/01.CIR.0000146904.13677.E4
Abstract: Background— Functional mitral valve regurgitation plays a key role in the symptomatic severity and progression of heart failure. In an ovine model of dilated cardiomyopathy, we examined the chronic functional consequences of mitral regurgitation reduction using a recently developed novel percutaneous mitral annular reduction (PMAR) device. Methods and Results— Fourteen adult sheep were paced right ventricularly at 180 to 190 bpm for 5 weeks, leading to the development of moderate mitral valve regurgitation. After echocardiographic, hemodynamic, and neurohormonal analysis, 9 animals underwent PMAR. All animals were subsequently paced for another 28 days, and a final echocardiographic and hemodynamic study was conducted. Animals that had undergone PMAR showed significantly increased negative and positive dP/dt, whereas pulmonary capillary wedge pressure and mitral valve regurgitation were significantly reduced compared with those at device implant despite continued pacing. In conjunction, significant improvements in plasma norepinephrine and brain natriuretic peptide were apparent. Conclusions— The application of PMAR in animals with pacing-induced dilated cardiomyopathy and functional mitral valve regurgitation resulted in continued improvements in hemodynamic and neurohormonal parameters.
Publisher: Elsevier BV
Date: 10-1992
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.RESUSCITATION.2013.12.010
Abstract: Currently many emergency medical services (EMS) that provide advanced cardiac life support (ACLS) at scene do not routinely transport out-of-hospital cardiac arrest (OHCA) patients without sustained return of spontaneous circulation (ROSC). This is due to logistical difficulties and historical poor outcomes. However, new technology for mechanical chest compression has made transport to hospital safer and extracorporeal membrane oxygenation during cardiopulmonary resuscitation (ECPR) enabling further intervention, may result in ROSC. We aimed to explore the characteristics and outcomes of patients with OHCA who were transported to hospital with ongoing CPR in the absence of ROSC, who might benefit from this new technology. The Victorian Ambulance Cardiac Arrest Registry (VACAR) was searched for adult OHCA with an initial shockable rhythm between 2003 and 2012. There were 5593 OHCA meeting inclusion criteria. Analysis was performed on 3095 (55%) of patients who did not achieve sustained ROSC in the field. Of these only 589 (20%) had ongoing CPR to hospital. There was a significant decline in rates of transport over the study period. Predictors of transport with ongoing CPR included younger patients, decreased time to first shock and intermittent ROSC prior to transport. Survival to hospital discharge occurred in 52 (9%) of patients who had ongoing CPR to hospital. In an EMS that provides ACLS at scene, patients without ROSC in the field who receive CPR to hospital have poor outcomes. Developing a system which provides safe transport with ongoing CPR to a hospital that provides ECPR, should be considered.
Publisher: Wiley
Date: 05-08-2014
DOI: 10.1111/APHA.12344
Abstract: Hypertension is a major clinical complication of obesity. Our previous studies show that abnormal uptake of the nitric oxide precursor L-arginine, via the cationic amino acid transporter-1 (CAT1), contributes to endothelial dysfunction in cardiovascular disease. In this study, we tested the hypothesis that abnormal L-arginine transport may be a key mediator of obesity-induced hypertension. Mean arterial pressure (MAP) was monitored by telemetry in conscious wild-type (WT n = 13) mice, and transgenic mice with endothelial-specific overexpression of CAT1 (CAT+ n = 14) fed a normal or a high fat diet for 20 weeks. Renal angiotensin II (Ang II), CAT1 mRNA and plasma nitrate/nitrite levels were then quantified. In conjunction, plasma nitrate/nitrite levels were assessed in obese normotensive (n = 15) and obese hypertensive subjects (n = 15). Both genotypes of mice developed obesity when fed a high fat diet (P ≤ 0.002). Fat fed WT mice had 13% greater MAP and 78% greater renal Ang II content, 42% lesser renal CAT1 mRNA levels and 42% lesser plasma nitrate/nitrite levels, than WT mice fed a normal fat diet (P ≤ 0.02). In contrast, none of these variables were significantly altered by high fat feeding in CAT+ mice (P ≥ 0.36). Plasma nitrate/nitrite levels were 17% less in obese hypertensives compared with obese normotensives (P = 0.02). Collectively, these data indicate that obesity-induced down-regulation of CAT1 expression and subsequent reduced bioavailability of nitric oxide may contribute to the development of obesity-induced hypertension.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Informa UK Limited
Date: 1997
DOI: 10.3109/10641969709083171
Abstract: Recent experiments in laboratory animals have challenged the conventional view that the dominant effect of CNS noradrenergic neurons in cardiovascular control is sympathetic nervous inhibition and blood pressure reduction, describing instead sympathetic activation. We have tested whether such a stimulant effect on sympathetic outflow is also evident in human hypertension. CNS norepinephrine turnover was estimated from the combined overflow of norepinephrine, MHPG and DHPG into the internal jugular veins. Cerebral blood flow scans allowed differentiation between cortical and subcortical jugular venous drainage. In patients with pure autonomic failure, jugular overflow of norepinephrine and metabolites was not reduced, indicating brain neurons and not cerebrovascular sympathetics was the source. In healthy men, CNS norepinephrine turnover and muscle sympathetic nerve activity were directly related (p < 0.02). Administration of the ganglion blocker, trimethaphan, caused a compensatory five-fold increase in jugular overflow of MHPG. Conversely, intravenous clonidine reduced CNS norepinephrine turnover by approximately 50%, this possibly representing a mechanism of drug action. In cardiac failure patients, sympathetic nervous activation was associated with a trebling of CNS norepinephrine turnover (p < 0.01). In untreated patients with essential hypertension, the sympathetic activation present was associated with 250% higher CNS norepinephrine turnover (p < 0.01), but in subcortical brain regions only. A close and direct relation exists between brain norepinephrine turnover and human sympathetic nervous activity. CNS release of norepinephrine, presumably in the forebrain where noradrenergic neurons are sympathoexcitatory and pressor, mediates increased sympathetic nerve firing in patients with essential hypertension.
Publisher: Oxford University Press (OUP)
Date: 06-2016
Publisher: Elsevier BV
Date: 12-1997
DOI: 10.1016/S0002-9149(97)00844-8
Abstract: Recent demonstration that the level of sympathetic nervous drive to the failing heart in patients with severe heart failure is a major determinant of prognosis, and that mortality in heart failure is decreased by beta-adrenergic blockade with carvedilol, indicates the clinical relevance of cardiac neuroscience research. Important initial findings were observations that the plasma concentration of the sympathetic neurotransmitter, norepinephrine, is elevated in heart failure, and that overall clinical outcome is related to plasma norepinephrine concentration (although heart failure severity may be a confounder). Sympathetic nerve recording (clinical microneurography) and radiotracer methods measuring regional sympathetic activity in the heart (cardiac norepinephrine "spillover") have now largely supplanted antecubital venous norepinephrine measurements as research tools, with newer methods providing information on regional sympathetic function that was previously lacking. The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with norepinephrine release from the failing heart at rest in untreated patients increased up to 50-fold, which is similar to the level of release in healthy hearts during near maximal exercise. There is lesser stimulation of the sympathetic outflows to the kidneys and skeletal muscle. In early mild heart failure, it is only the cardiac sympathetic nerves that are activated. This preferential activation of cardiac sympathetic outflow contributes to arrhythmia development and probably to progression of heart failure and has been linked to mortality in mild and severe heart failure. The central nervous system mechanisms involved in the sympathetic nervous activation present in patients with heart failure remain uncertain. Increased intracardiac diastolic pressure seems to be one peripheral reflex stimulus with increased forebrain norepinephrine turnover being an important central mechanism.
Publisher: Wiley
Date: 23-01-2012
DOI: 10.1111/J.1540-8167.2011.02255.X
Abstract: Pulmonary hypertension (PH) is common to a range of cardiopulmonary conditions and is associated with atrial arrhythmias. However, little is known of the isolated atrial effects of PH and right atrial dilatation (RA) in humans. To avoid the confounding effects of PH-associated disease states, we performed detailed electrophysiological (EP) and electroanatomic (EA) mapping of the RA in patients with idiopathic PH. Eight PH patients (mean pulmonary arterial [PA] pressure 39.0 ± 15.8 mmHg) and 16 age-matched controls (mean PA pressure 11.5 ± 4.1 mmHg, P < 0.0001) were studied. Corrected sinus node recovery times (cSNRT), atrial effective refractory periods (ERPs), conduction delay at the crista terminalis (CT), and inducibility of atrial fibrillation (AF) were evaluated. EA mapping (pacing cycle length 600 and 300 milliseconds) was performed to determine RA global and regional voltage, conduction velocities, atrial activation times, fractionated electrograms and double potentials. Patients with PH demonstrated a prolongation in cSNRT without significant change in atrial ERP and an increase in AF inducibility. PH was associated with lower tissue voltage (1.8 ± 0.4 mV in PH vs 2.2 ± 0.4 mV in controls, P = 0.02), increased low voltage areas (13.7 ± 8.2% in PH vs 6.2 ± 3.7% in controls, P < 0.01) and the presence of electrically silent areas. Conduction velocities were slower (global 67.3 ± 5.6 cm/s vs 92.8 ± 4.0 cm/s, P < 0.001) and fractionated electrograms and double potentials were more prevalent (14.7 ± 4.4% vs 6.3 ± 4.1, P < 0.01) in PH compared with controls, respectively. Idiopathic PH is associated with RA remodeling characterized by: generalized conduction slowing with marked regional abnormalities reduced tissue voltage and regions of electrical silence. These changes provide important insights into the isolated effects of PH fundamental to a range of clinical conditions associated with AF.
Publisher: American Physiological Society
Date: 09-1998
DOI: 10.1152/AJPHEART.1998.275.3.H906
Abstract: ANG II has been implicated in the hypertrophic response in ventricular myocytes by acting at the angiotensin type 1 (AT 1 ) receptor. However, the role of the angiotensin type 2 (AT 2 ) receptor in the adult heart is not as clearly understood. In adult rat ventricular myocytes (ARVM) and cardiac microvascular endothelial cells (CMEC), we examined the role of ANG II signaling, via AT 1 and AT 2 receptors, on the activation of the extracellular signal-regulated protein kinases (ERKs) and on the expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1. ANG II caused no detectable increase in ERK activity or in c- fos mRNA abundance in ARVM but increased ERK activity within 5 min in CMEC and increased c- fos mRNA levels. However, in the presence of the selective phosphoprotein phosphatase (PP-2A/PP-1) inhibitor okadaic acid (OA), a sustained increase in ERK activity, as well as in c- junNH 2 -terminal protein kinase activity, in ARVM was observed. ANG II increased MKP-1 mRNA levels within 15 min in ARVM and CMEC. In contrast to the response in endothelial cells, however, ANG II activation of MKP-1 in ARVM was mediated by AT 2 -receptor activation. Thus there is constitutive as well as inducible suppression of ERKs and c- junNH 2 -terminal protein kinases by MKP and PP-2A/PP-1 in the adult cardiac myocyte phenotype.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1995
Publisher: Wiley
Date: 14-03-2016
DOI: 10.1111/JCE.12948
Abstract: Non-sustained ventricular tachycardia (NSVT) is a risk factor for sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We aimed to assess whether diffuse ventricular fibrosis on cardiac magnetic resonance (CMR) imaging could be a surrogate marker for ventricular arrhythmias in patients with HCM. A total of 100 patients with HCM (mean age 51 ± 13 years, septal wall thickness 20 ± 5 mm) underwent CMR with a 1.5 T scanner to determine the presence of ventricular late gadolinium enhancement (LGE) for focal fibrosis, and post-contrast T1 mapping for diffuse ventricular fibrosis. The presence of NSVT was determined by Holter monitoring and a subset of high risk patients received an implantable cardioverter-defibrillator (ICD). NSVT was detected in 23 of 100 patients with HCM. Focal ventricular fibrosis (by LGE) was observed in 87%, with no significant difference between patients with (96%) or without NSVT (86%, P = 0.19). However, LGE mass was greater in patients with (16.5 ± 19.1 g) versus without NSVT (7.6 ± 10.2 g, P < 0.01). NSVT was associated with a significant reduction in ventricular T1 relaxation time (422 ± 54 milliseconds) versus patients without NSVT (512 ± 115 milliseconds P < 0.001). There was significant reduction in ventricular T1 relaxation time in patients with (430 ± 48 milliseconds) versus without aborted SCD (495 ± 113 milliseconds P = 0.01) over a mean follow-up of 40 ± 10 months. On multivariate analysis post-contrast ventricular T1 relaxation time and septal wall thickness were the only predictors of NSVT. Post-contrast T1 relaxation time on CMR is associated with ventricular arrhythmias in patients with HCM. Diffuse ventricular fibrosis may be an important marker of arrhythmic risk in patients with HCM.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-01-2018
DOI: 10.1161/CIRCULATIONAHA.117.032094
Abstract: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%. REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control ( P =0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group ( P =0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group ( P =1.0). In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. URL: clinicaltrials.gov . Unique identifier: NCT02600234.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.JCRC.2019.05.011
Abstract: The purpose of this study was to systematically investigate the reporting of selection criteria and outcome measures, and to examine definitions of complications used in venoarterial extracorporeal membrane oxygenation studies (V-A ECMO). Medline, EMBASE and the Cochrane central register were searched for V-A ECMO studies from January 2005 to July 2017. Studies with ≤99 patients or without patient centered outcomes were excluded. Two reviewers independently assessed search results and undertook data extraction. Forty-six studies met the inclusion criteria, and all were retrospective, observational studies. Inconsistent reporting of selection criteria, ECMO management and outcome measures was common. In-hospital mortality was the most common primary outcome (41% of studies), followed by 30-day mortality (11%). Bleeding was the most frequent complication reported, most commonly defined as "bleeding requiring transfusion" (median ≥ 2 Units/day). Significant variation in reporting and definitions was also evident for vascular, neurological renal and infectious complications. This systematic review provides clinicians with the most commonly reported selection criteria, outcome measures and complications used in ECMO practice. However non-standardized definitions and inconsistent reporting limits their ability to inform practice. New consensus driven definitions of complications and patient centred outcomes are urgently needed.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.JACC.2012.07.065
Abstract: The purpose of this study was to evaluate diffuse myocardial fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF). Diffuse myocardial fibrosis is a hallmark of cardiomyopathy. Unlike replacement fibrosis, it is not visualized on delayed-enhancement cardiac magnetic resonance (CMR) imaging, but may be quantified with contrast-enhanced T(1) mapping methods. In atrial fibrillation (AF), it may be induced by arrhythmia or reflect pre-existing cardiomyopathy. Ninety subjects underwent CMR using a clinical 1.5-T scanner: 23 controls, 40 paroxysmal AF patients, and 27 persistent AF patients. Cardiac morphology and function was evaluated from CMR cine imaging. A histologically validated T(1) mapping sequence was used to calculate post-contrast T(1) relaxation time (T(1) time) of the LV myocardium as an index of diffuse myocardial fibrosis. Age was similar across controls, paroxysmal AF patients, and persistent AF patients (54 ± 12 years, 58 ± 9 years, and 56 ± 10 years, p = NS). Persistent AF patients had larger indexed left atrium volume (55 ± 18 ml vs. 41 ± 12 ml and 47 ± 14 ml) and lower ejection fraction (54 ± 10% vs. 65 ± 6% and 61 ± 8%) than controls and paroxysmal AF patients (p < 0.05). Post-contrast ventricular T(1) time differed across all groups (controls, 535 ± 86 ms paroxysmal AF, 427 ± 95 ms persistent AF, 360 ± 84 ms p < 0.001). Univariate predictors of post-contrast ventricular T(1) time included age, sex, AF category, ejection fraction, LV mass, congestive heart failure, and body mass index. After multivariate analysis, age, AF category, and ejection fraction remained independent predictors. Post-contrast ventricular T(1) mapping identifies diffuse LV fibrosis in patients with AF and provides new insights into the association between AF and adverse ventricular remodeling.
Publisher: Elsevier BV
Date: 11-2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-06-2006
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.HEALUN.2008.02.003
Abstract: The VentrAssist (VA) is a novel, continuous flow left ventricular assist device (LVAD). The purpose of this trial was to investigate the safety and efficacy of the VA in elderly patients with end-stage heart failure. In this prospective trial, patients requiring circulatory support either as destination therapy (DT) or as a bridge to transplant (BTT) were implanted with a VA device. Between June 2003 and August 2006, 9 elderly patients (mean age 65 years) were implanted. The median support time was 454 (range 73 to 977) days for the DT and 35 (range 26 to 508) days for the BTT cohort. All patients survived implantation 30-day mortality was 22% (n = 2). The adverse event profile was encouraging, with no embolic neurologic events and minimal sepsis. Cumulative trial support time was 7.3 patient-years. The VentrAssist shows promise as a safe and reliable "third-generation" VAD. Having demonstrated potential as a DT and prolonged BTT device, extended clinical trials are warranted.
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0735-1097(95)00332-0
Abstract: In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study. These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.
Publisher: SAGE Publications
Date: 2018
Abstract: Heart failure is highly prevalent with more than 50% of cases being patients with a preserved ejection fraction (HFPEF), a figure that is projected to increase due to the changing risk factor landscape, in particular the ageing population. Overall mortality is similar to patients with heart failure with reduced ejection fraction (HFREF), as are the rates of hospitalisation. Patients with HFPEF have more comorbid conditions with fewer therapeutic options available. In this review, we explore the epidemiology of hospitalisation of HFPEF, the impact of current treatment modalities, and the potential of future therapies.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.CARDFAIL.2014.01.005
Abstract: A treatment based on an interatrial shunt device has been proposed for counteracting elevated pulmonary capillary wedge pressure (PCWP) in patients with heart failure and mildly reduced or preserved ejection fraction (HFpEF). We tested the theoretical hemodynamic effects of this approach with the use of a previously validated cardiovascular simulation. Rest and exercise hemodynamics data from 2 previous independent studies of patients with HFpEF were simulated. The theoretical effects of a shunt between the right and left atria (diameter up to 12 mm) were determined. The interatrial shunt lowered PCWP by ~3 mm Hg under simulated resting conditions (from 10 to 7 mm Hg) and by ~11 mm Hg under simulated peak exercise conditions (from 28 to 17 mm Hg). Left ventricular cardiac output decreased ~0.5 L/min at rest and ~1.3 L/min at peak exercise, with corresponding increases in right ventricular cardiac output. However, because of the reductions in PCWP, right atrial and pulmonary artery pressures did not increase. A majority of these effects were achieved with a shunt diameter of 8-9 mm. The direction of flow though the shunt was left to right in all of the conditions tested. The interatrial shunt reduced left-sided cardiac output with a marked reduction in PCWP. This approach may reduce the propensity for heart failure exacerbations and allow patients to exercise longer, thus attaining higher heart rates and cardiac outputs with the shunt compared with no shunt. These results support clinical investigation of this approach and point out key factors necessary to evaluate its safety and hemodynamic effectiveness.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.JACC.2017.08.041
Abstract: Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy. The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF. This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months. A total of 301 patients were screened 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 ± 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 ± 13% in the CA group compared with 4.4 ± 13% in the MRC group (p < 0.0001) and normalized (LVEF ≥50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7% p = 0.0069) and normalization at 6 months (73% vs. 29% p = 0.0093). AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, particularly in the absence of ventricular fibrosis on CMR. This outcome challenges the current treatment paradigm that rate control is the appropriate strategy in patients with AF and LVSD. (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction [CAMERA-MRI] ACTRN12613000880741).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-04-2022
Abstract: This study aimed to assess whether there are disparities in incidence rates, care, and outcomes for patients with chest pain attended by emergency medical services according to socioeconomic status (SES) in a universal health coverage setting. This was a population‐based cohort study of in idually linked ambulance, emergency, hospital admission, and mortality data in the state of Victoria, Australia, from January 2015 to June 2019 that included 183 232 consecutive emergency medical services attendances for adults with nontraumatic chest pain (mean age 62 [SD 18] years 51% women) and excluded out‐of‐hospital cardiac arrest and ST‐segment–elevation myocardial infarction. Age‐standardized incidence of chest pain was higher for patients residing in lower SES areas (lowest SES quintile 1595 versus highest SES quintile 760 per 100 000 person‐years P .001). Patients of lower SES were less likely to attend metropolitan, private, or revascularization‐capable hospitals and had greater comorbidities. In multivariable models adjusted for clinical characteristics and final diagnosis, lower SES quintiles were associated with increased risks of 30‐day and long‐term mortality, readmission for chest pain and acute coronary syndrome, lower acuity emergency department triage categorization, emergency department length of stay hours, and emergency department or emergency medical services discharge without hospital admission and were inversely associated with use of prehospital ECGs and transfer to a revascularization‐capable hospital for patients presenting to non‐percutaneous coronary intervention centers. In this study, lower SES was associated with a higher incidence of chest pain presentations to emergency medical services and differences in care and outcomes. These findings suggest that substantial disparities for socioeconomically disadvantaged chest pain cohorts exist, even in the setting of universal health care access.
Publisher: American Thoracic Society
Date: 02-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-04-2000
Abstract: Abstract —Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained. Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (n=11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (n=11, P .05). In a rat model of CHF, a 40% reduction ( P .05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content ( P .05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 μmol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. The full text of this article is available at www.circresaha.org.
Publisher: Elsevier BV
Date: 11-2004
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.JACC.2008.12.007
Abstract: It is estimated that approximately 50% of the heart failure population has a normal left ventricular ejection fraction, a complex broadly referred to as heart failure with normal left ventricular ejection fraction (HFNEF). While these patients have been considered in epidemiologic studies and clinical trials to represent a single pool of patients, limited more detailed studies indicate that HFNEF patients are a very heterogeneous group, with a number of key pathophysiologic mechanisms. This review summarizes and critically analyzes available data on the pathophysiology of HFNEF, placing it into context with a recently developed diagnostic algorithm. We evaluate the utility of commonly applied echocardiographic measures and biomarkers and integrate mechanistic observations into potential future therapeutic directions.
Publisher: Elsevier
Date: 1997
Publisher: Elsevier
Date: 1997
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.JACC.2007.03.047
Abstract: The purpose of this study was to develop a clinically applicable high-efficiency percutaneous means of therapeutic gene delivery to the failing heart. Substantial advances in the understanding of the cellular and molecular basis of heart failure (HF) have recently fostered interest in the potential utility of gene and cell therapy as novel therapeutic approaches. However, successful clinical translation is currently limited by the lack of safe, efficient, and selective delivery systems. We developed a novel percutaneous closed-loop recirculatory system that provides homogeneous myocardial delivery for gene transfer in the failing large animal heart. After 4 weeks' rapid pacing in adult sheep to induce HF, the animals were randomly allocated to receive either adenovirus expressing a pseudophosphorylated mutant (AdS16E) of phospholamban (PLN) or Ad-beta-galactosidase (AdLacZ). Two weeks after gene delivery, in the presence of continued pacing, left ventricular (LV) ejection fraction had significantly improved in the AdS16E-treated animals (27 +/- 3% to 50 +/- 4% p < 0.001), whereas a further decline occurred in the AdLacZ group (34 +/- 4% to 27 +/- 3% p < 0.05). In conjunction, AdS16E delivery resulted in significant reductions in LV filling pressures and end-diastolic diameter (both p < 0.05). In conjunction, AdS16E-treated animals showed significant improvement in the expression of PLN and Ca2+-adenosine triphosphatase activity. In separate animals, recirculating AdLacZ delivery was shown to achieve superior myocardial gene expression in contrast to intracoronary delivery and was associated with lower systemic expression. We report the development of a novel closed-loop system for cardiac gene therapy. Using this approach delivery of AdS16E reversed HF progression in a large animal HF model.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.HEALUN.2008.10.002
Abstract: We report the clinical course of a 16-year-old girl in remission from non-Hodgkin's lymphoma who presented in cardiogenic shock due to a severe anthracycline cardiomyopathy. The patient was initially stabilized using central extracorporeal membrane oxygenation support, followed by conversion to a left ventricular assist device. Unexpected evidence of cardiac recovery 9 months after implant enabled device weaning during a 3-month period, culminating in successful device explantation 1 year after implant. The patient survives 18 months after explant in New York Heart Association class I, on conventional heart failure medical management and metabolic therapy.
Publisher: Wiley
Date: 09-09-2020
DOI: 10.1002/EHF2.12908
Abstract: Heart failure with preserved ejection fraction (HFpEF) is characterized by complex pathophysiology including an impaired diastolic reserve. We recently showed that milrinone favourably modifies filling pressures at rest and during exertion in HFpEF patients however, the responsible mechanism is uncertain. The objective of this study was to develop a clearer understanding of the acutely modifiable physiologic parameters that may be targeted in HFpEF. We conducted computer modelling simulations based on invasive haemodynamic assessments, by right heart catheterization, in HFpEF patients at baseline and in response to milrinone. Our aim was to develop a detailed understanding of the physiologic mechanisms, which accounted for the observed actions. The resultant circulatory model of HFpEF encompassed the left ventricular (LV) end‐systolic and end‐diastolic pressure–volume relations, together with stressed blood volume, heart rate, and arterial mechanics. To support the modelled action of milrinone, we conducted complementary LV conductance catheter and echocardiography studies in sheep to evaluate LV end‐systolic and end‐diastolic pressure–volume relations. In HFpEF patients, the acute haemodynamic effects of intravenous milrinone ( n = 10) administration compared with placebo ( n = 10) included significant reductions in right atrial pressure (7 ± 1 to 3 ± 1 mmHg, P 0.001) and pulmonary capillary wedge pressure (13 ± 1 to 8 ± 1 mmHg, P 0.001), while cardiac index increased (2.77 ± 0.19 to 3.15 ± 0.14 L/min/m 2 , P 0.05), and mean arterial pressure remained unchanged (95 ± 2 to 93 ± 3 mmHg, P = not significant). Computer simulations showed that these haemodynamic effects were explained by a concomitant 31% reduction in stressed blood volume together with 44% increase in LV end‐systolic elastance (LV E es ). In idually, changes in these parameters were not sufficient to explain the haemodynamic effects of milrinone. In vivo studies conducted in sheep ( n = 5) showed that milrinone reduced LV filling pressure (8.0 ± 0.8 to 2.7 ± 0.6 mmHg, P 0.01) and increased LV E es (0.96 ± 0.07 to 2.07 ± 0.49, P 0.05), while no significant effect on LV stiffness was observed (0.038 ± 0.003 to 0.034 ± 0.008, P = not significant). These data demonstrate that stressed blood volume in HFpEF represents a relevant physiologic target in HFpEF however, concomitant modulation of other cardiovascular parameters including LV contractility may be required to achieve desirable haemodynamic effects.
Publisher: Elsevier BV
Date: 04-2010
Publisher: Springer Science and Business Media LLC
Date: 1998
DOI: 10.1007/BF01584366
Abstract: Immunotherapy has dramatically influenced and changed therapeutical approach in non-small cell lung cancer (NSCLC) in recent five years. Even though we can reach long-term response to this treatment in approximately 20% of patients with NSCLC, we are still not able to identify this cohort of patients based on predictive biomarkers. In our study we have focused on tumor mutation burden (TMB), one of the potential biomarkers which could predict effectiveness of check-point inhibitors, but has several limitations, especially in multiple approaches to TMB quantification and ununiform threshold. We determined the value of TMB in tumor tissue (tTMB) and blood (bTMB) in 20 patients with early stage NSCLC using original custom gene panel LMB_TMB1. We evaluated various possibilities of TMB calculation and concluded that TMB should be counted from both somatic non-synonymous and synonymous mutations. Considering various factors, we established cut-offs of tTMB in/excluding HLA genes as ≥22 mut/Mb and 12 mut/Mb respectively, and cut-offs of bTMB were defined as ≥21 mut/Mb and ≥5 mut/Mb, respectively. We also observed trend in correlation of somatic mutations in HLA genes with overall survival of patients.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.HEALUN.2008.02.012
Abstract: The increasing prevalence of chronic heart failure has stimulated the ongoing development of left ventricular assist devices (LVADs) for both bridge-to-transplant (BTT) and destination therapy (DT). The aim of this prospective, multicenter clinical trial was to determine the efficacy and safety of a third-generation LVAD, the VentrAssist, in a BTT cohort. Patients (n = 33) with end-stage chronic heart failure who required circulatory support as BTT therapy were implanted with a VentrAssist device. The primary outcome was survival until transplant or transplant eligibility with the device in situ at trial end-point (Day 154 after implant). The secondary outcomes were pump flow index and end-organ function. Safety, patient functional status and resource use were also assessed. At trial end-point, the success rate was 82% (39.4% transplanted, 42.4% transplant-eligible). The LVAD pump flow index (median >or=2.7 liters/min/m(2)) was sufficient to maintain an adequate circulation and significantly improve end-organ function. Of the 77 protocol-defined serious adverse events, most occurred within 30 days of implantation. No patients died as a direct result of pump failure or malfunction. After implantation, patient functional status improved, with 70% of patients achieving hospital discharge, and resource use was reduced. This trial demonstrated a favorable efficacy and safety profile for use of the VentrAssist LVAD in BTT patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2008
DOI: 10.1097/ALN.0B013E31818629DB
Abstract: Endothelial function is impaired with hyperhomocysteinemia. Plasma homocysteine is increased by nitrous oxide anesthesia. The current study was designed to determine whether endothelial function is impaired after surgery and whether this is made worse by exposure to nitrous oxide. The authors studied 59 patients with cardiovascular disease undergoing noncardiac surgery. Patients were randomly allocated to nitrous oxide-based anesthesia (n = 25) or nitrous oxide-free anesthesia (control, n = 34). Endothelial function was measured by flow-mediated dilation of the brachial artery before and 24 h after surgery. In addition, blood was drawn at both time points for the measurements of plasma homocysteine, folate, L-arginine, L-citrulline, asymmetric dimethylarginine, and nitrate concentrations. The median duration of general anesthesia was 4.5 h. Patients had significantly lower flow-mediated dilation after surgery (5.1 +/- 3.3 to 3.0 +/- 4.1% P = 0.001). Duration of anesthesia affected endothelial function. In the nitrous oxide group, there was an inverse correlation with flow-mediated dilation (r = -0.60, P = 0.004), but in the control group, there was a positive correlation (r = 0.61, P & 0.001). When compared with control, nitrous oxide exposure was associated with a significant increase in postoperative homocysteine (mean difference, 4.9 microm 95% confidence interval, 2.8-7.0 microm P & 0.0005) and decrease in flow-mediated dilation (3.2% 95% confidence interval, 0.1-5.3% P = 0.001). Nitrous oxide exposure was not associated with change in nitric oxide substrates. Nitrous oxide-based anesthesia increased plasma homocysteine and significantly impaired endothelial function in patients undergoing noncardiac surgery. Nitrous oxide-based anesthesia could be a risk factor for postoperative cardiovascular morbidity.
Publisher: Oxford University Press (OUP)
Date: 05-2005
DOI: 10.1016/J.CARDIORES.2005.02.012
Abstract: The documentation of preferential activation of the cardiac sympathetic outflow in patients with heart failure swept aside an entrenched notion that there was a functional sympathetic denervation of the failing heart and provided a theoretical basis for the clinical evaluation of beta-adrenergic blocker therapy in this condition. The demonstration that heightened sympathetic nervous system activity is central to the pathogenesis and progression of congestive heart failure (CHF) has now led to the rational use of beta-adrenoceptor blockade in CHF. More recently, it has also emerged that the aging heart exhibits some of the characteristic changes in autonomic control which are seen in CHF. Accordingly, alterations in cardiac sympathetic nerve function are now thought to contribute also to the pathophysiology of the aging heart. Furthermore, there is evidence that in humans, sympathoexcitatory rostral projections of brainstem noradrenergic neurons to the forebrain are important in the sympathetic nervous activation of both heart failure and aging. Given these similarities, in this review we compare and contrast the neurobiology of the sympathetic nervous system in the failing heart and the healthy, aging heart, and consider whether the sympathetic activation accompanying aging may, perhaps, underlie and contribute to the neural pathophysiology of heart failure. Our conclusion is, on balance, that this proposition is not supported by the available evidence.
Publisher: Hindawi Limited
Date: 09-12-2008
DOI: 10.1002/HUMU.20891
Abstract: We previously identified the polymorphism ss52051869 in the 3'UTR of human SLC7A1, and demonstrated that it might participate in the apparent link between altered endothelial function, decreased L-arginine and nitric oxide (NO) metabolism, and a genetic predisposition to essential hypertension. Here, we demonstrate that the major allele contains a consensus sequence for the transcription factor SP1 and binds to SP1, in contrast, the minor allele fails to bind to SP1. Resequencing of the entire SLC7A1 coding sequence failed to find other informative polymorphisms, indicating that ss52051869 plays a key role in the biochemical and clinical association. In conjunction, the short and long variants of the 3'UTR of SLC7A1 contain three and four potential microRNA-122 (miR-122) binding sites, respectively. We found that the minor allele is more frequently associated with SLC7A1 bearing a long 3'UTR, while the major allele is more likely to accompany a short 3'UTR only (P=0.034). As such, reporter genes containing the long 3'UTR from SLC7A1 show much less gene expression than those containing short 3'UTR from SLC7A1, regardless of their allele status (P<0.01), suggesting that an alternative polyadenylation event and/or miRNA-122 binding sites may also play a role in controlling gene expression. It is therefore possible that binding of miR-122 to the 3'UTR may cause the depression of gene expression, contributing to the lesser level of SLC7A1 and the endothelial dysfunction seen in hypertensive subjects. Taken together, these data provide novel insights into the mechanism by which ss52051869 influences SLC7A1 gene expression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2004
DOI: 10.1097/00004872-200410000-00014
Abstract: It is unknown whether beta-adrenoceptor-mediated vasodilatation is altered in early hypertension and whether it can be modulated by L-arginine. We measured changes in forearm blood flow by plethysmography in response to acetylcholine (9 and 37 microg/min), sodium nitroprusside (200 and 800 ng/min) and the beta-receptor agonist, isoproterenol (50 and 200 ng/min) in 12 patients with essential hypertension (group EH) and in healthy volunteers with (group PFH n = 14) and without (group NFH n = 14) a family history of essential hypertension, before and during concomitant infusion of L-arginine (10 micromol/min). In five in iduals from each group, infusion of acetylcholine and isoproterenol was repeated during the concurrent blockade of nitric oxide synthesis by N-monomethyl-L-arginine (L-NMMA 4 micromol/min). The response to acetylcholine was reduced in groups EH and PFH compared with group NFH (both P < 0.05), whereas the vasodilator effects of isoproterenol and sodium nitroprusside were similar in all three groups. Acetylcholine- and isoproterenol-induced vasodilatation did not change during infusion of the nitric oxide precursor, L-arginine, in group NFH, but were significantly enhanced by L-arginine in groups PFH and EH [forearm blood flow before and after isoproterenol 200 ng/min: group PFH 11.8 +/- 1.02 and 13.3 +/- 1.08 ml/min, respectively (P < 0.05) group EH: 11.3 +/- 1.57 and 14.9 +/- 1.91 ml/min, respectively (P < 0.01)]. Co-infusion of L-NMMA blunted the response to acetylcholine and isoproterenol in group NFH (P < 0.05), but did not significantly modify vasodilatation in groups PFH and EH. Although beta-adrenergic vasodilatation seemed to be unaltered in early hypertension, L-arginine enhanced the response to isoproterenol, whereas concomitant inhibition of nitric oxide synthase by L-NMMA had no significant effect. These findings suggest that the nitric oxide component of isoproterenol-mediated vasodilatation is impaired in early hypertension and possibly compensated by increased beta-adrenoceptor responsiveness of smooth muscle cells. In this setting, supplementation of the nitric oxide precursor, L-arginine, enhances the vasodilator response to beta-adrenergic stimulation.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2010
DOI: 10.1007/S12265-010-9190-X
Abstract: Although there has been considerable interest in the utilization of gene and cellular therapy for heart disease in recent years, there remain critical questions prior to widespread promotion of therapy, and key among these issues is the delivery method used for both gene therapy and cellular therapy. Much of the failure of gene and cellular therapy can be explained by the biological therapy itself however, certainly there is a critical role played by the delivery technique, in particular, those that have been adapted from routine clinical use such as intravenous and intracoronary injection. Development of novel techniques to deliver gene and cellular therapy has ensued with some preclinical and even clinical success, though questions regarding safety, invasiveness, and repeatability remain. Here, we review techniques for gene and cellular therapy delivery, both existing and adapted techniques, and novel techniques that have emerged recently at promoting improved efficacy of therapy without the cost of systemic distribution. We also highlight key issues that need to be addressed to improve the chances of success of delivery techniques to enhance therapeutic benefit.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0735-1097(01)01172-X
Abstract: We sought to assess the effects of brain natriuretic peptide (BNP) on systemic and regional sympathetic nervous activity (SNA) in both patients with congestive heart failure (CHF) and healthy control subjects. Although the response of SNA to atrial natriuretic peptide (ANP) has been well documented, the response of SNA to BNP is largely unknown. We assessed cardiac and whole-body SNA using the norepinephrine (NE) tracer dilution method before and after infusion of two doses of BNP (3 and 15 ng/kg body weight per min) in 11 patients with stable CHF (ejection fraction 24 +/- 2%) and 12 age-matched healthy control subjects. In addition, renal SNA and hemodynamic variables were assessed at baseline and after the higher BNP dose. Low dose BNP did not change blood pressure or whole-body NE spillover, but reduced cardiac NE spillover in both groups by 32 +/- 13 pmol/min (p < 0.05). In both groups, high dose BNP reduced pulmonary capillary pressure by 5 +/- 1 mm Hg (p < 0.001) and mean arterial pressure by 6 +/- 3 mm Hg (p < 0.05), without a concomitant increase in whole-body NE spillover however, cardiac NE spillover returned to baseline levels. Renal NE spillover remained virtually unchanged in healthy control subjects (501 +/- 120 to 564 +/- 115 pmol/min), but was reduced in patients with CHF (976 +/- 133 to 656 +/- 127 pmol/min, p < 0.01). Our results demonstrate a sympathoinhibitory effect of BNP. Cardiac sympathetic inhibition was observed at BNP concentrations within the physiologic range, whereas high dose BNP, when arterial and filling pressures fell and reflex sympathetic stimulation was expected, systemic and cardiac SNA equated to baseline values. There was inhibition of renal SNA in patients with CHF, but not in healthy control subjects. Whether this effect is specific to BNP or related to reduced filling pressure remains to be determined.
Publisher: American Astronomical Society
Date: 02-2012
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.AMJCARD.2019.09.019
Abstract: In patients with heart failure and preserved or mildly reduced ejection fractions (EF ≥40%), implantation of an interatrial shunt device (IASD) resulted in heterogenous changes of the left atrial (LA) volume. Baseline characteristics that correlate with a favorable decrease in LA volume are unknown. We hypothesized that a larger ratio of left to right atrial volume at baseline would correlate strongly with LA volume decongestion following IASD implantation. Reduce Elevated LA Pressure in Patients With Heart Failure was a multicenter study of the safety and feasibility of IASD implantation. Sixty-four patients with EF ≥40% underwent device implantation along with baseline conventional echocardiograms, speckle tracking echocardiography, and resting and exercise hemodynamics. Higher LA compliance (-4.2%, p = 0.048) and right atrial reservoir strain (-0.8%, p = 0.005) were independently associated with a percent decrease in the systolic LA volume index from baseline to 6-months. In conclusion, greater LA volume reduction following IASD implantation is associated with higher baseline compliance of the left atrium and higher reservoir strain of the right atrium.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.HRTHM.2013.06.019
Abstract: Atrial fibrillation (AF) and systolic heart failure (HF) frequently coexist. Restoration of sinus rhythm by catheter ablation may result in a variable improvement in left ventricular (LV) function. Late-gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging identifies irreversible structural change and may predict incomplete recovery of LV function. To prospectively select patients with AF and symptomatic HF but without LV LGE and report the impact of AF ablation on LV function. Patients with AF and symptomatic HF (LV ejection fraction <50%) resistant to at least 1 antiarrhythmic drug and prior electrical cardioversion underwent contrast-enhanced CMR. LGE-negative patients underwent pulmonary vein isolation and left atrial roof line with continued antiarrhythmic medications until follow-up CMR 6 months postablation. Sixteen patients (aged 52 ± 11 years mean AF duration 37 ± 39 months left atrial size 44 ± 13 mL/m(2)) underwent AF ablation. At 6 months, 15 of the 16 patients maintained sinus rhythm and underwent CMR. LV ejection fraction increased from 40% ± 10% at baseline to 60% ± 6% (P < .001) and LV end-systolic volume index decreased from 52 ± 12 to 36 ± 9 mL/m(2) (P < .001). Left atrial size decreased from 44 ± 13 to 36 ± 11 mL/m(2) (P < .01). In patients with AF and LV dysfunction in the absence of LGE on CMR, ventricular function normalizes following the restoration of sinus rhythm. CMR may assist in the selection of patients with combined AF and systolic HF most likely to benefit from catheter ablation.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.AMJCARD.2010.10.011
Abstract: Survival rates after out-of-hospital cardiac arrest (OHCA) continue to be poor. Recent evidence suggests that a more aggressive approach to postresuscitation care, in particular combining therapeutic hypothermia with early coronary intervention, can improve prognosis. We performed a single-center review of 125 patients who were resuscitated from OHCA in 2 distinct treatment periods, from 2002 to 2003 (control group) and from 2007 to 2009 (contemporary group). Patients in the contemporary group had a higher prevalence of cardiovascular risk factors but similar cardiac arrest duration and prehospital treatment (adrenaline administration and direct cardioversion). Rates of cardiogenic shock (48% vs 41%, p = 0.2) and decreased conscious state on arrival (77% vs 86%, p = 0.2) were similar in the 2 cohorts, as was the incidence of ST-elevation myocardial infarction (33% vs 43%, p = 0.1). The contemporary cohort was more likely to receive therapeutic hypothermia (75% vs 0%, p <0.01), coronary angiography (77% vs 45%, p <0.01), and percutaneous coronary intervention (38% vs 23%, p = 0.03). This contemporary therapeutic strategy was associated with better survival to discharge (64% vs 39%, p <0.01) and improved neurologic recovery (57% vs 29%, p <0.01) and was the only independent predictor of survival (odds ratio 5.5, 95% confidence interval 1.2 to 26.2, p = 0.03). Longer resuscitation time, presence of cardiogenic shock, and decreased conscious state were independent predictors of poor outcomes. In conclusion, modern management of OHCA, including therapeutic hypothermia and early coronary angiography is associated with significant improvement in survival to hospital discharge and neurologic recovery.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2011
DOI: 10.1038/NMETH.1740
Abstract: NKX2-5 is expressed in the heart throughout life. We targeted eGFP sequences to the NKX2-5 locus of human embryonic stem cells (hESCs) NKX2-5(eGFP/w) hESCs facilitate quantification of cardiac differentiation, purification of hESC-derived committed cardiac progenitor cells (hESC-CPCs) and cardiomyocytes (hESC-CMs) and the standardization of differentiation protocols. We used NKX2-5 eGFP(+) cells to identify VCAM1 and SIRPA as cell-surface markers expressed in cardiac lineages.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.JCRC.2015.05.022
Abstract: This study was designed to examine the long-term survival of patients who survived to be weaned from venoarterial extracorporeal membrane oxygenation (VA ECMO) and to determine which factors present at initiation and during ECMO predict long-term survival. We further sought to develop the preliminary long-term outcome after VA ECMO score that would predict patient outcome and to assess its accuracy at various time points. We conducted a retrospective, observational cohort study of all patients with cardiogenic shock treated with VA ECMO at the Alfred Hospital, Australia, from January 2007 until February 2013. Overall, 125 patients underwent ECMO, and 104 patients were successfully weaned and formed the study population, with a median follow-up of 21 months (range, 0-84). Survival rates of those weaned from ECMO at 3 months, 12 months, and 2 years were 87%, 79%, and 71%, respectively, corresponding to overall survival rates at 3 months of 90 (72%) of 124 at 12 months, 80 (65%) of 122 and 24 months, 57 (57%) of 100. Ischemic heart disease, higher lactate and higher bilirubin at initiation of VA ECMO, and a longer duration of renal replacement therapy during ECMO were all independently associated with decreased length of survival. Long-term survival was found to be highly related to the number of these risk factors present up to 2 years afterward. Good long-term survival can be achieved in patients who have been successfully weaned from VA-ECMO. The factors present at initiation and during ECMO can relate to altered risk of long-term survival.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.HEALUN.2020.12.006
Abstract: Right ventricular (RV) failure after left ventricular assist device (VAD) implantation is a difficult problem. One solution is the implantation of continuous-flow VADs in a biventricular configuration. Disappointing survival and a concerning incidence of right-sided pump thrombosis have been previously reported. From May 2017 to April 2020, a total of 12 patients underwent implantation of HeartMate 3 (HM3) biventricular VADs (BiVADs) as a bridge to cardiac transplantation. The right-sided pump was implanted in the right atrium in all cases. Adverse events and patient outcomes were determined. Patients were male, and the mean age was 44 years. The etiology was dilated cardiomyopathy (6 patients), sarcoid heart disease (2 patients), ischemic cardiomyopathy (1 patient), anthracycline cardiomyopathy (1 patient), non-compaction cardiomyopathy (1 patient), and arrhythmogenic RV cardiomyopathy with biventricular involvement (1 patient). There was 1 death from multisystem failure. There were 3 episodes of right VAD thrombus (thrombosis or clot ingestion) 1 managed medically, 1 recognized intraoperatively treated with clot retrieval, and 1 requiring pump exchange. There were 3 driveline infections. At 18 months after the procedure, 5 patients (41.7%) had undergone cardiac transplantation, 5 patients (41.7%) were alive and on biventricular support, 1 patient had died (8.3%), and 1 patient had VAD explantation for myocardial recovery (8.3%). Actuarial survival at 18 months was 91.7%. In this small study, HM3 BiVAD in these critically ill patients was used with low mortality. This suggests that the timely deployment of biventricular support with HM3 can be associated with favorable outcomes.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.JACC.2009.07.042
Abstract: This study examined myocardial microvascular emboli and obstruction, and related these to plaque in the epicardial coronary arteries supplying the affected microvessels. Epicardial coronary thrombosis often causes microemboli and microvascular obstruction. The consequences of myocardial microvessel obstruction and myocyte necrosis are substantial, yet histopathologic characterization of epicardial coronary artery plaque has been incompletely characterized. This study examined myocardial microvascular emboli, and related these to plaque in the coronary arteries supplying the microvessels. Hearts from sudden coronary death patients underwent examination for coronary artery plaque type and cardiac microemboli. Forty-four hearts were available for evaluation. Mean age at death was 51 +/- 15 years. Coronary artery analysis found 26 plaque ruptures and 21 erosions, and a mean of 4.5 microemboli per heart. Microemboli and microvascular obstruction occurred most often from eroded plaques. Microemboli and occluded intramyocardial vessels were most common in the left anterior descending coronary artery, and all vessels contained fibrin and platelets. Mean stenoses of the culprit lesion was 74% in those with emboli and 75% in those without (p = NS). Intramyocardial microemboli were more common in plaque erosion than in rupture. Microvessels <200 mum were most often those that were occluded. Microemboli and microvascular obstruction are common in patients dying of acute coronary thrombosis. Plaque erosion is more likely to cause emboli in vessels <200 mum. These emboli and microvessel obstruction have a prominent clinical role since myonecrosis is often associated with these findings.
Publisher: Wiley
Date: 2012
DOI: 10.1111/J.1445-5994.2011.02606.X
Abstract: Cardiac magnetic resonance imaging (CMR) has matured into a robust, accurate and highly reproducible imaging modality for the assessment of cardiac function and ischaemic heart disease. The unique physical properties of CMR permit depiction of pathology-specific tissue contrast based on differences in tissue composition, such as myocardial oedema, necrosis and fibrosis. This can be imaged at high spatial resolution allowing characterisation of the acuity of an ischaemic event, the presence and extent of myocardial ischaemia, necrosis and viability. Prognostically important information obtained from CMR evaluation of ischaemic heart disease, such as left ventricular ejection fraction, infarct size and transmurality, infarct location and the presence of intraventricular mechanical dyssynchrony may be used to guide coronary revascularisation, device and medical therapies.
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0140-6736(02)11737-5
Abstract: Alterations in monoaminergic neurotransmission in the brain are thought to underlie seasonal variations in mood, behaviour, and affective disorders. We took blood s les from internal jugular veins in 101 healthy men, to assess the relation between concentration of serotonin metabolite in these s les and weather conditions and season. We showed that turnover of serotonin by the brain was lowest in winter (p=0.013). Moreover, the rate of production of serotonin by the brain was directly related to the prevailing duration of bright sunlight (r=0.294, p=0.010), and rose rapidly with increased luminosity. Our findings are further evidence for the notion that changes in release of serotonin by the brain underlie mood seasonality and seasonal affective disorder.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.JACC.2013.01.090
Abstract: Adjuvant radiation therapy in the management of early stage breast cancer, Hodgkin's disease, and to a lesser extent other thoracic malignancies has led to a significant improvement in disease-specific survival. Cardiovascular disease is now the most common nonmalignancy cause of death in radiation-treated cancer survivors, most often occurring decades after treatment. The spectrum of radiation-induced cardiac disease is broad, potentially involving any component of the heart. The relative risk of coronary artery disease, congestive heart failure, valvular heart disease, pericardial disease, conduction abnormalities, and sudden cardiac death is particularly increased. Over the years contemporary techniques have been introduced to reduce cardiac morbidity and mortality in radiation-treated cancer survivors however, the long-term effects on the heart still remain unclear, mandating longer follow-up. Awareness and early identification of potential cardiac complications is crucial in cancer survivors, with the management often being quite complex. This review examines the epidemiology of radiation-induced cardiac disease together with its pathophysiology and explores the available treatment strategies and the potential utility of various screening strategies for affected cancer survivors.
Publisher: American Physiological Society
Date: 03-2002
DOI: 10.1152/AJPREGU.00335.2001
Abstract: Investigating aging effects on the sympathetic nervous system and ascertaining underlying central nervous system (CNS) mechanisms mediating sympathetic stimulation is clinically pertinent because of the possible interconnection of cardiovascular disease development with age-dependent sympathetic nervous changes. Because of previous evidence linking human CNS neuronal noradrenergic function and sympathetic activity, we investigated the influence of aging on brain norepinephrine turnover in 22 healthy men aged 20–30 yr and 16 healthy men aged 60–75 yr by measuring the internal jugular venous overflow of norepinephrine and its lipophilic metabolites. Sympathoneural and adrenal medullary function was also studied, using plasma catecholamine isotope dilution methodology and regional central venous s ling. In the older men there was increased norepinephrine turnover in suprabulbar subcortical brain regions, 317 ± 50 ng/min compared with 107 ± 18 ng/min in younger men. A differentiated sympathetic nervous activation was also present in older men. Overall, levels of both cardiac and hepatomesenteric norepinephrine spillover were directly correlated with subcortical norepinephrine turnover. These findings suggest that in sympathetic nervous activation accompanying aging, as has previously been demonstrated with the sympathetic nervous stimulation in human hypertension and heart failure, there is an underlying sympathoexcitatory influence of noradrenergic projections to suprabulbar subcortical regions.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2007
DOI: 10.2174/092986707780831078
Abstract: Coronary heart disease (CHD) remains the greatest killer in the Western world, and although the death rate from CHD has been falling, the current increased prevalence of major risk factors including obesity and diabetes, suggests it is likely that CHD incidence will increase over the next 20 years. In conjunction with preventive strategies, major advances in the treatment of acute coronary syndromes and myocardial infarction have occurred over the past 20 years. In particular the ability to rapidly restore blood flow to the myocardium during heart attack, using interventional cardiologic or thrombolytic approaches has been a major step forward. Nevertheless, while 'reperfusion' is a major therapeutic aim, the process of ischemia followed by reperfusion is often followed by the activation of an injurious cascade. While the pathogenesis of ischemia-reperfusion is not completely understood, there is considerable evidence implicating reactive oxygen species (ROS) as an initial cause of the injury. ROS formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks, all potentially damaging to normal cellular function. ROS have been shown to be generated following routine clinical procedures such as coronary bypass surgery and thrombolysis, due to the unavoidable episode of ischemia-reperfusion. Furthermore, they have been associated with poor cardiac recovery post-ischemia, with recent studies supporting a role for them in infarction, necrosis, apoptosis, arrhythmogenesis and endothelial dysfunction following ischemia-reperfusion. In normal physiological condition, ROS production is usually homeostatically controlled by endogenous free radical scavengers such as superoxide dismutase, catalase, and the glutathione peroxidase and thioredoxin reductase systems. Accordingly, targeting the generation of ROS with various antioxidants has been shown to reduce injury following oxidative stress, and improve recovery from ischemia-reperfusion injury. This review summarises the role of myocardial antioxidant enzymes in ischemia-reperfusion injury, particularly the glutathione peroxidase (GPX) and the thioredoxin reductase (TxnRed) systems. GPX and TxnRed are selenocysteine dependent enzymes, and their activity is known to be dependent upon an adequate supply of dietary selenium. Moreover, various studies suggest that the supply of selenium as a cofactor also regulates gene expression of these selenoproteins. As such, dietary selenium supplementation may provide a safe and convenient method for increasing antioxidant protection in aged in iduals, particularly those at risk of ischemic heart disease, or in those undergoing clinical procedures involving transient periods of myocardial hypoxia.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1038/MT.2015.78
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1994
Abstract: Although heart rate variability (HRV) at 0.1 Hz has been proposed as a noninvasive clinical measure of cardiac sympathetic nerve firing, this premise has not been sufficiently validated by comparison with techniques such as microneurography and the measurement of norepinephrine spillover from the heart that more directly reflect presynaptic sympathetic activity. We compared the three techniques under conditions of effective cardiac sympathetic denervation, pure autonomic failure (n = 4), dopamine beta-hydroxylase deficiency (n = 1), and after cardiac transplantation (n = 9) as well as in the context of sympathetic nervous activation in cardiac failure (n = 15) and with aging (n = 10). Age-matched comparisons were made in each case with healthy in iduals drawn from a pool of 52 volunteers. In pure autonomic failure and early after transplantation, cardiac norepinephrine spillover was negligible, and HRV was low. Late after transplantation, however, cardiac norepinephrine spillover returned to normal levels, and HRV remained low. In comparison to younger subjects (18 to 35 years old), older in iduals (60 to 75 years old) had higher muscle sympathetic nerve activity (young, 22.9 +/- 1.9 old, 31.3 +/- 5.8 bursts per minute P .05) and cardiac norepinephrine spillover (young, 14.3 +/- 2.5 old, 20.1 +/- 3.0 ng/min P .05). In contrast, total HRV was reduced by 89%, and at 0.1 Hz it was reduced by 93% (P .05). Cardiac failure was also characterized by elevated cardiac norepinephrine spillover (cardiac failure patients, 59 +/- 4 healthy volunteers, 18 +/- 3 ng/min P .01) but reduced 0.1 Hz HRV (cardiac failure patients, 49 +/- 17 healthy volunteers, 243 +/- 4 ms2 P .05). HRV at 0.1 Hz depends on factors in addition to cardiac sympathetic nerve firing rates, including multiple neural reflexes, cardiac adrenergic receptor sensitivity, postsynaptic signal transduction, and electrochemical coupling, and is not directly related to cardiac norepinephrine spillover, which is a more direct measure of the sympathetic nerve firing rate.
Publisher: American Psychiatric Association Publishing
Date: 04-2003
DOI: 10.1176/APPI.AJP.160.4.793
Abstract: Aside from diminished daily functional capacity, in iduals with depression are at greatly higher risk of suicide. Given that both endogenous depression severity and the incidence of suicide peak during the spring and summer months, it would seem that an environmental cue-one that generates alterations in brain neuronal activity that result in depressed affect or suicidal ideation-might be important. The authors examined the frequency of suicide and its relation to meteorological factors in the state of Victoria between January 1990 and April 1999. The incidence of suicide had its nadir in winter and zenith in the spring and summer and paralleled closely the number of bright sunlight hours. This pattern was particularly marked for violent suicide. During the decade, the suicide rate significantly increased among men between 21 and 60 years of age and women between 41 and 60. The incidence of suicide in southeastern Australia displays a clear seasonal pattern, being positively linked with prevailing levels of sunlight. The rate of suicide increased in the latter half of the last decade.
Publisher: Wiley
Date: 06-12-2001
DOI: 10.1046/J.1440-1681.2001.03566.X
Abstract: 1. Although the importance of sympathetic nervous activation in the pathogenesis of essential hypertension is well documented, the exact pathophysiology of the sympathetic nervous dysfunction present remains to be delineated. There are several possible explanations for the increased spillover of noradrenaline from the kidneys and heart to plasma, a key piece of evidence supporting the neurogenic basis of essential hypertension, in addition to the obvious one of an increased rate of sympathetic nerve firing. 2. The possibility that there may be an increase in the density of sympathetic innervation in human hypertension, well documented in the spontaneously hypertensive rat, is currently under investigation by us. 3. Adrenaline cotransmission is present in the cardiac sympathetic nerves of patients with essential hypertension, presumptive evidence of their exposure to high levels of stress and a possible basis for the observed increase in cardiac noradrenaline spillover, through presynaptic augmentation of noradrenaline release. 4. Phenotypic evidence exists also of faulty noradrenaline reuptake into the sympathetic nerves of the heart in essential hypertension, an abnormality that would lify the sympathetic neural signal by impairing removal of noradrenaline from the synaptic cleft.
Publisher: Informa Healthcare
Date: 11-2002
DOI: 10.1517/14656566.3.11.1569
Abstract: Chronic heart failure (CHF) is increasing in prevalence worldwide, particularly in the elderly. Accordingly, this epidemic is likely to translate into a major increase in healthcare costs. Systolic heart failure is the most common cause of CHF presentations. Although the causes vary, the most common single aetiological factor is ischaemic heart disease, which accounts for approximately 50% of heart failure presentations. Research into CHF pharmacotherapy has been copious, with the focus principally centred on systolic heart failure. The evidence base for pharmacotherapy in CHF is amongst the largest currently in clinical medicine. There have been multiple trials establishing the mortality and morbidity benefits of pharmacotherapy. Amongst these, large scale trials of angiotensin-converting enzyme inhibitors, beta-blockers and spironolactone have provided a sound basis for evidence-based treatment approaches to the CHF patient. Recently research interest has increased in biomedical engineering with studies being performed in biventricular pacing and mechanical hearts. Early data with biventricular pacing or cardiac resynchronisation therapy is encouraging. Diastolic heart failure alone accounts for at least 20 - 40% of CHF presentations and whilst it may occur in isolation, is most commonly seen in association with systolic heart failure. In this study, we present a broad overview of the current therapeutic modalities for the management of CHF, with particular emphasis on pharmacotherapy.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.CYTO.2014.06.017
Abstract: Activin A, a member of the transforming growth factor-β superfamily, is stimulated early in inflammation via the Toll-like receptor (TLR) 4 signalling pathway, which is also activated in myocardial ischaemia-reperfusion. Neutralising activin A by treatment with the activin-binding protein, follistatin, reduces inflammation and mortality in several disease models. This study assesses the regulation of activin A and follistatin in a murine myocardial ischaemia-reperfusion model and determines whether exogenous follistatin treatment is protective against injury. Myocardial activin A and follistatin protein levels were elevated following 30 min of ischaemia and 2h of reperfusion in wild-type mice. Activin A, but not follistatin, gene expression was also up-regulated. Serum activin A did not change significantly, but serum follistatin decreased. These responses to ischaemia-reperfusion were absent in TLR4(-/-) mice. Pre-treatment with follistatin significantly reduced ischaemia-reperfusion induced myocardial infarction. In mouse neonatal cardiomyocyte cultures, activin A exacerbated, while follistatin reduced, cellular injury after 3h of hypoxia and 2h of re-oxygenation. Neither activin A nor follistatin affected hypoxia-reoxygenation induced reactive oxygen species production by these cells. However, activin A reduced cardiomyocyte mitochondrial membrane potential, and follistatin treatment ameliorated the effect of hypoxia-reoxygenation on cardiomyocyte mitochondrial membrane potential. Taken together, these data indicate that myocardial ischaemia-reperfusion, through activation of TLR4 signalling, stimulates local production of activin A, which damages cardiomyocytes independently of increased reactive oxygen species. Blocking activin action by exogenous follistatin reduces this damage.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2023
Publisher: American Physiological Society
Date: 15-06-2012
DOI: 10.1152/AJPRENAL.00084.2011
Abstract: Low renal nitric oxide (NO) bioavailability contributes to the development and maintenance of chronic hypertension. We investigated whether impaired l-arginine transport contributes to low renal NO bioavailability in hypertension. Responses of renal medullary perfusion and NO concentration to renal arterial infusions of the l-arginine transport inhibitor l-lysine (10 μmol·kg −1 ·min −1 30 min) and subsequent superimposition of l-arginine (100 μmol·kg −1 ·min −1 30 min), the NO synthase inhibitor N G -nitro-l-arginine (2.4 mg/kg iv bolus), and the NO donor sodium nitroprusside (0.24 μg·kg −1 ·min −1 ) were examined in Sprague-Dawley rats (SD) and spontaneously hypertensive rats (SHR). Renal medullary perfusion and NO concentration were measured by laser-Doppler flowmetry and polarographically, respectively, 5.5 mm below the kidney surface. Renal medullary NO concentration was less in SHR (53 ± 3 nM) compared with SD rats (108 ± 12 nM P = 0.004). l-Lysine tended to reduce medullary perfusion (−15 ± 7% P = 0.07) and reduced medullary NO concentration (−9 ± 3% P = 0.03) while subsequent superimposition of l-arginine reversed these effects of l-lysine in SD rats. In SHR, l-lysine and subsequent superimposition of l-arginine did not significantly alter medullary perfusion or NO concentration. Collectively, these data suggest that renal l-arginine transport is impaired in SHR. Renal l-[ 3 H]arginine transport was less in SHR compared with SD rats ( P = 0.01). Accordingly, we conclude that impaired arginine transport contributes to low renal NO bioavailability observed in the SHR kidney.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2000
Abstract: Abstract —Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the NE transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, infusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index .0 kg/m 2 ), 19 overweight (body mass index .0 kg/m 2 ) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives. Spillover of NE from the heart was increased in lean hypertensives only (mean±SD 33.4±20.6 versus 16.1±11.7 ng/min in lean normotensives, P .05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentration of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942±1068 versus 3055±888 pg/mL in healthy subjects, P .05). The fractional extraction of plasma tritiated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65±0.19 versus 0.81±0.11 in healthy subjects, P .05). Cardiac release of the tritiated NE metabolite [ 3 H]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [ 3 H]NE by the transporter, was reduced in lean hypertensives only (992±1435 versus 4588±3189 dpm/min in healthy subjects, P .01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through lification of the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.
Publisher: Wiley
Date: 07-01-2014
DOI: 10.1002/CCD.25348
Abstract: To evaluate the impact of a device-mediated modification of the injection pressure profile on iodinated contrast volumes during coronary angiography and percutaneous coronary intervention (PCI). The development of iodinated contrast-induced acute kidney injury (AKI) is associated with significant morbidity and mortality in patients undergoing coronary angiography and intervention, particularly in the setting of ST-elevation myocardial infarction. Iodinated contrast volume is a recognized risk factor for iodinated contrast-induced AKI. Mitigation of iodinated contrast loss due to coronary iodinated contrast reflux represents a potential means to reduce iodinated contrast volume. We assessed the effectiveness of injection pressure modulation using an iodinated contrast conservation system (CCS), in 21 patients undergoing diagnostic coronary angiography or PCI. System activation was associated with a marked reduction in iodinated contrast injection compared with standard imaging (3.5 ± 1.1 vs. 5.4 ± 1.7 mL, P < 0.001). Paired images were obtained in 59 instances with significantly less iodinated contrast use with CCS use (3.3 ± 1.1 vs. 5.5 ± 1.6 mL, P < 0.001), with comparable image quality in 98% of cases. Modulation of iodinated contrast injection pressure provides a novel potential means to reduce iodinated contrast volumes by attenuating inefficient losses due to ostial reflux. Future studies are required to define the ability of the CCS to reduce total iodinated contrast volume and to impact upon the risk of iodinated contrast-induced AKI.
Publisher: Elsevier BV
Date: 2008
Publisher: Wiley
Date: 05-11-2018
DOI: 10.1113/EP087189
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2006
DOI: 10.1161/01.HYP.0000231509.27406.42
Abstract: Endothelial dysfunction is a hallmark of cardiovascular disease, and the l -arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with l -arginine and NO metabolism however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher ( P =0.01) than nonsmokers, whereas citrulline (17% P .05) and N-hydroxy- l -arginine (34% P .05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy- l -arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial l -arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease.
Publisher: Portland Press Ltd.
Date: 10-2019
DOI: 10.1042/CS20190851
Abstract: The precise mechanisms underlying resistant hypertension remain elusive. Reduced nitric oxide (NO) bioavailability is frequently documented in chronic kidney disease, obesity, diabetes and advanced age, all of which are risk factors for resistant hypertension. Sympathetic overactivity and chronic activation of the renin–angiotensin system are salient features of resistant hypertension. Interestingly, recent data indicate that renal sympathetic overactivity can reduce the expression of neuronal nitric oxide synthase in the paraventricular nucleus. Reduced NO levels in the paraventricular nucleus can increase sympathetic outflow and this can create a vicious cycle contributing to resistant hypertension. Angiotensin II can reduce l-arginine transport and hence NO production. Reduced NO levels may reduce the formation of angiotensin 1-7 d ening the cardio-protective effects of the renin–angiotensin system contributing to resistant hypertension. In addition, interleukin-6 (IL-6) is demonstrated to be independently associated with resistant hypertension, and IL-6 can reduce NO synthesis. Despite this, NO levels have not been quantified in resistant hypertension. Findings from a small proof of concept study indicate that NO donors can reduce blood pressure in patients with resistant hypertension but more studies are required to validate these preliminary findings. In the present paper, we put forward the hypothesis that reduced NO bioavailability contributes substantially to the development of resistant hypertension.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2016
DOI: 10.1038/SREP22413
Abstract: Neprilysin (NEP) and endothelin converting enzyme-1 (ECE-1) are two enzymes that degrade amyloid beta in the brain. Currently there are no molecules to stimulate the activity of these enzymes. Here we report, the discovery and characterisation of a peptide referred to as K49-P1-20, from the venom of Bothrops asper which directly enhances the activity of both ECE-1 and NEP. This is evidenced by a 2- and 5-fold increase in the Vmax of ECE-1 and NEP respectively. The K49-P1-20 concentration required to achieve 50% of maximal stimulation (AC 50 ) of ECE-1 and NEP was 1.92 ± 0.07 and 1.33 ± 0.12 μM respectively. Using BLITZ biolayer interferometry we have shown that K49-P1-20 interacts directly with each enzyme. Intrinsic fluorescence of the enzymes change in the presence of K49-P1-20 suggesting a change in conformation. ECE-1 mediated reduction in the level of endogenous soluble amyloid beta 42 in cerebrospinal fluid is significantly higher in the presence of K49-P1-20 (31 ± 4% of initial) compared with enzyme alone (11 ± 5% of initial N = 8, P = 0.005, unpaired t -test). K49-P1-20 could be an excellent research tool to study mechanism(s) of enzyme stimulation, and a potential novel drug lead in the fight against Alzheimer’s disease.
Publisher: American Physiological Society
Date: 04-2011
DOI: 10.1152/AJPHEART.01184.2010
Abstract: Elevated QT interval variability is a predictor of malignant ventricular arrhythmia, but the underlying mechanisms are incompletely understood. A recent study in dogs with pacing-induced heart failure suggests that QT variability is linked to cardiac sympathetic nerve activity. The aim of this study was to determine whether increased cardiac sympathetic activity is associated with increased beat-to-beat QT interval variability in patients with essential hypertension. We recorded resting norepinephrine (NE) spillover into the coronary sinus and single-lead, short-term, high-resolution, body-surface ECG in 23 patients with essential hypertension and 9 normotensive control subjects. To assess beat-to-beat QT interval variability, we calculated the overall QT variability (QTVN) as well as the QT variability index (QTVi). Cardiac NE spillover (12.2 ± 6.5 vs. 20.7 ± 14.7, P = 0.03) and QTVi (−1.75 ± 0.36 vs. −1.42 ± 0.50, P = 0.05) were significantly increased in hypertensive patients compared with normotensive subjects. QTVN was significantly correlated with cardiac NE spillover ( r 2 = 0.31, P = 0.001), with RR variability ( r 2 = 0.20, P = 0.008), and with systolic blood pressure ( r 2 = 0.16, P = 0.02). Linear regression analysis identified the former two as independent predictors of QTVN. In conclusion, elevated repolarization lability is directly associated with sympathetic cardiac activation in patients with essential hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2001
DOI: 10.1161/01.CIR.103.19.2336
Abstract: Background —Depressed ventricular performance and neurohormonal activation are key pathophysiological features of congestive heart failure (CHF). Although angiotensin-converting enzyme inhibitors and β-adrenoceptor blockers exert beneficial effects in CHF, mortality remains unacceptably high, and the development of further therapeutic approaches is warranted. Recent data suggest that continuous positive airway pressure (CPAP) may be of benefit in the treatment of CHF, although the mechanism for this action is incompletely understood. Methods and Results —In the present study, we examined the effect of short-term CPAP (10 cm H 2 O for 10 minutes) on hemodynamics (Swan Ganz catheter) and total systemic and cardiac sympathetic activity (norepinephrine spillover method) in 14 CHF patients in New York Heart Association class III. The application of CPAP was associated with a fall in cardiac output (4.8±0.3 to 4.4±0.2 L/min P .05) and a significant reduction in cardiac norepinephrine spillover (370±58 to 299±55 pmol/min P .05), although total systemic norepinephrine spillover was unchanged. Conclusion —The short-term application of CPAP results in an inhibition of cardiac sympathetic nervous activity. Further investigation into the potential value of long-term CPAP in CHF patients is warranted.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-03-2002
Abstract: Background — Although it is established that heightened sympathetic drive exists in congestive heart failure (CHF), the reflex processes by which this may occur and the sites in the central nervous system that may be responsible for mediating this process are not yet fully elucidated. Methods and Results — Eight patients with moderate to severe CHF and 8 healthy control subjects underwent simultaneous arterial and bilateral internal jugular venous blood s ling and cerebral venous blood pool scanning for anatomical determination of the origin of internal jugular venous blood flow. We estimated sympathetic nervous activity by measuring total body norepinephrine (NE) spillover using radiotracer methodology and determined brain NE turnover by measuring the internal jugular overflow of NE and its lipophilic metabolites, 3-methoxy-4-hydroxyphenylglycol and 3,4-dihydroxyphenylglycol. Suprabulbar subcortical turnover of NE was significantly greater in CHF patients than in the healthy group (2.77±0.75 versus 0.66±0.40 nmol/min, P .05). There was a significant positive correlation between suprabulbar subcortical turnover of NE and total body NE spillover ( r =0.62, P =0.01). Conclusions — This study, for the first time, demonstrates elevated suprabulbar subcortical noradrenergic activity in human CHF and identifies a positive correlation between this and the level of whole-body NE spillover. The findings suggest that the activation of noradrenergic neurons projecting rostrally from the brain stem mediates sympathetic nervous stimulation in CHF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2003
Publisher: Wiley
Date: 09-1994
DOI: 10.1111/J.1440-1681.1994.TB02574.X
Abstract: 1. The full range of vascular reactivity was investigated in the hindlimb circulation of conscious, autonomically blocked rabbits with experimental (adriamycin-induced) cardiomyopathy. 2. Adriamycin treatment caused a significant reduction in left ventricular systolic function, as assessed by echocardiography (left ventricular fractional shortening, controls vs adriamycin treatment 36.7 +/- 1.7% vs 27.3 +/- 2.6%, P < 0.05). 3. Under pharmacological autonomic effector block, the range of the vasodilator response (resistance range, from resting to full vasodilatation) to acetylcholine was reduced by 41% (P < 0.05) and by 37% for adenosine (P < 0.05). Despite these changes the sensitivity (ED50) of the responses were unaltered. 4. The ED50 of constrictor responses to noradrenaline and angiotensin II were similarly unaltered, in conjunction with a non-significant attenuation of the constrictor-response range. 5. These results suggest that in this model of experimental left ventricular dysfunction, the capacity of the hindlimb circulation to respond to regionally infused endothelium dependent vasodilators is attenuated.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.HLC.2013.08.007
Abstract: Iron deficiency has been reported to be highly prevalent in idiopathic pulmonary arterial hypertension (iPAH) patients, with the potential to influence cardiac performance, pulmonary artery pressures and the pulmonary vascular response to hypoxia. Iron status was evaluated in 29 iPAH patients, and was related to haemodynamic, echocardiographic and exercise parameters. Iron deficiency was present in 44.8% of all iPAH patients, although anaemia was only present in 13.8%. Iron-deficient patients had similar exercise capacity (6MWD: 446±141 m), compared to iron-sufficient patients (421±193 m), however 46.2% of iron deficient patients had NYHA FC 3 or higher, compared to 12.5% in non-iron deficient group. Additionally iron-deficient patients showed increased mean pulmonary arterial pressure (63.3±12.2 mmHg iron deficient vs. 38.8±16.7 mmHg non-iron deficient) and reduced cardiac index (1.3±0.2 L/min/m(2) iron deficient vs. 2.5±0.4 L/min/m(2) non-iron deficient). Iron deficiency is highly prevalent in iPAH, and the extent of iron deficiency is related to haemodynamics and NYHA functional class. While the exact mechanism of iron deficiency is unknown, our study suggests that treatment of iron deficiency should be considered in iPAH patients.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.BIOCEL.2007.10.027
Abstract: The action of oxidatively modified low-density lipoprotein on vascular endothelial cells has been proposed to be a crucial process leading to endothelial dysfunction and atherogenesis. However, the biochemical mechanism for such action is not clear. We have previously shown that arginine uptake and metabolism are major determinants of endothelial function in heart failure and hypertension. In the present study we therefore aimed to assess the effects of oxidized LDL, a major pro-atherogenic molecule, on endothelial l-arginine metabolism and its uptake. Endothelial cells were exposed to oxidized LDL or native LDL for 24h, and the resultant effects on (1) the intracellular content of arginine and its major metabolites including citrulline, N(G)-hydroxy-l-arginine, asymmetric dimethylarginine, symmetric dimethylarginine and ornithine, (2) [3H]-l-arginine uptake and, (3) the pattern of distribution of cationic amino acid transporter 1, the principal l-arginine transporter, by confocal microscopy. Oxidized LDL (100 microg/mL) reduced intracellular arginine and N(G)-hydroxy-l-arginine contents by 56 and 71% (P<0.05), respectively, with a concomitant 205% increase in ADMA (P<0.05). In conjunction, oxidized LDL reduced endothelial uptake of [3H]-arginine by 60%. Furthermore, incubation of endothelial cells with oxLDL led to internalization of cationic amino acid transporter 1. We demonstrate a novel mechanism, reduced l-arginine transport, by which oxidized LDL impairs the ability of the endothelium to generate nitric oxide.
Publisher: Portland Press Ltd.
Date: 08-1995
DOI: 10.1042/CS0890145
Abstract: 1. To investigate the link between post-prandial thermogenesis and sympathetic nervous activation we have studied the effects of a single large meal on regional sympathetic nervous activity in healthy, lean subjects. 2. In nine male subjects, noradrenaline spillover was measured from the heart, kidney and liver using isotope dilution, both while fasting and after consumption of a high-energy liquid meal of composition 53% carbohydrate, 32% fat and 15% protein (energy value 2.64–3.51 MJ). Regional oxygen consumption, whole-body oxygen consumption and, in a subset of subjects, muscle sympathetic nerve firing (microneurography) were also measured. 3. Both whole-body oxygen consumption (P & 0.03) and total body spillover of noradrenaline (P & 0.01) rose after the meal, with peak increases of 24% and 56% respectively. Spillover of noradrenaline from the heart was unchanged, that from the hepatosplanchnic circulation increased marginally (0.377 nmol/min to 0.480 nmol/min, P = 0.09), while renal noradrenaline spillover more than doubled (0.440 nmol/min to 0.937 nmol/min, P & 0.05). Skeletal muscle sympathetic nerve activity (peroneal nerve) increased from 7.7 bursts/min at rest to peak at 17.9 bursts/min 60 min after the meal in the three subjects in whom stable recordings were obtained. 4. The meal increased oxygen consumption in the kidneys and liver significantly, from 11.5 ± 1.6 ml/min to 14.5 ± 1.1 ml/min and from 46 ± 7 ml/min to 57 ± 6 ml/min respectively (P & 0.05), but not in the heart. 5. Consumption of a large meal produces a substantial and relatively selective increase in sympathetic outflow to the kidneys and skeletal muscle. While resting regional oxygen consumptions and noradrenaline spillovers were related, the changes that occurred in each were unrelated, so that no direct relationship could be demonstrated between post-prandial thermogenesis and sympathetic activity.
Publisher: Springer Science and Business Media LLC
Date: 2000
Publisher: Wiley
Date: 06-2004
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1007/S10557-019-06921-W
Abstract: Drug-eluting balloon catheters (DEBc) coated with paclitaxel (PTX) have been associated with potential safety concerns. An efficacious but less toxic balloon coating may reduce these outcomes. We evaluated a novel DEBc, Epi-Solve, coated with metacept-3 (MCT-3), a member of the histone deacetylase inhibitor (HDACi) class of epigenetic agents, in a large animal model of neointimal hyperplasia (NIH). Plain balloon angioplasty (PABA) catheters were ultrasonically coated with MCT-3 to generate Epi-Solve DEBc. An ovine model of NIH formation was established utilising partial left common carotid artery (LCA) ligation. Twenty-eight days post neointima (NI) induction, PABA, Epi-Solve or PTX-coated DEBc were deployed at the site of induced NI formation. Twenty-eight days post-intervention, ligated vessels were evaluated for attenuation of NI formation, gene expression profiles and immunohistochemical analysis. Epi-Solve DEBc demonstrated attenuation of NIH over no intervention and a trend to inhibition of NIH over PABA. Gene expression analysis and immunohistochemical studies identified significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA. Epi-Solve is a novel HDACi-coated DEBc which demonstrates significant anti-proliferative and anti-inflammatory signatures and reduced vascular endothelial cell activation compared to PABA in an ovine model and may afford endothelial protection.
Publisher: Wiley
Date: 16-01-2014
DOI: 10.1111/APHA.12215
Abstract: Oxidative stress may play an important role in the pathogenesis of hypertension. The aim of our study is to examine whether increased expression of the predominant endothelial l-arginine transporter, cationic amino acid transporter-1 (CAT1), can prevent oxidative stress-induced hypertension. Wild-type mice (WT n = 9) and endothelial CAT1 overexpressing (CAT+) mice (n = 6) had telemetry probes implanted for the measurement of mean arterial pressure (MAP), heart rate (HR) and locomotor activity. Minipumps were implanted for infusion of the superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA 30 mg kg(-1) day(-1) 14 days) or its saline vehicle. Baseline levels of MAP, HR and locomotor activity were determined before and during chronic DETCA administration. Mice were then killed, and their plasma and kidneys collected for analysis of F2 -isoprostane levels. Basal MAP was less in CAT+ (92 ± 2 mmHg n = 6) than in WT (98 ± 2 mmHg n = 9 P < 0.001). During DETCA infusion, MAP was increased in WT (by 4.2 ± 0.5% P < 0.001) but not in CAT+, when compared to appropriate controls (PDETCA*genotype = 0.006). DETCA infusion increased total plasma F2 -isoprostane levels (by 67 ± 11% P = 0.05) in WT but not in CAT+. Total renal F2 -isoprostane levels were greater during DETCA infusion in WT (by 72% P < 0.001), but not in CAT+, compared to appropriate controls. Augmented endothelial l-arginine transport attenuated the prohypertensive effects of systemic and renal oxidative stress, suggesting that manipulation of endothelial CAT1 may provide a new therapeutic approach for the treatment of cardiovascular disease associated with oxidative stress.
Publisher: Oxford University Press (OUP)
Date: 06-2016
Publisher: Oxford University Press (OUP)
Date: 19-06-2018
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1016/J.JACC.2008.06.049
Abstract: The purpose of this study was to investigate a noninvasive method for quantifying diffuse myocardial fibrosis with cardiac magnetic resonance imaging (CMRI). Diffuse myocardial fibrosis is a fundamental process in pathologic remodeling in cardiomyopathy and is postulated to cause increased cardiac stiffness and poor clinical outcomes. Although regional fibrosis is easily imaged with cardiac magnetic resonance, there is currently no noninvasive method for quantifying diffuse myocardial fibrosis. We performed CMRI on 45 subjects (25 patients with heart failure, 20 control patients), on a clinical 1.5-T CMRI scanner. A prototype T(1) mapping sequence was used to calculate the post-contrast myocardial T(1) time as an index of diffuse fibrosis regional fibrosis was identified by delayed contrast enhancement. Regional and global systolic function was assessed by cine CMRI in standard short- and long-axis planes, with echocardiography used to evaluate diastology. An additional 9 subjects underwent CMRI and endomyocardial biopsy for histologic correlation. Post-contrast myocardial T(1) times correlated histologically with fibrosis (R = -0.7, p = 0.03) and were shorter in heart failure subjects than controls (383 +/- 17 ms vs. 564 +/- 23 ms, p < 0.0001). The T(1) time of heart failure myocardium was shorter than that in controls even when excluding areas of regional fibrosis (429 +/- 22 ms vs. 564 +/- 23 ms, p < 0.0001). The post-contrast myocardial T(1) time shortened as diastolic function worsened (562 +/- 24 ms in normal diastolic function vs. 423 +/- 33 ms in impaired diastolic function vs. 368 +/- 20 ms in restrictive function, p < 0.001). Contrast-enhanced CMRI T(1) mapping identifies changes in myocardial T(1) times in heart failure, which appear to reflect diffuse fibrosis.
Publisher: Frontiers Media SA
Date: 09-07-2018
Publisher: Elsevier BV
Date: 05-2019
Publisher: Springer Science and Business Media LLC
Date: 24-07-2008
DOI: 10.1038/GT.2008.120
Abstract: Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p. medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t(max) low dose -220+/-70, P>0.05 medium dose 125+/-53, P<0.05 high dose 287+/-104, P 0.05 medium dose 1+/-2, P>0.05 high dose 6.5+/-3.9, P<0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.
Publisher: Elsevier BV
Date: 2011
Publisher: Portland Press Ltd.
Date: 2002
DOI: 10.1042/CS20010107
Publisher: Wiley
Date: 03-2015
DOI: 10.1111/ECHO.12928
Abstract: We aimed to determine the accuracy of the echocardiographic assessment of cardiac index (CI) in subjects with preserved left ventricular ejection fraction (LVEF). Thirty-three subjects with LVEF >50%, normal sinus rhythm, and a broad spectrum of hemodynamic profiles underwent echocardiography immediately followed by right heart catheterization. As gold standards, CI was assessed using thermodilution [CI (TD)] and the Fick method [CI (F)]. Echocardiographic CI was assessed by four methods: from the left ventricular outflow tract (LVOT) velocity time integral and the LVOT diameter as measured [CI (LVOTm)] as well as estimated from body surface area [CI (LVOTe)], and from stroke volume indices assessed using the biplane [CI (BP)] and monoplane [CI (MP)] methods. The mean CI (TD), CI (F), CI (LVOTm), CI (LVOTe), CI (BP), and CI (MP) were 3.0 ± 0.9, 3.1 ± 0.7, 2.8 ± 0.6, 3.3 ± 0.6, 2.0 ± 0.6, and 2.2 ± 0.7 L/min/m(2) . There were modest correlations between CI (TD) and CI (F) and all four noninvasive measures of CI with r(2) values ranging from 0.09 to 0.30. CI (LVOTm) underestimated CI (TD) and CI (F) by 0.3 and 0.3 L/min/m(2) , CI (LVOTe) overestimated CI (TD) and CI (F) by 0.3 and 0.2 L/min/m(2) , and CI (BP) and CI (MP) underestimated CI (TD) and CI (F) by 1.1 and 1.1 L/min/m(2) and 0.9 and 0.9 L/min/m(2) , respectively, with large limits of agreement for all comparisons. In subjects with nondilated left ventricles with preserved LVEF, flow- or volume-based measures of CI by 2D echocardiography may not accurately reflect CI (TD) and CI (F). Further larger studies are required to verify our findings and to evaluate the accuracy of contrast and 3D echocardiography in this setting.
Publisher: Elsevier BV
Date: 08-2010
Publisher: Springer Science and Business Media LLC
Date: 17-12-2009
DOI: 10.1038/GT.2009.163
Publisher: American Physiological Society
Date: 1995
DOI: 10.1152/AJPREGU.1995.268.1.R278
Abstract: To study the effect of aging on human sympathetic nervous function, we applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20-30 yr) and older (aged 60-75 yr) healthy men. Mean plasma norepinephrine concentration was 66% higher in older men, attributable to 22% lower norepinephrine plasma clearance (P 0.05) and 29% higher norepinephrine spillover to plasma (difference not statistically significant). Regional venous s ling disclosed that sympathetic outflow to all organs was not activated by aging. Renal norepinephrine spillover was normal in older men. Although spillover of norepinephrine from the heart was increased in older men, 21.1 +/- 11.4 ng/min compared with 11.4 +/- 8.6 ng/min (P 0.05), diminished norepinephrine reuptake rather than increased cardiac sympathetic nerve firing was the most likely cause, although somewhat reduced intracardiac methylation of norepinephrine with aging also possibly contributed. The extraction of tritiated norepinephrine from plasma during transit through the heart was reduced, suggesting neuronal norepinephrine reuptake was lowered and overflow of the norepinephrine precursor dihydroxyphenylalanine and metabolites dihydroxyphenylglycol and 3-methoxy-4-hydroxy phenylglycol was normal, indicating that norepinephrine synthesis and release were not increased.
Publisher: Oxford University Press (OUP)
Date: 19-08-2016
DOI: 10.1093/JAC/DKW295
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.CLINTHERA.2015.08.005
Abstract: The purpose of this article was to review the clinical management of patients with heart failure with preserved ejection fraction (HFPEF). For this critical review, electronic databases (MEDLINE, EMBASE, PubMed) were searched for relevant basic research studies and randomized clinical trials recently published or presented at major meetings. Details of in-progress or planned studies were obtained from the ClinicalTrials.gov website. The range of publication dates was the year 2000 to 2015. Search terms included HFPEF, heart failure with preserved ejection fraction, HFPSF, heart failure with preserved systolic function, diastolic heart failure, diastolic dysfunction, HFNEF, heart failure with normal ejection fraction, treatment, management, therapy. Patients with HFPEF account for up to half of all patients with a clinical diagnosis of HF. Key contributing factors include hypertension, obesity, and atrial fibrillation, and other chronic diseases, including diabetes, chronic obstructive pulmonary disease, and anemia, frequently coexist. To date, large-scale clinical trials, particularly those focused on antagonism of the renin-angiotensin-aldosterone system, have provided limited evidence of clinical benefit. The aggressive management of contributing factors, including hypertension, atrial fibrillation, and myocardial ischemia, is key in the management of HFPEF. New insights into the mechanisms and thus the identification of potential therapeutic strategies are urgently required.
Publisher: BMJ
Date: 06-01-2016
DOI: 10.1136/HEARTJNL-2015-308636
Abstract: Supplemental oxygen therapy may increase myocardial injury following ST-elevation myocardial infarction (STEMI). In this study, we aimed to evaluate the effect of the dose and duration of oxygen exposure on myocardial injury after STEMI. Descriptive analysis of data from a multicentre, prospective, randomised, controlled trial of 441 patients with STEMI randomised to supplemental oxygen therapy or room air breathing. The primary endpoint was myocardial infarct size as assessed by cardiac biomarkers, troponin (cTnI) and creatine kinase (CK). Oxygen therapy was commenced by paramedics, and continued for up to 12 h postintervention in hospital. Supplemental oxygen exposure was calculated as the area under the dose×time curve for oxygen administration over the first 12 h, and then assessed for its association with cTnI/CK release using multivariable linear regression. The median supplemental oxygen exposure was 1746 L (IQR: 960-2858). After adjustment for potential confounders, every 100 L increase in oxygen exposure in the first 12 h was associated with a 1.4% (95% CI 0.6% to 2.2%, p<0.001) and 1.2% (95% CI 0.7% to 1.8%, p<0.001) increase in the mean peak cTnI and CK, respectively. Excluding patients who developed cardiogenic shock, recurrent myocardial infarction or desaturations (SpO2<94%) during admission, every 100 L increase in oxygen exposure was associated with a 1.2% (95% CI 0.2% to 2.1%, p=0.01) and 1.0% (95% CI 0.3% to 1.7%, p=0.003) increase in the mean peak cTnI and CK, respectively. The median supplemental oxygen exposure of 1746 L would result in a 21% (95% CI 3% to 37%) increase in infarct size according to the cTnI profile. Supplemental oxygen exposure in the first 12 h after STEMI was associated with a clinically significant increase in cTnI and CK release.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.JACC.2010.04.040
Abstract: The purpose of this study was to invasively investigate the hemodynamic response to exercise in patients with heart failure with normal ejection fraction (HFNEF) and to evaluate the ability of the peak early diastolic transmitral velocity to peak early diastolic annular velocity ratio (E/e') to reflect exercise hemodynamics. There is little information regarding the hemodynamic response to exercise in HFNEF. Patients with HFNEF (n = 14) and asymptomatic controls (n = 8) underwent right-side heart catheterization at rest and during supine cycle ergometer exercise and echocardiography with measurement of resting and peak exercise E/e'. Resting pulmonary capillary wedge pressure (PCWP) (10 +/- 4 mm Hg vs. 10 +/- 4 mm Hg p = 0.94) was similar in HFNEF patients and controls, but stroke volume index (SVI) (p = 0.02) was lower, and systemic vascular resistance index (SVRI) (p = 0.01) was higher in patients. Patients stopped exercise at lower work rate (0.63 +/- 0.29 W/kg vs. 1.13 +/- 0.49 W/kg p = 0.006). Although peak exercise PCWP was similar in both groups (23 +/- 6 mm Hg vs. 20 +/- 7 mm Hg p = 0.31), the peak PCWP/work rate ratio was higher in patients compared with controls (46 +/- 31 mm Hg/W/kg vs. 20 +/- 9 mm Hg/W/kg p = 0.03). Peak exercise SVI (p = 0.001) was lower and SVRI was higher (p = 0.01) in patients. Resting E/e' was modestly elevated in patients (13.2 +/- 4.1 vs. 9.5 +/- 3.4 p = 0.04). Peak exercise E/e' did not differ between the groups (11.1 +/- 3.4 vs. 9.4 +/- 3.4 p = 0.28). The HFNEF patients achieved a similar peak exercise PCWP to that of asymptomatic controls, at a much lower workload. This occurs at a lower SVI and in the setting of higher SVRI. The E/e' does not reflect the hemodynamic changes during exercise in HFNEF patients.
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/10253890701300904
Abstract: Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous s ling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous s ling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.
Publisher: Wiley
Date: 02-2010
DOI: 10.1111/J.1540-8183.2009.00511.X
Abstract: Despite pharmacological advances for heart failure, morbidity and mortality remain unacceptably high. As a result, alternative approaches such as cell therapy have been suggested to hold potential promise. However, a major obstacle is the optimization of cell delivery to the heart. Therefore, we investigated the efficacy of a percutaneous recirculation system for the delivery of cells to the heart. Ovine fibroblasts were delivered to the ovine heart (3 x 10(7) cells) using the V-Focus system, a "closed" recirculatory system that draws blood from the coronary sinus and returns it to the coronary artery via an oxygenator, or intracoronary (IC) infusion, followed by a 2-hour recovery period. Animals were euthanized and cardiac tissue collected to determine presence of cells. There was a significant difference (P < 0.05) in the number of cells delivered to the heart by the V-Focus compared to direct coronary infusion for left ventricular freewall (V-Focus 1.39 +/- 0.63/mm(2), IC 0.11 +/- 0.06/mm(2)), septum (V-Focus 3.18 +/- 0.88/mm(2), IC 0.38 +/- 0.19/mm(2)), and right ventricle (V-Focus 0.46 +/- 0.23/mm(2), IC 0.05 +/- 0.04/mm(2)). These results suggest that potential therapeutic cells are optimally delivered to the large animal heart using the V-Focus cardiac delivery system in an ovine heart.
Publisher: Elsevier BV
Date: 12-2016
Publisher: Wiley
Date: 03-2011
Abstract: Down-regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF. Heart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1-SERCA, using a percutaneous, recirculating system for gene delivery over a 10 min period. Left ventricular mechanics was investigated by echocardiography and conductance catheter measurements in sheep receiving AAV2/1-SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1-SERCA2a-treated group, despite continued pacing, as measured by fractional shortening (delta absolute FS, control -4.2 ± 1.5% vs. treatment 4.4 ± 1.5% P < 0.01) and conductance catheterization (delta Ees, control -1.22 ± 0.60 vs. treatment 0.65 ± 0.51 P < 0.05). Western blots showed an increase in SERCA protein in AAV2/1-SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1-SERCA. In a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.HLC.2016.02.022
Abstract: Renal dysfunction and heart failure commonly co-exist it is termed the cardiorenal syndrome (CRS). This combination of renal and cardiac impairment presents a substantial clinical challenge and is associated with adverse prognosis. The pathogenesis of the CRS is complex, including chronic activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, together with reduced renal perfusion. Chronic activation of the RAAS can impair mitochondrial function, and increase mitochondrial derived oxidative stress which in turn can lead to renal injury and sodium and water retention. For ex le, it has been shown that exogenous Ang II augments renal mitochondrial oxidative stress, reduces GFR and induces albuminuria in rats with heart failure. Administration of Ang II also augmented renal mitochondrial dysfunction in aged mice. Current treatments for CRS, including angiotensin-converting enzyme inhibitors, exert limited renal protection if any at all. Therefore, novel treatments particularly those that can target renal mechanisms downstream to chronic activation of the renal renin-angiotensin system are likely to exert renoprotection in the setting of CRS.
Publisher: Elsevier BV
Date: 10-1998
DOI: 10.1016/S0165-1838(98)00107-6
Abstract: Although the underlying mechanisms no doubt differ, activation of the sympathetic nervous system is an important pathophysiological feature in primary arterial hypertension, in portal hypertension accompanying hepatic cirrhosis, and in heart failure, and is a logical therapeutic target for centrally acting sympathetic nervous system suppressant drugs. Portal hypertension: The sympathetic outflows to skeletal muscle vasculature, the heart, the kidneys and to the hepatomesenteric circulation are stimulated in patients with alcoholic cirrhosis of the liver, perhaps as a reflex response to the vasodilatation and vascular shunting present. Acute dosing with clonidine produces dose dependent reduction in noradrenaline spillover from visceral organs and reduction in hepatic vein wedge pressure, with preservation of hepatic blood flow and negligible fall in arterial pressure. These findings indicate the clinical potential of drugs such as clonidine, moxonidine and rilmenidine for chronically lowering portal venous pressure in cirrhosis. Arterial hypertension: Activation of the sympathetic outflow to the heart, kidneys and skeletal muscle vasculature is commonly present in younger (< 45 years) patients with essential hypertension. The sympathetic stimulation appears to have adverse consequences in hypertensive patients beyond blood pressure elevation. Neural vasoconstriction in skeletal muscle has metabolic effects by impairing glucose delivery, which is a basis for insulin resistance and hyperinsulinemia. Within the heart a trophic effect of sympathetic activation on cardiac growth, contributing to the development of left ventricular hypertrophy, and an arrhythmogenic effect are also likely. Cardiac failure: The cardiac sympathetic nerves are preferentially stimulated in severe heart failure, with norepinephrine release from the failing heart at rest being increased as much as 50-fold, similar to the level seen in healthy people during near maximum exercise. This preferential activation of the cardiac sympathetic outflow contributes to arrhythmogenesis and possibly to progression of the heart failure, and has been directly linked to mortality a high rate of spillover of noradrenaline from the heart is a strong, independent predictor of poor prognosis in severe cardiac failure. The mechanisms underlying sympathetic nervous stimulation are not entirely clear. Increased intracardiac diastolic pressure seems to be one peripheral signal, and increased forebrain norepinephrine turnover an important central mechanism. Following the demonstration of the beneficial effect of the beta-adrenergic blocker, carvedilol, and with second generation centrally acting sympathetic suppressants now under clinical investigation, elucidation of the abnormalities in central nervous control of sympathetic outflow in heart failure has become clinically relevant.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1996
Abstract: Background Increased availability of norepinephrine (NE) for activation of cardiac adrenoceptors (increased cardiac adrenergic drive) and depletion of myocardial NE stores may contribute to the pathophysiology and progression of congestive heart failure. This study used a comprehensive neurochemical approach to examine the mechanisms responsible for these abnormalities. Methods and Results Subjects with and without congestive heart failure received intravenous infusions of [ 3 H]NE. Cardiac spillover, reuptake, vesicular-axoplasmic exchange, and tissue stores of NE were assessed from arterial and coronary venous plasma concentrations of endogenous and [ 3 H]-labeled NE and dihydroxyphenylglycol. Tyrosine hydroxylase activity was assessed from plasma dopa, and NE turnover was assessed from measurements of NE metabolites. NE release and reuptake were both increased in the failing heart however, the efficiency of NE reuptake was reduced such that cardiac spillover of NE was increased disproportionately more than neuronal release of NE. Cardiac NE stores were 47% lower and the rate of vesicular leakage of NE was 42% lower in the failing than in the normal heart. Cardiac spillover of dopa and NE turnover were increased similarly in congestive heart failure. Conclusions Increased neuronal release of NE and decreased efficiency of NE reuptake both contribute to increased cardiac adrenergic drive in congestive heart failure. Decreased vesicular leakage of NE, secondary to decreased myocardial stores of NE, limits the increase in cardiac NE turnover in CHF. Decreased NE store size in the failing heart appears to result not from insufficient tyrosine hydroxylation but from chronically increased NE turnover and reduced efficiency of NE reuptake and storage.
Publisher: Wiley
Date: 12-1997
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.AMJCARD.2018.06.009
Abstract: Although heart transplantation and mechanical circulatory support are effective therapies for patients with advanced heart failure (HF), many patients are ineligible due to co-morbidities. Continuous home intravenous with positive inotropes such as milrinone are used in these patients to improve quality of life. We hypothesized that, unlike previous studies with oral milrinone, a slow-release formulation that provides stable lower plasma levels may be better tolerated and provide symptomatic benefit. Accordingly, we developed an extended release milrinone formulation (CRD-102) and evaluated its effects in 26 patients with no-option Stage D HF. One month after open-label therapy there were significant improvements in NYHA class, Minnesota Living with Heart Failure score and 6-minute walk distance. There was no evidence of hypotension or increased arrhythmic burden. In conclusion, the present study demonstrates evidence of beneficial actions of extended release milrinone in advanced HF. Longer-term randomized clinical trial data are required.
Publisher: Elsevier BV
Date: 11-2020
DOI: 10.1016/J.HEALUN.2020.07.015
Abstract: Driveline infections remain a major complication of ventricular assist device (VAD) implantation. This study aimed to characterize in vivo microbial biofilms associated with driveline infections and host tissue integration of implanted drivelines. A total of 9 infected and 13 uninfected drivelines were obtained from patients with VAD undergoing heart transplantation in Australia between 2016 and 2018. Each driveline was sectioned into 11 pieces of 1.5 cm in length, and each section was examined by scanning electron microscopy (SEM) and viable counts for microbial biofilms. Microorganisms were cultured and identified. Host tissue integration of clinical drivelines was assessed with micro-computed tomography (CT) and SEM. An in vitro interstitial biofilm assay was used to simulate biofilm migration in the driveline tunnel, and time-lapse microscopy was performed. Of the 9 explanted, infected drivelines, all had organisms isolated from varying depths along the velour section of the drivelines, and all were consistent with the swab culture results of the clinically infected exit site. SEM and micro-CT suggested insufficient tissue integration throughout the driveline velour, with microgaps observed. Clinical biofilms presented as microcolonies within the driveline tunnel, with human tissue as the sub-stratum, and were resistant to anti-microbial treatment. Biofilm migration mediated by a dispersal-seeding mechanism was observed. This study of explanted infected drivelines showed extensive anti-microbial-resistant biofilms along the velour, associated with microgaps between the driveline and the surrounding tissue. These data support the enhancement of tissue integration into the velour as a potential preventive strategy against driveline infections by preventing biofilm migration that may use microgaps as mediators.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2007
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.CARDFAIL.2016.03.006
Abstract: The mechanisms for cognitive impairment in heart failure (HF) are unclear. We investigated the relative contributions of cerebral blood flow velocity (BFV), oxidative stress, and inflammation to HF-associated cognitive impairment. Thirty-six HF patients (≥60 years) and 40 healthy controls (68 ± 7 vs 67 ± 5 years, P > .05 69% vs 50% male, P > .05) completed the Cognitive Drug Research computerized assessment battery and Stroop tasks. Common carotid (CCA) and middle cerebral arterial BFV were obtained by transcranial Doppler. Blood s les were collected for oxidant (diacron-reactive oxygen metabolites F2-isoprostanes), antioxidant (coenzyme Q10 CoQ10), and inflammatory markers (high-sensitivity C-reactive protein). Compared with controls, patients exhibited impaired attention (Cognitive Drug Research's Power of Attention domain, congruent Stroop) and executive function (incongruent Stroop). Multiple regression modeling showed that CCA-BFV and CoQ10 but not group predicted performance on attention and executive function. Additionally, in HF patients, CCA-BFV and CoQ10 (β = -0.34 vs β = -0.35) were significant predictors of attention, and CCA-BFV (β = -0.34) was a predictor of executive function. Power of Attention and executive function is impaired in older HF patients, and reduced CCA-BFV and CoQ10 are associated with worse cognition. Interventions addressing these mechanisms may improve cognition in older HF patients.
Publisher: Oxford University Press (OUP)
Date: 02-07-2012
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.HLC.2012.10.012
Abstract: Both heart and renal failure are characterised by increased systemic oxidative stress and endothelial dysfunction and occur in the cardiorenal syndrome (CRS). The aim of the present study was to assess the impact of N-acetylcysteine (NAC), a potent antioxidant, on endothelial function, B-type natriuretic peptide (BNP) and renal function in patients with CRS. In a double blind, placebo controlled manner, we randomised nine stable outpatients with both heart failure (LVEF 7 days) and crossover to the other treatment. Eight patients completed the study and all data (N=9) was used in the analysis. Mean forearm blood flow improved significantly with NAC with mean ratio of improvement of 1.99 (SEM: ±0.49) for NAC and 0.73 (SEM: ±0.23) for placebo with a p-value of 0.047. There was no significant difference in BNP (p=0.25), renal function (p=0.71) or NYHA class (p=0.5). No deaths occurred during the trial. In this pilot trial of patients with CRS, NAC therapy was associated with improved forearm blood flow. This may represent a general improvement in endothelial function and warrants further investigation of antioxidant therapy in these patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2022
DOI: 10.1161/HYPERTENSIONAHA.122.19350
Abstract: Blood pressure (BP) variability is an independent risk factor for cardiovascular events. Recent evidence supports a role for the gut microbiota in BP regulation. However, whether the gut microbiome is associated with BP variability is yet to be determined. Here, we aimed to investigate the interplay between the gut microbiome and their metabolites in relation to BP variability. Ambulatory BP monitoring was performed in 69 participants from Australia (55.1% women mean±SD, 59.8±7.26 years body mass index, 25.2±2.83 kg/m 2 ). These data were used to determine nighttime dipping, morning BP surge (MBPS) and BP variability as SD. The gut microbiome was determined by 16S ribosomal RNA (rRNA) sequencing and metabolite levels by gas chromatography. We identified specific taxa associated with systolic BP variability, nighttime dipping, and MBPS. Notably, Alistipesfinegoldii and Lactobacillus spp. were only present in participants within the normal ranges of BP variability, MBPS and dipping, while Prevotella spp. and Clostridium spp., were found to be present in extreme dippers and the highest quartiles of BP SD and MBPS. There was a negative association between MBPS and microbial α- ersity (r=−0.244, P =0.046). MBPS was also negatively associated with plasma levels of microbial metabolites called short-chain fatty acids (r=−0.305, P =0.020), particularly acetate (r=−0.311, P =0.017). Gut microbiome ersity, levels of microbial metabolites, and the bacteria Alistipesfinegoldii and Lactobacillus were associated with lower BP variability and Clostridium and Prevotella with higher BP variability. Thus, our findings suggest the gut microbiome and metabolites may be involved in the regulation of BP variability.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.YJMCC.2007.03.900
Abstract: Reactive oxygen species such as superoxide are implicated in cardiac hypertrophy, but their contribution to the cardiac complications of insulin resistance is unresolved. We tested the hypothesis that the antioxidant tempol attenuates cardiac hypertrophy in insulin-resistant mice. Mice with cardiac GLUT4 deletion (GLUT4-knockout), superimposed on global GLUT4 suppression (GLUT4-knockdown) were administered tempol for 4 weeks. Age-matched GLUT4-knockdown littermates were used as controls (14 mice/group). GLUT4-knockout mice exhibited marked cardiac hypertrophy: heart to body weight ratio was increased 61+/-7% and expression of the hypertrophic genes beta-myosin heavy chain and B-type natriuretic peptide (BNP) were elevated 5.5+/-0.7- and 6.2+/-1.5-fold relative to control, respectively. Pro-fibrotic pro-collagen III expression was also higher (3.8+/-0.7-fold) in the GLUT4-knockout myocardium (all p<0.001). Both gp91(phox) and Nox1 subunits of NADPH oxidase were also upregulated, 4.9+/-1.2- and 9.3+/-2.8-fold (both p<0.01). Tempol treatment significantly attenuated all of these abnormalities in GLUT4-knockout mice. Heart to body weight ratio was decreased, as was fold expression of beta-myosin heavy chain (to 3.8+/-0.8), BNP (to 2.5+/-0.5), pro-collagen III (to 1.9+/-0.4), gp91(phox) (to 0.9+/-0.3) and Nox1 (to 2.3+/-0.1, all p<0.05 versus untreated GLUT4-knockout mice). In addition, tempol upregulated ventricular expression of both thioredoxin-2 (confirming an antioxidant action) and glycogen synthase kinase-3beta (GSK-3beta). Tempol did not elicit any other significant changes in control mice. Cardiac superoxide generation, however, was not altered by GLUT4-knockout or tempol. In conclusion, tempol treatment reduced morphological and molecular evidence of cardiac hypertrophy in the GLUT4-knockout insulin-resistant mouse in vivo, even at doses insufficient to lower cardiac superoxide. Parallel reductions in pro-collagen III and NADPH oxidase have important implications for our understanding of the molecular basis of cardiac hypertrophy in the setting of insulin resistance. Antioxidants may offer new alternatives in this disorder.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2003
DOI: 10.1161/01.HYP.0000055779.93635.A2
Abstract: This study examined the effects of low doses of intravenous clonidine on regional and global sympathetic nervous system activity in heart failure. In heart failure, adrenoceptor-blocking treatments have a limited sphere of activity. Centrally acting sympatholytic therapies should be further investigated, with a specific emphasis on targeting cardiac and renal sympathetic overactivity. In 10 patients with moderate-severe congestive heart failure, we examined the effect of intravenous clonidine on systemic, cardiac, and renal sympathetic activity and on brain monoamine turnover using the norepinephrine spillover method. In addition, we assessed the effect of clonidine on cardiac release of the sympathetic cotransmitter neuropeptide Y. A dose of 1 μg/kg of clonidine resulted in a fall in cardiac (326±73 to 160±40 pmol/min, P .001), renal (2.5±0.6 to 1.5±0.3 nmol/min, P =0.01), and global norepinephrine spillover (4.0±0.6 to 3.1±0.5 nmol/min, P .01), with a significantly disproportionate reduction in cardiac versus total-body sympathetic activity ( P .05). No significant changes in cardiac neuropeptide Y release or in central monoamine turnover were demonstrated. Clonidine, at modest doses, significantly attenuates cardiac and renal sympathetic tone in heart failure. In addition to the beneficial effects of antiadrenergic therapy in the heart, the renal sympatholytic effect may counter the salt and water retention that is a hallmark of the condition.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.TCM.2006.02.003
Abstract: The term endothelial dysfunction (ED) generally refers to a pathological circumstance in which normal endothelial regulation of vasomotor tone is disturbed. ED has been described in a broad range of cardiovascular and related disease states. In association, deranged endothelial function also has the potential to result in abnormal platelet aggregation and monocyte adhesion. Over the past decade, it has become apparent that reduced availability of nitric oxide is a key mechanism for ED. A range of biochemical disturbances, including depressed L-arginine, have been shown to be associated with ED, and recent evidence indicates this may be genetically determined.
Publisher: Wiley
Date: 04-2016
DOI: 10.14814/PHY2.12757
Publisher: Wiley
Date: 05-2006
DOI: 10.1016/J.EJHEART.2005.09.001
Abstract: The determinants of release of brain natriuretic peptide (BNP) in heart failure (HF) are incompletely understood, particularly, the effect of heart rhythm and haemodynamic stress. To investigate the effect of haemodynamic stress on cardiac BNP release in HF and differentiate this response for atrial fibrillation (AF) and sinus rhythm (SR). In 18 HF patients (ejection fraction<40%, 9 in AF and 9 in SR) haemodynamics and BNP levels were measured from arterial and coronary sinus s les at baseline, after 10 min of 20 degrees passive head up tilt (HUT) and after 10 min of isometric handgrip (IHG) exercise. From these data, we calculated a transcardiac BNP gradient and compared results between the AF and SR cohort. During haemodynamic stress in both groups, there were no significance differences in left sided filling pressures. At baseline, there were no differences in BNP measurements between the SR and AF group. The transcardiac BNP gradient increased significantly in the SR (p=0.02) but not the AF cohort, after HUT. During IHG exercise, there was a significant decrease in cardiac BNP release in the AF cohort (p=0.03) but not the SR cohort. These data imply in HF, cardiac rhythm influences cardiac BNP release in response to haemodynamic stress.
Publisher: Aerospace Medical Association
Date: 09-2020
Abstract: BACKGROUND: From 2007, the Federal Aviation Administration (FAA) permitted pilots who have had a heart transplant to be considered for recertification under special issuance at the third-class level. The objective of this study was to evaluate certification safety and determine if any adverse outcome occurred in this airman group as a consequence of this policy. METHODS: Methods involved collecting data from the FAA Document Imaging Workflow System to identify airmen undergoing cardiac transplantation since 2007, and examining medical and safety-related outcomes through the National Transportation Safety Board-related accident database and the Centers for Disease Control and Prevention National Death Index. RESULTS: Included in the study were 36 airmen, with 16 recertified at the class 3 level and 20 denied certification. No aviation accidents or recorded deaths occurred in the group of 16 airmen undergoing recertification. Of these airmen, 13 underwent a second successful recertification and 6 underwent a third attempt, with 5 being successful. Two airmen have declared their intention to fly under BasicMed. Of the 20 airmen denied recertification, 16 were denied for failure to provide information. There were three deaths in this denied group. DISCUSSION: The policy allowing third-class heart transplant recipient recertification appears to be safe. Aviation safety is not being compromised by allowing these airmen to resume flying, with the exception that recertification should continue under the special issuance system and not through BasicMed. Norris A, Skaggs V, Kaye D, De Voll J, McGiffin D. Selective recertification of pilots who have undergone a cardiac transplant . Aerosp Med Hum Perform. 2020 91(9):732736.
Publisher: Springer New York
Date: 02-12-2016
DOI: 10.1007/978-1-4939-6588-5_19
Abstract: Cardiac gene delivery has become an important issue following the emergence of gene therapy for the possible treatment of heart failure. Despite many advances in the management of heart failure (HF), treatment options for many patients with advanced HF remain limited. At a cellular and molecular level, many of the fundamental alterations that contribute to the pathogenesis of HF are becoming better understood and this has resulted in the discovery of new therapeutic targets in animal models of HF, in particular in the area of gene therapy.Numerous small animal and preclinical studies have examined the efficacy of delivering genes targeting various signaling pathways that are affected as the heart fails. However, the translation of this work into the clinic has been difficult due to the requirement for large scale targeted delivery of the gene. This methods chapter describes a percutaneous method of recirculation that we have employed to successfully deliver potential therapeutic agents, including genes, to the heart.
Publisher: American College of Physicians
Date: 05-08-2003
DOI: 10.7326/0003-4819-139-3-200308050-00008
Abstract: Peripheral vasodilatation is central to the pathogenesis of the accompanying hyperkinetic circulatory state and portal hypertension in cirrhotic patients. Selective intestinal decontamination with norfloxacin has been demonstrated to partially correct nitric oxide production in the forearm vasculature of cirrhotic patients. To examine the effects of selective intestinal decontamination on regional and systemic hemodynamics in cirrhotic patients. Randomized, double-blind, placebo-controlled, crossover study. Alfred Hospital, Melbourne, Australia. 14 patients with alcohol-related cirrhosis and 14 matched healthy controls. Norfloxacin, 400 mg twice daily, for 4 weeks. Venous occlusion plethysmography was used to determine forearm blood flow. Cardiac output and the hepatic venous pressure gradient were determined after cardiac catheterization. Glomerular filtration rate was assessed by measuring inulin clearance. Serum levels of endotoxin were determined by chromogenic Limulus amebocytelysate assay. Norfloxacin significantly diminished serum endotoxin levels (average change, -2.14 EU/mL [95% CI, -3.6 to -0.68 EU/mL]). Derived systemic vascular resistance increased significantly with norfloxacin (2.94 units [CI, 0.74 to 5.11 units]) and was accompanied by an increase in mean arterial pressure (8.70 mm Hg [CI, 2.65 to 14.73]), a trend toward decreased cardiac output (-1.207 L/min [range, 0.05 to -2.37 L/min]), a decrease in forearm blood flow (-0.99 mL/100 mL per min [CI, -1.80 to -0.17 mL/100 mL per min]), and a trend toward reduced hepatic venous pressure gradient (-2.43 mm Hg [CI, -5.2 to 0.34 mm Hg]). Norfloxacin did not significantly alter glomerular filtration rate. Selective intestinal decontamination with norfloxacin partially reverses the hyperdynamic circulatory state in cirrhotic patients without harming splanchnic or renal hemodynamics.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JCHF.2019.01.006
Abstract: This study sought to discern which central (e.g., heart rate, stroke volume [SV], filling pressure) and peripheral factors (e.g., oxygen use by skeletal muscle, body mass index [BMI]) during exercise were most strongly associated with the presence of heart failure and preserved ejection fraction (HFpEF) as compared with healthy control subjects exercising at the same workload. The underlying mechanisms limiting exercise capacity in patients with HFpEF are not fully understood. In patients with HFpEF (n = 108), the hemodynamic response at peak exercise was measured using right-sided heart catheterization and was compared with that in healthy control subjects (n = 42) at matched workloads to reveal hemodynamic differences that were not attributable to the workload performed. The patients studied were prospectively included in the REDUCE-LAP HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trials and HemReX (Effect of Age on the Hemodynamic Response During Rest and Exercise in Healthy Humans) study. Univariable and multivariable logistic regression models were used to analyze variables associated with HFpEF versus control subjects. Compared with healthy control subjects, pulmonary capillary wedge pressure (PCWP) and SV were the only independent hemodynamic variables that were associated with HFpEF, a finding explaining 66% (p < 0.0001) of the difference between the groups. When relevant baseline characteristics were added to the base model, only BMI emerged as an additional independent variable, in total explaining of 90% of the differences between groups (p < 0.0001): PCWP (47%), BMI (31%), and SV (12%). The study identified 3 key variables (PCWP, BMI, and SV) that independently correlate with the presence of patients with HFpEF compared with healthy control subjects exercising at the same workload. Therapies that decrease left-sided heart filling pressures could improve exercise capacity and possibly prognosis.
Publisher: Hindawi Limited
Date: 08-09-2015
DOI: 10.1111/JOCS.12632
Abstract: A case is described of cardiogenic shock that occurred following use of sotalol in a patient with severe left ventricular dysfunction. The patient required left ventricular assist device (LVAD) placement with subsequent myocardial recovery to a degree that allowed eventual device removal following 140 days of support.
Publisher: Elsevier BV
Date: 03-2019
Publisher: SAGE Publications
Date: 04-1994
Publisher: American Physiological Society
Date: 02-2012
DOI: 10.1152/PHYSIOLGENOMICS.00111.2011
Abstract: Chronic atrial fibrillation (AF) is a complication associated with the dilated atria of patients with valvular heart disease and contributes to worsened pathology. We examined microRNA (miRNA) expression profiles in right and left atrial appendage tissue from valvular heart disease (VHD) patients. Right atrial (RA) appendage from patients undergoing coronary artery bypass grafting and left atrial (LA) appendage from healthy hearts, not used for transplant, were used as controls. There was no detectable effect of chronic AF on miRNA expression in LA tissue, but miRNA expression in RA was strongly influenced by AF, with 47 miRNAs (15 higher, 32 lower) showing differential expression between the AF and control sinus rhythm groups. VHD induced different changes in miRNA expression in LA compared with RA. Fifty-three (12 higher, 41 lower) miRNAs were altered by VHD in LA, compared with 5 (4 higher, 1 lower) in RA tissue. miRNA profiles also differed between VHD-LA and VHD-RA (13 higher, 26 lower). We conclude that VHD and AF influence miRNA expression patterns in LA and RA, but these are affected differently by disease progression and by the development of AF. These findings provide new insights into the progression of VHD.
Publisher: Springer Science and Business Media LLC
Date: 02-2007
DOI: 10.1038/NRD2219
Abstract: Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of beta-blockers and antagonists of the renin-angiotensin system, there is still a major unmet need for better therapies for many patients with heart failure. However, disappointment related to late-stage clinical failures of a number of novel agents, including endothelin antagonists and tumour-necrosis factor blockers, has reduced the impetus of drug development in this field. Here, we review possible targets for heart failure therapy that have emerged from recent progress in our understanding of the underlying disease mechanisms, and highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.
Publisher: Public Library of Science (PLoS)
Date: 12-11-2013
Publisher: Public Library of Science (PLoS)
Date: 30-11-2018
Publisher: BMJ
Date: 11-2018
DOI: 10.1136/HEARTJNL-2017-312114
Abstract: Most cardiovascular disease (CVD) occurs in patients over the age of 60. However, most evidence-based current cardiovascular guidelines lack evidence in an older population, due to the under-representation of older patients in randomised trials. Blood pressure rises with age due to increasing arterial stiffness, and stricter control results in improved outcomes. Myocardial ischaemia is also more common with increasing age, due to a combination of coronary artery disease and myocardial changes. However, despite higher rates of adverse outcomes, older patients are offered guideline-based therapy less frequently. Frailty is an independent predictor of mortality in adults over the age of 60, yet remains poorly assessed slow gait speed is a key marker for the development of frailty and for adverse outcomes following intervention. Few trials have assessed frailty independent of age however, there is evidence that non-frail older patients derive significant benefit from therapy, highlighting the urgent need to include frailty as a measure in clinical trials of treatment in CVD. In this review, the authors appraise the literature in regard to the cardiovascular changes with ageing, specifically in relation to the systemic and coronary circulation and with a particular emphasis on frailty and its implication in the evaluation and treatment of CVD.
Publisher: Public Library of Science (PLoS)
Date: 02-05-2013
Publisher: Elsevier BV
Date: 11-2003
Abstract: Central sleep apnea (CSA) associated with Cheyne-Stokes respiration in patients with congestive heart failure (CHF) is thought to be an acquired pattern of respiratory control instability related, at least in part, to elevated sympathetic nervous system activity. The effect of restoring heart function to normal with heart transplantation in patients with CHF and CSA has only been reported within weeks of the transplant and with varying results. The purpose of the study was to evaluate the impact of successful heart transplant on sympathetic nervous system activity and CSA severity in patients with CHF. Controlled prospective trial. University hospital. Twenty-two patients with CHF (13 patients with CSA, and 9 patients with no sleep-disordered breathing [SDB]). Polysomnography, left ventricular ejection fraction (LVEF), and overnight urinary norepinephrine excretion (UNE) were measured before and > 6 months after successful heart transplantation. In the CSA group, there was a fall in apnea-hypopnea index (AHI) [mean +/- SD, 28 +/- 15 to 7 +/- 6/h p < 0.001] and UNE (48.1 +/- 30.9 to 6.1 +/- 4.8 nmol/mmol creatinine, p < 0.001) associated with normalization of LVEF (19.2 +/- 9.3% to 53.7 +/- 6.1%, p < 0.001) at 13.2 +/- 8.3 months following heart transplantation. Of the CSA group following transplantation, seven patients had no SDB (AHI < 5/h), three patients had persistent CSA (AHI, 12.3 +/- 0.9/h) and four patients acquired obstructive sleep apnea (OSA) [AHI, 11.2 +/- 7.4/h]. In comparison, none of the control group acquired CSA or OSA after transplantation. We conclude that CSA may persist despite normalization of heart function and sympathetic nerve activity.
Publisher: Informa UK Limited
Date: 1994
DOI: 10.3109/08037059409101522
Abstract: In this study we aimed to elucidate the role of central noradrenergic, dopaminergic, adrenergic and serotonergic neuronal systems in the development of essential hypertension. Fifteen untreated essential hypertensive subjects (aged 44 +/- 3 years) and 32 healthy volunteers (aged 38 +/- 3 years) participated in this study. By combining direct blood s ling techniques with cerebral blood flow scans we were able to differentiate between cortical and subcortical venous drainage of the brain. Veno-arterial MHPG, HVA and 5-HIAA plasma concentration gradients combined with internal jugular vein plasma flows were used, according to the Fick Principle, to derive metabolite spillovers which in turn were used as indicators of central noradrenergic, dopaminergic and serotonergic neuronal activity, respectively. These amine systems, in both the brainstem and forebrain, have been implicated in the regulation of sympathetic outflow and blood pressure. Total body noradrenaline spillover to plasma was concurrently measured to assess the relationship between central monoamine turnover and sympathetic activity. Compared to their healthy counterparts the hypertensive subjects had an elevated release of MHPG from subcortical brain regions (1.4 +/- 0.3 v 0.5 +/- 0.2 nmol/min, p < 0.05). An inverse relationship between blood pressure and subcortical HVA overflow existed, with the HVA overflow being significantly lower in the hypertensives (0.5 +/- 0.2 v 2.1 +/- 0.5 nmol/min, p < 0.05). Subcortical 5-HUAA overflow did not differ between the two groups, and adrenaline spillover from the brain was not detected in either group. Subcortical MHPG overflow was significantly correlated with total body NA spillover to plasma (p < 0.05). These results indicate that reciprocal aberrations in subcortical noradrenaline and dopamine turnover exist in essential hypertension. Although the physiological significance of this remains to be unequivocally elucidated we postulate that elevated subcortical noradrenergic activity, presumably in the forebrain where noradrenergic neurons are pressor, may cause sympathoexcitation and play a role in the development of essential hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2022
DOI: 10.1161/CIRCOUTCOMES.121.008638
Abstract: Empagliflozin is the first medication to demonstrate clinical benefit in patients with heart failure with preserved ejection fraction, but its cost-effectiveness is unknown. We aimed to evaluate the cost-effectiveness of adding empagliflozin to standard therapy in patients with heart failure with preserved ejection fraction. A Markov model from the perspective of the Australian health care system was constructed to compare empagliflozin plus standard care to standard care alone among a hypothetical cohort of patients with heart failure with preserved ejection fraction. Clinical probabilities were derived from The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction). Costs and utilities were derived from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. Deterministic and probabilistic sensitivity analyses were performed to assess model uncertainty. Costs and benefits were discounted at 5% annually. Over a lifetime, the addition of empagliflozin to standard care prevented 167 heart failure hospitalizations and 155 heart failure-related urgent care visits for every 1000 patients treated and increased mean quality-adjusted survival by 0.16 quality adjusted life-years per patient. Mean lifetime costs in the empagliflozin and standard care groups were AUD$63 218 and AUD$58 478 per patient, respectively. This resulted in an incremental cost-effectiveness ratio of AUD$29 202 per quality adjusted life-year gained. In probabilistic sensitivity analyses, empagliflozin was cost-effective in 85% of 10 000 Monte Carlo simulations at a willingness-to-pay threshold of AUD$50 000 per quality adjusted life-year gained. In patients with heart failure with preserved ejection fraction, adding empagliflozin to standard care is likely to be cost-effective when compared with standard care alone in the Australian health care setting.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.AHJ.2011.11.011
Abstract: The role of routine supplemental oxygen for patients with uncomplicated acute myocardial infarction (AMI) has recently been questioned. There is conflicting data on the possible effects of hyperoxia on ischemic myocardium. The few clinical trials examining the role of oxygen in AMI were performed prior to the modern approach of emergent reperfusion and advanced medical management. Air Verses Oxygen In myocarDial infarction study (AVOID Study) is a prospective, multi-centre, randomized, controlled trial conducted by Ambulance Victoria and participating metropolitan Melbourne hospitals with primary percutaneous coronary intervention capabilities. The purpose of the study is to determine whether withholding routine supplemental oxygen therapy in patients with acute ST-elevation myocardial infarction but without hypoxia prior to reperfusion decreases myocardial infarct size. AVOID will enroll 490 patients, >18 years of age with acute ST-elevation myocardial infarction of less than 12 hours duration. There is an urgent need for clinical trials examining the role of oxygen in AMI. AVOID will seek to clarify this important issue. Results from this study may have widespread implications on the treatment of AMI and the use of oxygen in both the pre-hospital and hospital settings.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1038/S41598-017-13644-1
Abstract: Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of mi nimal m ethylat i on c lassifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality s les remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.
Publisher: Elsevier BV
Date: 05-1999
DOI: 10.1016/S0735-1097(99)00042-X
Abstract: The aim of the present study was to evaluate the influence of amiodarone on neurochemical parameters of sympathetic nervous activity in patients with congestive heart failure. Unlike most antiarrhythmic agents, amiodarone has been shown to exert a beneficial effect on survival in some studies of patients with congestive heart failure. The pharmacology of this agent is complex, and as such, the mode of its action is unclear in humans. Some experimental studies suggest that amiodarone exerts a sympatholytic effect. To evaluate the effect of amiodarone on sympathetic nervous activity, we measured the total systemic and cardiac norepinephrine (NE) spillover rate by isotope dilution in 58 patients with severe heart failure (left ventricular ejection fraction 20 +/- 1%), 22 of whom were receiving chronic amiodarone treatment. Release rates for dihydroxyphenylalanine (DOPA, a precursor of NE), and endogenous and radiolabeled dihydroxyphenylglycol (DHPG and 3H-DHPG, intraneuronal metabolites of NE and 3H-NE, respectively) were also determined to assess sympathetic neuronal integrity. Amiodarone-treated patients had significantly lower cardiac spillover rates for NE (42%, p = 0.001), DOPA (74%, p < 0.001), DHPG (44%, p < 0.01) and 3H-DHPG (51%, p < 0.01) than those patients not treated with amiodarone. Hemodynamic assessment of amiodarone-treated patients revealed higher cardiac output (4.4 +/- 0.2 vs. 3.7 +/- 0.2 liters/min, p < 0.01), and slightly lower pulmonary capillary wedge pressure (18 +/- 2 vs. 22 +/- 1, p = NS) than in untreated patients. After correction for the potential confounding effect of hemodynamic differences, amiodarone-treated patients continued to demonstrate significantly lower spillover rates of NE, DOPA and DHPG from the heart. These data indicate that amiodarone may exert beneficial effects on the failing human heart through a sympatholytic process, and this action appears to be relatively cardioselective.
Publisher: Wiley
Date: 23-06-2017
DOI: 10.1002/CPT.723
Abstract: Heart failure (HF) with preserved ejection fraction (HFPEF) is responsible for half of all HF cases and will be the most common form of HF within the next 5 years. Previous studies of pharmacological agents in HFPEF have proved neutral or negative, in part due to phenotypic heterogeneity and complex underlying mechanisms. This review summarizes the key molecular and cellular pathways characterized in HFPEF as well as current and future therapies that target these mechanisms.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2007
Publisher: Elsevier BV
Date: 09-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-07-2018
DOI: 10.1161/CIRCULATIONAHA.118.034271
Abstract: Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preecl sia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex-specific diagnostic criteria, improved risk stratification models, and targeted therapies.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.PHARMTHERA.2007.08.001
Abstract: The amino acid l-arginine participates in a variety of key biochemical and physiological activities, including its well-recognized role as the key substrate for nitric oxide (NO) biosynthesis. The current review describes the cellular influences on arginine metabolism with particular focus on the transport of l-arginine in the endothelium. It details the processes by which intracellular and extracellular levels of l-arginine may influence nitric oxide production and further documents the imbalance that is evident in various cardiovascular disease states. In man, impairment of l-arginine transport has been observed in hypertension, heart failure, and renal disease, and it may thus be a relevant therapeutic target for rectification of nitric oxide pathogenesis in these conditions.
Publisher: Elsevier BV
Date: 05-2008
DOI: 10.1016/J.CARDFAIL.2007.12.005
Abstract: Atrial fibrillation (AF) is a common comorbidity in heart failure (HF) patients and is classically associated with acceleration in the rate of HF progression. The precise mechanism for this interaction is unclear, but comprises "bidirectional" aspects in which AF promotes HF and HF also increases the likelihood of AF. We therefore studied the relationship between AF in an ovine model of pacing-induced congestive HF, in an attempt to identify the mechanisms that underpin the apparent synergistic relationship between AF and HF. Sixteen adult sheep were paced at 190 beats/min for 21 days (HF). AF was induced in 8 of these animals at 14 days' pacing using programmed extrastimuli (HF + AF). Left ventricular hemodynamics and the pattern of cardiac neurohormonal activation, via coronary sinus (CS) s ling, were determined at rest and during submaximal exercise testing in both groups at 21 days and after AF reversion (by atrial defibrillation) at 21 days. CS norepinephrine (NE), endothelin (ET-1), and brain natriuretic peptide (BNP) levels were significantly increased in HF + AF animals, whereas LV end-diastolic pressure (EDP) and LV dP/dt max were significantly reduced compared with moderate HF alone. Cardioversion significantly reduced CS NE and BNP levels and improved contractility in AF + HF animals. In a further 6 animals, we explored the mechanism by which HF increases susceptibility to AF, with specific emphasis on the influence of functional mitral regurgitation. The elimination of MR in HF animals using a percutaneous mitral annular reduction device significantly decreased the inducibility of AF. AF induction significantly depresses left ventricular function and causes activation of myocardial neurohormones. In conjunction, the presence of functional MR increases susceptibility to AF and this may be attenuated by MR reduction by percutaneous mitral annular reduction.
Publisher: Wiley
Date: 18-12-2009
Publisher: Springer Science and Business Media LLC
Date: 29-10-2012
Abstract: The presence of myocardial fibrosis is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) sequences can detect regional, but not diffuse myocardial fibrosis. Post-contrast T 1 mapping is an emerging CMR technique that may enable the non-invasive evaluation of diffuse myocardial fibrosis in HCM. The purpose of this study was to non-invasively detect and quantify diffuse myocardial fibrosis in HCM with CMR and examine its relationship to diastolic performance. We performed CMR on 76 patients - 51 with asymmetric septal hypertrophy due to HCM and 25 healthy controls. Left ventricular (LV) morphology, function and distribution of regional myocardial fibrosis were evaluated with cine imaging and LGE. A CMR T 1 mapping sequence determined the post-contrast myocardial T 1 time as an index of diffuse myocardial fibrosis. Diastolic function was assessed by transthoracic echocardiography. Regional myocardial fibrosis was observed in 84% of the HCM group. Post-contrast myocardial T 1 time was significantly shorter in patients with HCM compared to controls, consistent with diffuse myocardial fibrosis (498 ± 80 ms vs. 561 ± 47 ms, p 0.001). In HCM patients, post-contrast myocardial T 1 time correlated with mean E/e’ (r = −0.48, p 0.001). Patients with HCM have shorter post-contrast myocardial T 1 times, consistent with diffuse myocardial fibrosis, which correlate with estimated LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic function in HCM.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2002
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.YJMCC.2008.09.712
Abstract: The endothelium plays a vital role in the maintenance of vascular tone and structural vascular integrity, principally mediated via the actions of nitric oxide (NO). L-arginine is the immediate substrate for NO synthesis, and the availability of extracellular L-arginine is critical for the production of NO. Activation of protein kinase C (PKC) dependent signalling pathways are a feature of a number of cardiovascular disease states, and in this study we aimed to systematically evaluate the mechanism by which PKC regulates L-arginine transport in endothelial cells. In response to PKC activation (PMA 100 nM, 30 min), [(3)H]L-arginine uptake by bovine aortic endothelial cells (BAEC) was reduced to 45+4% of control (p<0.05). This resulted from a 53% reduction in the Vmax (p<0.05), with no change in the K(m) for L-arginine. Western blot analysis and confocal microscopy revealed no change in the expression or membrane distribution of CAT-1, the principal BAEC L-arginine transporter. Moreover in (32)P-labeling studies, PMA exposure did not result in CAT-1 phosphorylation. We therefore explored the possibility that PKC altered and interaction with MARCKS protein, a candidate membrane associated protein. By co-immunoprecipitation we show that CAT-1 interacts with, a membrane associated protein, that was significantly inhibited by PKC activation (p<0.05). Moreover antisense inhibition of MARCKS abolished the PMA effect on L-arginine transport. PKC dependent mechanisms regulate the transport of L-arginine, mediated via process involving MARCKS.
Publisher: JMIR Publications Inc.
Date: 26-09-2021
Abstract: eart failure self-management is essential to avoid decompensation and readmissions. Mobile apps seem promising in supporting heart failure self-management, and there has been a rapid growth in publications in this area. However, to date, systematic reviews have mostly focused on remote monitoring interventions using nonapp types of mobile technologies to transmit data to health care providers, rarely focusing on supporting patient self-management of heart failure. his study aims to systematically review the evidence on the effect of heart failure self-management apps on health outcomes, patient-reported outcomes, and patient experience. our databases (PubMed, Embase, CINAHL, and PsycINFO) were searched for studies examining interventions that comprised a mobile app targeting heart failure self-management and reported any health-related outcomes or patient-reported outcomes or perspectives published from 2008 to December 2021. The studies were independently screened. The risk of bias was appraised using Cochrane tools. We performed a narrative synthesis of the results. The protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews CRD42020158041). total of 28 articles (randomized controlled trials [RCTs]: n=10, 36%), assessing 23 apps, and a total of 1397 participants were included. The most common app features were weight monitoring (19/23, 83%), symptom monitoring (18/23, 78%), and vital sign monitoring (15/23, 65%). Only 26% (6/23) of the apps provided all guideline-defined core components of heart failure self-management programs: education, symptom monitoring, medication support, and physical activity support. RCTs were small, involving altogether 717 participants, had ≤6 months of follow-up, and outcomes were predominantly self-reported. Approximately 20% (2/10) of RCTs reported a significant improvement in their primary outcomes: heart failure knowledge ( i P /i =.002) and self-care ( i P /i =.004). One of the RCTs found a significant reduction in readmissions ( i P /i =.02), and 20% (2/10) of RCTs reported higher unplanned clinic visits. Other experimental studies also found significant improvements in knowledge, self-care, and readmissions, among others. Less than half of the studies involved patients and clinicians in the design of apps. Engagement with the intervention was poorly reported, with only 11% (3/28) of studies quantifying app engagement metrics such as frequency of use over the study duration. The most desirable app features were automated self-monitoring and feedback, personalization, communication with clinicians, and data sharing and integration. obile apps may improve heart failure self-management however, more robust evaluation studies are needed to analyze key end points for heart failure. On the basis of the results of this review, we provide a road map for future studies in this area.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-07-2021
Abstract: Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial‐derived metabolites such as short‐chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors. We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α‐ ersity (eg, number of microbes) and β‐ ersity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF ( P =0.001). We did not find an association between β‐ ersity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so ( P =0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short‐chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day P =0.016). We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.INJURY.2017.02.025
Abstract: The aim of this study was to evaluate the incidence and severity of blunt cardiac injury (BCI) as determined by cardiac magnetic resonance imaging (CMR), and to compare this to currently used diagnostic methods in severely injured patients. We conducted a prospective, pilot cohort study of 42 major trauma patients from July 2013 to Jan 2015. The cohort underwent CMR within 7 days, enrolling 21 patients with evidence of chest injury and an elevated Troponin I compared to 21 patients without chest injury who acted as controls. Major adverse cardiac events (MACE) including ventricular arrhythmia, unexplained hypotension requiring inotropes, or a requirement for cardiac surgery were recorded. 6/21 (28%) patients with chest injuries had abnormal CMR scans, while all 21 control patients had normal scans. CMR abnormalities included myocardial oedema, regional wall motion abnormalities, and myocardial haemorrhage. The left ventricle was the commonest site of injury (5/6), followed by the right ventricle (2/6) and tricuspid valve (1/6). MACE occurred in 5 patients. Sensitivity and specificity values for CMR at predicting MACE were 60% (15-95) and 81% (54-96), which compared favourably with other tests. In this pilot trial, CMR was found to give detailed anatomic information of myocardial injury in patients with suspected BCI, and may have a role in the diagnosis and management of patients with suspected BCI.
Publisher: Asian Spine Journal (ASJ)
Date: 31-08-2023
Abstract: Study Design: Retrospective cohort study.Purpose: To compare radiographic outcomes between unilateral and bilateral cage placement in transforaminal lumbar interbody fusions (TLIF) and to determine if the rate of fusion at the 1-year postoperative point was different in patients who received bilateral versus unilateral cages.Overview of Literature: There is no clear evidence to dictate whether bilateral or unilateral cages promote superior radiographic or surgical outcomes in TLIF.Methods: Patients years old who underwent primary one- or two-level TLIFs at our institution were identified and propensitymatched in a 3:1 fashion (unilateral:bilateral). Patient demographics, surgical characteristics, and radiographic outcomes, including vertebral endplate obliquity, segmental lordosis, subsidence, and fusion status, were compared between groups.Results: Of the 184 patients included, 46 received bilateral cages. Bilateral cage placement was associated with greater subsidence (1.06±1.25 mm vs. 0.59±1.16 mm, i /i =0.028) and enhanced restoration of segmental lordosis (5.74°±14.1° vs. −1.57°±10.9°, i /i =0.002) at the 1-year postoperative point, while unilateral cage placement was associated with an increased correction of endplate obliquity (−2.02°±4.42° vs. 0.24°±2.81°, i /i .001). Bilateral cage placement was significantly associated with radiographic fusion on bivariate analysis (89.1% vs. 70.3%, i /i =0.018) and significantly predicted radiographic fusion on multivariable regression analysis (estimate, 1.35 odds ratio, 3.87 95% confidence interval, 1.51–12.05 i /i =0.010).Conclusions: Bilateral interbody cage placement in TLIF procedures was associated with restoration of lumbar lordosis and increased fusion rates. However, endplate obliquity correction was significantly greater for patients who received a unilateral cage.
Publisher: Oxford University Press (OUP)
Date: 21-05-2007
Abstract: We investigated whether biventricular (BiV) pacing favourably affects cardiac sympathetic activity in heart failure (HF). In 10 HF patients treated with BiV pacing, we assessed cardiac sympathetic activity by metaiodobenzylguanidine ((123)I-MIBG) imaging. Patients were randomized in a double-blinded crossover fashion, for two weeks of either inactivation of BiV pacing or BiV pacing, with crossover to the alternate group for a further two weeks. After randomization blocks, cardiac (123)I-MIBG imaging and a 6 min walk test were performed. BiV pacing was associated with significant improvements in cardiac (123)I-MIBG uptake reflected by increases in early (BiV 1.71 +/- 0.09 vs. non-BiV 1.63 +/- 0.06, P = 0.03) and late (at 4 h) heart to mediastinal ratio of uptake (BiV 1.54 +/- 0.08 vs. non-BiV 1.45 +/- 0.06, P = 0.03). Additionally, pulmonary (123)I-MIBG uptake, measured as lung to mediastinal ratio, significantly improved (P = 0.009). Six-minute walk and systolic blood pressure tended to improve with BiV vs. non-BiV pacing (P = 0.09). In patients with stable HF, BiV pacing is associated with long-term improvements in cardiac sympathetic nerve activity, as reflected by improvements in cardiac (123)I-MIBG uptake. This is a potential mechanism for morbidity and mortality benefits observed in larger studies.
Publisher: Wiley
Date: 11-2012
DOI: 10.1111/J.1445-5994.2012.02866.X
Abstract: The mortality rate post admission to hospital after successful resuscitation from out-of-hospital cardiac arrest is high, with significant variation between regions and in idual institutions. While prehospital factors such as age, bystander cardiopulmonary resuscitation and total cardiac arrest time are known to influence outcome, several aspects of post-resuscitative care including therapeutic hypothermia, coronary intervention and goal-directed therapy may also influence patient survival. Regional systems of care have improved provider experience and patient outcomes for those with ST elevation myocardial infarction and life-threatening traumatic injury. In particular, hospital factors such as hospital size and interventional cardiac care capabilities have been found to influence patient mortality. This paper reviews the evidence supporting the possible development and implementation of Australian cardiac arrest centres.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.BIOCEL.2009.08.008
Abstract: Under conditions of oxidative stress it is well known that the bioavailability of nitric oxide (NO) is known to be significantly reduced. This process is in part due to the combination of NO with superoxide radicals to form peroxynitrite (ONOO(-)). While this process inactivates NO per se, it is not certain to which extent this process may also further impair ongoing NO production. Given the pivotal role of arginine availability for NO synthesis we determined the impact of ONOO(-) on endothelial arginine transport and intracellular arginine metabolism. Peroxynitrite reduced endothelial [(3)H]-L-arginine transport and increased the rate of arginine efflux in a concentration-dependent manner (both p<0.05). In conjunction, exposure to ONOO(-) significantly reduced the intracellular concentration of L-arginine, N(G)-hydroxy-L-arginine (an intermediate of NO biosynthesis) and citrulline by 46%, 45% and 60% respectively (all p<0.05), while asymmetric dimethyl arginine (ADMA) levels rose by 180% (p<0.05). ONOO(-) exposure did not alter the cellular distribution of the principal L-arginine transporter, CAT1, rather the effect on CAT1 activity appeared to be mediated by protein nitrosation. Conclusion Peroxynitrite negatively influences NO production by combined effects on arginine uptake and efflux, most likely due to a nitrosative action of ONOO(-) on CAT-1.
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0165-1838(95)00041-U
Abstract: The plasma level and urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the principal metabolite of noradrenaline in the brain, are often used as indicators of central nervous system noradrenergic activity. Using percutaneously placed catheters, we studied the regional inputs into the plasma MHPG pool in 62 healthy volunteers. Veno-arterial plasma concentration differences and regional organ blood flows were used to quantify the relative amounts of MHPG contributed by various sites into plasma. Positive veno-arterial concentration gradients were found across the forearm, cardiac and jugular vessels in the healthy subjects. By far the majority of MHPG in plasma was derived from skeletal muscle, 5.3 +/- 1.8 nmol/min, with only minimal contribution (0.9 +/- 0.2 nmol/min) from the brain. Thus, to obtain an accurate indication of central nervous system noradrenergic activity the confounding influences of regional MHPG production must be excluded. 34 patients with chronic congestive heart failure, 6 patients with pure autonomic failure and 9 recent heart transplant recipients were used to investigate the possible effects of chronic sympathetic nervous system overactivity and sympathetic underactivity and denervation on peripheral MHPG production and plasma MHPG concentration. To examine the utility of plasma MHPG determinations as an indicator of acute alterations in sympathetic nervous activity we examined the influence of a variety of laboratory stressors on the arterial level and cardiac production of MHPG. The resting arterial plasma MHPG concentration mirrored sympathetic function in the patients with cardiac failure (sympathetic activation) and pure autonomic failure (sympathetic denervation), with mean MHPG plasma concentrations being 180 and 40% of those in healthy subjects. Cardiac MHPG production was increased in heart failure patients, and near zero with the cardiac sympathetic denervation accompanying transplantation and pure autonomic failure. In contrast, acute reflex stimulation of sympathetic nervous activity was not associated with parallel changes in the arterial level or cardiac production of MHPG. Measurements of peripheral plasma MHPG levels provide an index of prevailing sympathetic nervous function in clinical models of sympathetic overactivity and denervation, but are insensitive to acute sympathetic nervous system responses.
Publisher: Informa Healthcare
Date: 11-2003
DOI: 10.1517/14656566.4.11.1889
Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia. Its prevalence is increasing and accordingly, so is its burden on healthcare systems throughout the world. The pathophysiology of AF is complex and poorly understood, which of itself presents a major challenge to the management of this important condition. AF is associated with increased morbidity and mortality, particularly in patients with underlying left ventricular dysfunction. Once AF occurs, it is often difficult to 'cure' and as such, the major focus of therapy is currently ided essentially between a rate control strategy and a need to revert to and maintain sinus rhythm. Both approaches seek to minimise the associated symptoms and complications. Over the past two decades, numerous pharmacological approaches to the management of AF have been employed, many of which have been shown to be relatively ineffective or confounded by major complications. Accordingly, recent research and interest has focused on non-pharmacological electrophysiological therapies to either cure AF or improve symptoms. This review summarises the current approaches to the management AF and provides some new insights into emerging therapies for this common clinical problem.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2020
Publisher: Elsevier BV
Date: 11-2001
Publisher: Elsevier BV
Date: 08-2020
Publisher: Springer Science and Business Media LLC
Date: 11-03-2021
DOI: 10.1038/S41586-021-03412-7
Abstract: Transmission of SARS-CoV-2 is uncontrolled in many parts of the world control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant
Publisher: Springer Science and Business Media LLC
Date: 25-04-2019
Publisher: Informa UK Limited
Date: 1995
DOI: 10.3109/10641969509087081
Abstract: We applied transmitter washout methodology, s ling internal jugular venous plasma via a percutaneously placed catheter, to study CNS norepinephrine release in humans and its relation to peripheral sympathetic activity. Norepinephrine overflows into the venous drainage of the brain, as do its precursor, DOPA, and metabolites DHPG and MHPG, indicating that the blood-brain barrier provides an incomplete impediment to their outward flux from the brain. Pharmacological testing with two drugs which altered CNS norepinephrine turnover, the tricyclic antidepressant desipramine and the ganglionic blocker, trimethaphan, demonstrated a direct relation existed between CNS norepinephrine release and sympathetic nerve firing rates. In essential hypertension, the sympathetic activation commonly present was associated with, and possibly caused by increased CNS release of norepinephrine, manifested in elevated overflow of norepinephrine, MHPG and DHPG from the brain. Bilateral jugular s ling, coupled with a cerebral venous sinus scan to delineate the drainage pattern, demonstrated that this increased norepinephrine release was confined to subcortical forebrain regions.
Publisher: Wiley
Date: 13-05-2011
Publisher: Wiley
Date: 13-05-2020
DOI: 10.1111/BPH.15065
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2022
Publisher: Elsevier BV
Date: 07-2020
DOI: 10.1016/J.HLC.2019.08.014
Abstract: Cardiovascular diseases (CVDs) and diabetes are two of the most important public health problems. Outcomes for patients with these disorders vary considerably, likely due to the added influence of a range of interacting clinical, metabolic, environmental, lifestyle, genetic and psychosocial risk factors associated with these diseases. The Baker Biobank study was designed to characterise these factors to inform better risk prediction, earlier diagnosis and better treatment of CVDs and diabetes. This paper describes the detailed methods for the establishment of the Baker Biobank. The study collected extensive phenotypic detail about the participants recruited from Victoria, Australia. Data and s les were collected at the Departments of Cardiology and Respiratory Medicine at the Alfred Hospital and Healthy Hearts Program at the Baker Institute. A total of 6,530 adults with age 18-69 years were recruited into the Biobank. The majority of these participants (63%) were male. The mean (standard deviation [SD]) age of the Biobank Cohort at the time of data collection was 57(15) years. The study collected data on socio-demographic characteristics, behavioural and lifestyle factors, anthropometric measurements, medical and medication history, and blood levels of various biomarkers. The study also collected and stored Guthrie cards, serum, plasma, buffy coat, whole blood collected in Tempus tubes (for RNA extraction). For some s les extracted DNA and RNA is stored. The Biobank data is also linked to echocardiogram, hospital admission, pathology and mortality datasets. The Baker Biobank data and s les are available for health researchers with approval of Biobank Steering Group and Human Research Ethics Committee. The Baker Biobank provides valuable data and s les into the study of the interplay among cardiovascular diseases risk factors and their impact on morbidity and mortality in Australia.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2016
DOI: 10.1038/SREP24333
Abstract: Scientific Reports 6: Article number: 22413 published online: 02 March 2016 updated: 22 April 2016 The Acknowledgements section in this Article is incomplete. “We wish to thank William He and Steven Fernandez for technical support. This research was supported by funding from the J.o. & J.R. Wicking Trust & Mason Foundation a strategic rant awarded to Dr.
Publisher: American Physiological Society
Date: 10-2005
DOI: 10.1152/AJPHEART.01010.2004
Abstract: Cardiac-specific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restrain such deleterious outcomes. To test this, we examined 5- to 6-mo-old transgenic (TG) mice that overexpress NGF in heart and their wild-type (WT) littermates using echocardiography, invasive catheterization, histology, and catecholamine assays. In TG mice, hypertrophy of the right ventricle was evident (+67%), but the left ventricle was only mildly affected (+17%). Left ventricular (LV) fractional shortening and fractional area change values as indicated by echocardiography were similar between the two groups. Catheterization experiments revealed that LV ±dP/d t values were comparable between TG and WT mice and responded similarly upon isoproterenol stimulation, which indicates lack of β-adrenergic receptor dysfunction. Although norepinephrine levels in TG LV tissue were approximately twofold those of WT tissue, TG plasma levels of the neuronal norepinephrine metabolite dihydroxyphenyglycol were fivefold those of WT plasma. A greater neuronal uptake activity was also observed in TG LV tissue. In conclusion, overexpression of NGF in heart leads to sympathetic hyperinnervation that is not associated with detrimental effects on LV performance and is likely due to concomitantly enhanced norepinephrine neuronal uptake.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-07-2009
DOI: 10.1161/CIRCULATIONAHA.109.849885
Abstract: Background— Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care. Methods and Results— Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction %, and a 6-minute walk distance between 150 and 450 m were enrolled in the CARILLON Mitral Annuloplasty Device European Union Study (AMADEUS). Percutaneous mitral annuloplasty was achieved through the coronary sinus with the CARILLON Mitral Contour System. Echocardiographic FMR grade, exercise tolerance, New York Heart Association class, and quality of life were assessed at baseline and 1 and 6 months. Of the 48 patients enrolled in the trial, 30 received the CARILLON device. Eighteen patients did not receive a device because of access issues, insufficient acute FMR reduction, or coronary artery compromise. The major adverse event rate was 13% at 30 days. At 6 months, the degree of FMR reduction among 5 different quantitative echocardiographic measures ranged from 22% to 32%. Six-minute walk distance improved from 307±87 m at baseline to 403±137 m at 6 months ( P .001). Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, improved from 47±16 points at baseline to 69±15 points at 6 months ( P .001). Conclusions— Percutaneous reduction in FMR with a novel coronary sinus–based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.
Publisher: Wiley
Date: 21-02-2007
DOI: 10.1111/J.1399-0012.2007.00644.X
Abstract: The aim of this paper was to review the outcomes of cardiac transplantation with regards to short- and long-term survival, focusing particularly on patients who receive organs with long ischemic times and the resource utilization necessary to support such patients through their postoperative period. A retrospective review of 420 consecutive cardiac transplants in a single institution was undertaken. The five- and 10-yr survival rates for the entire group were 0.76 (95% CI: 0.72-0.80) and 0.60 (0.54-0.66). There was no decrease in mid- or long-term survival in patients who received organs with ischemic times over 300 min. Longer donor organ ischemic time was not associated with increased 30 d mortality but was significantly associated with longer intensive care bed stay, increased incidence of primary graft failure, need for mechanical support, and complications such as acute renal failures. Although using donor organs with longer ischemic times for cardiac transplantation does not impact on survival, there is a significantly increased utilization of resources to ensure these patients survive the postoperative period.
Publisher: American Astronomical Society
Date: 20-06-2011
Publisher: Elsevier BV
Date: 10-2016
Publisher: Wiley
Date: 08-1999
DOI: 10.1046/J.1440-1681.1999.03102.X
Abstract: 1. The sodium-calcium exchanger (NCX) plays an important role in Ca2+ homeostasis. In the heart, NCX participates in the control of contraction and relaxation and in large vessel endothelial cells some data suggest that NCX could influence nitric oxide (NO) generation. In this context, the cardiac microvasculature has received considerable attention as a mediator of myocardial performance, via the release of paracrine acting factors such as NO. Therefore, the aim of the current study was to characterize NCX expression and regulation in cardiac microvascular endothelial cells (CMEC). The NCX expression was also examined in neonatal ventricular cardiomyocytes where aspects of its function and regulation have been well characterized. 2. The presence of functional NCX in CMEC was confirmed by the presence of a consistent rise in intracellular Ca2+ concentration ([Ca2+]i) in response to removal of extracellular Na+. Furthermore, NCX mRNA expression was readily detectable in CMEC. 3. In order to examine the role of possible physiological regulators of NCX expression, the effect of intracellular Ca2+ loading, caused by 24 h exposure to 10 mumol/L ouabain, was investigated. In Ca(2+)-loaded CMEC, there was a substantially greater rise in [Ca2+]i during exposure to Na(+)-free buffer: 33 +/- 6 versus 124 +/- 25 nmol/L% (P < 0.05), consistent with increased protein expression. Consistent with these findings, northern blot analysis confirmed the presence of a two-fold increase in NCX mRNA in these cells. 4. These data indicate the presence of functional NCX in CMEC and identify [Ca2+]i as a potential physiological regulator of expression.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier
Date: 1997
Publisher: Wiley
Date: 30-06-2015
DOI: 10.1113/EP085250
Publisher: Elsevier BV
Date: 07-2008
Abstract: Heart failure (HF) is often associated with interstitial pulmonary edema and structural changes, resulting in thickening of the alveolar-capillary membrane and reductions in diffusing capacity of the lung for carbon monoxide (Dlco). Reduced Dlco reflects an impaired efficiency of gas exchange, which may increase plant gain, influence ventilatory control stability, and result in central sleep apnea (CSA). In this study, we test the hypothesis that reductions in Dlco would be associated with increased apnea-hypopnea index (AHI) in patients with CSA. Overnight polysomnography, pulmonary function tests, and arterial blood gas analyses were performed in 45 patients with chronic, stable HF. Univariate and multivariate regression analyses were performed in those patients with predominant CSA to test which variables were associated with AHI. Patients had a mean (+/-SD) age of 52.7+/-8.9 years, a mean left ventricular ejection fraction of 26.5+/-9.9%, and a mean AHI of 22.0+/-17.4 events per hour. In CSA patients, Dlco and Pao2 both correlated with total AHI (r=-0.43, p=0.046 and r=-0.53, p=0.011, respectively) and with supine AHI (r=-0.56, p=0.009 and r=-0.60, p=0.004, respectively). In a forward stepwise estimation model, Dlco, Pao2, and body mass index were independent predictors of total AHI, explaining 51% of variability, as was supine AHI, explaining 64% of variability. Dlco and Pao2 accounted for 37% of the variability in total AHI and 49% of the variability in supine AHI. In patients with HF and CSA, reductions in Dlco and Pao2 are independently associated with respiratory disturbance during sleep. The increase in ventilatory instability may be due to plant gain effects.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-09-2017
Abstract: Patients with heart failure with preserved ejection fraction ( HFpEF ) exhibit a range of cardiovascular phenotypic profiles modified by several common comorbidities. In particular, patients with HFpEF tend to be older however, it is unclear whether the effects of cardiovascular aging per se modify the expression of HFpEF . We therefore sought to investigate the interaction between age and physiologic profile in patients with HFpEF . We assessed the hemodynamic and metabolic profile of 40 patients with HFpEF . Patients underwent right heart catheterization at rest and during supine cycle ergometry, and were segregated into 2 groups by the median age of the cohort. Older patients with HFpEF demonstrated reduced resting cardiac output (4.8±1.2 L/min versus 5.7±1.1 L/min). With exercise, older patients demonstrated a marked rise in arteriovenous oxygen content difference (10.8±1.8 versus 7.9±2.4 mL, P ≤0.001), driven by enhanced oxygen extraction. There was no significant difference in peak pulmonary capillary wedge pressure (30±7 mm Hg versus 27±6, P =0.135), including when indexed to workload (pulmonary capillary wedge pressure/W, 0.88 mm Hg/W versus 0.92 P =0.83). Older patients with HFpEF display a different physiological phenotype compared with younger patients, with enhanced oxygen extraction and lower increment in cardiac output to increase oxygen consumption from rest to peak supine exercise. This finding highlights the importance in considering age when considering therapeutic options in patients with HFpEF .
Publisher: Elsevier BV
Date: 10-2003
Publisher: Elsevier BV
Date: 12-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-04-2020
DOI: 10.1161/CIRCULATIONAHA.119.043081
Abstract: High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites. One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg -1 ·d -1 ). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined. Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation. The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-11-2000
DOI: 10.1161/01.CIR.102.22.2707
Abstract: Background —The clinical features of congestive heart failure (CHF) result from a complex interaction between reduced ventricular function, neurohormonal activation, and impaired endothelial function. Although endothelial dysfunction has been well documented, the mechanisms that contribute to this abnormality remain unknown. Recent studies, however, indicate a potential therapeutic role for supplemental l -arginine, suggesting the presence of an underlying disorder of l -arginine metabolism. Methods and Results —We used 2 complementary approaches to assess l -arginine transport in control subjects and patients with CHF. During a steady-state intra-arterial infusion of [ 3 H] l -arginine (100 nCi/min), forearm clearance of [ 3 H] l -arginine was significantly reduced in CHF patients compared with forearm kinetics in control subjects (64±2 versus 133±14 mL/min, P =0.002). In conjunction with this, [ 3 H] l -arginine uptake by peripheral blood mononuclear cells (PBMCs) was also substantially reduced in heart failure patients compared with controls (V max 10.1±1.3 versus 49.8±7.1 pmol/10 5 cells per 5 minutes, P .001). In association with this finding, we observed a 76% ( P .01) reduction in mRNA expression for the cationic amino acid transporter CAT-1, as assessed by ribonuclease protection assay. Conclusions —These data document both in vivo and in vitro evidence for a marked depression of l -arginine transport in human CHF and therefore provide an explanation for the restorative actions of supplemental l -arginine on vascular function in CHF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-04-2011
Publisher: Elsevier BV
Date: 06-1995
Publisher: Elsevier BV
Date: 05-2019
Publisher: Public Library of Science (PLoS)
Date: 27-07-2015
Publisher: Springer Science and Business Media LLC
Date: 24-08-2017
DOI: 10.1038/NRCARDIO.2017.120
Abstract: Hypertension is the leading risk factor for heart disease and stroke, and is estimated to cause 9.4 million deaths globally every year. The pathogenesis of hypertension is complex, but lifestyle factors such as diet are important contributors to the disease. High dietary intake of fruit and vegetables is associated with reduced blood pressure and lower cardiovascular mortality. A critical relationship between dietary intake and the composition of the gut microbiota has been described in the literature, and a growing body of evidence supports the role of the gut microbiota in the regulation of blood pressure. In this Review, we describe the mechanisms by which the gut microbiota and its metabolites, including short-chain fatty acids, trimethylamine N-oxide, and lipopolysaccharides, act on downstream cellular targets to prevent or contribute to the pathogenesis of hypertension. These effects have a direct influence on tissues such as the kidney, the endothelium, and the heart. Finally, we consider the role of the gut microbiota in resistant hypertension, the possible intergenerational effect of the gut microbiota on blood pressure regulation, and the promising therapeutic potential of gut microbiota modification to improve health and prevent disease.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.IJCARD.2010.10.007
Abstract: In contrast to patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF HFREF) the prognostic role of heart rate (HR) and blood pressure (BP) in patients with HF and preserved LVEF (HFPEF) is not well known. The aim of this study was to characterize the relationship between HR and BP and outcomes in HFPEF and to compare it to HFREF. The association between HR and BP and outcomes (median follow-up: 38 months) was analyzed in patients with HFREF (LVEF ≤ 45% n=6792) and HFPEF (LVEF > 45% n=988) from the Digitalis Investigator Group trial. Mortality (35% vs. 23%) and HF hospitalization rates (31% vs. 20% p<0.001 for both) were higher in HFREF compared to HFPEF. In HFREF, higher HR and lower systolic and diastolic BP quartiles were associated with higher mortality and HF hospitalization rates. By contrast, there was no significant association between HR and BP respectively and mortality in HFPEF, and there was no significant association between systolic BP and hospitalization risk in HFPEF either. However, HF hospitalization rates were significantly related to increasing HR and decreasing diastolic BP quartile respectively (4.9, 6.8, 6.8, and 10.5 and 5.5, 8.1, 6.0, and 10.1 respectively events per 1000 person-years) in HFPEF. In HFPEF, there was also evidence of a significant J-shaped relationship between pulse pressure and mortality. The prognostic value of HR and BP differed substantially between HFREF and HFPEF. These data may provide a foundation for the design of novel interventions in HFPEF patients.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.ICCL.2014.03.013
Abstract: Contrast-induced nephropathy (CIN) is a common condition that is associated with short- and, likely, long-term adverse outcomes. Although periprocedural intravenous hydration is the simplest and most widely used technique to prevent CIN, the limited ability of this approach to mitigate the CIN risk in high-risk populations has provided an impetus to develop new preventive strategies. A range of potentially useful device-based approaches offers new preventive techniques. Well-designed and adequately powered randomized studies of these device-based therapies are urgently needed to determine the expanding role they will play in future clinical practice.
Publisher: Massachusetts Medical Society
Date: 11-11-2010
DOI: 10.1056/NEJMC1010535
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
DOI: 10.1161/01.HYP.0000103160.35395.9E
Abstract: There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex d ening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3 [H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for d ened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/IMJ.13050
Abstract: Meth hetamine abuse is a growing public health problem, and increasing numbers of patients are admitted with meth hetamine-associated cardiomyopathy (MAC). We sought to characterise the patterns of this disease and identify predictors of recovery. We retrospectively studied consecutive patients diagnosed with MAC between January 2006 and July 2015. We identified 20 patients (14 males, 6 females) with mean age 35 ± 9 years. Most had very severe systolic dysfunction (mean left ventricular ejection fraction (LVEF) 19.7 ± 11.4%) at presentation with 14 requiring inotropes and 5 requiring mechanical support. The pattern of systolic dysfunction was global in 14 patients, while 6 patients had a 'reverse Takotsubo' (RT) pattern with severely hypokinetic basal-mid segments and apical preservation. RT patients were predominantly female, had a short history of meth hetamine abuse and had higher cardiac enzyme levels. Patients with global dysfunction tended to have mid-wall fibrosis on cardiac magnetic resonance imaging. On follow-up transthoracic echocardiography, 6 out of 19 (32%) had normalisation of LVEF (LVEF ≥ 50%) within 6 weeks. Smaller left ventricular and left atrial size, shorter duration of meth hetamine use and RT pattern appeared to predict early recovery. A subset of MAC patients, particularly those with a RT pattern and lesser ventricular dilatation have the potential for early recovery of ventricular function. By contrast, those with evidence of myocardial fibrosis and ventricular enlargement have limited scope for recovery.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.HLC.2012.11.020
Abstract: Survival after out-of-hospital cardiac arrest remains limited. It is therefore imperative to develop new resuscitation techniques. We aimed to determine the potential role of extracorporeal membrane oxygenation assisted CPR (ECPR) in an animal model of refractory ischaemic cardiac arrest. Twelve sheep were assigned to either ECPR (n=6) or 'conventional' (n=6) resuscitation. All sheep had coronary occlusion, followed by induction of ventricular fibrillation (VF). CPR was than commenced for 10 min in both groups, followed by randomisation to ECPR or CPR for a further 10 min. At 23 min post induction of VF, advanced life support measures were commenced with direct cardioversion, adrenaline and amiodarone. Outcomes measures included rates of return of spontaneous circulation (ROSC), and analysis of VF wave form. Baseline haemodynamics were similar between the two groups. CPR consistently produced coronary perfusion pressures (CPP) greater than 15 mmHg in both groups, with significantly increased CPP post commencement of ECMO in the ECPR group (17.84±2 mmHg vs 22.94±3 mmHg, p=0.04). Number of shocks, pH, lactate and oxygenation were also comparable. Significantly greater rates of ROSC were seen in the ECPR sheep, 3/6 (50%) vs 0/6 (0%) (p=0.032), which was also associated with significantly increased VF litude measures (0.51±0.08 mV vs 0.42±0.06 mV, p=0.04). This study indicates that ECPR increases return of circulation and coronary perfusion pressure in a sheep model of ischaemic VF arrest. Our findings have supported the development of a pilot trial into the effectiveness and feasibility of ECPR in the clinical setting.
Publisher: Elsevier BV
Date: 12-1995
DOI: 10.1016/0165-1838(95)00063-4
Abstract: The use of the plasma noradrenaline (NA) concentration as an index of sympathetic nervous system (SNS) activity in the postprandial state is associated with several problems: (i) It does not take into account the contribution of alterations in clearance to the plasma NA level, (ii) when antecubital venous blood is s led, it reflects regional forearm rather than whole body SNS activity and (iii) no insight is gained into the regional pattern of SNS activation. These potential confounders were addressed in this study performed in 17 healthy young men. The validity of plasma NA measurements in assessing postprandial changes in sympathetic nervous activation was evaluated in relation to that of whole body and regional plasma NA spillover, derived using isotope dilution methodology. Plasma clearance of NA is significantly altered following a meal, with a transient elevation in the early postprandial phase which may lead to an underestimation of SNS activation when assessed from arterial plasma NA levels. Forearm plasma NA spillover increases postprandially, such that despite significant postprandial elevations in arterial plasma NA, the plasma arterial contribution to antecubital venous plasma NA levels is maintained at less than 40%, the rest being derived locally from the forearm. This makes venous plasma s les unsuitable for the assessment of SNS activation in organs and vascular sites distant from the s ling site. The kidneys and skeletal muscle are the major regional sites of postprandial sympathetic nervous activation, while cardiac plasma NE spillover is unaltered postprandially. This regional pattern of SNS activation postprandially must be taken into account when relating increments in plasma NA levels to specific physiological events.
Publisher: Public Library of Science (PLoS)
Date: 17-07-2015
Publisher: Elsevier BV
Date: 08-2011
Publisher: Oxford University Press (OUP)
Date: 02-1993
DOI: 10.1093/CVR/27.2.204
Abstract: The aim was to determine the pharmacological reactivity of human small resistance arteries in patients with cardiac failure. Small arteries (< 300 microns internal diameter) were removed from gluteal skin biopsy specimens and mounted in a double myograph for isometric force recording. Arteries from six patients with congestive heart failure contracted to only 65% of the maximum response recorded in nine arteries from normal volunteers when activated by potassium chloride (124 mM), noradrenaline (1 microM), or both. The lesser contraction in congestive heart failure vessels with no significant shift in sensitivity (EC50) was also observed in concentration-response studies with noradrenaline, angiotensin I, and angiotensin II. The concentration-contraction curves for serotonin showed only 40% of the maximum contractility to K+ in normal arteries, and this ratio was similar in congestive heart failure arteries. Normal arteries precontracted with noradrenaline (1 microM) relaxed in response to sodium nitroprusside, calcitonin gene related peptide, and the endothelium dependent agonist acetylcholine in congestive heart failure vessels there was a marked loss of the relaxation response only to acetylcholine. These results suggest that in chronic congestive heart failure skin resistance arteries have impaired contraction responses probably independent of any receptor down regulation. The loss of endothelium dependent vasodilatation to acetylcholine suggests that EDRF release is impaired. These changes may well play an important role in the disturbances of peripheral vascular function associated with heart failure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-1999
DOI: 10.1161/01.CIR.99.12.1574
Abstract: Background —Recent studies suggest that acute pulmonary congestion induces hyperventilation and that hyperventilation-related hypocapnia leads to ventilatory control instability and central sleep apnea. Whether chronic pulmonary congestion due to congestive heart failure (CHF) is associated with central apnea is unknown. We hypothesized that CHF patients with central apnea would have greater pulmonary capillary wedge pressure (PCWP) than patients without central apnea and that PCWP would correlate with central apnea severity. Methods and Results —Seventy-five stable CHF patients underwent right heart catheterization and, on the basis of overnight sleep studies, were ided into central apnea (n=33), obstructive apnea (n=20), or nonapnea groups (apnea-hypopnea index [AHI] events per hour). Mean PCWP was significantly greater in the central than in the obstructive and nonapnea groups (mean±SEM [range]: 22.8±1.2 [11 to 38] versus 12.3±1.2 [4 to 21] versus 11.5±1.5 [3 to 28] mm Hg, respectively P .001). Within the central apnea group, PCWP correlated with the frequency and severity of central apnea (AHI: r =0.47, P =0.006) and degree of hypocapnia (Pa co 2 : r =−0.42, P =0.017). Intensive medical therapy in 7 patients with initially high PCWP and central apneas reduced both PCWP (29.0±2.6 [20 to 38] to 22.0±1.8 [17 to 27] mm Hg P .001) and central apnea frequency (AHI) (38.5±7.7 [7 to 62] to 18.5±5.3 [1 to 31] events per hour P =0.005). Conclusions —PCWP is elevated in CHF patients with central apneas compared with those with obstructive apnea or without apnea. Moreover, a highly significant relationship exists between PCWP, hypocapnia, and central apnea frequency and severity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-01-2016
Publisher: Springer Science and Business Media LLC
Date: 07-02-2017
DOI: 10.1038/NCOMMS14232
Abstract: Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43. The pathological importance of the biased agonism of Cmpd17b is demonstrable as superior cardioprotection in both in vitro (cardiomyocytes and cardiofibroblasts) and MI injury in mice in vivo. These findings reveal new insights for development of small molecule FPR agonists with an improved cardioprotective profile for treating MI.
Publisher: Wiley
Date: 27-02-2008
DOI: 10.1111/J.1440-1681.2008.04904.X
Abstract: 1. In searching for biological evidence that essential hypertension is caused by chronic mental stress, a disputed proposition, parallels are noted with panic disorder, which provides an explicit clinical model of recurring stress responses. 2. There is clinical comorbidity panic disorder prevalence is increased threefold in essential hypertension. Plasma cortisol is elevated in both. 3. In panic disorder and essential hypertension, but not in health, single sympathetic nerve fibres commonly fire repeatedly within an in idual cardiac cycle this appears to be a signature of stress exposure. For both conditions, adrenaline cotransmission is present in sympathetic nerves. 4. Tissue nerve growth factor is increased in both (nerve growth factor is a stress reactant). There is induction of the adrenaline synthesizing enzyme, phenylethanolamine-N-methyltransferase, in sympathetic nerves, an explicit indicator of mental stress exposure. 5. The question of whether chronic mental stress causes high blood pressure, still hotly debated, has been reviewed by an Australian Government body, the Specialist Medical Review Council. Despite the challenging medicolegal implications, the Council determined that stress is one proven cause of hypertension, this ruling being published in the 27 March 2002 Australian Government Gazette. This judgement was reached after consideration of the epidemiological evidence, but in particular after review of the specific elements of the neural pathophysiology of essential hypertension, described above.
Publisher: SAGE Publications
Date: 14-05-2013
Abstract: This single visit study examined whether endothelial function, in addition to cardiovascular (CV) risk factors and plasma microparticle content, was normalised in 15 patients with type 2 diabetes + acute coronary syndrome (ACS) (6 weeks–6 months post cardiac event) undergoing standard clinical care compared to 16 sex- and age-matched healthy controls. While total and low-density lipoprotein (LDL) cholesterol levels were well controlled in the patients with type 2 diabetes + ACS, residual CV risk profiles such as increased body mass index (BMI), systolic blood pressure, glucose levels and triglycerides and lower high-density lipoprotein (HDL) levels were still apparent. Endothelium-dependent responses to acetylcholine (ACh) were significantly lower in type 2 diabetes + ACS patients compared to controls. Correspondingly, the reactive hyperaemic index (RHI) was lower in the patient cohort. Endothelial microparticle (EMP) levels (CD31 + , CD41 − ) were 40% lower in the patient cohort. Simultaneous analysis of platelet microparticle (PMP) levels (CD41 + ) showed no difference between cohorts. Patients with type 2 diabetes suffering from recent ACS exhibit residual CV risk factors despite being on standard clinical care. In addition, these patients continue to present with endothelial dysfunction despite having lower levels of EMPs.
Publisher: Wiley
Date: 08-1994
DOI: 10.1111/J.1440-1681.1994.TB02567.X
Abstract: 1. During follow-up of 59 cardiac transplant recipients over 2 or more years, a small group of subjects was observed who displayed an unpredictable, relatively marked, reduction in plasma cholesterol. 2. A significant proportion of these subjects were subsequently observed as having experienced a marked decline in left ventricular function at the time of routine radionuclide ventriculography. 3. While the mechanism for this fall in cholesterol is unclear, the observation of such an unexpected reduction in total cholesterol, late after heart transplantation should be considered significant and prompt further investigation including an assessment of allograft function.
Publisher: Japanese Circulation Society
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 29-05-2018
DOI: 10.1038/S41598-018-26115-Y
Abstract: Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM fibrotic cardiomyopathy, ischemia-reperfusion, I/R treatment with β-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and erse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced β-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism.
Publisher: Wiley
Date: 26-09-2017
DOI: 10.1002/EJHF.976
Publisher: Elsevier BV
Date: 06-2023
Publisher: Wiley
Date: 25-10-2016
Abstract: Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo-β-lactamases (MBL) have evolved to inactivate most of the commonly used β-lactam antibiotics. AIM-1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM-1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate-limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1996
Abstract: Abstract Cardiac myocytes have recently been shown to express a constitutive Ca 2+ -sensitive isoform of NO synthase (NOS3), although the mechanism(s) responsible for activation of NOS3 and its physiological function remain to be determined. Since the activity of NOS3 is known to be regulated in part by the intracellular Ca 2+ activity ([Ca 2+ ] i ) in endothelial cells, we determined whether increasing myocyte [Ca 2+ ] i by uniform electric field pacing was accompanied by an increase in NOS3 activity, detected as nitrite accumulation in the medium. A higher [Ca 2+ ] i with increasing pacing frequencies was shown to be accompanied by a time-dependent accumulation of nitrite in medium that bathed adult rat ventricular myocytes stimulated at 3 Hz. Nitrite release by paced cells was significantly attenuated by treatment with either the NO synthase inhibitor nitro- l- arginine (L-NA, 1 mmol/L) or the intracellular Ca 2+ chelator BAPTA-AM (20 μmol/L). Paced myocytes also exhibited a frequency- and time-dependent increase in intracellular cGMP content that could be inhibited significantly by either L-NA or the soluble guanylate cyclase inhibitor LY83583 (5 μmol/L). To determine whether the increase in NOS3 activity with pacing affected contractile function, myocytes were sequentially paced at frequencies from 0.5 to 3 Hz. Methylene blue, L-NA, and LY83583 all increased the litude of shortening of myocytes paced at 3 Hz. Furthermore, a significantly greater positive inotropic response to high extracellular Ca 2+ (3 mmol/L) was demonstrated by myocytes pretreated with L-NA compared with control cells. These data indicate that myocyte NOS3 activity is regulated in part by [Ca 2+ ] i , whether induced by changes in pacing frequency or [Ca 2+ ] o , and depresses myocyte contractile responsiveness to higher stimulation frequencies.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.HLC.2017.05.124
Abstract: Atrioventricular node ablation (AVNA) is generally reserved for patients whose atrial fibrillation (AF) is refractory all other therapeutic options, since the recipients will often become pacemaker dependent. In such patients, this approach may prove particularly useful, especially if a tachycardia-induced cardiomyopathy is suspected. Historically, an "ablate and pace" approach has involved AVNA and right ventricular pacing, with or without an atrial lead. There is also an evolving role for atrioventricular node ablation in patients with AF who require cardiac resynchronisation therapy for treatment of systolic heart failure. A mortality benefit over pharmacotherapy has been demonstrated in observational studies and this concept is being further investigated in multi-centre randomised control trials.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JACC.2011.01.059
Abstract: This study sought to determine the potential pathophysiological link between anemia and disease severity, and adverse outcome in heart failure (HF). Anemia frequently accompanies advanced HF however, the pathophysiological mechanism responsible for the association between anemia and more severe HF remains uncertain. We hypothesized that a depletion of myocardial iron content may provide the biological link. Complementary clinical and basic studies were performed. Hemodynamic, biochemical, and echocardiographic investigations were performed in 9 healthy controls and 25 patients with advanced HF (left ventricular ejection fraction: 23 ± 10%). Tissue iron content and type 1 transferrin receptor (Tfr1) expression were assessed in human myocardial tissue, and the regulation of Tfr1 expression was studied in isolated cardiomyocytes. HF patients displayed evidence of iron deficiency as measured by lower serum iron (p < 0.05) and transferrin saturation (TFS) (p < 0.05). When subclassified according to the presence of anemia, TFS was lower in anemic compared with nonanemic HF patients, whereas TFS in nonanemic HF patients was intermediate. In association, myocardial iron content was reduced in HF versus non-HF s les (0.49 ± 0.07 μg/g vs. 0.58 ± 0.09 μg/g, p < 0.05), and there was a significant reduction (p < 0.05) in the myocardial mRNA expression of Tfr1, which plays a key role in cellular iron transport. In the context of HF, catecholamines and aldosterone both down-regulated Tfr1 expression in isolated cardiomyocytes. This study suggests the presence of iron depletion in the failing human heart, providing a potential link for the association between anemia and adverse prognosis in HF.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2016
DOI: 10.1161/CIRCHEARTFAILURE.116.003662
Abstract: Heart failure with preserved ejection fraction has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure, particularly during exercise, is a key contributor to morbidity and mortality. Preliminary analyses have demonstrated that a novel interatrial septal shunt device that allows shunting to reduce the left atrial pressure provides clinical and hemodynamic benefit at 6 months. Given the chronicity of heart failure with preserved ejection fraction, evidence of longer-term benefit is required. Patients (n=64) with left ventricular ejection fraction ≥40%, New York Heart Association class II–IV, elevated pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during supine bicycle exercise) participated in the open-label study of the interatrial septal shunt device. One year after interatrial septal shunt device implantation, there were sustained improvements in New York Heart Association class ( P .001), quality of life (Minnesota Living with Heart Failure score, P .001), and 6-minute walk distance ( P .01). Echocardiography showed a small, stable reduction in left ventricular end-diastolic volume index ( P .001), with a concomitant small stable increase in the right ventricular end-diastolic volume index ( P .001). Invasive hemodynamic studies performed in a subset of patients demonstrated a sustained reduction in the workload corrected exercise pulmonary capillary wedge pressure ( P .01). Survival at 1 year was 95%, and there was no evidence of device-related complications. These results provide evidence of safety and sustained clinical benefit in heart failure with preserved ejection fraction patients 1 year after interatrial septal shunt device implantation. Randomized, blinded studies are underway to confirm these observations. URL: www.clinicaltrials.gov . Unique identifier: NCT01913613.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-06-2015
DOI: 10.1161/CIRCULATIONAHA.114.014494
Abstract: Oxygen is commonly administered to patients with ST-elevation–myocardial infarction despite previous studies suggesting a possible increase in myocardial injury as a result of coronary vasoconstriction and heightened oxidative stress. We conducted a multicenter, prospective, randomized, controlled trial comparing oxygen (8 L/min) with no supplemental oxygen in patients with ST-elevation–myocardial infarction diagnosed on paramedic 12-lead ECG. Of 638 patients randomized, 441 patients had confirmed ST-elevation–myocardial infarction and underwent primary end-point analysis. The primary end point was myocardial infarct size as assessed by cardiac enzymes, troponin I, and creatine kinase. Secondary end points included recurrent myocardial infarction, cardiac arrhythmia, and myocardial infarct size assessed by cardiac magnetic resonance imaging at 6 months. Mean peak troponin was similar in the oxygen and no oxygen groups (57.4 versus 48.0 μg/L ratio, 1.20 95% confidence interval, 0.92–1.56 P =0.18). There was a significant increase in mean peak creatine kinase in the oxygen group compared with the no oxygen group (1948 versus 1543 U/L means ratio, 1.27 95% confidence interval, 1.04–1.52 P =0.01). There was an increase in the rate of recurrent myocardial infarction in the oxygen group compared with the no oxygen group (5.5% versus 0.9% P =0.006) and an increase in frequency of cardiac arrhythmia (40.4% versus 31.4% P =0.05). At 6 months, the oxygen group had an increase in myocardial infarct size on cardiac magnetic resonance (n=139 20.3 versus 13.1 g P =0.04). Supplemental oxygen therapy in patients with ST-elevation–myocardial infarction but without hypoxia may increase early myocardial injury and was associated with larger myocardial infarct size assessed at 6 months. URL: www.clinicaltrials.gov . Unique identifier: NCT01272713.
Publisher: Elsevier BV
Date: 04-1996
DOI: 10.1016/0735-1097(95)00611-7
Abstract: We sought to examine the efficacy of dietary supplementation of L-arginine on endothelium-dependent vasodilation in patients with congestive heart failure. Endothelial dysfunction, as evidenced by a diminished response to such vasodilators as acetylcholine, is well defined in patients with heart failure. These responses are improved by intraarterial infusion with L-arginine. Because L-arginine is a semi-essential amino acid, we investigated the effects of dietary L-arginine on endothelium-dependent vasodilation in these patients. Twenty patients with heart failure (New York Heart Association functional class III/IV, mean [+/- SE] age 51.3 +/- 1.7 years) and seven healthy control subjects (mean age 52.6 +/- 3.3 years) were studied. All patients continued taking their usual treatment. Responses to acetylcholine and sodium nitroprusside were determined using forearm plethysmography. Patients with heart failure received either L-arginine (20 g/day every day for 28 days) or placebo (vehicle syrup in equal amounts) in a double-blind protocol. The calculated power of the study was between 62% and 80% to detect a 30% to 40% change in area under the dose-response (forearm vascular resistance) curve. Responses to acetylcholine, but not to sodium nitroprusside, were significantly attenuated in patients with heart failure compared with control subjects (mean area under curve [AUC], control subjects vs. patients with heart failure: 1,125.4 +/- 164.5 vs. 617.3 +/- 116.6 U, p < 0.05, by Student t test). A significant increase in urea and aspartate transaminase levels in patients receiving active L-arginine treatment was observed. Responses to acetylcholine (AUC before vs. after L-arginine: 641.5 +/- 126.7 vs. 695.9 +/- 151.9 U) and sodium nitroprusside were not affected by either L-arginine or placebo. Endothelial dysfunction was apparent in patients with heart failure despite rigorous vasoactive treatment. Oral administration with L-arginine was ineffective in influencing endothelial function in these patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2010
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.HEALUN.2006.03.023
Abstract: Scintigraphy using iodine-123-metaiodobenzylguanidine (I-123-MIBG) has been used to demonstrate that >50% of orthotopically transplanted hearts undergo partial cardiac sympathetic re-innervation and that this occurs no earlier than 1 year post-transplant. This study used planar and singe-photon emission computed tomography (SPECT) I-123 MIBG scintigraphy to show that cardiac re-innervation was not detectable in any of the 8 patients studied 1.1 to 6.3 years post-heterotopic transplantation. Thus, potential for cardiac re-innervation varies according to the type of procedure performed.
Publisher: Elsevier BV
Date: 08-2005
DOI: 10.1016/J.HEALUN.2005.01.014
Abstract: The VentrAssist device left ventricular assist system, designed for permanent implantation, is a novel centrifugal pump with a hydrodynamically suspended rotor. The first human implant was into a 72-year-old man with New York Heart Association (NYHA) class IV heart failure due to idiopathic dilated cardiomyopathy. The implant and recovery were uneventful, and the patient survives at 17 months, is NYHA class II, and lives at home. This device shows promise in end-stage heart failure for permanent implantation and bridge to transplantation.
Publisher: American Physiological Society
Date: 07-2004
DOI: 10.1152/AJPHEART.01094.2003
Abstract: Whereas l-arginine is clearly recognized as the precursor for nitric oxide synthesis, and its entry into endothelial cells via system y + transport is established, few data exist regarding the acute regulation of this transport process. We specifically investigated the effect of ACh and isoprenaline (Iso) on l-arginine uptake in the human forearm and in cultured bovine aortic endothelial cells (BAEC). Sixteen healthy males were studied. During a steady-state intra-arterial infusion of [ 3 H]l-arginine (100 nCi/min), the effects of ACh (9.25 and 37 μg/min), Iso (25–50 and 200 μg/min), and sodium nitroprusside (SNP) (1–2 and 8 μg/min) on forearm plasma flow (FPF), l-[ 3 H]arginine uptake, and l-[ 3 H]citrulline release were determined. In parallel experiments, the effects of ACh, Iso, and SNP on l-[ 3 H]arginine uptake were studied in BAEC. l-Arginine uptake was inversely related to FPF ( r = −0.50 P 0.005). At a similar FPF (ACh 56.82 ± 9.25, Iso 58.49 ± 5.56, SNP 57.92 ± 4.96 ml/min P = ns), intra-arterial ACh significantly increased forearm uptake of l-[ 3 H]arginine (54,655 ± 8,018 dpm/min), compared with that observed with either Iso (40,517.23 ± 6,841 dpm/min P = 0.01) or SNP (36,816 ± 4,650 dpm/min P = 0.011). This was associated with increased ACh-induced l-[ 3 H]citrulline release compared with Iso and SNP ( P = 0.046). Similarly, in BAEC, ACh significantly increased l-[ 3 H]arginine uptake compared with control, Iso, or SNP (ACh 12.0 × 10 7 ± 1.83 × 10 7 vs. control 6.67 × 10 7 ± 1.16 × 10 7 vs. Iso 7.35 × 10 7 ± 1.63 × 10 7 vs. SNP 6.01 × 10 7 ± 1.11 × 10 7 fmol·min −1 ·mg −1 at 300 μmol/l l-arginine P = 0.043). Taken together, these data indicate that ACh stimulates l-arginine uptake in cultured endothelial cells and in human forearm circulation, indicating the potential for acute modulation of endothelial l-arginine uptake.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2021
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCHF.2019.06.011
Abstract: This study sought to evaluate the effects of the Carillon device on mitral regurgitation severity and left ventricular remodeling. Functional mitral regurgitation (FMR) complicates heart failure with reduced ejection fraction and is associated with a poor prognosis. In this blinded, randomized, proof-of-concept, sham-controlled trial, 120 patients receiving optimal heart failure medical therapy were assigned to a coronary sinus-based mitral annular reduction approach for FMR or sham. The pre-specified primary endpoint was change in mitral regurgitant volume at 12 months, measured by quantitative echocardiography according to an intention-to-treat analysis. Patients (69.8 ± 9.5 years of age) were randomized to either the treatment (n = 87) or the sham-controlled (n = 33) arm. There were no significant differences in baseline characteristics between the groups. In the treatment group, 73 of 87 (84%) had the device implanted. The primary endpoint was met, with a statistically significant reduction in mitral regurgitant volume in the treatment group compared to the control group (decrease of 7.1 ml/beat [95% confidence interval [CI]: -11.7 to -2.5] vs. an increase of 3.3 ml/beat [95% CI: -6.0 to 12.6], respectively p = 0.049). Additionally, there was a significant reduction in left ventricular volumes in patients receiving the device versus those in the control group (left ventricular end-diastolic volume decrease of 10.4 ml [95% CI: -18.5 to -2.4] vs. an increase of 6.5 ml [95% CI: -5.1 to 18.2] p = 0.03 and left ventricular end-systolic volume decrease of 6.2 ml [95% CI: -12.8 to 0.4] vs. an increase of 6.1 ml [95% CI: -1.42 to 13.6] p = 0.04). The Carillon device significantly reduced mitral regurgitant volume and left ventricular volumes in symptomatic patients with functional mitral regurgitation receiving optimal medical therapy. (Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation [REDUCE FMR] NCT02325830).
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.PHARMTHERA.2015.05.011
Abstract: A highly complex interplay exists between the heart and kidney in the setting of both normal and abnormal physiology. In the context of heart failure, a pathophysiological condition termed the cardiorenal syndrome (CRS) exists whereby dysfunction in the heart or kidney can accelerate pathology in the other organ. The mechanisms that underpin CRS are complex, and include neuro-hormonal activation, oxidative stress and endothelial dysfunction. The endothelium plays a central role in the regulation of both cardiac and renal function, and as such impairments in endothelial function can lead to dysfunction of both these organs. In particular, reduced bioavailability of nitric oxide (NO) is a key pathophysiologic component of endothelial dysfunction. The synthesis of NO by the endothelium is critically dependent on the plasmalemmal transport of its substrate, L-arginine, via the cationic amino acid transporter-1 (CAT1). Impaired L-arginine-NO pathway activity has been demonstrated in idually in heart and renal failure. Recent findings suggest abnormalities of the L-arginine-NO pathway also play a role in the pathogenesis of CRS and thus this pathway may represent a potential new target for the treatment of heart and renal failure.
Publisher: Wiley
Date: 02-2006
DOI: 10.1111/J.1445-5994.2006.01001.X
Abstract: Heart failure (HF) is increasingly common and, despite advances in pharmacotherapeutic management, often progresses. Progression is marked by structural and electrical changes-remodelling. In approximately one-third of patients, ventricular dilatation is accompanied by intraventricular conduction delays, most commonly the left bundle branch block (LBBB). The presence of LBBB is associated with mechanical dyssynchrony of the heart. Cardiac resynchronisation therapy (CRT), the use of special pacemakers with or without implantable cardioverter defibrillators, aims to resynchronise the failing heart, improving myocardial contraction without increased energetics. Several, large, randomised clinical trials have now established the benefit of CRT in a select group of HF patients, providing functional and, recently shown, mortality benefits. However, a substantial proportion of patients are considered non-responders to CRT, and studies are now underway to identify the patients most likely to respond to CRT.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1993
Abstract: Hypertension frequently complicates the use of cyclosporine A (CyA) therapy, and it has been suggested that sympathoexcitation may be the underlying mechanism in this form of hypertension. To further investigate the possibility of a neurogenic mechanism for this hypertensive effect, we studied the effects of CyA on renal blood flow (n = 11), forearm blood flow (n = 8), and sympathetic nervous system activity, assessed by renal and whole-body radiolabeled norepinephrine plasma kinetics and muscle sympathetic nerve firing (using microneurography) in cardiac transplant recipients receiving CyA and a reference group of healthy age-matched control subjects (n = 17). In 11 cardiac transplant patients (2 hours after cyclosporine dose), renal blood flow was significantly lower than that in 8 control subjects (680 +/- 88 vs 1285 +/- 58 mL/min, P .001). In 5 of these transplant patients, renal blood flow was measured before and for 2 hours after oral cyclosporine and fell progressively over this period, by 37% (P .01). Total body and renal norepinephrine spillover rates in transplant patients were similar to those in control subjects (3070 +/- 538 vs 2618 +/- 313 pmol/min and 579 +/- 124 vs 573 +/- 95 pmol/min, respectively), and there was no progressive effect in the 2 hours after cyclosporine dosing. Forearm blood flow was increased 2 hours after CyA administration (1.74 +/- 0.31 to 3.12 +/- 0.50 mL x 100 mL-1 x min-1, P .001), whereas mean arterial blood pressure and noninvasively determined cardiac output (indirect Fick method) were unchanged. Muscle sympathetic nerve discharge rates recorded in 6 of these transplant patients were not different from those in 9 healthy control subjects (37.9 +/- 10.1 vs 41.3 +/- 2.3 bursts per 100 beats per minute). During 90 to 120 minutes of recording after cyclosporine dosing, nerve firing rates remained unchanged. CyA therapy causes acute renal vasoconstriction without accompanying systemic hemodynamic effects. These renal effects are nonneural, not being attributable to sympathoexcitation.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.TOXLET.2019.03.002
Abstract: Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.
Publisher: American Physiological Society
Date: 02-2008
Publisher: Public Library of Science (PLoS)
Date: 10-04-2012
Publisher: Oxford University Press (OUP)
Date: 15-05-2002
Publisher: Asian Spine Journal (ASJ)
Date: 30-04-2023
Abstract: Study Design: Single-center retrospective cohort.Purpose: To compare surgical outcomes of patients based on lumbar drain variables relating to output and duration. Overview of Literature: The use of drains following lumbar spine surgery, specifically with respect to hospital readmission, postoperative hematoma, postoperative anemia, and surgical site infections, has been controversial.Methods: Patients aged ≥18 years who underwent lumbar fusion with a postoperative drain between 2017 and 2020 were included and grouped based on hospital readmission status, last 8-hour drain output ( mL cutoff), or drain duration (2 days cutoff). Total output of all drains, total output of the primary drain, drain duration in days, drain output per day, last 8-hour output, penultimate 8-hour output, and last 8-hour delta (last 8-hour output subtracted by penultimate 8-hour output) were collected. Continuous and categorical data were compared between groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis were performed to determine whether drain variables can predict hospital readmission, postoperative blood transfusions, and postoperative anemia. Alpha was 0.05.Results: Our cohort consisted of 1,166 patients with 111 (9.5%) hospital readmissions. Results of regression analysis did not identify any of the drain variables as independent predictors of hospital readmission, postoperative blood transfusion, or postoperative anemia. ROC analysis demonstrated the drain variables to be poor predictors of hospital readmission, with the highest area under curve of 0.524 (drain duration), corresponding to a sensitivity of 61.3% and specificity of 49.9%.Conclusions: Drain output or duration did not affect readmission rates following lumbar spine surgery.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1993
Abstract: The presence of cardiac reinnervation in humans after cardiac transplantation has been widely debated, based on the application of differing methods for the assessment of neuronal function. Some of these techniques have been rather indirect consequently, the time course and extent of cardiac reinnervation remains uncertain. To test for the presence of cardiac reinnervation after transplantation, we examined neurochemical (radiolabeled norepinephrine [NE] kinetics) and functional markers (power spectral analysis, heart rate response to exercise) of cardiac sympathetic nerve integrity in 15 cardiac transplantation recipients and 25 healthy control subjects of similar age. Cardiac transplantation subjects were studied 9 weeks to 8 years after cardiac transplantation (10 "early" patients 18 months and 5 "late" patients 2 years after cardiac transplantation). At rest, cardiac NE spillover was markedly attenuated early after transplantation (11.2 +/- 18.3 pmol/min) compared with subjects late after transplantation (105 +/- 11 pmol/min, P .01) or in healthy control subjects (103 +/- 15 pmol/min, P .01). Heart rate variability (measured by total spectral power) was significantly reduced in cardiac transplantation recipients compared with control subjects (59.4 +/- 30 vs 1673 +/- 516 milliseconds squared P .05), with evidence of a trend toward increasing spectral power late after transplantation. During exercise, the cardiac NE spillover was significantly lower in early cardiac transplantation recipients when compared with control subjects (163 +/- 50 vs 1876 +/- 418 pmol/min, P .01). Late cardiac transplantation subjects showed a response intermediate (1080 +/- 254 pmol/min) between that of the early cardiac transplantation and control groups. However, measurements of the neuronal reuptake process for NE (assessed by the fractional extraction of plasma labeled NE across the heart and tritiated dihydroxyphenylglycol release) were significantly depressed in both early and late cardiac transplantation subjects. The present study demonstrates a partial restoration of cardiac sympathetic nerve function in humans up to 8 years after heart transplantation.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.HLC.2017.05.117
Abstract: There are emerging epidemics of atrial fibrillation (AF) and heart failure in most developed countries, with a significant health burden. Due to many shared pathophysiological mechanisms, which facilitate the maintenance of each condition, AF and heart failure co-exist in up to 30% of patients. In the circumstance where known structural causes of heart failure (such as myocardial infarction) are absent, patients presenting with both conditions present a unique challenge, particularly as the temporal relationship of each condition can often remain elusive from the clinical history. The question of whether the AF is driving, or significantly contributing to the left ventricular (LV) dysfunction, rather than merely a consequence of heart failure, has become ever more pertinent, especially as catheter ablation now offers a significant advancement over existing rhythm control strategies. This paper will review the inter-related physiological drivers of AF and heart failure before considering the implications from the outcomes of recent clinical trials in patients with AF and heart failure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2017
DOI: 10.1097/MAT.0000000000000490
Abstract: Mechanical circulatory support using left ventricular assist devices (LVADs) has been demonstrated to improve survival in patients with advanced heart failure. Left ventricular assist device therapy also promotes reverse ventricular remodeling, which in some cases has led to sufficient myocardial recovery to allow LVAD removal. Identification of suitable patients for LVAD removal however remains challenging. We investigated the hypothesis that invasive assessment of exercise hemodynamics may provide additional information in relation to the assessment of contractile reserve in potential candidates for LVAD explant.
Publisher: Oxford University Press (OUP)
Date: 22-08-2005
Abstract: In this study, we investigated for a potential mechanism by which atrial fibrillation (AF) might convey a worse prognosis in congestive heart failure (CHF). Specifically, we aimed to determine whether AF impaired cardiac sympathetic response to baroreceptor unloading in comparison to sinus rhythm (SR) in CHF. Eighteen CHF patients (ejection fraction 30+/-2%, age 59+/- 2 years), nine in SR and nine in AF, were enrolled. A right heart study and cardiac sympathetic tone assessment by coronary sinus catheter were performed at baseline and after 10 min of 20 degrees and 30 degrees of passive head up tilt (HUT). Filling pressures fell significantly during HUT in both SR and AF groups (AF, P=0.002 SR, P<0.001). The cardiac sympathetic response to HUT was significantly attenuated by AF compared with SR (P=0.014). In conjunction, right atrial appendages were collected from 23 cardiac surgery patients, 12 in SR and 11 in AF to investigate the presence of fibrosis. AF was associated with a significant increase in the collagen density (P=0.025). AF is associated with impaired cardiac sympathetic response to baroreceptor unloading compared with SR in CHF, possibly secondary to atrial fibrosis.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.JACC.2010.06.062
Abstract: The purpose of this study was to evaluate the association between regional myocardial fibrosis and ventricular arrhythmias in patients with cardiomyopathy. Patients with heart failure are at risk of sudden cardiac death (SCD). Current guidelines recommend implantable cardioverter-defibrillator (ICD) devices for a subgroup based on impaired left ventricular function. A significant proportion of devices never discharge, hence a more accurate method for targeting those at risk is desirable. We prospectively enrolled 103 patients meeting criteria for ICD implantation for primary prevention of SCD. Cardiac magnetic resonance imaging was performed before device implantation. Regional fibrosis was identified with late gadolinium enhancement (LGE). Median follow-up was 573 days (interquartile range: 379 to 863 days). The LGE identified regional fibrosis in 31 of 61 (51%) patients with nonischemic cardiomyopathy (NICM) and in all 42 patients with ischemic cardiomyopathy (ICM). There was a 29% (9 of 31) discharge rate in the NICM group with LGE compared with a 14% (6 of 42) discharge rate in the ICM group (p = NS). There were no ICD discharges in the NICM group without LGE, which was significantly lower than the rate observed in both the ICM patients (p = 0.04) and the NICM patients with LGE (p < 0.01). Left ventricular ejection fraction was similar in patients with and without device therapy (24 ± 12% vs. 26 ± 8%, p = NS) and those with or without LGE (25 ± 9% vs. 26 ± 9%, p = NS). Patients with advanced cardiomyopathy and myocardial fibrosis demonstrated by LGE on cardiac magnetic resonance imaging have a high likelihood of appropriate ICD therapy. Correspondingly, absence of LGE may indicate a lower risk for malignant ventricular arrhythmias.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.JACC.2017.11.019
Abstract: Heart failure is a complex clinical syndrome, the incidence and prevalence of which is increased in diabetes mellitus, pre-diabetes, and obesity. Although this may arise from underlying coronary artery disease, it often occurs in the absence of significant major epicardial coronary disease, and most commonly manifests as heart failure with preserved ejection fraction. Despite epidemiological evidence linking diabetes to heart failure incidence and outcome, the presence of a distinct primary "diabetic" cardiomyopathy has been difficult to prove, because the link between diabetes and heart failure is confounded by hypertension, microvascular dysfunction, and autonomic neuropathy. Nonetheless, several mechanistic associations at systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. This review seeks to describe recent advances and limitations pertinent to integrating molecular mechanisms, clinical screening, and potential therapeutic avenues for this condition.
Publisher: The Endocrine Society
Date: 02-1995
DOI: 10.1210/JCEM.80.2.7852502
Abstract: In contrast to the sympathetic nervous system, which is activated by aging in at least some sympathetic nervous outflows, epinephrine release from the adrenal medulla appears to be either normal or low in the elderly. Using isotope dilution methodology, we studied the effect of aging on the secretion of epinephrine in 19 men, aged 20-30 yr, and 15 men, aged 60-75 yr. Measurements were made both at rest and during the application of laboratory stressors, as diminished adrenal medullary responsiveness possibly contributes to the impairment of some cardiovascular and metabolic responses to stress described previously in the elderly. Epinephrine secretion at rest was lower in the older men (mean +/- SEM, 0.86 +/- 0.10 nmol/min) than in the younger men (1.45 +/- 0.17 nmol/min P < 0.05). Due to 20% lower plasma epinephrine clearance in the older men (P < 0.01), the reduction in the plasma concentration of epinephrine (0.37 +/- 0.03 vs. 0.52 +/- 0.06 nmol/L P = 0.06) was proportionally less than that in epinephrine secretion. In the younger men, epinephrine secretion doubled or tripled during mental stress, isometric exercise, and dynamic exercise. Epinephrine responses to the stressors were reduced in older men, being equivalent to only 44% (P < 0.05), 44% (P = 0.1), and 33% (P = 0.01) of the corresponding responses in the younger men. After uptake from plasma, in some circumstances epinephrine is released from sympathetic nerves as a cotransmitter, where it can augment the release of the major sympathetic transmitter, norepinephrine. We also measured regional extraadrenal release of epinephrine from the heart to test whether the previously described increased release of norepinephrine from the cardiac sympathetic nerves with aging might result from facilitator effects of epinephrine released as a cotransmitter. At rest, epinephrine was released from the heart (9.4 +/- 2.6 pmol/min) in older men only (P < 0.01) despite the fact that adrenal medullary secretion of epinephrine was reduced. Failure of epinephrine and norepinephrine spillover from the heart to increase in parallel in the elderly during the sympathetic excitation accompanying exercise suggested that epinephrine lay outside the sympathetic nerves, perhaps arising from extraneuronal synthesis in the heart. We have not yet tested whether extraneuronal, in contrast to neuronal, epinephrine release in the heart could contribute to the observed higher rates of norepinephrine release in the elderly.
Publisher: Wiley
Date: 12-04-2016
DOI: 10.1002/EJHF.517
Abstract: Differential microRNA expression in peripheral blood has been observed in patients with heart failure, suggesting their value as potential biomarkers and likely contributors to disease mechanisms. In the present study, we aimed to evaluate the transcardiac gradient of 84 cardio-microRNAs in healthy and failing hearts to determine which microRNAs are released or absorbed by the myocardium in heart failure. Eight healthy volunteers and nine patients with congestive heart failure were included. Arterial and coronary sinus blood s les were collected, and microRNAs were extracted. The expression of microRNAs was analysed using real-time PCR by the miScript miRNA PCR Array Human Cardiovascular Disease. In coronary sinus s les, the microRNAs miR-16-5p, miR-27a-3p, miR-27b-3p, miR-29b-3p, miR-29c-3p, miR-30e-5p, miR-92a-3p, miR-125b-5p, miR-140-5p, miR-195-5p, miR-424-5p, and miR-451a were significantly down-regulated, and let-7a-5p, let-7c-5p, let-7e-5p, miR-23b-3p, miR-107, miR-155-5p, miR-181a-5p, miR-181b-5p and miR-320a were up-regulated in heart failure. Left ventricular filling pressure was negatively correlated with miR-195, miR-16, miR-29b-3p, miR-29c-3p, miR-451a, and miR-92a-3p. The failing heart released let-7b-5p, let-7c-5p, let-7e-5p, miR-122-5p, and miR-21-5p, and absorbed miR-16-5p, miR-17-5p, miR-27a-3p, miR-30a-5p, miR-30d-5p, miR-30e-5p, miR-130a-3p, miR-140-5p, miR-199a-5p, and miR-451a. In silico analyses suggest that the transcardiac gradient of microRNAs in heart failure may target pathways related to heart disease. We determined the transcardiac gradient of cardio-microRNAs in failing hearts, which supports the use of these microRNAs as potential biomarkers. The microRNAs described here may have a role in the pathophysiology of heart failure as they might be involved in pathways related to disease progression, including fibrosis.
Publisher: Elsevier BV
Date: 04-2009
DOI: 10.1016/J.HEALUN.2009.01.007
Abstract: Studies in explanted hearts from patients supported with a left ventricular assist device (LVAD) suggest that no or a less pronounced reverse remodeling process occurs in the right ventricle (RV) during LVAD support. The intermediate-term functional changes in RV function in patients with refractory heart failure (HF) supported with a continuous LVAD are not well characterized. Serial transthoracic echocardiograms and simultaneous measurements of biochemical surrogates of disease severity and organ perfusion were obtained in 20 patients (aged 57 +/- 17 years) with refractory HF before and after implantation of a continuous-flow LVAD (VentrAssist, Ventracor Ltd, Chatswood, Australia). After a median (interquartile range) follow-up of 140 days (34-367 days), RV diameter was reduced (36 +/- 7 vs 33 +/- 4 mm p = 0.04), as was right atrial area (27 +/- 5 vs 24 +/- 6 cm(2) p = .04). There was a trend toward a reduction in tricuspid annulus plane systolic excursion (14 +/- 6 vs 13 +/- 5 mm p = .05). RV fractional area change (26% +/- 13% vs 27% +/- 10% p = .53) and global RV dysfunction graded visually using a scale from 0 (absent) to 3 (severe dysfunction) did not change from pre-implant to follow-up (2 [1-2] vs 1.5 [0.5-2] p = .18). The degree of global RV dysfunction at follow-up was closely related to the degree of RV dysfunction at the pre-implant study (r = 0.69 p = .001). Changes in global RV dysfunction were inversely related to changes in glomerular filtration rate (r = -0.49 p = .03). During continuous-flow LVAD support, pre-existing RV dysfunction does not worsen in the intermediate term.
Publisher: Oxford University Press (OUP)
Date: 12-2020
Publisher: Dustri-Verlgag Dr. Karl Feistle
Date: 02-2005
DOI: 10.5414/NHP34045
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.RESUSCITATION.2014.09.010
Abstract: Many patients who suffer cardiac arrest do not respond to standard cardiopulmonary resuscitation. There is growing interest in utilizing veno-arterial extracorporeal membrane oxygenation assisted cardiopulmonary resuscitation (E-CPR) in the management of refractory cardiac arrest. We describe our preliminary experiences in establishing an E-CPR program for refractory cardiac arrest in Melbourne, Australia. The CHEER trial (mechanical CPR, Hypothermia, ECMO and Early Reperfusion) is a single center, prospective, observational study conducted at The Alfred Hospital. The CHEER protocol was developed for selected patients with refractory in-hospital and out-of-hospital cardiac arrest and involves mechanical CPR, rapid intravenous administration of 30 mL/kg of ice-cold saline to induce intra-arrest therapeutic hypothermia, percutaneous cannulation of the femoral artery and vein by two critical care physicians and commencement of veno-arterial ECMO. Subsequently, patients with suspected coronary artery occlusion are transferred to the cardiac catheterization laboratory for coronary angiography. Therapeutic hypothermia (33 °C) is maintained for 24h in the intensive care unit. There were 26 patients eligible for the CHEER protocol (11 with OHCA, 15 with IHCA). The median age was 52 (IQR 38-60) years. ECMO was established in 24 (92%), with a median time from collapse until initiation of ECMO of 56 (IQR 40-85) min. Percutaneous coronary intervention was performed on 11 (42%) and pulmonary embolectomy on 1 patient. Return of spontaneous circulation was achieved in 25 (96%) patients. Median duration of ECMO support was 2 (IQR 1-5) days, with 13/24 (54%) of patients successfully weaned from ECMO support. Survival to hospital discharge with full neurological recovery (CPC score 1) occurred in 14/26 (54%) patients. A protocol including E-CPR instituted by critical care physicians for refractory cardiac arrest which includes mechanical CPR, peri-arrest therapeutic hypothermia and ECMO is feasible and associated with a relatively high survival rate.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1046/J.1444-2892.2003.00240.X
Abstract: Opiates have been used for thousands of years in the form of opium for relief of pain or fever and to induce sleep. However, it was only in the 1970s that the endogenous ligands for the opiate receptors were identified and termed opioid peptides. Opioid peptides activate G protein-coupled receptors in the central and autonomic nervous system, with marked effects on the regulation of pain perception, body temperature, respiration, heart rate and blood pressure. Cardiovascular regulatory effects of endogenous opioids were initially considered to originate from neural centres in the central nervous system, facilitating a regulatory role in neuro-transmission, as demonstrated by the presynaptic co-release from sympathetic neurones of norepinephrine with enkephalin or acetylcholine with enkephalin. However, opioid peptides of myocardial origin have also recently been shown to play a key role in local regulation of the heart. This brief review highlights the key features of the enkephalin opioids in the heart and the current understanding of their role in development, ageing, cardioprotection, hypertension, hypertrophy, and heart failure.
Publisher: Massachusetts Medical Society
Date: 02-01-2020
Publisher: Informa UK Limited
Date: 2006
Abstract: Biventricular pacing has been an exciting recent advance in the management of drug-refractory heart failure. This new therapy has evolved as much from necessity as scientific observation, since benefits derived from pharmacotherapy currently appear to have reached their peak. Clinical trials of biventricular pacing are establishing morbidity and mortality benefits in heart failure. New challenges in the use of these pacemakers are now arising. These include the accurate diagnosis of ventricular dyssynchrony and, hence, potential responders to the refinement of implantation of the left ventricular lead to the appropriate dyssynchronous ventricular area and optimization of pacemaker programming. This review gives a general overview of the principles and the current evidence for the use of biventricular pacemakers in the treatment of heart failure. In addition, a discussion of current research and future projects is included.
Publisher: Elsevier BV
Date: 12-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2021
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.CARDFAIL.2008.07.236
Abstract: In heart failure (HF), renal dysfunction is associated with an adverse prognosis. Impaired renal perfusion from left ventricular dysfunction is thought to be a principal underlying mechanism. Less is known about the influence of venous congestion, including the potential contribution of tricuspid regurgitation (TR). Echocardiograms and a simultaneous (+/-1 day) blood s le from 196 HF patients were analyzed. Patients with at least moderate TR (n = 78) had larger right-sided cardiac cavities, higher right ventricular systolic pressure, lower estimated glomerular filtration rate (eGFR), higher serum urea nitrogen (SUN), and SUN/creatinine ratio than patients with less than moderate TR (n = 118). In multivariate linear regression analysis, TR severity (P = .003), older age (P < .001), and loop diuretic use (P = .008) were independently associated with lower eGFR, and use of inhibitors of the renin-angiotensin-aldosterone system was associated with higher eGFR (P = .001). TR severity (P < .001) and older age (P < .001) were independently associated with higher SUN. TR severity (P = .004) and smaller left ventricular end-diastolic diameter (P = .048) were independent predictors of a higher SUN/creatinine ratio (P = .004). Although a causal relationship cannot be proven, we suggest that significant TR contributes to renal dysfunction in HF patients, probably by elevation of central and renal venous pressure.
Publisher: Wiley
Date: 11-10-2018
DOI: 10.1002/EHF2.12350
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.AHJ.2017.02.032
Abstract: The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included.
Publisher: Oxford University Press (OUP)
Date: 09-2003
DOI: 10.1016/S0195-668X(03)00393-2
Abstract: In this study we sought to assess the influence of atrial fibrillation (AF) on sympathetic nervous system overactivity in congestive heart failure (CHF) patients. We studied 133 consecutive patients with moderate to severe CHF. Subjects underwent haemodynamic assessment (right heart catheterization) and assessment of total systemic and cardiac sympathetic activity by the norepinephrine (NE) spillover method. The study population included 108 patients in sinus rhythm (SR) and 25 in AF. While AF patients had a lower cardiac output (CO) (SR vs AF: 4.2+/-0.1 vs 3.7+/-0.2l/min, P 0.05) and cardiac NE spillover (SR vs AF: 339+/-21 vs 393+/-49 pmol/min, P>0.05) were not significantly different between the two groups, while the systemic clearance rate for NE was lower in the AF group (SR vs AF: 2.2+/-0.1 vs 1.6+/-0.1l/min, P<0.05). Congestive heart failure patients in AF do not appear to have heightened sympathetic tone compared to CHF patients in SR.
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0024-3205(98)00005-8
Abstract: It has been suggested that the myocardial production of nitric oxide, as a consequence of expression of the inducible isoform of nitric oxide synthase (NOS), plays an important role in the pathophysiology of heart failure. We determined the net cardiac production of nitrogen oxides (NOx), as a measure of NOS activity, by performing arterial and coronary sinus s ling in healthy control subjects (n=6) and patients with end-stage heart failure (n=10). The arterial plasma NOx concentration was significantly elevated in heart failure patients (58.4 +/- 7.0 vs 36.9 +/- 4.9 microM, p<0.05). However, we found net extraction of NOx across the heart, with no difference between the two groups. Therefore, the heart does not appear to be a source of NOx in heart failure, and this study does not support a pathophysiological role for NOx in this condition.
Publisher: The Endocrine Society
Date: 07-1999
DOI: 10.1210/JC.84.7.2270
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 1997
Abstract: Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y–like immunoreactivity and norepinephrine concentrations in s les taken from the brachial artery coronary sinus and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [ 3 H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous s le neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119±5% of arterial, n=7) and after a meal (132±12%, n=7), with neuropeptide Y overflows of 6±2 and 11±2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norepinephrine concentrations as an index for quantifying sympathetic neural responses regulating the systemic circulation.
Publisher: Wiley
Date: 18-06-2009
DOI: 10.1002/JCB.22235
Abstract: Myocardial injury due to ischemia-reperfusion (I-R) damage remains a major clinical challenge. Its pathogenesis is complex including endothelial dysfunction and heightened oxidative stress although the key driving mechanism remains uncertain. In this study we tested the hypothesis that the I-R process induces a state of insufficient L-arginine availability for NO biosynthesis, and that this is pivotal in the development of myocardial I-R damage. In neonatal rat ventricular cardiomyocytes (NVCM), hypoxia-reoxygenation significantly decreased L-arginine uptake and NO production (42 +/- 2% and 71 +/- 4%, respectively, both P < 0.01), maximal after 2 h reoxygenation. In parallel, mitochondrial membrane potential significantly decreased and ROS production increased (both P < 0.01). NVCMs infected with adenovirus expressing the L-arginine transporter, CAT1, and NVCMs supplemented with L-arginine both exhibited significant (all P < 0.05) improvements in NO generation and mitochondrial membrane potentials, with a concomitant significant fall in ROS production and lactate dehydrogenase release during hypoxia-reoxygenation. In contrast, L-arginine deprived NVCM had significantly worsened responses to hypoxia-reoxygenation. In isolated perfused mouse hearts, L-arginine infusion during reperfusion significantly improved left ventricular function after I-R. These improved contractile responses were not dependent on coronary flow but were associated with a significant decrease in nitrotyrosine formation and increases in phosphorylation of both Akt and troponin I. Collectively, these data strongly implicate reduced L-arginine availability as a key factor in the pathogenesis of I-R injury. Increasing L-arginine availability via increased CAT1 expression or by supplementation improves myocardial responses to I-R. Restoration of L-arginine availability may therefore be a valuable strategy to ameliorate I-R injury.
Publisher: JMIR Publications Inc.
Date: 31-03-2022
DOI: 10.2196/33839
Abstract: Heart failure self-management is essential to avoid decompensation and readmissions. Mobile apps seem promising in supporting heart failure self-management, and there has been a rapid growth in publications in this area. However, to date, systematic reviews have mostly focused on remote monitoring interventions using nonapp types of mobile technologies to transmit data to health care providers, rarely focusing on supporting patient self-management of heart failure. This study aims to systematically review the evidence on the effect of heart failure self-management apps on health outcomes, patient-reported outcomes, and patient experience. Four databases (PubMed, Embase, CINAHL, and PsycINFO) were searched for studies examining interventions that comprised a mobile app targeting heart failure self-management and reported any health-related outcomes or patient-reported outcomes or perspectives published from 2008 to December 2021. The studies were independently screened. The risk of bias was appraised using Cochrane tools. We performed a narrative synthesis of the results. The protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews CRD42020158041). A total of 28 articles (randomized controlled trials [RCTs]: n=10, 36%), assessing 23 apps, and a total of 1397 participants were included. The most common app features were weight monitoring (19/23, 83%), symptom monitoring (18/23, 78%), and vital sign monitoring (15/23, 65%). Only 26% (6/23) of the apps provided all guideline-defined core components of heart failure self-management programs: education, symptom monitoring, medication support, and physical activity support. RCTs were small, involving altogether 717 participants, had ≤6 months of follow-up, and outcomes were predominantly self-reported. Approximately 20% (2/10) of RCTs reported a significant improvement in their primary outcomes: heart failure knowledge (P=.002) and self-care (P=.004). One of the RCTs found a significant reduction in readmissions (P=.02), and 20% (2/10) of RCTs reported higher unplanned clinic visits. Other experimental studies also found significant improvements in knowledge, self-care, and readmissions, among others. Less than half of the studies involved patients and clinicians in the design of apps. Engagement with the intervention was poorly reported, with only 11% (3/28) of studies quantifying app engagement metrics such as frequency of use over the study duration. The most desirable app features were automated self-monitoring and feedback, personalization, communication with clinicians, and data sharing and integration. Mobile apps may improve heart failure self-management however, more robust evaluation studies are needed to analyze key end points for heart failure. On the basis of the results of this review, we provide a road map for future studies in this area.
Publisher: SAGE Publications
Date: 02-09-2019
Abstract: Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain. We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant. Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy ( P .05, log rank test). In patients treated with basiliximab, early administration ( hours) was associated with a higher freedom from acute rejection compared to ≥24 hours, (72% vs 29%, P .05). The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy however, it was only effective when administered within 24 hours.
Publisher: Elsevier BV
Date: 03-2019
Publisher: SAGE Publications
Date: 12-03-2015
Abstract: Microvascular complications are now recognized to play a major role in diabetic complications, and understanding the mechanisms is critical. Endothelial dysfunction occurs early in the course of the development of complications the precise mechanisms remain poorly understood. Mitochondrial dysfunction may occur in a diabetic rat heart and may act as a source of the oxidative stress. However, the role of endothelial cell-specific mitochondrial dysfunction in diabetic vascular complications is poorly studied. Here, we studied the role of diabetes-induced abnormal endothelial mitochondrial function and the resultant endothelial dysfunction. Understanding the role of endothelial mitochondrial dysfunction in diabetic vasculature is critical in order to develop new therapies. We demonstrate that hyperglycaemia leads to mitochondrial dysfunction in microvascular endothelial cells, and that mitochondrial inhibition induces endothelial dysfunction. Additionally, we show that resveratrol acts as a protective agent resveratrol-mediated mitochondrial protection may be used to prevent long-term diabetic cardiovascular complications.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-12-2002
DOI: 10.1161/01.RES.0000047506.52381.90
Abstract: Altered nitric oxide (NO) bioavailability has been ascribed an important role in the pathophysiology of congestive heart failure (CHF). In the peripheral vasculature, we recently demonstrated a depression of l -arginine transport in association with pharmacological evidence of reduced endothelial function. In contrast, increased myocardial NO generation has been proposed to account for a component of the reduced myocardial contractility in CHF, although this remains controversial. We determined the whole body clearance rate and cardiac fractional extraction of l -arginine during a steady-state intravenous infusion of [ 3 H] l -arginine (300 nCi/min) in 9 healthy control subjects and 7 patients with moderate to severe CHF. In patients with CHF, there was a 30% reduction in the transcardiac extraction of [ 3 H] l -arginine compared with controls ( P .05), which was accompanied by a trend toward reduced [ 3 H] l -citrulline release ( P =0.06). In conjunction, the systemic clearance rate of [ 3 H] l -arginine was significantly lower in patients with CHF (778±148 versus 1278±144 mL/min, P .05). In association with these biochemical indices, we observed a 38% reduction ( P .05) in the mRNA expression of the cationic amino acid transporter CAT-1 in ventricular myocardial s les from patients with CHF compared with healthy unused donor myocardium, whereas myocardial NOS enzymatic activity and NOS protein were unchanged. These data indicate the presence of a significant reduction in the myocardial uptake of l -arginine in patients with CHF. Furthermore, this abnormality seems to be part of a systemic downregulation of l -arginine transport.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.ECHO.2013.06.003
Abstract: The ratio of tricuspid regurgitation velocity (TRV) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) has been studied as a reliable measure to distinguish elevated from normal pulmonary vascular resistance (PVR). The equation TRV/TVIRVOT × 10 + 0.16 (PVRecho) has been shown to provide a good noninvasive estimate of PVR. However, its role in patients with significantly elevated PVR (> 6 Wood units [WU]) has not been conclusively evaluated. The aim of this study was to establish the validity of the TRV/TVIRVOT ratio as a correlate of PVR. The role of TRV/TVIRVOT was also compared with that of a new ratio, TRV(2)/TVIRVOT, in patients with markedly elevated PVR (>6 WU). Data from five validation studies using TRV/TVIRVOT as an estimate of PVR were compared with invasive PVR measurements (PVRcath). Multiple linear regression analyses were generated between PVRcath and both TRV/TVIRVOT and TRV(2)/TVIRVOT. Both PVRecho and a new derived regression equation based on TRV(2)/TVIRVOT: 5.19 × TRV(2)/TVIRVOT - 0.4 (PVRecho2) were compared with PVRcath using Bland-Altman analysis. Logistic models were generated, and cutoff values for both TRV/TVIRVOT and TRV(2)/TVIRVOT were obtained to predict PVR > 6 WU. One hundred fifty patients remained in the final analysis. Linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92). There was a better correlation between PVRcath and TRV(2)/TVIRVOT (r = 0.79, P 6 WU. Moreover, PVRecho2 compared better with PVRcath than PVRecho using Bland-Altman analysis in the entire cohort and in patients with PVR > 6 WU. TRV(2)/TVIRVOT and TRV/TVIRVOT both predicted PVR > 6 WU with good sensitivity and specificity. TRV/TVIRVOT is a reliable method to identify patients with elevated PVR. In patients with TRV/TVIRVOT > 0.275, PVR is likely > 6 WU, and PVRecho2 derived from TRV(2)/TVIRVOT provides an improved noninvasive estimate of PVR compared with PVRecho.
Publisher: Elsevier BV
Date: 03-2016
Publisher: Elsevier BV
Date: 03-1999
Abstract: Cardiac myocytes express the calcium-responsive nitric oxide synthase (eNOS or NOS3). Activation of NOS3 by increased intracellular Ca2+ concentration, [Ca2+]i, has been demonstrated to decrease myocyte contractile responsiveness, although this appears to occur in a Ca2+-independent manner. Therefore, the aim of this study was to examine the possibility that contractile activity could be modulated by an NO-mediated alteration in the phosphorylation status of troponin I, which is known to alter myofilament sensitivity to Ca2+. During pacing at 3 Hz, 32P-labeled myocytes exhibited a 59 +/- 9% increase in TnI phosphorylation compared to quiescent cells (p < 0.05), an effect that was significantly attenuated by either methylene blue or l-nitroarginine (l-NA). While exposure to methylene blue significantly increased the contractile litude of paced myocytes, this was not accompanied by an alteration in intracellular Ca2+. These data indicate that the NO-mediated effects on myocyte contraction may be elicited through an alteration in myofilament Ca2+ sensitivity that results from an alteration in the phosphorylation status of troponin I.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2000
DOI: 10.1097/00005344-200000004-00001
Abstract: Regional sympathetic activity can be studied in humans using electrophysiological methods measuring sympathetic nerve firing rates and neurochemical techniques providing quantification of noradrenaline spillover to plasma from sympathetic nerves in in idual organs. Essential hypertension: Such measurements in patients with essential hypertension disclose activation of the sympathetic outflows to skeletal muscle blood vessels, the heart and kidneys, particularly in younger patients. This sympathetic activation, in addition to underpinning the blood pressure elevation, most likely also contributes to left ventricular hypertrophy, and to the commonly associated metabolic abnormalities of insulin resistance and hyperlipidaemia. Antihypertensive drugs, such as moxonidine, which act primarily by inhibiting the sympathetic nervous system, should have additional clinical benefits beyond those attributable to blood pressure reduction, in protecting against hypertensive complications. Obesity-related hypertension: Understanding the neural pathophysiology of hypertension in the obese has been difficult. In normotensive obesity, renal sympathetic tone is doubled, but cardiac noradrenaline spillover (a measure of sympathetic activity in the heart) is only 50% of normal. In obesity-related hypertension, there is a comparable elevation of renal noradrenaline spillover, but without suppression of cardiac sympathetics (cardiac sympathetic activity being more than double that of normotensive obese and 25% higher than in healthy volunteers). Increased renal sympathetic activity in obesity may be a 'necessary' cause for the development of hypertension (and predisposes to hypertension development), but apparently is not a 'sufficient' cause. The discriminating feature of the obese who develop hypertension is the absence of the adaptive suppression of cardiac sympathetic tone seen in the normotensive obese. Heart failure: In cardiac failure, the sympathetic nerves of the heart are preferentially stimulated. Noradrenaline release from the failing heart at rest in untreated patients is increased as much as 50-fold, similar to the level seen in the healthy heart during near-maximal exercise. Activation of the cardiac sympathetic outflow provides adrenergic support to the failing myocardium, but at a cost of arrhythmia development and progressive myocardial deterioration. Psychosomatic heart disease: No more than 50% of clinical coronary heart disease is explicable in terms of classical cardiac risk factors. There is gathering evidence that psychological abnormalities, particularly depressive illness, anxiety states, including panic disorder and mental stress, are involved here, 'triggering' clinical cardiovascular events, and possibly also contributing to atherosclerosis development. The mechanisms of increased cardiac risk attributable to mental stress and psychiatric illness are not entirely clear, but activation of the sympathetic nervous system seems to be of prime importance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2013
DOI: 10.1161/CIRCEP.113.000681
Abstract: Successful arrhythmia ablation normalizes ejection fraction (EF) in tachycardia-mediated cardiomyopathy, but recurrent heart failure and late sudden death have been reported. The aim of this study was to characterize the left ventricle (LV) of tachycardia-mediated cardiomyopathy patients long after definitive arrhythmia cure. Thirty-three patients with a history of successfully ablated incessant focal atrial tachycardia 64±36 months prior, and 20 healthy controls were recruited. At ablation, 18 patients had EF % (AT-low EF) that recovered within 3 months from 37±12 to 56±4% ( P .001), whereas 15 patients had EF % (AT-normal EF). No subjects had EF of 50% to 55%. Subjects underwent echocardiography with speckle tracking and contrast-enhanced cardiac MRI with ventricular T 1 mapping as an index of diffuse fibrosis. Contrast-enhanced cardiac MRI was performed using a clinical 1.5-T scanner and 0.2 mmol/kg gadolinium-diethylene triamine penta-acetic acid for contrast. Subject characteristics were similar across the 3 groups. Compared with AT-normal EF patients and controls, AT-low EF patients had lower EF (60±6 versus 64±4 and 65±4% P .05), greater indexed LV end-diastolic volume (102±34 versus 84±14 and 85±16 mL/m 2 P .05), and greater indexed LV end-systolic volume (41±11 versus 31±7 and 30±8 mL/m 2 P .01) on contrast-enhanced cardiac MRI. Compared with controls, AT-low EF patients had reduced global LV corrected T 1 time (442±53 versus 529±61 P .05) consistent with diffuse fibrosis. Tachycardia-mediated cardiomyopathy patients exhibit differences in LV structure and function including diffuse fibrosis long after arrhythmia cure, indicating that recovery is incomplete.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-03-2017
DOI: 10.1161/CIRCULATIONAHA.116.024545
Abstract: Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here, we evaluated the effect of a high-fiber diet and supplementation with the short-chain fatty acid acetate on the gut microbiota and the prevention of cardiovascular disease. Gut microbiome, cardiorenal structure/function, and blood pressure were examined in sham and mineralocorticoid excess–treated mice with a control diet, high-fiber diet, or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets. We found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria independently of mineralocorticoid excess. Both fiber and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence of Bacteroides acidifaciens . Compared with mineralocorticoid-excess mice fed a control diet, both high-fiber diet and acetate supplementation significantly reduced systolic and diastolic blood pressures, cardiac fibrosis, and left ventricular hypertrophy. Acetate had similar effects and markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fiber and acetate were accompanied by the downregulation of cardiac and renal Egr1 , a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation. We also observed the upregulation of a network of genes involved in circadian rhythm in both tissues and downregulation of the renin-angiotensin system in the kidney and mitogen-activated protein kinase signaling in the heart. A diet high in fiber led to changes in the gut microbiota that played a protective role in the development of cardiovascular disease. The favorable effects of fiber may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.
Publisher: Elsevier BV
Date: 2021
Publisher: American Society for Microbiology
Date: 10-2017
DOI: 10.1128/AAC.00707-17
Abstract: The aim of this study was to develop a population pharmacokinetic (PK) model for teicoplanin across childhood age ranges to be used as Bayesian prior information in the software constructed for in idualized therapy. We developed a nonparametric population model fitted to PK data from neonates, infants, and older children. We then implemented this model in the BestDose multiple-model Bayesian adaptive control algorithm to show its clinical utility. It was used to predict the dosages required to achieve optimal teicoplanin predose targets (15 mg/liter) from day 3 of therapy. We performed in idual simulations for an infant and a child from the original population, who provided early first dosing interval concentration-time data. An allometric model that used weight as a measure of size and that also incorporated renal function using the estimated glomerular filtration rate (eGFR), or the ratio of postnatal age (PNA) to serum creatinine concentration (SCr) for infants months old, best described the data. The median population PK parameters were as follows: elimination rate constant (Ke) = 0.03 · (wt/70) −0.25 · Renal (h −1 ) V = 19.5 · (wt/70) (liters) Renal = eGFR 0.07 (ml/min/1.73 m 2 ), or Renal = PNA/SCr (μmol/liter). Increased teicoplanin dosages and alternative administration techniques (extended infusions and fractionated multiple dosing) were required in order to achieve the targets safely by day 3 in simulated cases. The software was able to predict in idual measured concentrations and the dosages and administration techniques required to achieve the desired target concentrations early in therapy. Prospective evaluation is now needed in order to ensure that this in idualized teicoplanin therapy approach is applicable in the clinical setting. (This study has been registered in the European Union Clinical Trials Register under EudraCT no. 2012-005738-12.)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
Publisher: Elsevier BV
Date: 05-2015
Publisher: American Physiological Society
Date: 02-1997
DOI: 10.1152/AJPHEART.1997.272.2.H875
Abstract: Although it has been recently shown that nitric oxide (NO) and its congeners (NO(x)), including nitrosothiols, may modify catecholamine turnover in the brain, it is not known whether NO(x) affect norepinephrine (NE) uptake by sympathetic neurons. The nitrosothiol NO donor S-nitroso-acetylpenicillamine (SNAP, 100 microM for 1 h) elicited a concentration-dependent reduction in desipramine-sensitive [3H]NE uptake into PC-12 cells (66 +/- 3% P 0.01) or cultured rat superior cervical ganglia (74 +/- 5% P 0.001), whereas desipramine-insensitive [3H]NE uptake was unaffected, indicating a selective effect on uptake-1-mediated transport. Short-term coculture of PC-12 cells with microvascular endothelial cells expressing the cytokine-inducible NO synthase (NOS2) also exhibited a reduction in [3H]NE uptake (33 +/- 3%, P 0.001) that could be prevented by the addition of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA, 1 mM). Endogenous production of NO(x) by nerve growth factor-pretreated PC-12 cells also exhibited an L-NMMA-inhibitable reduction in [3H]NE uptake. Whereas SNAP resulted in a 10-fold elevation of PC-12 guanosine 3',5'-cyclic monophosphate (cGMP) content (P 0.01), its effect on [3H]NE uptake was not mimicked by exposure to 8-bromo-cGMP. However, the inhibitory effect of SNAP on uptake-1-mediated [3H]NE transport could be attenuated by 1 mM cysteine, a sulfhydryl compound that could act as a sink for NO(x)-mediated nitrosation reactions, although cysteine did not affect the increase in intracellular cGMP with SNAP. These data suggest that an endogenous NO(x) source(s) modifies the activity of the uptake-1 catecholamine transporter in postganglionic sympathetic neurons, which, as we demonstrate, express both NOS1 and NOS3 isoforms, possibly by S-nitrosothiol-mediated nitrosation of regulatory sites on the transporter.
Publisher: Elsevier BV
Date: 07-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2010
Publisher: SAGE Publications
Date: 2018
Abstract: Over 2000 genotypes in the cystic fibrosis (CF) gene have been described. These genotypic differences result in variable clinical manifestations of CF, with severity of disease dependent on CF transmembrane conductance (CFTR) protein function. CFTR is widely distributed in nucleated cells, including cardiac myocytes, but the effect of genotype on cardiac function is not known. This retrospective review of echocardiographic data is from a single adult CF centre between 2000 and 2015. Patients were cohorted based on the functional classification of genotype. ‘Severe’ patients had both CF genes from functional classification groups 1-3 ‘mild’ patients had one or no gene from these groups, or in the event of the second gene being unknown were pancreatic sufficient. Genotype and echocardiography were recorded during the inclusion period in 100 patients, 79 of whom were classified as having severe genotypes. Although the severe group were younger they had a lower fractional shortening (33.66 ± 6.6 vs 36.9 ± 6.3, P .05), left atrial area (14.9 ± 3.6 versus 18.0 ± 4.2 cm 2 P .01) and volume (39.9 ± 18.7 versus 51.0 ± 18.7 mL P .05) and showed a trend to lower left ventricular ejection fraction. This study is the first to show that in CF, severity of genotype (functional classification) is associated with cardiac impairment. Patients with severe CF genotype and cardiac dysfunction should be identified to evaluate cardiac response to gene-modifying treatments prior to consideration for lung transplantation.
Publisher: AMPCo
Date: 11-2006
DOI: 10.5694/J.1326-5377.2006.TB00690.X
Abstract: Chronic heart failure (CHF) is found in 1.5%-2.0% of Australians. Considered rare in people aged less than 45 years, its prevalence increases to over 10% in people aged >/= 65 years. CHF is one of the most common reasons for hospital admission and general practitioner consultation in the elderly (>/= 70 years). Common causes of CHF are ischaemic heart disease (present in > 50% of new cases), hypertension (about two-thirds of cases) and idiopathic dilated cardiomyopathy (around 5%-10% of cases). Diagnosis is based on clinical features, chest x-ray and objective measurement of ventricular function (eg, echocardiography). Plasma levels of B-type natriuretic peptide (BNP) may have a role in diagnosis, primarily as a test for exclusion. Diagnosis may be strengthened by a beneficial clinical response to treatment(s) directed towards amelioration of symptoms. Management involves prevention, early detection, amelioration of disease progression, relief of symptoms, minimisation of exacerbations, and prolongation of survival.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.TRIM.2007.07.006
Abstract: Investigation into the contribution of the immune system and inflammatory cascade to acute rejection (AR) and cardiac allograft vasculopathy (CAV) has implicated vascular endothelial growth factor (VEGF). The endomyocardial biopsy (EB) has proved invaluable in the diagnosis of AR, and in providing information concerning the biological processes occurring following transplantation. The association between VEGF and AR and the development of CAV was examined in endomyocardial biopsies (EBs) from a cohort of 76 heart transplant recipients. VEGF mRNA levels were quantified through real time RT-PCR in 712 EBs, obtained at routine intervals during post-operative monitoring. VEGF and leukocyte and endothelial markers were assessed in a subset of biopsies through immunohistochemistry. The results of generalised linear modelling, adjusting for covariates, revealed VEGF mRNA expression was 19% greater during severe AR as compared to no rejection (p=0.007). Immunohistochemical results supported these findings. Mean VEGF mRNA levels were not significant predictors for the development of CAV (p=0.554). However the risk of cardiac related death increased 9-fold for a 1 unit increase in mean VEGF expression (p=0.006). Similarly, a single unit increase in mean AR severity equated to a 10-fold increase in the risk of cardiac related death (p<0.005). Our data suggest that increased VEGF expression is strongly associated with severe AR and cardiac related death.
Publisher: Portland Press Ltd.
Date: 06-2004
DOI: 10.1042/CS20030265
Abstract: The aim of the present study was to investigate the effects of CPAP (continuous positive airway pressure) support on myocardial energetics in patients with CHF (congestive heart failure). CPAP has been shown to decrease left ventricular afterload and to produce favourable short- and long-term haemodynamic and neurohormonal benefits in CHF patients. The mechanisms responsible for these actions are not completely understood. We measured the haemodynamic and myocardial metabolic response to the acute (10 min) application of CPAP in CHF patients. Myocardial VO2 (O2 consumption) and VCO2 (CO2 production) were measured by simultaneous arterial and coronary sinus blood s ling. The application of CPAP resulted in a significant decrease in left ventricular stroke work (97±12 to 83±9 g·m P& .05) and myocardial VO2 (0.32±0.03 to 0.25±0.01 ml of O2/beat P& .05). Myocardial mechanical efficiency, however, was unchanged. CPAP application decreases myocardial work and VO2. This effect on myocardial energetics could account for some of the favourable effects of CPAP in CHF patients.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2020
Publisher: Wiley
Date: 06-1994
DOI: 10.1111/J.1476-5381.1994.TB13111.X
Abstract: 1. The vascular reactivity of resistance arteries isolated from gluteal skin biopsies and veins isolated from forearms of subjects fed marine oils were examined. 2. Twenty seven healthy adult males were randomly allocated to one of two different treatment groups. The first group received maxEPA (eicosapentaenoic acid 0.178 g g-1 docosahexaenoic acid 0.116 g g-1) capsules 10 g per day for 28 days while the second group received an equivalent amount of mixed oil placebo capsules. Biopsies were performed on day 29 (13 for gluteal sections 14 for forearm vein biopsies). Subcutaneous arteries and veins were mounted in myographs and standard organ baths, respectively. 3. The internal diameter of the subcutaneous arteries at a calculated transmural pressure of 100 mmHg averaged 183.7 +/- 10.3 microns in the maxEPA group and 182.6 +/- 19.8 microns in the placebo controls. Arteries from subjects on maxEPA demonstrated increased sensitivity to angiotensin II (maxEPA vs placebo: -log EC50 (M) -8.36 +/- 0.18 vs -7.91 +/- 0.14) but not to noradrenaline or 5-hydroxytryptamine. Concentration-response curves to acetylcholine, substance P and sodium nitroprusside obtained for noradrenaline precontracted vessels were unaltered with marine oil treatment as was the concentration-response curve to calcium in K(+)-depolarized vessels. 4. Vein internal diameter at a calculated transmural pressure of 20 mmHg averaged 3.06 +/- 0.23 mm in the maxEPA group and 2.96 +/- 0.89 in the placebo group. Responses to noradrenaline, 5-hydroxytryptamine, angiotensin II and endothelin-1 were obtained in the absence and presence of indomethacin (1 microM) in veins from both maxEPA and placebo-treated subjects. Neither dietary supplementation with marine oils nor indomethacin had any effect on the responses obtained to these agonists.5. The major finding of the present study was that in general, maxEPA supplementation did not affect responses to various vasoactive substances on isolated subcutaneous arteries or forearm veins. An exception was the observation of an enhanced response to angiotensin II in subcutaneous resistance arteries studied in vitro. This effect was selective for angiotensin II and was not apparent in veins isolated from the forearm.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-02-2023
Abstract: In patients with aortic stenosis (AS), the presence of mitral regurgitation (MR) can lead to underestimation of AS severity and worse clinical outcomes. The objective of this study was to characterize the magnitude of the effects of concomitant MR on hemodynamic indicators of AS severity using clinical data and a computational cardiovascular simulation. Echocardiographic data from 1427 patients with severe AS were used to inform a computational cardiovascular system model, and varying degrees of MR and AS were simulated. Hemodynamic data, including left ventricular and aortic pressure waveforms, were generated for all simulations. Simulated reduction in mean transaortic pressure gradient (MPG) associated with MR was then used to calculate the adjusted MPG in the clinical cohort. MR was present in 861 (60%) patients. Compared with patients without MR, patients with MR had a lower aortic‐valve area (0.83±0.2 cm 2 versus 0.75±0.2 P .001) and were more likely to have a low‐gradient pattern (MPG mm Hg) (45% versus 54% P .001). Simulations showed that the presence of concomitant mild, moderate, and severe MR with AS was accompanied by a mean reduction in MPG of 10%, 29%, and 40%, respectively. For patients with MR, their calculated adjusted MPG was on average 24% higher than their MPG (52±22 versus 42±16 mm Hg). Of the 467 patients with low‐gradient AS and MR, 240 (51%) would reclassify as high gradient based on their adjusted MPG. Concomitant MR results in lower MPG and reduced forward flow compared with isolated AS. Careful quantitation of MR should be factored into the assessment of AS severity to mitigate for potential underestimation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2023
Abstract: Cardiogenic shock is characterized by tissue hypoxia caused by circulatory failure arising from inadequate cardiac output. In addition to treating the pathologic process causing impaired cardiac function, prompt hemodynamic support is essential to reduce the risk of developing multiorgan dysfunction and to preserve cellular metabolism. Pharmacologic therapy with the use of vasopressors and inotropes is a key component of this treatment strategy, improving perfusion by increasing cardiac output, altering systemic vascular resistance, or both, while allowing time and hemodynamic stability to treat the underlying disease process implicated in the development of cardiogenic shock. Despite the use of mechanical circulatory support recently garnering significant interest, pharmacologic hemodynamic support remains a cornerstone of cardiogenic shock management, with over 90% of patients receiving at least 1 vasoactive agent. This review aims to describe the pharmacology and hemodynamic effects of current pharmacotherapies and provide a practical approach to their use, while highlighting important future research directions.
Publisher: BMJ
Date: 17-09-2019
DOI: 10.1136/HEARTJNL-2019-314770
Abstract: The aim of the meta-analysis was to determine the association of obesity and heart failure (HF) and the cardiac impact of intentional weight loss following bariatric surgery on cardiac structure and myocardial function in obese subjects. MEDLINE, Embase and Web of Science were searched up to 3 April 2018. Studies reporting association and prognostic impact of obesity in HF and the impact of intentional weight loss following bariatric surgery on cardiac structure and myocardial function in obesity were included in the meta-analysis. 4959 citations were reviewed. After exclusions, 29 studies were analysed. A ‘J curve’ relationship was observed between body mass index (BMI) and risk of HF with maximum risk in the morbidly obese (1.73 (95% CI 1.30 to 2.31), p .001, n=11). Although ‘obesity paradox’ was observed for all-cause mortality, the overweight group was associated with lower cardiovascular (CV) mortality (OR=0.86 (95% CI 0.79 to 0.94), n=11) with no significant differences across other BMI groups. Intentional weight loss induced by bariatric surgery in obese patients (n=9) without established HF, atrial fibrillation or known coronary artery disease, was associated with a reduction in left ventricular mass index (p .0001), improvement in left ventricular diastolic function (p≤0.0001) and a reduction in left atrial size (p=0.02). Despite the increased risk of HF with obesity, an ‘obesity paradox’ is observed for all-cause mortality. However, the nadir for CV mortality is observed in the overweight group. Importantly, intentional weight loss was associated with improvement in indices of cardiac structure and myocardial function in obese patients. APP 74412.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-05-2022
DOI: 10.1161/CIRCULATIONAHA.122.059486
Abstract: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance .5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome—a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status—was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86] P =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68] P =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00] P =0.004). In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Portland Press Ltd.
Date: 02-1999
DOI: 10.1042/CS0960191
Abstract: The afferent signals that evoke changes in energy intake with regard to body weight regulation are presumed to arise partly from body stores, with the most likely candidate being adipose tissue depots. However, clinical investigation of the neuronal circuitry involved in the central nervous system's processing of such satiety signals remains largely unexplored. Using percutaneously placed catheters in either the right or left internal jugular veins, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters in 64 weight-stable male subjects with varying degrees of adiposity. Veno-arterial plasma concentration differences and internal jugular blood or plasma flow were used, according to the Fick Principle, to quantify the amount of neurotransmitter stemming from the brain. By combining this technique with a noradrenaline and adrenaline isotope dilution method for examining neuronal transmitter release, we were able to examine the association between central nervous system neurotransmitters and efferent sympathetic nervous outflow and adrenomedullary function in human obesity. We found that brain 5-hydroxytryptamine (serotonin) turnover is chronically elevated in proportion to adiposity and is increased postprandially to a similar degree in lean and obese in iduals. There was no difference in the degree of sympathetic nervous activity or rate of adrenaline secretion in the subjects examined. It therefore seems that in human obesity, in the face of a chronic elevation in peripheral satiety signals, brain serotonergic processes are switched on accordingly, but the subsequent physiological response involving a reduction in food intake, increased thermogenesis and sympathetic activity is in some way impeded.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2003
DOI: 10.1161/01.HYP.0000070024.59313.AE
Abstract: A deficient l -arginine–nitric oxide system is implicated in cortisol-induced hypertension. We investigate whether abnormalities in l -arginine uptake contribute to this deficiency. Eight healthy men were recruited. Hydrocortisone acetate (50 mg) was given orally every 6 hours for 24 hours after a 5-day fixed-salt diet (150 mmol/d). Crossover studies were performed 2 weeks apart. Thirty milliliters of blood was obtained for isolation of peripheral blood mononuclear cells after each treatment period. l -Arginine uptake was assessed in mononuclear cells incubated with l -arginine (1 to 300 μmol/L), incorporating 100 nmol/L [ 3 H]- l -arginine for a period of 5 minutes at 37°C. Forearm [ 3 H]- l -arginine extraction was calculated after infusion of [ 3 H]- l -arginine into the brachial artery at a rate of 100 nCi/min for 80 minutes. Deep forearm venous s les were collected for determination of l -arginine extraction. Plasma cortisol concentrations were significantly raised during the active phase (323±43 to 1082±245 mmol/L, P .05). Systolic blood pressure was elevated by an average of 7 mm Hg. Neither l -arginine transport into mononuclear cells (placebo vs active, 26.3±3.6 vs 29.0±2.1 pmol/10 000 cells per 5 minutes, respectively, at an l -arginine concentration of 300 μmol/L) nor l -arginine extraction in the forearm (at 80 minutes, placebo vs active, 1 868 904±434 962 vs 2 013 910±770 619 disintegrations per minute) was affected by cortisol treatment ie, that l -arginine uptake is not affected by short-term cortisol treatment. We conclude that cortisol-induced increases in blood pressure are not associated with abnormalities in the l -arginine transport system.
Publisher: European Respiratory Society (ERS)
Date: 05-2004
DOI: 10.1183/09031936.04.00060404
Abstract: Previous small-scale studies of the effect of sleep-disordered breathing (SDB) on prognosis in congestive heart failure (CHF) are either lacking or conflicting. The aim of this study was to assess the impact of the presence and type of SDB on mortality in a patient group with severe CHF referred to a specialised heart failure centre. Out of 78 patients ((mean +/- SD) 53 +/- 9 yrs, left ventricular ejection fraction 19.9 +/- 7.2% and pulmonary capillary wedge pressure 16.5 +/- 8.3 mmHg) followed-up over a median period of 52 months, 29% had no apnoea (CHF-N), 28% had obstructive sleep apnoea (CHF-OSA) and 42% had central sleep apnoea (CHF-CSA). At 52 months, their overall mortality was 40%, and combined mortality and transplantation was 72%. Mortality rates were similar between the three apnoea groups. Survivors had a similar prevalence of SDB (71%) as the nonsurvivors (70%). Although a significant increase in mortality was evident at 500 days in those patients with either CHF-SDB or CHF-CSA as compared with CHF-N, this was not significant at final follow-up (52 months) using Kaplan Meier analysis. Multivariate analysis identified transplantation but not SDB type or severity as a significant predictor of survival. In conclusion, sleep-disordered breathing impacts upon early (500 day), but not long-term (52 month), mortality in a specialised heart failure centre.
Publisher: Springer Science and Business Media LLC
Date: 2002
Abstract: The influence of ageing on the sympathetic nervous system and adrenal medulla was studied neurochemically in humans, using isotopic dilution measurement of regional and whole body catecholamine release to plasma in humans. With ageing, sympathetic activation was evident in the heart, and the gut and liver at rest. The mechanism appeared to be by activation of sympathoexcitatory noradrenergic suprabulbar projections from the brainstem. Sympathetic nervous responses with stressors were augmented. Conversely, adrenal medullary release of epinephrine was subnormal in the elderly, at rest and during stress.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0735-1097(01)01121-4
Abstract: The aim of this study was to investigate the role of peripheral presynaptic alpha-2 adrenergic receptors in modulating norepinephrine (NE) release in congestive heart failure (CHF). Activation of the sympathetic nervous system is a hallmark of CHF. Clonidine, an imidazoline and adrenergic agonist with high selectivity for the alpha-2 adrenoceptor, has been shown to reduce generalized sympathetic activity in heart failure after parenteral administration. If it could be shown that peripheral presynaptic alpha-2 adrenoceptors are inhibitory to NE release, then they could be targeted for future therapy, and as a corollary, potentially circumvent unwanted side effects arising from stimulation of alpha-2 adrenoceptors in the brain. Additionally, it could be concluded that these receptors form the basis for an auto-inhibitory feedback to further NE release. Fifteen healthy volunteers and 10 patients with heart failure received intra-arterial clonidine via the brachial artery (0.05 microg and 0.48 microg/100 ml forearm/min). Radio-tracer techniques were employed for studying NE kinetics. Intra-arterial clonidine caused a dose-dependent decrease in forearm spillover of NE in healthy in iduals (low dose, high dose: 26%, 49%: p < 0.05, p < 0.001, respectively). In the patient group, no decrease in forearm spillover was demonstrated after local administration. The difference in response between the two groups was statistically significant (p = 0.004). Peripheral sympathoneural alpha-2 adrenoceptors are functionally important in inhibiting NE release in the healthy human. In heart failure, this function is lost. This finding offers further insights into the mechanisms responsible for high circulating levels of NE in patients with heart failure. In addition, it suggests that selective targeting of peripheral presynaptic alpha-2 adrenoceptors will not achieve sympathoinhibition in heart failure.
Publisher: Therapeutic Guidelines Limited
Date: 03-02-2020
Publisher: American Society for Clinical Investigation
Date: 15-01-1996
DOI: 10.1172/JCI118414
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2023
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.HLC.2006.12.010
Abstract: We present a case of a patient with longstanding transfusion-dependent congenital dyserythropoietic anaemia (CDA) who developed cardiomyopathy despite iron chelation therapy. She presented with severe heart failure that responded poorly to conventional therapy, recovering only when therapy was augmented with metabolic agents including antioxidants and with increased iron chelation. The present case gives support to the concept of treating oxidatively induced heart failure with metabolic and antioxidant therapy. This therapy may have wider application in refractory heart failure and in the prevention of cardiomyopathy in patients receiving regular red cell transfusions who are at risk of transfusional haemosiderosis.
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.HEALUN.2003.12.005
Abstract: Postpartum cardiomyopathy is rare form of cardiac failure, with the potential for cardiac function to recover to normal. When medical therapy fails to control symptoms or haemodynamic stability, circulatory support with a ventricular assist device may be considered as a bridge to cardiac transplantation. We describe 2 patients with severe postpartum cardiomyopathy, in whom cardiac function recovered sufficiently during mechanical circulatory assistance to enable device explantation. Bacteremia during device support was treated with chronic suppressive antibiotics, yet after cannula explantation and ventricular repair, residual infection led to destruction of the primary repair, with formation of a left ventricular pseudoaneurysm. This is a complication of device support not previously reported. Surgery was necessary to repair the infected ventricular cannula site. Both patients recovered however one patient developed recurrent cardiomyopathy 4 months later.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-01-1995
Abstract: Background Aging increases human sympathetic nervous activity at rest. Because of the probable importance of neural stress responses in the heart as triggers for clinical end points of coronary artery disease, it is pertinent to investigate whether sympathetic nervous responses to stresses are increased by aging. Methods and Results We applied kinetic methods for measuring the fluxes to plasma of neurochemicals relevant to sympathetic neurotransmission in younger (aged 20 to 30 years) and older (aged 60 to 75 years) healthy men during mental stress (difficult mental arithmetic), isometric exercise (sustained handgrip), and dynamic exercise (supine cycling). The increase in total norepinephrine spillover to plasma with mental stress was unaffected by age. In contrast, the increase in cardiac norepinephrine spillover was two to three times higher in the older subjects ( P .05). The probable mechanism of this higher cardiac norepinephrine spillover was reduced neuronal reuptake of the transmitter, because age had no influence on the overflow of the norepinephrine precursor, dihydroxyphenylalanine, or intraneuronal metabolite, dihydroxyphenylglycol (levels of these two substances reflect rates of cardiac norepinephrine synthesis and intraneuronal metabolism), and the transcardiac extraction of plasma radiolabeled norepinephrine was lower in the older subjects ( P .05). An almost identical pattern of neurochemical response was seen with isometric exercise. During cycling, total norepinephrine spillover was 16% lower in the older men, but cardiac norepinephrine spillover was 53% higher. Conclusions Reduced norepinephrine reuptake increases the overflow of the neurotransmitter to plasma from the aging heart during stimulation of the cardiac sympathetic outflow. Failure of transmitter inactivation at postjunctional receptors with aging would lify the neural signal, and in the presence of myocardial disease could trigger adverse stress-induced cardiovascular events, particularly when accompanied by an age-dependent reduction in vagal tone. Reduction of postsynaptic adrenergic responsiveness with aging, however, might protect against this, as indicated by our finding that in no case was the heart rate increase during stress greater in older men, despite their having larger increases in cardiac norepinephrine spillover.
Publisher: Wiley
Date: 07-2000
Publisher: Wiley
Date: 20-01-2020
DOI: 10.1002/EHF2.12557
Publisher: Oxford University Press (OUP)
Date: 11-2007
Publisher: Elsevier BV
Date: 03-2004
Publisher: Bentham Science Publishers Ltd.
Date: 09-2009
DOI: 10.2174/156652409789105499
Abstract: B-type natriuretic peptide (BNP), initially identified in brain tissues, is now recognized as a key cardiac hormone. Numerous studies over the last decade have demonstrated that both exogenous and endogenous BNP prevent left ventricular (LV) hypertrophy in experimental settings, largely via activation of particulate guanylyl cyclase (pGC)-coupled receptors. BNP represents somewhat of a paradox, in that upregulation of BNP expression is widely used as a diagnostic marker for LV hypertrophy, diastolic dysfunction and heart failure in the clinic. We and others have postulated that BNP serves as an endogenous brake on the LV myocardium, seeking to curb the runaway train of signaling pathways that drive the progression from LV hypertrophy though remodeling, heart failure and death. This review summarizes the mechanisms of BNP's antihypertrophic actions, the role for cyclic GMP-mediated inhibition of pro-hypertrophic signaling, and BNP's impact on LV function. The improved understanding of the mechanisms of BNP regulation of LV hypertrophy and function that has emerged from both the experimental and clinical experience with this peptide provides new insight into the potential that BNP pharmacotherapy still offers for patients with LV hypertrophy.
Publisher: Oxford University Press (OUP)
Date: 23-06-2023
DOI: 10.1093/EURHEARTJ/EHAD375
Abstract: Lifestyle risk factors are a modifiable target in atrial fibrillation (AF) management. The relative contribution of in idual lifestyle risk factors to AF development has not been described. Development and validation of an AF lifestyle risk score to identify in iduals at risk of AF in the general population are the aims of the study. The UK Biobank (UKB) and Framingham Heart Study (FHS) are large prospective cohorts with outcomes measured & years. Incident AF was based on International Classification of Diseases version 10 coding. Prior AF was excluded. Cox proportional hazards regression identified independent AF predictors, which were evaluated in a multivariable model. A weighted score was developed in the UKB and externally validated in the FHS. Kaplan–Meier estimates ascertained the risk of AF development. Among 314 280 UKB participants, AF incidence was 5.7%, with median time to AF 7.6 years (interquartile range 4.5–10.2). Hypertension, age, body mass index, male sex, sleep apnoea, smoking, and alcohol were predictive variables (all P & 0.001) physical inactivity [hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.96–1.05, P = 0.80] and diabetes (HR 1.03, 95% CI 0.97–1.09, P = 0·38) were not significant. The HARMS2-AF score had similar predictive performance [area under the curve (AUC) 0.782] to the unweighted model (AUC 0.802) in the UKB. External validation in the FHS (AF incidence 6.0% of 7171 participants) demonstrated an AUC of 0.757 (95% CI 0.735–0.779). A higher HARMS2-AF score (≥5 points) was associated with a heightened AF risk (score 5–9: HR 12.79 score 10–14: HR 38.70). The HARMS2-AF risk model outperformed the Framingham-AF (AUC 0.568) and ARIC (AUC 0.713) risk models (both P & 0.001) and was comparable to the CHARGE-AF risk score (AUC 0.754, P = 0.73). The HARMS2-AF score is a novel lifestyle risk score which may help identify in iduals at risk of AF in the general community and assist population screening.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.EJPHAR.2017.04.026
Abstract: Endoplasmic reticulum (ER) stress contributes to progression of diabetic nephropathy, which promotes end-stage renal failure in diabetic patients. This study was undertaken to investigate the actions of tempol and ramipril, pharmacological agents that target the consequences of NADPH oxidase, on diabetic nephropathy in a rat model of type 1 diabetes, with an emphasis on markers of ER stress. Male Sprague-Dawley rats were injected intravenously with a single bolus of streptozotocin (55mg/kg) to induce type 1 diabetes. An additional age-matched group of rats was administered with citrate vehicle as controls. After 4 weeks of untreated diabetes, rats received tempol (1.5mM/kg/day subcutaneously, n=8), ramipril (1mg/kg/day in drinking water, n=8) or remained untreated for an additional 4 weeks (n=7). After 8 weeks of diabetes in total, kidneys were collected for histological analysis, gene expression and protein abundance. Tempol and ramipril blunted diabetes-induced upregulation of NADPH oxidase isoforms (Nox4, Nox2, p47
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2013
Publisher: Elsevier BV
Date: 10-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2006
Publisher: AMPCo
Date: 02-2004
Publisher: Wiley
Date: 09-1998
DOI: 10.1111/J.1440-1681.1998.TB02271.X
Abstract: 1. There is accumulating evidence for a range of abnormalities in the nitric oxide (NO) signalling cascade in human cardiovascular disorders. 2. In the present review we assess the literature detailing such evidence in early (hyperlipidaemia) and end-stage (heart failure) disease, with emphasis on the mechanisms by which the disturbances are thought to occur. 3. Strategies for the correction of disturbed NO signalling in these states are reviewed and include both prescribed pharmacological interventions, such as lipid-lowering therapy and novel uses of angiotensin-converting enzyme inhibitors, as well as non-pharmacological interventions, such as exercise and dietary supplementation with L-arginine and n-3 polyunsaturated fatty acids. 4. In addition to a decreased production/function of NO, the possible detrimental effects of a chronic elevation in NO production in patients with liver cirrhosis, together with a novel use of antibiotics to correct this perturbation, is outlined.
Publisher: IEEE
Date: 12-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2012
DOI: 10.1161/CIRCHEARTFAILURE.112.968321
Abstract: Despite adequate rate control, the combination of atrial fibrillation with heart failure (HF) has been shown, in a number of studies, to hasten HF progression. In this context, we aimed to test the hypothesis that an irregular ventricular rhythm causes an alteration in ventricular cardiomyocyte excitation–contraction coupling which contributes to the progression of HF. We investigated the effects of electrical field stimulation (average frequency 2 Hz) in an irregular versus regular drive train pattern on the expression of calcium-handling genes and proteins in rat ventricular myocytes. The effect of rhythm on intracellular calcium transients was examined using Fura-2AM fluorescence spectroscopy. In conjunction, calcium-handling protein expression was examined in left ventricular s les obtained from end-stage HF patients, in patients with either persistent atrial fibrillation or sinus rhythm. Compared with regularly paced ventricular cardiomyocytes, in cells paced irregularly for 24 hours, there was a significant reduction in the expression of sarcoplasmic reticulum calcium (Ca 2+ ) ATPase together with reduced serine-16 phosphorylation of phospholamban. These findings were accompanied by a 59% reduction ( P .01) in the peak Ca2+ transient in irregulary paced myocytes compared with those with regular pacing. Consistent with these observations, we observed a 54% ( P .05) decrease in sarcoplasmic reticulum Ca 2+ ATPase protein expression and an 85% ( P .01) reduction in the extent of phosphorylation of phospholamban in the left ventricular myocardium of HF patients in atrial fibrillation compared with those in sinus rhythm. Together, these data demonstrate that ventricular rhythmicity contributes significantly to excitation–contraction coupling by altering the expression and activity of key calcium-handling proteins. These data suggest that control of rhythm may be of benefit in patients with HF.
Publisher: Elsevier BV
Date: 04-2019
Publisher: Wiley
Date: 09-10-2018
DOI: 10.1002/EJHF.1332
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2016
DOI: 10.1161/CIRCHEARTFAILURE.116.003025
Abstract: Heart failure with preserved ejection fraction (HFpEF), a major public health problem with high morbidity and mortality rates, remains difficult to manage because of a lack of effective treatment options. Although HFpEF is a heterogeneous clinical syndrome, elevated left atrial pressure—either at rest or with exertion—is a common factor among all forms of HFpEF and one of the primary reasons for dyspnea and exercise intolerance in these patients. On the basis of clinical experience with congenital interatrial shunts in mitral stenosis, it has been hypothesized that the creation of a left-to-right interatrial shunt to decompress the left atrium (without compromising left ventricular filling or forward cardiac output) is a rational, nonpharmacological strategy for alleviating symptoms in patients with HFpEF. A novel transcatheter interatrial shunt device has been developed and evaluated in patients with HFpEF in single-arm, nonblinded clinical trials. These studies have demonstrated the safety and potential efficacy of the device. However, a randomized, placebo-controlled evaluation of the device is required to further evaluate its safety and efficacy in patients with HFpEF. In this article, we give the rationale for a therapeutic transcatheter interatrial shunt device in HFpEF, and we describe the design of REDUCE Elevated Left Atrial Pressure in Heart Failure (REDUCE LAP-HF I), the first randomized controlled trial of a device-based therapy to reduce left atrial pressure in HFpEF. URL: www.clinicaltrials.gov . Unique identifier: NCT02600234.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1995
Abstract: Background Congestive heart failure is a debilitating disease characterized by impaired cardiac function with accompanying activation of a variety of neural and hormonal counterregulatory systems. Abnormal activity of the sympathetic nervous system and renin-angiotensin-aldosterone axis and a predisposition to the generation of fatal ventricular arrhythmias are often associated with the development of the disease. Although the underlying cause of sudden death in these patients remains to be unequivocally elucidated, abnormally increased cardiac sympathetic nervous activity may be involved. Methods and Results Twenty-two patients with severe congestive heart failure (New York Heart Association functional class III or IV with left ventricular ejection fraction of 18±1%) and 29 healthy male volunteers participated in this study. By combining direct s ling of internal jugular venous blood via a percutaneously placed catheter with a norepinephrine and epinephrine isotope dilution method for examining neuronal transmitter release, we were able to quantify the release of central nervous system monoamine and indoleamine neurotransmitters and investigate their association with the increased efferent sympathetic ouflow that is variably present in treated patients with this condition. Mean cardiac norepinephrine spillover was 145% higher in treated heart failure patients than in healthy subjects ( P .05), with norepinephrine release from the heart in 6 of 22 patients being more than the highest control value. Raised internal jugular venous spillover of epinephrine (26±12 versus 2±4 pmol/min, P .05) and of norepinephrine and its metabolites (2740±480 versus 875±338 pmol/min, P .05), indicative of increased central nervous system turnover of both catecholamines, occurred in cardiac failure and was quantitatively linked to the degree of activation of the cardiac sympathetic nervous outflow, as was the jugular overflow of the principal serotonin metabolite, 5-hydroxyindoleacetic acid. Conclusions An association between the degree of activation of central monoaminergic neurons and the level of sympathetic nervous tone in the heart was identified in treated patients with heart failure. Epinephrine neurons in the brain may contribute to the sympathoexcitation that is seen in this condition, with the activation of sympathoexcitatory noradrenergic neurons, most likely those of the forebrain, playing an accessory role.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-11-2018
Publisher: Oxford University Press (OUP)
Date: 11-2001
DOI: 10.1016/S0895-7061(01)02081-7
Abstract: Although the importance of sympathetic nervous activation in the pathogenesis of essential hypertension is well documented, the exact pathophysiology of the sympathetic nervous dysfunction present remains to be delineated. This review details three relatively new findings of disturbed sympathetic neurobiology in hypertension. Adrenaline cotransmission is present in the cardiac sympathetic nerves of patients with essential hypertension, as it is in patients with panic disorder, providing presumptive evidence of exposure to high levels of mental stress in hypertensive patients. In lean patients with hypertension there is also evidence of faulty noradrenaline reuptake into the sympathetic nerves of the heart, an abnormality lifying the sympathetic neural signal by impairing removal of noradrenaline from the synaptic cleft. If both abnormalities are present in the sympathetic nerves of the kidneys also (which we did not test), there would most probably be a direct contribution to hypertension development. In the kidneys the causal chain between sympathetic overactivity and the development of hypertension is stronger than for the heart. In obesity-related hypertension there is evidence that renal sympathetic tone is high, based on approximately a doubling of the measured rate of spillover of noradrenaline into the renal veins. This increase in sympathetic outflow to the kidneys appears to be a necessary but apparently not a sufficient cause for the development of clinical hypertension, commonly being present also in overweight people with blood pressure in the normotensive range. High renal sympathetic tone in the latter, of course, may well still contribute to elevation of their pressure level, although not on such a scale as to cause clinical hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-12-2004
DOI: 10.1161/01.CIR.0000149748.79945.52
Abstract: Background— Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor l -arginine is related to decreased endothelial function. Methods and Results— Radiotracer kinetics ([ 3 H] l -arginine) were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects (n=12) and in 2 groups of healthy volunteers with (n=15) and without (n=15) a family history of hypertension. In conjunction, forearm blood flow responses to acetylcholine and sodium nitroprusside were measured before and after a supplemental intra-arterial infusion of l -arginine. In vivo and in vitro measures of l -arginine transport were substantially reduced in the essential hypertension and positive family history groups compared with the negative family history group however, no difference was detected in peripheral blood mononuclear cell mRNA or protein expression levels for the cationic amino acid transporter CAT-1. Plasma concentrations of l -arginine and N G , N G′ -dimethylarginine (ADMA) did not differ between groups. l -Arginine supplementation improved the response to acetylcholine only in subjects with essential hypertension and positive family history. Conclusions— Similar to their hypertensive counterparts, normotensive in iduals at high risk for the development of hypertension are characterized by impaired l -arginine transport, which may represent the link between a defective l -arginine/NO pathway and the onset of essential hypertension. The observed transport defect is not due to apparent alterations in CAT-1 expression or elevated endogenous ADMA.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2011
DOI: 10.1161/CIRCHEARTFAILURE.110.960831
Abstract: Extensive evidence implicates aldosterone excess in the development and progression of cardiovascular disease states including hypertension, metabolic syndrome, cardiac hypertrophy, heart failure, and cardiorenal fibrosis. Recent studies show that activation of inflammatory cascade may play a specific role in the sequelae of mineralocorticoid activation, although the linking mechanism remains unclear. We tested the possibility that secondary stimulation of the stromal-derived factor 1/CXC chemokine receptor 4 (SDF-1/CXCR4) pathway plays a contributory role. We investigated the effect of the highly selective CXCR4 antagonist AMD3465 (6 mg/kg per day for 6 weeks through minipump) in dexoycorticosterone acetate (DOCA)-treated, uninephrectomized mice. CXCR4 antagonism significantly attenuated the induction of cardiac fibrosis, renal fibrosis, hypertension, and left ventricular hypertrophy by DOCA. Mineralocorticoid excess also stimulated the accumulation of T-lymphocytes in the heart and kidney and this was significantly blunted by CXCR4 inhibition. Taken together, these data strongly implicate the SDF-1/CXCR4 axis in the pathogenesis of mineralocorticoid excess induced hypertension, inflammation, and cardiorenal fibrosis. This insight provides a new potential therapeutic approach for the treatment of specific aspects of mineralocorticoid mediated cardiovascular disease.
Publisher: Elsevier BV
Date: 03-1998
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.JACC.2004.07.058
Abstract: In the present study, we aimed to evaluate the effect of adrenergic receptor polymorphisms on the response of myocardium to measured levels of cardiac adrenergic drive, and to evaluate whether polymorphisms of presynaptic adrenoceptors modified the rate of cardiac and systemic release of norepinephrine. Heightened sympathetic activity plays an important pathophysiologic role in congestive heart failure (CHF). Recently several functionally relevant polymorphisms of the alpha(2)-, beta(1)-, and beta(2)-adrenoceptors have been identified, and specific genotypes have been associated with the incidence or clinical severity of CHF. These adrenoceptors are known to be located both pre-synaptically (alpha(2) and beta(2)) and post-synaptically (beta(1) and beta(2)), raising the possibility that their association with clinical measures in CHF could be mediated either by modulation of the cardiac response to a given level of adrenergic drive or by altering norepinephrine release from sympathetic nerve terminals. We determined the beta(1)-, beta(2)-, and alpha(2C)-adrenoceptor genotype in 60 patients with severe CHF in conjunction with measurement of cardiac and systemic sympathetic activity using the radiotracer norepinephrine spillover method. We showed a strong relationship (r = 0.67, p < 0.001) between heart rate and the level of cardiac adrenergic drive, and heart rate for a given level of cardiac adrenergic drive was substantially greater in patients with the Arg/Arg16 beta(2)-adrenoceptor polymorphism (p = 0.02), whereas no such relationship existed for polymorphisms of the beta(1)-adrenoceptor. The genotype of the alpha(2C)- and beta(2)-adrenoceptors showed no relationship to the rate of norepinephrine release from cardiac sympathetic nerves. For the first time, we show that beta(2)-adrenoceptor polymorphisms significantly influence the relationship between heart rate and cardiac adrenergic drive in CHF, but do not affect the rate of norepinephrine release from sympathetic nerve terminals.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2006
Publisher: American Medical Association (AMA)
Date: 2008
DOI: 10.1001/ARCHGENPSYCHIATRY.2007.11
Abstract: The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood s ling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. Treatment for patients consisted of SSRI administration for approximately 12 weeks. Brain serotonin turnover before and after SSRI therapy. Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy P = .008). Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.
Publisher: Wiley
Date: 12-2014
Abstract: Observational studies indicate that psychological stress may contribute to the pathogenesis of hypertension and this may be further accentuated by factors such as endothelial dysfunction. On this basis, we aimed to determine whether oxidative stress enhances pressor responses to stressful stimuli and whether augmenting endothelial function by increasing the transport of L-arginine can counter the effects of oxidative stress. Telemetry probes were used to measure mean arterial pressure (MAP) in wild-type (WT n = 6) and endothelial cationic amino acid transporter-1 (CAT-1)-overexpressing (CAT+) mice (n = 6) before and during an aversive (restraint) and non-aversive (almond feeding) stressor. The superoxide dismutase inhibitor diethyldithiocarbamic acid (DETCA 30 mg/kg per day 14 days) was then administered via a minipump to induce oxidative stress. Stress responses to feeding and restraint were repeated during Days 11-12 of DETCA infusion. In WT mice, pressor responses to restraint and feeding were augmented during infusion of DETCA (35 ± 1 and 28 ± 1 mmHg, respectively) compared with respective pretreatment responses (28 ± 2 and 24 ± 1 mmHg, respectively P ≤ 0.01). In CAT+ mice, pressor responses to feeding were blunted during DETCA (20 ± 1 mmHg) compared with the control response (23 ± 1 mmHg P = 0.03). In these mice, pressor responses to restraint were similar before (28 ± 1 mmHg) and during (26 ± 1 mmHg) DETCA infusion (P = 0.26). We conclude that endothelial CAT-1 overexpression can counter the ability of oxidative stress to augment pressor responses to behavioural stress.
Publisher: American Astronomical Society
Date: 06-07-2012
Publisher: Oxford University Press (OUP)
Date: 11-2001
DOI: 10.1016/S0895-7061(01)02236-1
Abstract: As the world faces an obesity "epidemic," the mechanisms by which overweight is translated into insulin resistance, hypertension, and diabetes need to be better understood. Although the processes of transition remain uncertain, overactivity of the sympathetic nervous system appears pivotal. In obesity, there is stimulation of sympathetic outflow to the kidneys, evident in increased rates of spillover of noradrenaline into the renal veins, and to skeletal muscle vasculature, demonstrated with microneurography. The cause is unclear, but possibly involves the stimulatory action of leptin released from adipose tissue, or from within the brain, for which there is recent evidence in human obesity. The high renal sympathetic tone contributes to hypertension development by stimulating renin secretion and through promoting renal tubular reabsorption of sodium. Neurally mediated skeletal muscle vasoconstriction reduces glucose delivery and uptake in muscle. Impairment of glucose uptake by skeletal muscle is a hallmark of insulin resistance syndromes. Pharmacologic sympathetic nervous suppression within the central nervous system with imidazoline receptor-binding agents such as rilmenidine is a logical therapeutic approach for lowering blood pressure (BP) in patients with essential hypertension, in whom sympathetic activity is often increased. In addition, drugs of this class appear to have the capacity to favorably modify insulin sensitivity, which has particular relevance in the treatment of hypertensive diabetic patients. In the hypertension accompanying maturity onset obesity, with recent recommendations from advisory bodies setting lower goal BP, and with these lower targets often being reached only with combinations of antihypertensive agents, it is advisable that all drugs used in combination therapy have a favorable or at least a neutral effect on insulin resistance.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.JACEP.2018.04.013
Abstract: This study sought to determine if diffuse ventricular fibrosis improves in patients with atrial fibrillation (AF)-mediated cardiomyopathy following the restoration of sinus rhythm. AF coexists in 30% of heart failure (HF) patients and may be an underrecognized reversible cause of left ventricular systolic dysfunction. Myocardial fibrosis is the hallmark of adverse cardiac remodeling in HF, yet its reversibility is unclear. Patients with persistent AF and an idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%) were randomized to catheter ablation (CA) or ongoing medical rate control as a pre-specified substudy of the CAMERA-MRI (Catheter Ablation versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction-an MRI-Guided Multi-centre Randomised Controlled Trial) trial. All patients had cardiac magnetic resonance imaging scans (including myocardial T1 time), serum B-type natriuretic peptide, 6-min walk tests, and Short Form-36 questionnaires performed at baseline and 6 months. Sixteen patients with no history of AF or left ventricular systolic dysfunction were enrolled as normal controls for T1 time. Thirty-six patients (18 in each treatment arm) were included in this substudy. Demographics, comorbidities, and myocardial T1 times were well matched at baseline. At 6 months, patients in the CA group had a significant reduction in myocardial T1 time from baseline compared with the medical rate control group (-124 ms 95% confidence interval [CI]: -23 to -225 ms p = 0.0176), although it remained higher than that of normal controls at 6 months (p = 0.0017). Improvements in myocardial T1 time with CA were associated with significant improvements in absolute LVEF (+12.5% 95% CI: 5.9% to 19.0% p = 0.0004), left ventricular end-systolic volume (p = 0.0019), and serum B-type natriuretic peptide (-216 ng/l 95% CI: -23 to -225 ng/l p = 0.0125). The improvement in LVEF and reverse ventricular remodeling following successful CA of AF-mediated cardiomyopathy is accompanied by a regression of diffuse fibrosis. This suggests timely treatment of arrhythmia-mediated cardiomyopathy may minimize irreversible ventricular remodeling.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2008
DOI: 10.1007/S12017-008-8034-1
Abstract: Cardiovascular diseases including hypertension, myocardial infarction, stroke, and heart failure continue to account for the majority of deaths in the developed world. Whilst the incidence of these clinical disorders does increase with age, outcomes in affected patients tend to be disproportionately adverse with advancing years. In this context it is important to understand the various compensatory processes which become activated in cardiovascular disease. In particular, the autonomic nervous system is known to play a key pathogenic role in the cause and response to many of these conditions. The normal aging process is accompanied by a complex series of changes in the autonomic control of the cardiovascular system, favoring heightened cardiac sympathetic tone with parasympathetic withdrawal and blunted cardiovagal baroreflex sensitivity. Together these changes have the potential to further magnify the effects of concomitant cardiovascular disease. Attention to the mechanisms of these changes and the development of appropriate therapies may serve to reduce the added influence of age on outcome in patients experiencing cardiovascular disease.
Publisher: Elsevier BV
Date: 03-1994
DOI: 10.1016/0735-1097(94)90738-2
Abstract: The aim of this study was to characterize cardiac sympathetic nervous function in patients with severe heart failure and to investigate the influence of the cause of heart failure, hemodynamic variables and central nervous system catecholamine release on cardiac sympathetic tone. Although heart failure is generally accompanied by sympathoexcitation, the integrity of cardiac sympathetic nerve function in heart failure remains controversial, particularly in relation to nerve firing activity and to the capacity of sympathetic nerves to recapture norepinephrine. Additionally, the location of the afferent and central neural pathways implicated in heart failure-induced sympathoexcitation remains unclear. Radiotracer techniques were applied in 41 patients with severe heart failure and 15 healthy control subjects to study the biochemical aspects of whole body and cardiac sympathetic activity. Hemodynamic indexes of cardiac performance were measured in the heart failure group, and their association with sympathetic activity was studied. Jugular venous catechol spillover was measured to study the central noradrenergic control of sympathetic outflow. Sympathoexcitation was evident in the heart failure group, reflected by a 62% increase (p < 0.001) in total body and a 277% increase (p < 0.001) in cardiac norepinephrine spillover rates. These changes were accompanied by significant increases in the cardiac spillover of the norepinephrine precursor dihydroxyphenylalanine, the sympathetic cotransmitter neuropeptide Y and the extraneuronal metabolite 3-methoxy-4-hydroxyphenylglycol. The level of cardiac sympathetic activity was significantly correlated (r = 0.59, p < 0.001) with the mean pulmonary artery pressure. An increase in the spillover of dihydroxyphenylalanine and 3-methoxy-4-hydroxyphenylglycol from the brain was present, suggesting activation of central noradrenergic neurons. Cardiac sympathetic activation is present in severe heart failure, bearing a close relation with pulmonary artery pressures, independent of heart failure etiology. Activation of noradrenergic neurons in the brain is also present and may be the underlying central nervous mechanism of the sympathoexcitation observed in heart failure.
Publisher: American Medical Association (AMA)
Date: 10-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-10-2021
Abstract: Although a rapid rise in left atrial pressure during exertion is considered pathognomonic of heart failure with preserved ejection fraction (HFpEF), the fundamental circulatory determinants of this response are not clear, impacting upon the development of more effective therapies. We aimed to comprehensively describe the circulatory mechanics of patients with HFpEF at rest and during exercise in comparison with controls. We performed simultaneous right‐heart catheterization and echocardiography at rest and during exercise in 22 healthy control volunteers and 60 patients with confirmed HFpEF. Using detailed in idual patient‐level hemodynamic and left ventricular ejection fraction data we performed computer simulations to evaluate the circulatory parameters including the estimated stressed blood volumethat contribute to the resting and exercise pulmonary capillary pressure. At rest and during exercise, left ventricular stiffness (V 30 , the end‐diastolic pressure–volume relationship at a filling pressure of 30 mm Hg), left ventricular elastance, and arterial elastance were all significantly greater in HFpEF than in controls. Stressed blood volume was significantly greater in HFpEF (26.9±5.4 versus 20.2±4.7 mL/kg, P .001), becoming even more pronounced during exercise (40.9±3.7 versus 27.5±7.0 mL per 70 kg, P .001). During exercise, the magnitude of the change in stressed blood volume ( r =0.67, P .001) and left ventricular stiffness ( r =−0.44, P .001) were key determinants of the rise in pulmonary capillary wedge pressure. Further detailed modeling studies showed that the hemodynamic response to exercise results from a complex non‐linear interaction between circulatory parameters. The circulatory determinants of HFpEF physiology are complex. We identified stressed blood volume at rest and during exercise is a novel, key factor, therebyrepresenting an important potential therapeutic target.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Wiley
Date: 04-03-2016
DOI: 10.1002/CCD.26466
Abstract: Radiographic contrast administration is a major cause of acute kidney injury (AKI), worldwide. Currently, contrast induced acute kidney injury (CI-AKI) is the third leading cause of hospital acquired renal failure in the United States. Over 50% of these cases are the result of contrast exposure during cardiac catheterization. The predictive risk factors for and clinical impact of AKI following coronary procedures have been extensively studied and documented in the literature. Similar data, however, are lacking for AKI following angiography or endovascular interventions for lower extremity peripheral artery disease (PAD). The present review examined the published data available for AKI in patients undergoing peripheral procedures using MEDLINE searches. Specific data on number of peripheral cases, subject characteristics, hydration strategies, and AKI incidence rates was recorded. The systematic review resulted in 50 potentially relevant studies and ultimately 15 studies were selected for detailed analysis that included AKI incidence data on patients undergoing peripheral angiography or interventions. The summated studies included 11,311 patients and 10,316 peripheral procedures. The median incidence of AKI in the studies was 10%. The retrieved publications demonstrated significant variations in patient risk factors, definitions of AKI, and specificity of description of endovascular therapies. The incidence, risk factors, and outcomes related to AKI in the context of peripheral angiography or endovascular therapy remain poorly described in the literature and warrant further study in a prospective, systematic fashion. © 2016 Wiley Periodicals, Inc.
Publisher: Frontiers Media SA
Date: 18-09-2019
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 2007
DOI: 10.1002/BMC.750
Abstract: Oxidative stress plays an important role in pathogenesis of many diseases. Measurement of 3-nitrotyrosine (NO(2)Tyr), as a potential biomarker for nitric oxide-mediated damage, has recently been the focus of particular attention. We have developed an HPLC method with NBD-F pre-column derivatization followed by C(18) cartridge cleaning. Using this method we achieved limits of detection of 0.5 and 1.1 nm for NO(2)Tyr and tyrosine (Tyr), respectively, close to that achieved by LS-MS/MS. NO(2)Tyr and tyrosine concentrations were linear over the calibration ranges 0.5-100 nm and 1-320 microm, respectively, with correlation coefficients greater than 0.95. To evaluate the utility of this assay in plasma we analysed s les obtained from smokers and non-smoking subjects. Consistent with the presence of elevated oxidative stress, the plasma NO(2)Tyr concentration and NO(2)Tyr:Tyr ratio of smokers were 17.42 +/- 11.6 nm and 0.263 +/- 0.192 nm/microm with 3.8 and 3.9 times higher (both p < 0.05), respectively, than that of non-smoker controls (4.54 +/- 2.75 nm and 0.067 +/- 0.050 nm/microm, respectively). In conclusion, we have developed a novel HPLC assay for NO(2)Tyr without MS detection that is applicable to clinical studies addressing the pathophysiology and importance of oxidative stress.
Publisher: Elsevier BV
Date: 02-2020
Publisher: BMJ
Date: 21-06-2011
Abstract: Post-resuscitation care may influence outcome following transport to hospital after resuscitation from out-of-hospital cardiac arrest (OHCA). This study aimed to determine whether receiving hospital characteristics such as 24-h cardiac catheterisation services, total bed number or OHCA patient volume influence the rate of survival. Data were analysed from the Victorian Ambulance Cardiac Arrest Registry of patients from January 2003 to March 2010 who were transported to hospital with return of spontaneous circulation (ROSC) after OHCA. Ambulance paramedics attended 9971 patients with OHCA of suspected cardiac cause during the study period. Of these, 2902 (29%) achieved ROSC and were transported to one of 70 hospitals. 1816 (63%) were treated at hospitals with 24-h cardiac interventional services. After adjusting for differences in baseline characteristics, hospital factors significantly associated with survival were treatment at hospitals with 24-h cardiac interventional services (OR 1.40 95% CI 1.12 to 1.74, p=0.003) and patient reception between 08:00 and 17:00 hours (OR 1.34 95% CI 1.10 to 1.64, p=0.004). OHCA patient volume and total hospital bed number were not independently associated with outcome. Hospital characteristics are associated with improved survival in patients with OHCA. This finding has implications for the establishment of regionalised systems of care for patients who have been resuscitated from OHCA.
Publisher: Wiley
Date: 12-2008
Abstract: Patients with panic disorder provide a clinical model of stress. On a "good day," free from a panic attack, they show persistent stress-related changes in sympathetic nerve biology, including abnormal sympathetic nerve single-fiber firing ("salvos" of multiple firing within a cardiac cycle) and release of epinephrine as a cotransmitter. The coreleased epinephrine perhaps originates from in situ synthesis by phenylethanolamine N-methyltransferase (PNMT). In searching for biological evidence that essential hypertension is caused by mental stress--a disputed proposition--we note parallels with panic disorder, which provides an explicit clinical model of stress: (1) There is clinical comorbidity panic disorder prevalence is increased threefold in essential hypertension. (2) For both, epinephrine cotransmission is present in sympathetic nerves. (3) In panic disorder and essential hypertension, but not in health, single-fiber sympathetic nerve firing salvos occur. (4) Tissue nerve growth factor is increased in both conditions (nerve growth factor is a stress reactant). (5) There is induction of PNMT in sympathetic nerves. Essential hypertension exhibits a further manifestation of mental stress: there is activation of noradrenergic brain stem neurons projecting to the hypothalamus and amygdala. These pathophysiological findings strongly support the view that chronic mental stress is important in the pathogenesis of essential hypertension. A hypothesis now under test is whether in both disorders, under prevailing conditions of ongoing stress, PNMT induced in sympathetic nerves acts as a DNA methylase, causing the norepinephrine transporter (NET) gene silencing that is present in both conditions. PNMT can have an intranuclear distribution, binding to DNA. We have demonstrated that the reduced neuronal noradrenaline reuptake present in both disorders does have an epigenetic mechanism, with demonstrable reduction in the abundance of the transporter protein, the NET gene silencing being associated with DNA binding by the methylation-related inhibitory transcription factor MeCP2.
Publisher: Wiley
Date: 30-06-2006
DOI: 10.1002/CCD.20810
Abstract: While functional mitral regurgitation (MR) commonly accompanies heart failure and contributes to heart failure progression, mitral repair in the setting of HF is not routinely practiced because of the attendant significant morbidity and mortality. This limitation has fostered the development of percutaneous devices to reduce MR, and our group has recently reported the short- and long-term effectiveness of a percutaneous mitral annuloplasty device placed in the coronary sinus (Percutaneous Mitral Annuloplasty Device (PMAD), Cardiac Dimensions(R), Inc., Kirkland, WA) in reducing MR in experimental animal models of heart failure with associated MR. In this article, we report results of a "first-in-human" study of temporary placement of the PMAD device. The aim of this study was to demonstrate the feasibility and safety of temporary deployment of this device in patients with functional MR in association with heart failure. Five patients undergoing scheduled coronary angiography with heart failure and functional MR (mean age 52 +/- 9 [SD] years) were recruited, and four had anatomy suitable for deployment of the device. Transthoracic echocardiography and coronary angiography were performed before and after temporary placement and tensioning of the PMAD via the right internal jugular vein. Temporary deployment of the device resulted in a significant reduction in the septal-lateral mitral annular dimension from 35.5 +/- 4.7 to 32.2 +/- 4.6 mm (P = 0.02), with evidence of a reduction in the MR color Doppler area from 98.3 +/- 43.6 to 83.3 +/- 35.1 mm(2) (P = 0.09). There were no complications. This first-in-human study of a novel device for percutaneous treatment of functional MR has shown that temporary placement of this device in the coronary sinus/great cardiac vein of patients with heart failure and MR is feasible and safe. Evidence of temporary reduction in MR and a reduction in mitral annular area indicate promise for device effectiveness in chronic implantation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-10-2003
DOI: 10.1161/01.CIR.0000096051.23734.28
Abstract: Background— Mitral regurgitation (MR) frequently accompanies congestive heart failure (CHF) and is associated with poorer prognosis and more significantly impaired symptomatic status. Although surgical mitral valve annuloplasty has the potential to offer benefit, concerns about the combined surgical risk and possible effects on ventricular performance have limited progress. We evaluated the feasibility and short-term efficacy of a novel device placed in the coronary sinus to reduce MR in the setting of CHF. Methods and Results— CHF and MR were induced in 9 adult sheep by rapid ventricular pacing for 5 to 8 weeks. A mitral annular constraint device was implanted percutaneously through the right internal jugular vein in the coronary sinus and great cardiac vein to create a short-term stable reduction (24.9±2.5%) in the mitral annular septal-lateral dimension as assessed echocardiographically. Right and left heart pressures and cardiac output were determined before and 15 minutes after device implantation. MR extent was examined echocardiographically and expressed as a ratio of left atrial area (MR/LAA). After device placement, MR was substantially reduced from an MR/LAA of 42+6% to 4±3% ( P .01). In association, mean pulmonary wedge pressure was significantly reduced (26±3 to 18±3 mm Hg P .01) and mean cardiac output significantly increased (3.4±0.3 to 4.3±0.4 L/min P =0.01). Conclusions— In this model of CHF, percutaneous placement of a mitral annular constraint device in the coronary sinus resulted in the short-term elimination or minimization of MR and was accompanied in the short term by favorable hemodynamic effects.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-08-2003
DOI: 10.1161/01.CIR.0000081775.72651.B6
Abstract: Background— Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in hypertensive subjects. Sympathetic activation has been suggested to contribute to LV hypertrophy, but this has not yet been conclusively validated in humans. Methods and Results— We comprehensively assessed total systemic and regional sympathetic activity by radiotracer dilution methods and microneurography in 15 untreated hypertensive subjects with echocardiographic evidence of LV hypertrophy (EH+), 11 hypertensive subjects with similar blood pressure but without LV hypertrophy (EH−), and 10 age-matched normotensive control subjects (NT). LV mass index was 87±15 g/m 2 in NT, 106±11g/m 2 in EH−, and 138±17g/m 2 in EH+ ( P .001). Total body and renal norepinephrine spillover were higher in both hypertensive groups compared with NT (total norepinephrine spillover, NT 223±145 versus EH− 418±135 versus EH+ 497±303 ng/min renal norepinephrine spillover, NT 38.8±25.3 versus EH− 88.6±58.0 versus EH+ 103.4±56.2 ng/min both P .05). However, muscle sympathetic nerve activity (NT 25±6 versus EH− 38±20 versus EH+ 57±19 bursts per 100 heartbeats P .01) and cardiac norepinephrine spillover (NT 11.7±6.2 versus EH− 13.1±7.2 versus EH+ 28.6±17.4 ng/min P .01) were only increased in EH+. Cardiac norepinephrine spillover correlated positively with LV mass index in all subjects ( r =0.52 P .001). Conclusions— Our findings demonstrate that hypertensive LV hypertrophy is associated with increased sympathetic activity largely confined to the heart, suggesting that increased cardiac norepinephrine release is related to the development of LV hypertrophy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-07-2020
Abstract: Heart failure with preserved ejection fraction ( HF p EF ) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HF p EF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HF p EF . The Mil HFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double‐blind, placebo‐controlled pilot study in 23 patients with symptomatic HF p EF . Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6‐minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone‐treated patients compared with placebo (+10±13 versus −3±15 P =0.046). Six‐minute walk distance also tended to improve in the treatment group compared with placebo (+22 [−8 to 49] versus −47 [−97 to 12] P =0.092). Heart rate (−1±5 versus −2±9 bpm P =0.9) and systolic blood pressure (−3±18 versus +1±12 mm Hg P =0.57) were unchanged. Early filling velocity/early mitral annular velocity (−0.3±3.0 versus −1.9±4.8 P =0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HF p EF . Further longer‐term studies are warranted to establish the role of this therapeutic approach in HF p EF . URL : www.anzctr.org.au/ Unique identifier: ACTRN 12616000619448.
Publisher: Wiley
Date: 05-1998
DOI: 10.1046/J.1365-201X.1998.00348.X
Abstract: The Utah array powers cutting-edge projects for restoration of neurological function, such as BrainGate, but the underlying electrode technology has itself advanced little in the last three decades. Here, advanced dual-side lithographic microfabrication processes is exploited to demonstrate a 1024-channel penetrating silicon microneedle array (SiMNA) that is scalable in its recording capabilities and cortical coverage and is suitable for clinical translation. The SiMNA is the first penetrating microneedle array with a flexible backing that affords compliancy to brain movements. In addition, the SiMNA is optically transparent permitting simultaneous optical and electrophysiological interrogation of neuronal activity. The SiMNA is used to demonstrate reliable recordings of spontaneous and evoked field potentials and of single unit activity in chronically implanted mice for up to 196 days in response to optogenetic and to whisker air-puff stimuli. Significantly, the 1024-channel SiMNA establishes detailed spatiotemporal mapping of broadband brain activity in rats. This novel scalable and biocompatible SiMNA with its multimodal capability and sensitivity to broadband brain activity will accelerate the progress in fundamental neurophysiological investigations and establishes a new milestone for penetrating and large area coverage microelectrode arrays for brain-machine interfaces.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JACC.2019.08.1062
Abstract: Implantation of an interatrial shunt device (IASD) in patients with heart failure (HF) reduces left atrial hypertension by shunting oxygenated blood to the right heart and lungs. The attendant increases in pulmonary blood flow (Qp) and oxygen content may alter pulmonary vascular function, while left-to-right shunting might compromise systemic perfusion. The authors hypothesized that IASD would improve indexes of pulmonary artery (PA) function at rest and during exercise in HF patients without reducing systemic blood flow (Qs). This is a pooled analysis from 2 trials assessing the effects of the IASD on resting and exercise hemodynamics in HF patients (n = 79) with EF ≥40% with baseline and repeated hemodynamic evaluation between 1 and 6 months. Patients with pulmonary vascular resistance (PVR) >4 WU or right ventricular dysfunction were excluded. Qp and PA oxygen content increased by 27% and 7% following IASD. These changes were associated with salutary effects on pulmonary vascular function (17% reduction in PVR, 12% reduction in PA elastance [pulmonary Ea], and 24% increase in PA compliance). Qp increased during exercise to a greater extent following IASD compared with baseline, which was associated with reductions in exercise PVR and pulmonary Ea. Patients with increases in PA compliance following IASD experienced greater improvements in supine exercise duration. There was no reduction in Qs following IASD at rest or during exercise. Implantation of an IASD improves pulmonary vascular function at rest and during exercise in selected patients with HF and EF ≥40%, without compromising systemic perfusion. Further study is warranted to identify underlying mechanisms and long-term pulmonary hemodynamic effects of IASD. (REDUCE LAP-HF Trial [REDUCE LAP-HF] NCT01913613 and REDUCE LAP-HF Randomized Trial I [REDUCE LAP-HF I] NCT02600234).
Publisher: Elsevier BV
Date: 05-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-06-2023
Abstract: Transesophageal echocardiography–guided direct cardioversion is recommended in patients who are inadequately anticoagulated due to perceived risk of left atrial appendage thrombus (LAAT) however, LAAT risk factors remain poorly defined. We evaluated clinical and transthoracic echocardiographic parameters to predict LAAT risk in consecutive patients with atrial fibrillation (AF)/atrial flutter undergoing transesophageal echocardiography before cardioversion between 2002 and 2022. Regression analysis identified predictors of LAAT, combined to create the novel CLOTS‐AF risk score (comprising clinical and echocardiographic LAAT predictors), which was developed in the derivation cohort (70%) and validated in the remaining 30%. A total of 1001 patients (mean age, 62±13 years 25% women left ventricular ejection fraction, 49.8±14%) underwent transesophageal echocardiography, with LAAT identified in 140 of 1001 patients (14%) and dense spontaneous echo contrast precluding cardioversion in a further 75 patients (7.5%). AF duration, AF rhythm, creatinine, stroke, diabetes, and echocardiographic parameters were univariate LAAT predictors age, female sex, body mass index, anticoagulant type, and duration were not (all P .05). CHADS 2 VASc, though significant on univariate analysis ( P .001), was not significant after adjustment ( P =0.12). The novel CLOTS‐AF risk model comprised significant multivariable predictors categorized and weighted according to clinically relevant thresholds (Creatinine .5 mg/dL, Left ventricular ejection fraction %, Overload (left atrial volume index mL/m 2 ), Tricuspid Annular Plane Systolic Excursion (TAPSE) mm, Stroke, and AF rhythm). The unweighted risk model had excellent predictive performance with an area under the curve of 0.820 (95% CI, 0.752–0.887). The weighted CLOTS‐AF risk score maintained good predictive performance (AUC, 0.780) with an accuracy of 72%. The incidence of LAAT or dense spontaneous echo contrast precluding cardioversion in patients with AF who are inadequately anticoagulated is 21%. Clinical and noninvasive echocardiographic parameters may identify patients at increased risk of LAAT better managed with a suitable period of anticoagulation before undertaking cardioversion.
Publisher: Oxford University Press (OUP)
Date: 10-2006
DOI: 10.1016/J.CARDIORES.2006.07.006
Abstract: Reactive oxygen species (ROS) such as superoxide have been linked to the hypertrophic response of the heart to stimuli including angiotensin II (AngII), mechanical stretch, and pressure overload. We have previously demonstrated that cGMP and protein kinase G mediate the antihypertrophic actions of the natriuretic peptides in rat cardiomyocytes and isolated whole hearts. The impact of natriuretic peptides on cardiac ROS generation, however, has not been investigated. We tested the hypothesis that reduced superoxide accumulation contributes to the antihypertrophic action of atrial natriuretic peptide (ANP). Neonatal rat cardiomyocytes were cultured in serum-free medium with and without AngII (1 micromol/L) or endothelin-1 (ET(1), 60 nmol/L) in the presence and absence of ANP (1 micromol/L) or tempol (100 micromol/L). Hypertrophic responses, cardiomyocyte superoxide generation, and cardiomyocyte expression of NADPH oxidase were determined. AngII induced increases in cardiomyocyte size (to 176 +/- 9% n = 8 p < 0.001, at 48 h), beta-myosin heavy chain expression (to 4.0 +/- 1.6-fold n = 6 p < 0.05, at 48 h), c-fos expression (to 1.9 +/- 0.5-fold n = 7 p < 0.01, at 6 h), superoxide generation (to 181+/-21% n = 8 p < 0.005, at 24 h), and expression of the gp91phox subunit of NADPH oxidase (to 2.4 +/- 0.5-fold n = 7 p < 0.05, at 48 h). These effects were all significantly inhibited by ANP: cardiomyocyte size, beta-myosin heavy chain expression, c-fos expression, superoxide generation and gp91phox expression were reduced to 107 +/- 5% (n = 5 p < 0.05), 1.2 +/- 0.2-fold (n = 6 p < 0.05), 0.9 +/- 0.2-fold (n = 7 p < 0.05), 141 +/- 21% (n = 8 p < 0.05), and to 1.0 +/- 0.5-fold (n = 7 p < 0.05), respectively. These effects were mimicked by tempol. ANP and tempol also significantly inhibited ET1-induced increases in cardiomyocyte size and superoxide generation, but had no effect on markers of hypertrophy when studied alone. This data indicates that the antihypertrophic actions of ANP are accompanied by reduced levels of superoxide, suggesting an antioxidant action contributes to the antihypertrophic actions of ANP.
Publisher: Wiley
Date: 02-2003
DOI: 10.1046/J.1365-2125.2003.T01-1-01752.X
Abstract: As statin therapy has been demonstrated to augment endothelial function in sedentary hypercholesterolaemia (HC), we aimed to investigate the effects of atorvastatin therapy on endothelial function in physically active, HC men. Eleven physically active, HC males were recruited. Endothelial function [forearm blood flow response to brachial artery infusion of acetylcholine (Ach)] was assessed twice in each subject following atorvastatin or no therapy in a randomized crossover design. In addition, endothelial function was compared with an active, normolipidaemic control group (C). Atorvastatin therapy reduced total and LDL cholesterol, but had no effect on basal blood flow or endothelial function (peak ACh mean difference +/- standard error 0.75 +/- 1.75 ml min(-1) per 100 ml tissue) [95% confidence interval (CI) -3.1, 4.6]. In addition, there was no difference in endothelial function between the HC and C groups (-1.14 +/- 2.60 ml min(-1) per 100 ml tissue CI -6.53, 4.25). Statin therapy in HC patients with normal endothelial function does not augment endothelial function.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.CARDFAIL.2015.05.008
Abstract: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left atrial pressure during rest and/or exercise. The Reduce LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial will evaluate the safety and performance of the Interatrial Shunt Device (IASD) System II, designed to directly reduce elevated left atrial pressure, in patients with HFpEF. The Reduce LAP-HF Trial is a prospective, nonrandomized, open-label trial to evaluate a novel device that creates a small permanent shunt at the level of the atria. A minimum of 60 patients with ejection fraction ≥40% and New York Heart Association functional class III or IV heart failure with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg at rest or ≥25 mm Hg during supine bike exercise will be implanted with an IASD System II, and followed for 6 months to assess the primary and secondary end points. Safety and standard clinical follow-up will continue through 3 years after implantation. Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism). MACCE include death, stroke, myocardial infarction, or requirement of implant removal. Primary outcome measures for device performance include success of device implantation, reduction of PCWP at rest and during exercise, and demonstration of left-to-right flow through the device. Key secondary end points include exercise tolerance, quality of life, and the incidence of heart failure hospitalization. Reduce LAP-HF is the first trial intended to lower left atrial pressure in HFpEF by means of creating a permanent shunt through the atrial septum with the use of a device. Although the trial is primarily designed to study safety and device performance, we also test the pathophysiologic hypothesis that reduction of left atrial pressure will improve symptoms and quality of life in patients with HFpEF.
Publisher: Oxford University Press (OUP)
Date: 07-2001
Publisher: SAGE Publications
Date: 31-05-2017
Abstract: Diabetic cardiomyopathy is a major contributor to the increasing burden of heart failure globally. Effective therapies remain elusive, in part due to the incomplete understanding of the mechanisms underlying diabetes-induced myocardial injury. The objective of this study was to assess the direct impact of insulin replacement on left ventricle structure and function in a rat model of diabetes. Male Sprague-Dawley rats were administered streptozotocin (55 mg/kg i.v.) or citrate vehicle and were followed for 8 weeks. A subset of diabetic rats were allocated to insulin replacement (6 IU/day insulin s.c.) for the final 4 weeks of the 8-week time period. Diabetes induced the characteristic systemic complications of diabetes (hyperglycaemia, polyuria, kidney hypertrophy) and was accompanied by marked left ventricle remodelling (cardiomyocyte hypertrophy, left ventricle collagen content) and diastolic dysfunction (transmitral E/A, left ventricle-dP/dt). Importantly, these systemic and cardiac impairments were ameliorated markedly following insulin replacement, and moreover, markers of the diabetic cardiomyopathy phenotype were significantly correlated with the extent of hyperglycaemia. In summary, these data suggest that poor glucose control directly contributes towards the underlying features of experimental diabetic cardiomyopathy, at least in the early stages, and that adequate replacement ameliorates this.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.HLC.2018.02.007
Abstract: Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) is commonly assumed to represent myocardial fibrosis however, comparative human histological data are limited, and there is no consensus on the most accurate method for LGE quantitation. We evaluated the relationship between CMR assessment of regional fibrosis and infarct size assessment using serial biomarkers after ST elevation acute myocardial infarction (STEMI). Ninety-three patients treated for STEMI (59±10 years, 86% male) underwent CMR 6 months after infarction. Infarct size was quantified by CMR-LGE using manual and range of semi-automated thresholds (range: 2-10 standard deviations [SD]) above reference myocardium and the full width-half maximum (FWHM) technique, and compared with the rise in serum biomarkers. The agreement between CMR and biomarker in the identification of large infarcts based on peak troponin (TnI) levels was also analysed. Quantification methods had a strong influence on the infarct size assessment with CMR-LGE. Significant correlations were observed between LGE and biomarkers across all of the signal intensity thresholds. Whilst there was a wide variation with respect to the estimation of total LGE size (from 6.8±7.7 to 32.1±11.3 grams), the variation in the correlation with peak troponin level was much smaller (r-values ranging from 0.670 to 0.876). There was good agreement between CMR-LGE and biomarker assessment of infarct size the best agreement between CMR-LGE and large infarction using a threshold of 8SD for peak TnI>50ng/mL (Cohen's kappa (κ)=0.722), and a threshold of 4SD for peak TnI >95ng/mL (κ=0.761). The correlation between CMR-LGE quantification of infarct size and biomarker release following STEMI at a range of semi-automated thresholds was consistently strong, with good agreement between measures across a range of thresholds.
Publisher: Frontiers Media SA
Date: 19-02-2019
Publisher: Springer Science and Business Media LLC
Date: 19-04-2022
DOI: 10.1007/S10741-022-10236-8
Abstract: Heart failure with preserved ejection fraction is responsible for half of all heart failure and confers substantial morbidity and mortality, and yet to date, there have been no effective pharmacologic interventions. Although the pathophysiology is complex, the primary aetiology of exercise intolerance is due to an elevated left atrial pressure, particularly with exercise. In this context, device-based therapy has become a focus. Several companies have developed techniques to percutaneously create an iatrogenic left to right shunt at the atrial level, thereby reducing left atrial pressure and reducing transmitted pressures to the pulmonary circulation and reducing pulmonary congestion. In this review, we explore the pathophysiology, evidence base, benefits, and considerations of these devices and their place in the therapeutic landscape of heart failure with preserved ejection fraction.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2002
DOI: 10.1097/00004872-200206000-00033
Abstract: Since the pathophysiology of natriuretic peptides in chronic heart failure (HF) is not uniform, we hypothesized that atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) may also have differential effects in acute HF. Our aim was to compare the haemodynamic actions of ANP with BNP, using a classical vasodilator as the control, in greyhound dogs with acute pacing-induced HF. The right ventricles of eight anaesthetized dogs were paced (193 +/- 4 bpm) until pulmonary capillary pressure (PCP) increased to approximately 15 mmHg. In each animal, according to a randomized within-animal design, haemodynamic responses to equimolar (10 pmol/kg per min) infusions of ANP and BNP were compared with those to sodium nitroprusside (SNP). Acute pacing alone increased PCP from 6.6 +/- 0.7 to 15.7 +/- 0.3 mmHg, right atrial pressure (RAP) from 1.9 +/- 0.5 to 4.0 +/- 0.6 mmHg, and systemic vascular resistance (SVR) from 1706 +/- 110 to 2179 +/- 106 dyne s/cm5, and reduced cardiac output (CO) from 4.1 +/- 0.4 to 2.5 +/- 0.2 l/min and arterial pressure from 86.1 +/- 2.4 to 74.5 +/- 2.1 mmHg (all P < 0.01). BNP and SNP improved haemodynamics similarly (CO +13 +/- 3% and +9 +/- 5% PCP -12 +/- 2% and -12 +/- 2% RAP -28 +/- 9% and -34 +/- 6%, SVR -15 +/- 3% and -11 +/- 3%, all P < 0.01, except CO with SNP, not significant), but effects of BNP on preload outlasted those of SNP. By contrast, ANP did not improve the haemodynamics. Haematocrit was significantly higher during BNP infusion than with ANP (P < 0.05) or with SNP (P < 0.001). The haemodynamic responses to exogenous BNP and ANP in acute heart failure were strikingly different. Whereas ANP actions were blunted, BNP response was preserved. Hypothetically, the presence of a putative BNP receptor may explain this finding.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.CARDFAIL.2010.12.003
Abstract: The accuracy of Doppler echocardiography to estimate key hemodynamic parameters in subjects with normal left ventricular ejection fraction (LVEF) has not been fully investigated. Thirty-six subjects with LVEF >50% (median age 62 years), with a broad clinical profile, underwent Doppler echocardiography immediately followed by right heart catheterization. Correlation coefficients between invasive and noninvasive right atrial pressure (RAP), systolic (sPAP) and mean (mPAP) pulmonary artery pressure, cardiac output (CO), and pulmonary vascular resistance (PVR) were 0.39, 0.70, 0.72, 0.57, and 0.60 (P < .001 for all). There was no significant correlation between invasive and noninvasive (based on the peak early transmitral to peak early septal mitral annular velocity ratio) pulmonary capillary wedge pressure (PCWP r = 0.23 P = .18). Bland-Altman plots revealed variable bias but with consistently large limits of agreement for all noninvasive parameters, particularly PCWP. Areas under the receiver operating characteristic curve for noninvasive sPAP, CO, PVR, and PCWP to predict an invasively assessed mPAP ≥25 mm Hg, cardiac index 3 Wood units, and PCWP ≤15 mm Hg, respectively, were 0.92, 0.83, 0.70, and 0.58. Single Doppler echocardiography parameters are not accurate enough to reliably estimate key hemodynamic parameters, particularly PCWP, in subjects with normal LVEF.
Publisher: Portland Press Ltd.
Date: 10-2020
DOI: 10.1042/CS20200087
Abstract: Heart failure (HF) is associated with impaired L-arginine transport. In the present study, we tested the hypothesis that augmented L-arginine transport prevents the loss of kidney function in HF. Renal function was assessed in wildtype mice (WT), transgenic mice with HF (dilated cardiomyopathy, DCM) and double transgenic mice (double transgenic mice with DCM and CAT-1 overexpression, HFCAT-1) with HF and endothelial-specific overexpression of the predominant L-arginine transporter, cationic amino acid transporter-1 (CAT-1) (n=4-8/group). Cardiac function was assessed via echocardiography and left ventricular catheterisation. Renal function was assessed via quantification of albuminuria and creatinine clearance. Plasma nitrate and nitrite levels together with renal fibrosis and inflammatory markers were also quantified at study end. Albumin/creatinine ratio was two-fold greater in DCM mice than in WT mice (P=0.002), and tubulointerstitial and glomerular fibrosis were approximately eight- and three-fold greater, respectively, in DCM mice than in WT mice (P≤0.02). Critically, urinary albumin/creatinine ratio and tubulointerstitial and glomerular fibrosis were less in HFCAT-1 mice than in DCM mice (P& .05). Renal CAT-1 expression and plasma nitrate and nitrite levels were less in DCM mice compared with WT (P≤0.03) but was greater in HFCAT-1 mice than in DCM mice (P≤0.009). Renal expression of IL-10 was less in DCM mice compared with WT (P& .001) but was greater in HFCAT-1 mice compared with DCM mice (P=0.02). Our data provide direct evidence that augmented L-arginine transport prevents renal fibrosis, inflammation and loss of kidney function in HF.
Publisher: Wiley
Date: 28-02-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-07-2022
Abstract: Patients with suspected ST‐segment–elevation myocardial infarction (STEMI) and cardiac catheterization laboratory nonactivation (CCL‐NA) or cancellation have reportedly similar crude and higher adjusted risks of death compared with those with CCL activation, though reasons for these poor outcomes are not clear. We determined late clinical outcomes among patients with prehospital ECG STEMI criteria who had CCL‐NA compared with those who had CCL activation. We identified consecutive prehospital ECG transmissions between June 2, 2010 to October 6, 2016. Diagnoses according to the Fourth Universal Definition of myocardial infarction (MI), particularly rates of myocardial injury, were adjudicated. The primary outcome was all‐cause death. Secondary outcomes included cardiovascular death/MI/stroke and noncardiovascular death. To explore competing risks, cause‐specific hazard ratios (HRs) were obtained. Among 1033 included ECG transmissions, there were 569 (55%) CCL activations and 464 (45%) CCL‐NAs (1.8% were inappropriate CCL‐NAs). In the CCL activation group, adjudicated index diagnoses included MI (n=534, 94%, of which 99.6% were STEMI and 0.4% non‐STEMI), acute myocardial injury (n=15, 2.6%), and chronic myocardial injury (n=6, 1.1%). In the CCL‐NA group, diagnoses included MI (n=173, 37%, of which 61% were non‐STEMI and 39% STEMI), chronic myocardial injury (n=107, 23%), and acute myocardial injury (n=47, 10%). At 2 years, the risk of all‐cause death was higher in patients who had CCL‐NA compared with CCL activation (23% versus 7.9%, adjusted risk ratio, 1.58, 95% CI, 1.24–2.00), primarily because of an excess in noncardiovascular deaths (adjusted HR, 3.56, 95% CI, 2.07–6.13). There was no significant difference in the adjusted risk for cardiovascular death/MI/stroke between the 2 groups (HR, 1.23, 95% CI, 0.87–1.73). CCL‐NA was not primarily attributable to missed STEMI, but attributable to “masquerading” with high rates of non‐STEMI and myocardial injury. These patients had worse late outcomes than patients who had CCL activation, mainly because of higher rates of noncardiovascular deaths.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1016/J.YJMCC.2009.08.020
Abstract: Atrial fibrillation (AF) is commonly associated with chronic dilatation of the left atrium, both in human disease and animal models. The immediate signaling enzyme phospholipase C (PLC) is activated by mechanical stretch to generate the Ca2+-releasing messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) and sn-1,2-diacylglycerol (DAG), an activator of protein kinase C subtypes. There is also evidence that heightened activity of PLC, caused by the receptor coupling protein Gq, can contribute to atrial remodelling. We examined PLC activation in right and left atrial appendage from patients with mitral valve disease (VHD) and in a mouse model of dilated cardiomyopathy caused by transgenic overexpression of the stress-activated protein kinase, mammalian sterile 20 like kinase 1 (Mst1) (Mst1-TG). PLC activation was heightened 6- to 10-fold in atria from VHD patients compared with right atrial tissue from patients undergoing coronary artery bypass surgery (CABG) and was also heightened in the dilated atria from Mst1-TG. PLC activation in human left atrial appendage and in mouse left atria correlated with left atrial size, implying a relationship between PLC activation and chronic dilatation. Dilated atria from human and mouse showed heightened expression of PLCbeta1b, but not of other PLC subtypes. PLCbeta1b, but not PLCbeta1a, caused apoptosis when overexpressed in neonatal rat cardiomyocytes, suggesting that PLCbeta1b may contribute to chamber dilatation. The activation of PLCbeta1b is a possible therapeutic target to limit atrial remodelling in VHD patients.
Publisher: American Physiological Society
Date: 09-2004
DOI: 10.1152/AJPHEART.00725.2003
Abstract: The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI 2 ), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI 2 of IP and EP 1 prostanoid receptors elicits vasodilatation (via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1 μM) virtually abolished the increase in [ 3 H]phenylalanine incorporation (a marker of hypertrophy) induced either by endothelin-1 (ET-1 60 nM, n = 10, P 0.005) or by angiotensin II (1 μM, n = 6, P 0.005). Cicaprost also inhibited ET-1 induction of c- fos mRNA expression, an additional marker of hypertrophy in ARCM ( n = 5, P 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP 1 agonist iloprost (1 μM) in the presence of the EP 1 antagonist AH-6809 (3 μM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 ± 6% ( P 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 (1 μM, n = 5, P 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost ( P 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
DOI: 10.1161/CIRCHEARTFAILURE.117.004540
Abstract: Interatrial shunt device (IASD) effects have been described in patients with heart failure and ejection fractions (EFs) ≥40%. However, baseline characteristics that correlate with greatest hemodynamic effects are unknown. On the basis of fundamental principles, we hypothesized that larger pressure gradients between left and right atria would yield greater shunt flow and greater hemodynamic effects. REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a multicenter study that investigated IASD safety and performance. Sixty-four patients with EF ≥40% underwent device implantation followed by hemodynamic assessments at rest and exercise, including pulmonary capillary wedge pressure (PCWP, surrogate for left atrial pressure) and central venous pressure (CVP). At 6 months, IASD resulted in an average pulmonary-to-systemic blood flow ratio of 1.27 and increased exercise tolerance. The PCWP-CVP gradient (ie, the driving pressure for shunt flow) decreased at peak exercise from 16.8±6.9 to 11.4±5.5 mm Hg, because of increased CVP (17.5±5.4 to 20.3±7.9 mm Hg P =0.04) and decreased PCWP (34.1±7.6 to 31.6±8.0 mm Hg P =0.025). Baseline PCWP-CVP gradient during exercise correlated with changes of both PCWP-CVP and PCWP: Δ(PCWP-CVP)=10.0−0.89·(PCWP-CVP) baseline ( r 2 =0.56) and ΔPCWP=7.54−0.60·(PCWP-CVP) baseline ( P =0.001). Hemodynamics of patients with EF ≥50% and those with EF % responded similarly to IASD. In heart failure patients with EF ≥40%, IASD significantly reduced PCWP and PCWP-CVP at peak exercise. Patients with higher baseline PCWP-CVP gradient had greater reductions in both parameters at follow-up. Results were sustained through 12 months and were independent of whether EF was ≥50% or between 40% and 49%. Additional studies will help further define the baseline hemodynamic predictors of exercise, hemodynamic, and clinical efficacy of the IASD. URL: www.clinicaltrials.gov . Unique identifier: NCT01913613.
Publisher: Wiley
Date: 10-2001
DOI: 10.1016/S1388-9842(01)00164-7
Abstract: Congestive heart failure (CHF) is associated with a high readmission rate after diagnosis. We assessed the ability of a comprehensive management program (CMP) for CHF to reduce readmissions with secondary endpoints of improving quality of life, exercise capacity and targeted drug doses. Patients (pts) with: New York Heart Association Class (NYHA) III or IV CHF left ventricular ejection fraction <40% and stable outpatient therapy were assigned to a CMP of cardiology assessment intensive education and referral to a tailored exercise program. Forty-two pts (35 M, 7 F, mean age 54 years, S.D. 12 years) were enrolled. Two pts were transplanted, two died during follow-up and two were lost to follow-up. Hospital admissions were reduced by 87.2%, (mean 1.05, S.D. 0.98, admissions per pt to mean 0.08, S.D. 0.28, admissions per pt at 6-month follow-up P<0.0001). ACE-inhibitor dose increased by 42% (P<0.0008) and beta-blocker dose increased by 61% (P<0.0001). NYHA Class, 6-min walk and quality of life scores all improved significantly (P<0.0001). A CMP improves QOL and exercise capacity as well as substantially reducing hospital admissions in CHF pts. This study validates the benefit of intensive outpatient care of CHF.
Publisher: Elsevier BV
Date: 03-1998
DOI: 10.1016/S0735-1097(97)00525-1
Abstract: The present study was designed to identify the hemodynamic factor or factors that reflexly contribute to activation of the cardiac sympathetic nerves in patients with severe congestive heart failure (CHF). We and others have previously shown that activation of the sympathetic nervous system is a key feature of CHF in humans. Furthermore, the degree of sympathetic activation shows marked regional heterogeneity and is most pronounced in the heart. Recent studies have shown a significant positive relation between pulmonary artery pressure and the magnitude of cardiac sympathetic activation. Of particular importance, the degree of cardiac sympathoexcitation has also been shown to be strongly associated with mortality in CHF. We assessed total systemic and cardiac sympathetic activity (norepinephrine [NE] spillover method) in nine patients with severe CHF and significantly elevated pulmonary artery pressure (mean [+/-SEM] pulmonary artery pressure 46 +/- 3 mm Hg) at rest and during a titrated infusion of sodium nitroprusside (SNP). SNP infusion significantly reduced mean arterial blood pressure, pulmonary artery pressure and pulmonary capillary wedge pressure. During SNP infusion, the total body NE spillover rate (NESR) increased (from 7.9 +/- 1.7 to 11.2 +/- 3.1 nmol/min, p < 0.01), whereas the cardiac NESR decreased (from 522 +/- 86 to 409 +/- 71 pmol/min, p < 0.05). The ratio of cardiac/total NE spillover was also substantially reduced (from 7.8 +/- 1.3 to 4.9 +/- 0.9%, p < 0.001). There is a directionally opposite change in whole-body (increase) and cardiac (reduction) sympathetic nervous activity during SNP infusion, most likely due to unloading of arterial baroreceptors and specific cardiopulmonary baroreceptors, respectively, in severe CHF. These observations support the concept of a positive feedback relation between pulmonary artery pressure/filling pressure and cardiac sympathetic tone in CHF and serve to reinforce the importance of vasodilator therapy in this condition.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1111/J.1600-6143.2008.02456.X
Abstract: Renal impairment at the time of heart transplantation complicates the choice of subsequent immunosuppressive therapy. Calcineurin (CNI)-free regimens utilizing proliferation signal inhibitors (PSI) may mitigate against nephrotoxicity in this group however, their effectiveness remains unclear. We present our 7-year experience with de novo CNI-free, PSI-based immunosuppression after heart transplantation. Of the 152 patients transplanted between July 1999 and July 2006, de novo immunosuppression regimens were 49 CNI-free, PSI-based, 88 CNI, 15 combination of CNI+PSI. Pretransplant creatinine clearance improved within 6 months in the PSI group (0.69 +/- 0.34 mL/s vs. 1.00 +/- 0.54 mL/s, p < 0.05) but not the CNI (1.32 +/- 0.54 mL/s vs. 1.36 +/- 0.53 mL/s, p = ns) or CNI+PSI (1.20 +/- 0.24 mL/s vs. 1.20 +/- 0.41 mL/s, p = ns) groups. The PSI group had more episodes of early (<or=6 months) acute rejection, bacterial or fungal infections and pleural effusions but less CMV infection (p < 0.05 for all comparisons). Early CNI addition occurred in 37% of the PSI group for acute rejection. 33% of the entire cohort changed immunosuppression regimens over 3.6 +/- 2.2 years follow-up. De novo CNI-free, PSI-based immunosuppression in patients with significant renal dysfunction allowed significant posttransplantation renal recovery but with increased early acute rejection, bacterial and fungal infections and pleural effusions.
Publisher: SAGE Publications
Date: 07-2006
Abstract: Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses. The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients. Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic ‘co-morbidity’ perhaps underlies the clinical concordance. Brain neurotransmitters. Using internal jugular venous s ling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.
Publisher: Wiley
Date: 11-10-2017
DOI: 10.1002/EJHF.930
Abstract: Heart failure with preserved (HFpEF) and mid-range ejection fraction (HFmrEF) are becoming the most prevalent forms of heart failure. Patients with HFpEF/HFmrEF in atrial fibrillation (AF) have poorer survival and quality of life, but the mechanism underpinning this is unknown. We sought to investigate the influence of AF on the haemodynamic profile of HFpEF/HFmrEF patients at rest and during exercise. We invasively measured central haemodynamics at rest and during symptom-limited supine bicycle exercise in HFpEF/HFmrEF patients, 35 in sinus rhythm and 20 in AF with matched left ventricular ejection fraction. At rest, AF patients had significantly increased pulmonary capillary wedge pressure, lower cardiac index and reduced left ventricular stroke work index, despite similar resting heart rate. Under resting conditions, calculated oxygen consumption and systemic arteriovenous oxygen gradient were not different between the two groups. During supine cycling at similar levels of workload, AF patients exhibited a reduced capacity to increase their oxygen consumption and this was accompanied by a persistently impaired cardiac index and left ventricular stroke work index. The adverse interaction of AF and HFpEF/HFmrEF may be accounted for by an adverse impact on left ventricular systolic function and peripheral oxygen kinetics.
Publisher: American Diabetes Association
Date: 16-09-2011
DOI: 10.2337/DB10-1033
Abstract: Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D). The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE–fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium. β-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and β-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors. These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2012
DOI: 10.1161/CIRCINTERVENTIONS.111.966226
Abstract: Experimental studies suggest that deferoxamine (DFO) limits the generation of reactive oxygen species by chelating redox-active iron and thereby may reduce ischemia-reperfusion injury and myocardial infarct (MI) size. We investigated whether DFO administered before reperfusion by primary percutaneous coronary intervention (PPCI) would ameliorate oxidative stress and MI size. We randomly assigned 60 patients with ST-elevation–MI to receive an intravenous bolus of DFO (500 mg) immediately before PPCI followed by a 12-hour infusion (50 mg/kg of body weight) (n=28) or normal saline bolus and infusion (placebo group, n=32). MI size was measured by contrast-enhanced cardiac MRI (CMRI day 3±1), creatine kinase and troponin I area-under-the-curve, and severity of wall motion abnormality on echocardiography. Clinical follow-up including repeat CMRI and echocardiography were performed at 3 months (100±17 days). Oxidative stress was assessed by plasma F 2 -isoprostane levels. DFO and placebo groups were well balanced with respect to baseline characteristics, symptom- and door-to-balloon times, pre-PPCI coronary patency, and infarct-related artery location. Serum iron levels were decreased with DFO treatment after PPCI compared with placebo (3.0±2.5 versus 12.6±5.5 μmol/L, P .0001), which persisted until the end of the infusion. In DFO-treated patients, there was a significant reduction in plasma F 2 -isoprostane levels immediately after PPCI (2878±1461 versus 2213±579 pmol/L, P =0.04). However, there was no difference in CMRI-determined infarct size (DFO, 17.4±10.8%, versus placebo, 18.6±10.2% P =0.73), myocardial salvage index at 3 days or at 3 months, or the area-under-the-curve for creatine kinase or troponin I. Adjunctive DFO treatment after the onset of ischemia and continued periprocedurally ameliorates oxidative stress without limiting infarct size. URL: www.anzctr.org.au/ . Unique identifier: ACTRN12608000308392.
Publisher: Wiley
Date: 18-12-2012
Publisher: Elsevier BV
Date: 02-1999
Publisher: Wiley
Date: 08-2012
Publisher: Elsevier BV
Date: 08-2018
Publisher: Wiley
Date: 07-07-2011
DOI: 10.1111/J.1540-8167.2011.02125.X
Abstract: Hypertension (HT) is the most common modifiable risk factor for atrial fibrillation (AF), yet little is known of the atrial effects of chronic HT in humans. We aimed to characterize the electrophysiologic (EP) and electroanatomic (EA) remodeling of the right atrium (RA) in patients with chronically treated systemic HT and left ventricular hypertrophy (LVH) without a history of AF. Twenty patients with (systolic BP 145 ± 10 mmHg) and without (BP 119 ± 11 mmHg, P < 0.01) systemic HT underwent detailed conventional EP and EA voltage and activation mapping. We measured RA refractoriness at the coronary sinus and high septum at cycle lengths (CLs) 600 and 450 ms, and RA conduction velocities, activation times, and voltages at a global and regional level at CLs 600 ms and 300 ms. HT was associated with slowing of global (73 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) and regional conduction velocity particularly in the posterior RA (70 ± 17 cm/s vs 96 ± 12 cm/s in controls, P < 0.01) at the crista terminalis (fractionation and double potentials in HT 72%± 4 vs 43%± 23 in controls, P = 0.04). Mean RA voltage was similar between the 2 groups, however HT was associated with an increase in areas of low voltage (<0.5 mV HT 13% vs controls 9%, P = 0.04). Sustained AF was induced in 30% HT patients and no controls. Chronically treated systemic HT with LVH is accompanied by atrial remodeling characterized by: (i) global conduction slowing, (ii) regional conduction delay particularly at the crista terminalis, and (iii) increased AF inducibility. These changes may in part be responsible for the increased propensity to AF associated with systemic HT.
Publisher: Bentham Science Publishers Ltd.
Date: 11-2007
Publisher: Oxford University Press (OUP)
Date: 12-05-2014
DOI: 10.1093/EHJCI/JEU077
Abstract: In hypertrophic cardiomyopathy (HCM), attempts to associate genotype with phenotype have largely been unsuccessful. More recently, cardiac magnetic resonance (CMR) imaging has enhanced myocardial fibrosis characterization, while next-generation sequencing (NGS) can identify pathogenic HCM mutations. We used CMR and NGS to explore the link between genotype and fibrotic phenotype in HCM. One hundred and thirty-nine patients with HCM and 25 healthy controls underwent CMR to quantify regional myocardial fibrosis with late gadolinium enhancement (LGE) and diffuse myocardial fibrosis with post-contrast T1 mapping. Collagen content of myectomy specimens from nine HCM patients was determined. Fifty-six HCM patients underwent NGS for 65 cardiomyopathy genes, including 36 HCM-associated genes. Post-contrast myocardial T1 time correlated histologically with myocardial collagen content (r = -0.70, P = 0.03). Compared with controls, HCM patients had more LGE (4.6 ± 6.1 vs. 0%, P < 0.001) and lower post-contrast T1 time (483 ± 83 vs. 545 ± 49 ms, P < 0.001). LGE negatively correlated with left-ventricular (LV) ejection fraction and outflow tract obstruction, whereas lower post-contrast T1 time, suggestive of more diffuse myocardial fibrosis, was associated with LV diastolic impairment and dyspnoea. Patients with identifiable HCM mutations had more LGE (7.9 ± 8.6 vs. 3.1 ± 4.3%, P = 0.03), but higher post-contrast T1 time (498 ± 81 vs. 451 ± 70 ms, P = 0.03) than patients without. In HCM, contrast-enhanced CMR with T1 mapping can non-invasively evaluate regional and diffuse patterns of myocardial fibrosis. These patterns of fibrosis occur independently of each other and exhibit distinct clinical associations. HCM patients with recognized genetic mutations have significantly more regional, but less diffuse myocardial fibrosis than those without.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2005
DOI: 10.1097/01.HJH.0000166850.80344.CF
Abstract: Angiotensin (Ang) II may enhance the influence of the sympathetic nervous system at various levels by facilitating norepinephrine (NE) release. We investigated whether such an interaction is evident in the human heart and whether it has an impact on left ventricular (LV) structure. Ang I and Ang II concentrations were determined in arterial and coronary sinus (CS) plasma s les in a group of normotensive (n = 10) and hypertensive (n = 18) subjects. Total systemic and cardiac NE spillover was measured using isotope dilution methodology and LV structure by echocardiography. Arterial and CS concentrations of Ang I and Ang II were similar in both groups (Ang II CS, 5.8 +/- 4.0 versus 3.7 +/- 3.1 fmol/ml P = not significant), as was the Ang II/Ang I ratio (CS, 0.56 +/- 0.17 versus 0.54 +/- 0.22 fmol/fmol P = not significant). Total systemic (223 +/- 145 versus 374 +/- 149 ng/min P < 0.05) and cardiac NE spillover (11.7 +/- 6.3 versus 19.4 +/- 10.5 ng/min P < 0.05) were increased in hypertensive patients, as was LV mass index (LVMI) (86.7 +/- 14.7 versus 117.2 +/- 19.4 g/m P < 0.001). LVMI correlated with cardiac NE spillover (r = 0.47 P < 0.02). No correlation was evident between CS Ang II and cardiac NE spillover (r = 0.001 P = not significant) or LVMI (r = -0.20 P = not significant). Arterial Ang II tended to correlate with total systemic NE spillover (r = 0.34 P = 0.081). When hypertensive subjects were ided into two groups with either high or low CS Ang II concentration, cardiac NE spillover and LVMI did not differ between the two groups. These findings suggest a growth-promoting effect of increased cardiac sympathetic tone on cardiomyocytes in hypertensive patients, but do not support the notion of a significant role of Ang II for norepinephrine release and LV hypertrophy in the hypertensive human heart.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.IJCARD.2013.05.006
Abstract: Approximately half of all patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFPEF) and the prevalence of this form of HF is increasing. Although dyspnoea on exertion and diminished functional capacity is the key symptom of patients with HFPEF, current diagnostic criteria focus on resting indices of ventricular function. Specifically, current proposed criteria for the diagnosis of HFPEF, include clinical signs of HF normal left ventricular systolic function and evidence of abnormal diastolic performance and/or altered natriuretic peptides. By contrast, recent studies demonstrate that the key pathophysiologic features of HFPEF may not be evident at rest, and can only be detected during exertion. This review addresses the potential role of exercise testing using invasive haemodynamic or echocardiographic assessment in patients with suspected HFPEF in which current diagnostic criteria are not met.
Publisher: American Academy of Sleep Medicine (AASM)
Date: 15-12-2018
DOI: 10.5664/JCSM.7536
Publisher: Portland Press Ltd.
Date: 23-11-2005
DOI: 10.1042/CS20050171
Abstract: We have reported previously a decrease in the clearance of the NO (nitric oxide) precursor L-arginine in the forearm circulation of CHF (congestive heart failure) patients, suggesting a potential rate-limiting mechanism contributing to the common finding of endothelial dysfunction in CHF. Given data that show exercise training augments endothelial function in CHF, the aim of the present study was to investigate whether these improvements were due to an increase in L-arginine transport. Measures of L-arginine transport, endothelial function and exercise capacity were repeated before and after 8 weeks of ‘usual living’ or exercise training in 21 CHF patients [NYHA (New York Heart Association) class II/III]. Exercise capacity (6-min walk test) increased following exercise training (496±21 to 561±17 m P=0.005), whereas the control group demonstrated no change [488±18 to 484±21 m P=ns (not significant)]. Basal FBF (forearm blood flow) remained stable following exercise training (2.68±0.55 to 2.46±0.32 ml·min−1·100 ml−1 of tissue) and ‘usual living’ (2.16±0.37 to 2.91±0.55 min−1·100 ml−1 of tissue). FBF responses to ACh (acetylcholine) increased following exercise by 49.6±17.7% (area under curve P=0.01) demonstrating augmented endothelial function. FBF responses to SNP (sodium nitroprusside) were also improved following exercise training (30.8±8.2% P=0.02). There was no change in vascular function in the ‘usual living’ group. The clearance of L-arginine was significantly increased following involvement in the exercise programme (69.4±7.8 to 101.0±9.5 ml/min P=0.04), whereas there was no change in the ‘usual living’ group (78.4±17.5 to 81.0±14.9 ml/min P=ns). In conclusion, the augmentation in endothelial function observed following exercise may be due, in part, to an increase in the transport of L-arginine in CHF patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-03-2007
DOI: 10.1161/CIRCULATIONAHA.106.665836
Abstract: Background— Endothelial dysfunction because of reduced nitric oxide bioavailability is a key feature of essential hypertension. We have found that normotensive siblings of subjects with essential hypertension have impaired endothelial function accompanied by altered arginine metabolism. Methods and Results— We have identified a novel C/T polymorphism in the 3′UTR of the principal arginine transporter, solute carrier family 7 (cationic amino acid transporter, y+ system), member 1 gene ( SLC7A1 ). The minor T allele significantly attenuates reporter gene expression ( P .01) and is impaired in its capacity to form DNA-protein complexes ( P .05). In 278 hypertensive subjects the frequency of the T allele was 13.3% compared with 7.6% in 498 normotensive subjects ( P .001). Moreover, the overall genotype distribution observed in hypertensives differed significantly from that in normotensives ( P .001). To complement these studies, we generated an endothelial-specific transgenic mouse overexpressing l -arginine transporter SLC7A1 . The Slc7A1 transgenic mice exhibited significantly enhanced responses to the endothelium-dependent vasodilator acetylcholine (−log EC 50 for wild-type versus Slc7A1 transgenic: 6.87±0.10 versus 7.56±0.13 P .001). This was accompanied by elevated production of nitric oxide by isolated aortic endothelial cells. Conclusions— The present study identifies a key, functionally active polymorphism in the 3′UTR of SLC7A1 . As such, this polymorphism may account for the apparent link between altered endothelial function, l -arginine, and nitric oxide metabolism and predisposition to essential hypertension.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.AMJCARD.2014.04.011
Abstract: This study aimed to define the influence of healthy aging on the central hemodynamic response to exercise. Advancing age results in numerous alterations to the cardiovascular system and is a major risk factor to develop heart failure. In patients with suspected heart failure with preserved ejection fraction, there is an increasing interest in the incorporation of stress hemodynamic studies into the diagnostic evaluation pathway. However, many patients with suspected heart failure with preserved ejection fraction are older, and there are few data regarding the effect of aging on the normal central hemodynamic responses to exercise. Therefore, we examined 55 healthy patients using right-sided cardiac catheterization with exercise. Mean age was 49.6 years, with 36% older than 55 years. On exercise, the mean pulmonary artery pressure was higher with advancing age (r = 0.412, p = 0.002). Additionally, age was negatively associated with cardiac index (r = 0.407, p = 0.005). The exercise-induced rise in pulmonary capillary wedge pressure (r = 0.378, p = 0.004) was greater with advancing age. Pulse pressure measured during exercise (r = 0.541, p <0.01) increased with age, as did diastolic dysfunction assessed by E/A ratio (r = 0.569, p <0.001). In conclusion, aging was associated with decreased cardiac output and increased pulmonary artery pressure during exercise, which developed as the consequence of both increased pulmonary vasculature resistance and higher left ventricular filling pressures.
Publisher: Wiley
Date: 30-03-2013
Abstract: The prevalence of type 1 diabetes (T1D) is increasing worldwide and is associated with significant microvessel complications, of which nephropathy, retinopathy and neuropathy are the most commonly studied. Although clinically evident microvascular complications of diabetes are rarely seen in childhood, early vascular abnormalities develop during childhood and accelerate during puberty. Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis, which is regulated by endothelial nitric oxide synthase (NOS3) at several levels. Together, VEGF and NOS3 play an important role in the pathogenesis of the microvascular complications of diabetes. Genetic variations in NOS3 and VEGF critically regulate endothelial survival and function and increase the susceptibility of patients to develop severe microvessel complications. Identification of the risk factors for and improved understanding of the subclinical signs of these diabetic microvascular complications will enable implementation of therapeutic strategies, potentially changing the course of vascular complications and improving the prognosis of children, adolescents and young adults with diabetes. Moreover, early detection of these variations may have a prognostic value or may suggest interventional approaches to regulate these proteins in patients with diabetes.
Publisher: Wiley
Date: 03-2013
Abstract: Interstitial fibrosis is a key component of myocardial remodelling in heart failure (HF). Many studies have measured peripheral blood levels of procollagens and matrix metalloproteinases (MMPs), as a surrogate for myocardial matrix metabolism, particularly to evaluate the effect of interventions and their prognostic relevance. However, the relationship between peripheral biomarker levels and actual cardiac turnover in HF is not known. We aimed to determine whether peripheral levels of relevant biomarkers reflect cardiac release in patients with advanced HF. We determined whether the failing human heart releases collagen precursors [procollagen I N-terminal peptide (PINP) and procollagen III N-terminal peptide (PIIINP)], or key matrix metalloproteinases (MMP9) and MMP inhibitors [tissue inhibitor of metalloproteinase 1 (TIMP1)] by performing transcardiac blood s ling in healthy controls (n = 9) and in patients with advanced HF (n = 18, left ventricular ejection fraction 22 ± 2%). HF patients had higher arterial levels of PIIINP compared with controls (7.0 ± 0.7 vs. 4.0 ± 0.2 µg/L, P < 0.001). PIIINP was closely correlated with the pulmonary capillary wedge pressure (r = 0.54, P = 0.01) and the estimated glomerular filtration rate (r = -0.50, P = 0.01). Transcardiac blood s ling demonstrated that there was no net release of either PINP or PIIINP in controls or HF patients. The transcardiac MMP9 gradient was significantly lower in HF patients (P < 0.05), and was negatively correlated with left ventricular mass (r = -0.51, P = 0.01). Our study shows that the concentration of circulating levels of PINP, PIIINP, MMP9, and TIMP1 do not accurately reflect cardiac turnover. This study highlights the importance of performing transcardiac blood s ling to validate the utility of emerging cardiac biomarkers.
Publisher: Elsevier BV
Date: 12-1996
DOI: 10.1016/S1071-9164(96)80070-4
Abstract: Nitric oxide (NO) acts as an autocrine- and paracrine-acting signaling autacoid that, among other functions, has been shown to regulate cardiac contractile responsiveness to beta-adrenergic and muscarinic cholinergic agonists. Nitric oxide (NO) is formed by the oxidation of one of two equivalent guanidino nitrogens in L-arginine by O2 to form NO and L-citrulline. This reaction is catalyzed by a family of enzymes termed NO synthases. Three distinct isoforms of NOS have been identified, each the product of a separate gene. Cellular constituents of cardiac muscle, including ventricular myocytes as well as microvascular endothelial cells, have been shown to express the "endothelial constitutive" isoform of NO synthase (ecNOS or NOS3) in vivo, and both cell types also express the NO synthase isoform induced by specific inflammatory cytokines (iNOS or NOS2) in vivo and in vitro. While NO-dependent intracellular signalling in cardiac myocytes clearly involves the activation of guanylate cyclase and downstream signalling by cGMP, there is accumulating evidence that non-cGMP-dependent regulatory signalling events are also initiated by NO. In addition, decreased contractile responsiveness of cardiac myocytes to beta-adrenergic agonists, following induction of NOS2 by inflammatory cytokines, requires the presence of insulin and the co-induction of enzymes responsible for production of tetrahydrobiopterin, a NOS co-factor. Inappropriate or excessive production of NO by cardiac myocytes and by microvascular endothelial cells likely contributes to the cardiac contractile dysfunction characteristic of the systemic inflammatory response syndrome and cardiac allograft rejection.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2020
DOI: 10.1038/S41564-020-00838-Z
Abstract: Coronavirus disease 2019 (COVID-19) was first diagnosed in Scotland on 1 March 2020. During the first month of the outbreak, 2,641 cases of COVID-19 led to 1,832 hospital admissions, 207 intensive care admissions and 126 deaths. We aimed to identify the source and number of introductions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into Scotland using a combined phylogenetic and epidemiological approach. Sequencing of 1,314 SARS-CoV-2 viral genomes from available patient s les enabled us to estimate that SARS-CoV-2 was introduced to Scotland on at least 283 occasions during February and March 2020. Epidemiological analysis confirmed that early introductions of SARS-CoV-2 originated from mainland Europe (the majority from Italy and Spain). We identified subsequent early outbreaks in the community, within healthcare facilities and at an international conference. Community transmission occurred after 2 March, 3 weeks before control measures were introduced. Earlier travel restrictions or quarantine measures, both locally and internationally, would have reduced the number of COVID-19 cases in Scotland. The risk of multiple reintroduction events in future waves of infection remains high in the absence of population immunity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2003
DOI: 10.1161/01.HYP.0000066289.17754.49
Abstract: Results from animal experimentation suggest a 2-way interaction between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and conversely, with the sympathetic system exercising regulatory feedback inhibition over leptin release. We have now tested this hypothesis in humans. In the absence of results from leptin infusions, to test for sympathetic stimulation of leptin release, we sought a quantitative naturalistic linkage of sympathetic activity with leptin plasma concentration across a broad range of leptin values in men of widely differing adiposity. Renal norepinephrine spillover was correlated with plasma leptin ( r =0.628, P .01), but other measures of sympathoadrenal function did not. To test for sympathetic and adrenomedullary inhibition of leptin release, we studied clinical models of high sympathetic tone, heart failure, and essential hypertension, in which lowered plasma leptin levels might have been expected but were not found a model of low sympathetic activity, pure autonomic failure, in which plasma leptin level was normal (6.1±1.2 vs 12.8±3.1 ng/mL in healthy subjects) and a clinical model of reduced epinephrine secretion, healthy aging, in which plasma leptin level again was normal (5.7±1.1 ng/mL vs 4.0±0.9 ng/mL in men years and years, respectively). Paradoxically, leptin concentration was elevated in heart failure, caused entirely by reduced renal clearance of leptin release, 142.0±30.5 mL/min, compared with 56.9±18.9 mL/min ( P .05). These results provide some support for the view that leptin stimulates the sympathetic nervous system, at least for renal sympathetic outflow, but do not confirm the concept of regulatory feedback inhibition of leptin release by the sympathetic nervous system.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2006
Publisher: Public Library of Science (PLoS)
Date: 11-08-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2010
DOI: 10.1161/HYPERTENSIONAHA.110.156547
Abstract: Although B-type natriuretic peptide (BNP) is widely used as a biomarker for heart failure, the in vivo mechanical stimulus for its cardiac release remains poorly defined. We aimed to characterize the hemodynamic determinants of the transcardiac BNP gradient as a measure of myocardial BNP release by performing a detailed hemodynamic assessment in subjects with a broad spectrum of systolic and diastolic left ventricular dysfunction. Forty-two subjects underwent a detailed transthoracic echocardiographic study, right heart catheterization, and simultaneous BNP measurement in arterial and coronary sinus plasma. The transcardiac BNP gradient was lowest in subjects with normal left ventricular ejection fraction/high peak early diastolic annular velocity (n=11), intermediate in those with normal left ventricular ejection fraction/low peak early diastolic annular velocity (n=13), and highest in those with low left ventricular ejection fraction/low peak early diastolic annular velocity (n=18 29 ng/L (range: 15 to 78 ng/L) versus 88 ng/L (range: 34 to 172 ng/L) versus 1566 ng/L (range: 624 to 2349 ng/L P .001). Across the range of patients, left ventricular end-systolic wall stress ( r 2 =0.51) and peak systolic mitral annular velocity ( r 2 =0.47) showed the strongest correlation with higher transcardiac BNP gradient. In contrast, the transcardiac BNP gradient was weakly related to indices of diastolic load, including pulmonary capillary wedge pressure ( r 2 =0.27) and left ventricular end-diastolic wall stress ( r 2 =0.21). Across this spectrum of pathophysiology, left ventricular end-systolic wall stress appears to be the key mechanical stimulus influencing cardiac BNP release.
Publisher: Annual Reviews
Date: 02-2008
DOI: 10.1146/ANNUREV.MED.59.052407.103237
Abstract: Heart failure is a major cardiovascular disease, characterized by considerable morbidity and mortality. Despite major advances in the pharmacotherapy of heart failure, the options for patients with severe end-stage symptoms remain limited. However, recent developments in the identification of the molecular basis for the progressive nature of heart failure have identified a number of potentially important new therapeutic targets. In particular, key components of the cardiomyocyte calcium-handling pathway show characteristic changes in heart failure. A body of research examining the effect of restoration of these defects in experimental models of heart failure, whether in genetically engineered mouse models or by myocardial gene transfer, very strongly supports the calcium-handling pathway as a target for clinical intervention.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
DOI: 10.1097/00004872-200402000-00016
Abstract: Endothelial dysfunction is established in aged in iduals however, the mechanism(s) are not fully elucidated. We have previously identified l-arginine transport as a potential rate-limiting factor in nitric oxide (NO) production in heart-failure patients, characterized with endothelial dysfunction. We therefore aimed to investigate whether the age-related decline in endothelial function is due to reduced transport of the NO precursor, L-arginine. Thirty-seven healthy males aged between 19 and 69 were recruited. Throughout 40 min of intra-arterial (i.a.) infusion of [3H]L-arginine (100 nCi/min), venous blood s les were withdrawn for the determination of L-arginine clearance. Venous occlusion plethysmography was then used to record the forearm blood flow responses to i.a. infusions of acetylcholine (ACh 9.25 and 37 microg/min) and sodium nitroprusside (SNP 2 and 8 microg/min). While ACh-induced vasodilation decreased with age (37 microg/min young 15.87 +/- 1.30, middle-aged 9.59 +/- 1.33, older 10.42 +/- 1.12 ml/min per 100 ml tissue P = 0.001), there was no change in forearm [3H]L-arginine clearance (young 126.08 +/- 19.05, middle-aged 122.47 +/- 20.96, older 126.56 +/- 19.56 ml/min NS). Further [3H]L-arginine uptake studies in isolated peripheral blood mononuclear cells supported our in vivo findings, demonstrating no difference in [3H]L-arginine transport across the age spectrum. The present study excludes the hypothesis of impaired L-arginine transport as a potential mechanism for the age-related decline in endothelial function.
Publisher: Oxford University Press (OUP)
Date: 28-10-2014
DOI: 10.1093/EHJCI/JEU182
Abstract: Myocardial fibrosis is fundamental in the pathogenesis of heart failure. Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging is commonly assumed to represent myocardial fibrosis however, comparative human histological data are limited, especially in non-ischaemic cardiac disease. Diffuse interstitial myocardial fibrosis is increasingly recognized as central in the pathogenesis of cardiomyopathy and can be quantified using newer CMR techniques such as T1 mapping. We evaluated the relationship of CMR assessment of regional and diffuse fibrosis with human histology. Eleven patients on the waiting list for heart transplantation (43.5 ± 7.6 years, 64% male) and eight patients undergoing surgical myectomy for obstructive hypertrophic cardiomyopathy (57.1 ± 8.6 years, 63% male) were recruited and underwent CMR prior to cardiac transplantation or myectomy. Quantification of fibrosis in explanted hearts using digitally analysed Masson-trichrome-stained slides was validated against picrosirius red-stained slides analysed using Image J, with an excellent correlation (R = 0.95, P < 0.0001). Significant correlations were observed between LGE and histological fibrosis across a range of signal intensity thresholds in the explanted hearts (range: 2-10 standard deviations above reference myocardium), with maximal accuracy at a threshold of 6 SD (R = 0.91, P < 0.001). Assessment of interstitial myocardial fibrosis with post-contrast T1 times demonstrated a significant correlation on both segmental (R = -0.64, P = 0.002) and per-patient (R = -0.78, P = 0.003) analyses. CMR provides accurate, non-invasive assessment of regional myocardial fibrosis using LGE, while diffuse interstitial myocardial fibrosis is accurately assessed with post-contrast T1 mapping.
Publisher: Wiley
Date: 08-2006
DOI: 10.1111/J.1540-8159.2006.00447.X
Abstract: In this study, we aimed to compare the level of atrial sympathetic innervation in human atrial fibrillation (AF) to that in sinus rhythm (SR). Histological studies of atrial tissue obtained from animals with experimentally induced AF indicate that sympathetic hyperinnervation could play a role in the pathogenesis of AF. In 24 patients (12 in SR and 12 in AF) undergoing bypass surgery, we collected right atrial appendage tissue. In AF patients, left atrial appendage tissue was also acquired. The degree of sympathetic innervation was quantified by measuring the amount of staining for tyrosine hydroxylase (TH) and tissue norepinephrine (NE). In conjunction, nerve growth factor (NGF) mRNA expression was assessed by real-time polymerase chain reaction (PCR). Growth-associated protein 43 (GAP43) immunostaining was used to assess degree of new neural growth. When corrected for differences in tissue fibrosis, the expression of both TH (AF 0.45 +/- 0.1%, SR 0.09 +/- 0.03%, P = 0.02) and tissue NE (AF 358 +/- 49 pg/mg, SR 225 +/- 39 pg/mg, P = 0.04) was greater in atrial tissue of the AF cohort. The degree of atrial TH staining (P = 0.01) and NE content (P < 0.001) was also significantly greater in the right compared with left atrial s les in the AF cohort. There were no differences in NGF mRNA expression or GAP43 staining. This study provides evidence for the presence of heightened atrial sympathetic innervation in patients with persistent AF, suggesting autonomic remodeling may be part of atrial substrate for AF.
Publisher: Springer Science and Business Media LLC
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 03-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-03-2003
DOI: 10.1161/01.CIR.0000056520.17353.4F
Abstract: Background— Congestive heart failure (CHF) patients with central sleep apnea (CHF-CSA) have elevated plasma norepinephrine (NE) compared with CHF patients without apnea (CHF-N). Patients with CHF-CSA also demonstrate higher mean pulmonary artery pressure (PAP), which is suggestive of worse cardiac function. Whether CSA contributes to chronic elevation of sympathetic nerve activity or is associated with more severe CHF remains unknown. We measured awake total body and cardiac NE spillover and related these to measurements of cardiac hemodynamics and apnea severity in CHF patients with CSA, with normal breathing, and with obstructive sleep apnea (CHF-OSA). Methods and Results— A total of 55 CHF patients underwent right heart catheterization and measurements of total body and cardiac NE spillover using NE radioisotope dilution methodology. After polysomnography, patients were grouped by apnea type: 19 were CHF-N, 15 were CHF-OSA, and 21 were CHF-CSA. Compared with the CHF-N and CHF-OSA groups, the CHF-CSA group had significantly higher total body NE spillover (4.62±0.56 versus 4.47±0.54 versus 6.95±0.89 nmol/min, respectively P =0.03), cardiac NE spillover (0.25±0.05 versus 0.21±0.05 versus 0.42±0.06 nmol/min, respectively P =0.02) and mean PAP (23.5±2.4 versus 21.2±0.8 versus 30.4±0.2 mm Hg, respectively P .02). However, controlling for severity of CHF resulted in no significant differences in NE kinetics among the 3 groups. In a stepwise regression, only mean PAP independently correlated with total body ( r =0.33, P =0.03) and cardiac NE spillover ( r =0.44, P =0.002). Sleep apnea severity bore no relationship to markers of sympathetic nerve activity. Conclusion— Total body and cardiac sympathetic nerve activity are elevated in CHF-CSA compared with CHF-OSA and CHF-N patients and are related to heart failure not apnea severity.
Publisher: Wiley
Date: 29-06-2022
DOI: 10.1002/CCD.30300
Abstract: We examined the appropriateness of prehospital cardiac catheter laboratory activation (CCL‐A) in ST‐segment elevation myocardial infarction (STEMI) utilizing the University of Glasgow algorithm (UGA) and remote interventional cardiologist consultation. The incremental benefit of prehospital electrocardiogram (PH‐ECG) transmission on the diagnostic accuracy and appropriateness of CCL‐A has been examined in a small number of studies with conflicting results. We identified consecutive PH‐ECG transmissions between June 2, 2010 and October 6, 2016. Blinded adjudication of ECGs, appropriateness of CCL‐A, and index diagnoses were performed using the fourth universal definition of MI. The primary outcome was the appropriate CCL‐A rate. Secondary outcomes included rates of false‐positive CCL‐A, inappropriate CCL‐A, and inappropriate CCL nonactivation. Among 1088 PH‐ECG transmissions, there were 565 (52%) CCL‐As and 523 (48%) CCL nonactivations. The appropriate CCL‐A rate was 97% (550 of 565 CCL‐As), of which 4.9% ( n = 27) were false‐positive. The inappropriate CCL‐A rate was 2.7% (15 of 565 CCL‐As) and the inappropriate CCL nonactivation rate was 3.6% (19 of 523 CCL nonactivations). Reasons for appropriate CCL nonactivation ( n = 504) included nondiagnostic ST‐segment elevation ( n = 128, 25%), bundle branch block ( n = 132, 26%), repolarization abnormality ( n = 61, 12%), artefact ( n = 72, 14%), no ischemic symptoms ( n = 32, 6.3%), severe comorbidities ( n = 26, 5.2%), transient ST‐segment elevation ( n = 20, 4.0%), and others. PH‐ECG interpretation utilizing UGA with interventional cardiologist consultation accurately identified STEMI with low rates of inappropriate and false‐positive CCL‐As, whereas using UGA alone would have almost doubled CCL‐As. The benefits of cardiologist consultation were identifying “masquerading” STEMI and avoiding unnecessary CCL‐As.
Publisher: Wiley
Date: 08-2017
DOI: 10.1111/IMJ.13503
Publisher: Southern Medical Association
Date: 11-2008
Publisher: Public Library of Science (PLoS)
Date: 31-12-2012
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.JACC.2019.03.493
Abstract: High systolic blood pressure (SBP) increases cardiac afterload, whereas low diastolic blood pressure (DBP) may lead to impaired coronary perfusion. Thus, wide pulse pressure (high systolic, low diastolic [HSLD]) may contribute to myocardial ischemia and also be a predictor of adverse cardiovascular events. The purpose of this study was to determine the relationship between pre-procedural blood pressure and long-term outcome following percutaneous coronary intervention (PCI). The study included 10,876 consecutive patients between August 2009 and December 2016 from the Melbourne Interventional Group registry undergoing PCI with pre-procedural blood pressure recorded. Patients with ST-segment elevation myocardial infarction, cardiogenic shock, and out-of-hospital cardiac arrest were excluded. Patients were ided into 4 groups according to SBP (high ≥120 mm Hg, low 70 mm Hg, low ≤70 mm Hg). Mean pulse pressure was 60 ± 21 mm Hg. Patients with HSLD were older and more frequently women, with higher rates of hypercholesterolemia, renal impairment, diabetes, and multivessel and left main disease (all p ≤ 0.0001). There was no difference in 30-day major adverse cardiac events, but at 12 months the HSLD group had a greater incidence of myocardial infarction (p = 0.018) and stroke (p = 0.013). Long-term mortality was highest for HSLD (7.9%) and lowest for low systolic, high diastolic (narrow pulse pressure) at 2.1% (p = 0.0002). Cox regression analysis demonstrated significantly lower long-term mortality in the low systolic, high diastolic cohort (hazard ratio: 0.50 99% confidence interval: 0.25 to 0.98 p = 0.04). Pulse pressure at the time of index PCI is associated with long-term outcomes following PCI. A wide pulse pressure may serve as a surrogate marker for risk following PCI and represents a potential target for future therapies.
Publisher: Cambridge University Press (CUP)
Date: 28-11-2012
DOI: 10.1017/S0033291712002218
Abstract: Abnormalities in cortical thickness and subcortical structures have been studied in schizophrenia but little is known about corresponding changes in mania and brain structural differences between these two psychiatric conditions, especially early in the stage of the illness. In this study we aimed to compare cortical thickness and shape of the amygdala–hippoc al complex in first-episode schizophrenia (FES) and mania (FEM). Structural magnetic resonance imaging (MRI) was performed on 28 FES patients, 28 FEM patients and 28 healthy control subjects who were matched for age, gender and handedness. Overall, the shape of the amygdala was deformed in both patient groups, relative to controls. Compared to FEM patients, FES patients had significant inward shape deformation in the left hippoc al tail, right hippoc al body and a small region in the right amygdala. Cortical thinning was more widespread in FES patients, with significant differences found in the temporal brain regions when compared with FEM and controls. Significant differences were observed between the two groups of patients with FES and FEM in terms of the hippoc al shape and cortical thickness in the temporal region, highlighting that distinguishable brain structural changes are present early in the course of schizophrenia and mania.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2001
Abstract: Abstract —The precise mechanism by which β-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, β2-adrenoceptor–mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17±1% to 28±3% P .01) and left ventricular stroke work (87±13 to 119±21 g · m per beat P .05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33±0.04 to 0.42±0.04 P =0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.
Publisher: Elsevier BV
Date: 04-2003
Abstract: To compare and establish the relevance of the relative degree of sympathetic nervous system activity (SNSA) in groups of patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA), and in a control group. Elevated SNSA is a characteristic feature of CHF, as well as of OSA and nonhypercapnic central sleep apnea (CSA). OSA and CSA commonly occur with CHF however, the relative contribution of apnea-related hypoxemia and sleep fragmentation to the SNSA of patients with CHF is not known. This was a prospective, controlled, observational trial in which the overnight urinary norepinephrine (UNE) level, which is a measure of integrated overnight SNSA while asleep, was measured in 15 healthy male volunteers, 15 male OSA patients who did not have CHF, and 90 CHF patients (77 men). CHF patients also had right heart pressure measurements and then were grouped by the presence of sleep apnea. Compared with healthy in iduals, the mean (+/- SD) UNE level was significantly elevated in the OSA group and was even further elevated in the CHF group (13.4 +/- 5.6 vs 19.7 +/- 12.3 vs 32.2 +/- 20.2 nmol/mmol creatinine, respectively p < 0.001 [by analysis of variance]). Within the CHF group, the mean UNE levels were greatest in the CHF-CSA group compared with the CHF-OSA group and the CHF nonapnea group (43.9 +/- 24.1 vs 24.0 +/- 10.8 vs 22.4 +/- 8.9 nmol/mmol creatinine, respectively p < 0.001). Using a multivariate regression model, the variance of the UNE level in the CHF group was predicted, in descending order, by pulmonary capillary wedge pressure (14% variance), rapid eye movement sleep (8%), and the mean sleep pulse oximetry level (7%). Overnight SNSA is significantly greater in CHF patients than in OSA patients. Moreover, the hemodynamic severity of CHF contributes to the elevation of SNSA in CHF patients to a greater degree than apnea-related hypoxemia.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.EJPHAR.2015.10.046
Abstract: Reduced nitric oxide (NO) bioavailability plays a central role in the pathogenesis of myocardial ischemia-reperfusion injury (I-R), and reduced l-arginine transport via cationic amino acid transporter-1 is a key contributor to the reduced NO levels. Insulin can increase NO levels by increasing the transport of its substrate l-arginine but insulin alone exerts minimal cardiac protection in I-R. We hypothesized that combined insulin and l-arginine may provide cardioprotective effects in the setting of myocardial I-R. The effect of supplemental insulin, l-arginine and the combination was examined in cardiomyocytes exposed to hypoxia/reoxygenation and in isolated perfused mouse hearts undergoing ischemia/reperfusion. When compared to controls, cardiomyocytes treated upon reoxygenation with 1nM insulin+1mM l-arginine exhibited significant (all P<0.05) improvements in NO generation and mitochondrial membrane potential, with a concomitant fall in reactive oxygen species production and LDH release. Insulin also increased l-arginine uptake following hypoxia-reoxygenation (P<0.05 n=4-6). In langendorff perfused isolated mouse hearts, combined l-arginine-insulin treatment upon reperfusion significantly (all P<0.05 n=9-11) improved recovery of left ventricular developed pressure, rate pressure product and end diastolic pressure following ischemia, independent of any changes in post-ischemic coronary flow, together with significantly lower LDH release. The observed improvements were greater than l-arginine or insulin treatment alone. In isolated cardiomyocytes (n=3-5), 1nM insulin caused cationic amino acid transporter-1 to redistribute to the cellular membrane from the cytosol and the effects of insulin on l-arginine uptake were partially dependent on the PI3K/Akt pathway. l-arginine-insulin treatment may be a novel strategy to ameliorate I-R injury.
Publisher: Wiley
Date: 16-01-2019
DOI: 10.1002/EJHF.1399
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 04-2002
Abstract: The aim of this study was to develop a model of long-term progressive heart failure (HF). A cardiac output flowprobe was implanted on the pulmonary artery of 9 adult sheep weighing 40 to 50 kg. Rapid ventricular pacing for 21 days at 160 to 190 bpm (rate A) resulted in moderate HF. Animals were then paced at 205 to 215 bpm (rate B) for 42 days (severe HF) and for 28 days at rate B (advanced HF). Data were collected at baseline and moderate, severe, and advanced HF during submaximal exercise testing and by transthoracic echocardiography in sinus rhythm. There were marked increases in left ventricular (LV) area, mitral valve regurgitation, and LV end-diastolic pressure and decreases in LV wall thickness, LV ejection fraction, positive and negative dP/dt(max), and positive (dP/dt(max))/P throughout the pacing protocol. This ovine HF model incorporates the progressive nature of human HF and allows examination of both structural changes and hemodynamic parameters of HF during and after exercise challenge.
Publisher: Wiley
Date: 10-1999
Publisher: Wiley
Date: 21-09-2015
DOI: 10.1002/CCD.26155
Abstract: The AVERT(TM) Contrast Modulation System (AVERT) (Osprey Medical, MN) is designed to reduce contrast volume administration during angiography. The AVERT provides an adjustable resistance circuit which decreases the pressure head delivering contrast towards the patient. The AVERT has not been previously studied in patients undergoing peripheral digital subtraction angiography (DSA). The purpose of this study was (1) to evaluate contrast savings with the AVERT and (2) to evaluate the ability to generate clinically acceptable DSA images in the process. To better define the mechanism of action in the peripheral circulation, we also developed a bench model to study the effects of the AVERT on the hydrodynamics of contrast delivery. Patients undergoing lower extremity DSA (diagnostic or intervention, sheath or catheter) were studied. The following variables were recorded for each injection: starting control syringe contrast volume, contrast volume injected towards patient, contrast volume returned to AVERT reservoir, net contrast administered to the patient and % savings. The AVERT resistance was adjusted manually based on operator's discretion--balancing image quality and contrast savings. About 408 DSA angiographic sequences were obtained in 22 patients undergoing 29 procedures. Almost 68% of the patients had chronic kidney disease. An 82% presented with critical limb ischemia, 18% had claudication. There was an overall 37% ± 14% savings of contrast (31% for diagnostic DSA, 40% for interventional procedures). Overall 91% of all images were acceptable for clinical decision making. Specifically, 94% of diagnostic and 87% of interventional images were acceptable. Injection through a 4 Fr catheter (77% acceptable) resulted in poorer image quality as compared to a 5 Fr catheter (96% acceptable). Image quality for 5, 6, and 7 Fr sheath injections was 86%, 91%, 98%, respectively. The bench model of peripheral angiography demonstrated a significant reduction in reflux of contrast proximal to the end of the catheter without loss of antegrade image quality - confirming the in vivo findings. We demonstrate that the use of the AVERT device during peripheral angiography results in significant contrast savings without compromising image quality.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.HLC.2005.06.003
Abstract: We describe the case of 25-year-old man, with acute myeloid leukaemia, who presented with a myopericarditis syndrome 17 days post consolidation chemotherapy with high dose cytarabine and idarubicin. Transthoracic echocardiography showed marked transient increased left ventricular wall thickness associated with normal systolic contraction. In conjunction, pulsed tissue Doppler analysis revealed low early diastolic annular velocities, consistent with diastolic dysfunction. Endomyocardial biopsy showed severe interstitial myocardial oedema in the absence of a cellular infiltrate or myofibre damage. We believe this is the first case of subacute anthracycline toxicity described with the pathological findings of isolated myocardial oedema.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-07-2019
Abstract: Women have higher vascular stiffness with aging. The aim of this study was to characterize sex differences in vascular and ventricular structure and function, and to investigate the impact on the primary outcome in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). Data from the Americas cohort of the TOPCAT trial were analyzed. Patients with echocardiography (n=654) were compared according to sex, and achievement of the primary end point (a composite of death from cardiovascular causes and heart failure hospitalization) assessed. Echocardiography revealed higher arterial, systolic, and diastolic ventricular elastance and worse ventricular‐vascular coupling in women. Women had better overall survival and heart failure hospitalization outcomes (hazard ratio 0.74, 95% CI 0.57–0.98, P =0.034), however, determinants of achievement of the primary outcome differed between the sexes. Pulse pressure was a key determinant of outcome in women (hazard ratio 1.04, 95% CI 1–1.09, P =0.034) whereas in men heart rate (hazard ratio 1.61, 95% CI 1.02–2.52 per 10 mm Hg increase, P =0.04) and B‐type natriuretic peptide (hazard ratio 1.01, 95% CI 1–1.02 per 10 ng/mL increase P =0.02) were associated with poorer outcome. Outcomes in patients with heart failure with preserved ejection fraction appear to be differentially influenced by key physiological factors that vary according to sex. In women, ventricular‐vascular stiffening was the most significant determinant of outcome, whereas in men overall survival was influenced by heart rate and B‐type natriuretic peptide this highlights key sex differences in the pathophysiology and outcomes of heart failure with preserved ejection fraction and warrants further exploration. URL: clinicaltrials.gov . Unique identifier: NCT00094302.
Publisher: MDPI AG
Date: 14-06-2016
DOI: 10.3390/NU8060364
Publisher: Wiley
Date: 07-1995
Publisher: Elsevier BV
Date: 12-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2020
Abstract: Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left‐sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP‐protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left‐sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3‐ to 5‐mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.
Publisher: American Physiological Society
Date: 05-2004
DOI: 10.1152/AJPENDO.00489.2003
Abstract: The link between the human sympathoadrenalmedullary system and the adipocyte hormone leptin is controversial. We measured total and regional norepinephrine spillover, epinephrine secretion rate, and extra-adipocyte leptin release in 22 lean [body mass index (BMI) ] and 20 obese (BMI ) normotensive men who underwent arterial and central venous catheterization. Because plasma clearance of leptin is primarily by renal removal, for men at steady state we could estimate whole body leptin release to plasma from renal plasma leptin extraction. Whole body leptin release was 1,950 ± 643 (means ± SE) ng/min in obese men and 382 ± 124 ng/min in lean men ( P 0.05). Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Leptin is released from multiple nonadipocyte sites, which we tested by use of simultaneous arteriovenous blood s ling. We found a surprisingly large contribution of brain leptin release to the plasma leptin pool, 529 ± 175 ng/min ( % whole body leptin release), with greater leptin release in obese than in lean men, 935 ± 321 vs. 160 ± 59 ng/min ( P = 0.045). In parallel with leptin measurements, we also quantified brain serotonin turnover and jugular overflow of neuropeptide Y (NPY). Brain serotonin turnover was higher in obese than in lean men, 227 ± 112 vs. 21 ± 14 ng/min ( P = 0.019), as was overflow of NPY from the brain, 12.9 ± 1.4 vs. 5.3 ± 2.2 ng/min ( P = 0.042). These results suggest that leptin is released within the brain and at an increased rate in obese humans, in whom activation of brain serotonergic and NPY mechanisms also exists.
Publisher: Wiley
Date: 28-08-2008
DOI: 10.1111/J.1540-8159.2008.01152.X
Abstract: The presence of atrial fibrillation (AF) in congestive heart failure (CHF) is accompanied by increased mortality, although the exact mechanism is unclear. In previous studies, we have demonstrated cardiac baroreceptor abnormalities in association with AF and CHF. In this study, we sought to examine the effect of cardiac rhythm on the cardiac sympathetic response to exercise in CHF. In 13 CHF patients (six AF, seven SR, left ventricular ejection fraction 31 +/- 2%, age 61 +/- 1 years), we measured the hemodynamic and cardiac sympathetic response isometric handgrip (IHG) exercise. At baseline the groups were well matched. Baseline hemodynamics and cardiac sympathetic activity did not significantly differ between the cohorts. In response to IHG exercise, both groups demonstrated significant hemodynamic responses. In conjunction, the sinus rhythm (SR) group demonstrated a significant increase in cardiac sympathetic response to exercise (P = 0.04) while in contrast the AF group did not (P = 0.6). In this study, we demonstrate for the first time that the combination of AF and CHF is accompanied by a marked attenuation of the cardiac sympathetic response to acute hemodynamic stress. This implies AF is associated with a further impairment of baroreceptor response in CHF compared to SR. These findings present possible insights to the associated increased mortality and pathogenesis of AF with CHF.
Publisher: Wiley
Date: 08-2018
DOI: 10.1111/IMJ.13977
Abstract: Heart failure (HF) is a major cause of morbidity and mortality, requiring collaborative patient-centred care. Patient engagement is fundamental to long-term management patient-reported outcome measures are an increasingly recognised method of assessing medical interventions. A qualitative study of 31 patients with HF found they were twice as likely to use their own management strategies including electronic platforms rather than existing resources. Barriers to self-care included patient education, timely recognition of signs and symptoms of HF with an appropriate escalation plan, non-adherence and polypharmacy.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-12-2014
Abstract: Hypertension is a frequent risk factor for the development of heart failure with preserved ejection fraction ( HFPEF ). Progressive extracellular matrix accumulation has been presumed to be the fundamental pathophysiologic mechanism that leads to the transition to impaired diastolic reserve. However, the contribution of other mechanisms affecting active and passive components of diastolic function has not been comprehensively assessed. In this study, we investigated the potential role of impaired myocardial oxygen delivery in the pathophysiology of HFPEF . Patients with HFPEF , those with controlled hypertension, and healthy controls underwent simultaneous right‐heart catheterization, echocardiography, and paired arterial and coronary sinus blood gas s ling at rest and during supine‐cycle ergometry. Despite a lower workload ( HFPEF vs control, hypertension: 43±8 versus 114±12, 87±14 W P .001 and P .05, respectively), peak exercise pulmonary capillary wedge pressure was markedly higher in HFPEF patients compared with healthy and hypertensive controls (32±2 versus 16±1 and 17±1 mm Hg, both P .001). During exercise, the transcardiac oxygen gradient increased significantly in all groups however, the peak transcardiac oxygen gradient was significantly lower in HFPEF patients ( P .05). In addition, the left ventricular–work corrected transcardiac oxygen gradient remained significantly lower in HFPEF patients compared with controls ( P .001). The current study provides unique data suggesting that the abnormal diastolic reserve observed during exertion in HFPEF patients may, in part, be explained by impaired myocardial oxygen delivery due possibly to microvascular dysfunction. Further studies are required to confirm the structural and functional basis of these findings and to investigate the influence of potential therapies on this abnormality.
Publisher: Springer Science and Business Media LLC
Date: 18-12-2017
DOI: 10.1038/S41598-017-17927-5
Abstract: Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC mg/kg/day 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function ( P ≥ 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice ( P ≤ 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice ( P 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice ( P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter ( P 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM.
Publisher: American Astronomical Society
Date: 02-05-2012
Publisher: American Physiological Society
Date: 07-1995
DOI: 10.1152/AJPHEART.1995.269.1.H182
Abstract: A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of epinephrine. Radiotracer methods were applied in 42 patients with severe heart failure and 31 healthy volunteers to ascertain the rate at which epinephrine is released to plasma and to evaluate the contribution of extra-adrenal sources. The increase in arterial plasma epinephrine observed in the heart failure patients was explained principally by a 34% (P 0.001) reduction in the whole body clearance rate of epinephrine from plasma. Regional venous s ling from the heart, lungs, and hepatomesenteric beds was performed in a subgroup of the study population, revealing a significant increase in the release rate of epinephrine to plasma from these organs in heart failure which accounted for 26% of the whole body plasma epinephrine appearance rate. To establish whether the cardiac epinephrine release was of neuronal origin, a physical (cycling) or mental (difficult mental arithmetic) stressor was applied as a sympathoexcitatory stimulus, given that a proportional release of norepinephrine and epinephrine could be expected if sympathetic nerves were the source. These interventions caused significant increases in the regional spillover of norepinephrine to plasma but not that of epinephrine. These findings suggest that nonadrenal tissues contribute significantly to the whole body epinephrine release rate in heart failure and that this may arise from a site other than sympathetic neurons.
Publisher: Elsevier BV
Date: 06-1995
DOI: 10.1016/0024-3205(95)00269-C
Abstract: Veno-arterial plasma concentration differences and regional organ plasma flows were used to quantify the relative amounts of 5-hydroxyindoleacetic acid (5-HIAA) contributed by various sites into the peripheral circulation. Positive venoarterial concentration gradients were found in the hepatosplanchnic, forearm, cardiac and jugular vessels in the healthy subjects. The renal circulation was determined to be the principal site of 5-HIAA clearance, extracting 18 +/- 2 nmol/min. The gut was the greatest contributor to the total 5-HIAA plasma pool with the relative contributions of the various organs being as follows: hepatosplanchnic organs 58%, skeletal muscle 26%, brain 6% and the heart 3%. The source of 5-HIAA stemming from these regional beds remains unknown, it may derive from serotonin taken up by and deaminated in ubiquitous endothelial cells, enterochromaffin cells of the gut, peripheral serotonergic nerves, serotonin turnover in platelets or perhaps the metabolism of serotonin taken up by sympathetic nerves. To test the latter hypothesis we examined 23 patients with chronic congestive heart failure and 9 patients with pure autonomic failure to investigate the possible effects of sympathetic nervous system overactivity and underactivity on peripheral 5-HIAA production and plasma 5-HIAA concentration. The resting arterial plasma 5-HIAA concentration in the heart failure patients was increased three-fold. This elevated plasma 5-HIAA concentration was attributable to an increased rate of whole body 5-HIAA production. The arterial 5-HIAA plasma concentration in the autonomic failure patients was paradoxically elevated, being 70% greater than that of the healthy subjects. The increased 5-HIAA plasma concentration in these patients was accounted for by a reduction in 5-HIAA plasma clearance. In all subjects studied there was a weak relationship only between total body norepinephrine spillover to plasma and the arterial 5-HIAA plasma concentration. We found that in healthy subjects the overflow of 5-HIAA into the hepatic vein was significantly related to the underlying degree of sympathetic activity. It can be concluded that 5-HIAA is produced at a number of sites throughout the body with the arterial plasma concentration being dependent on both the level of production and plasma clearance. By far the majority of 5-HIAA in plasma is derived from the gut with only minimal contribution from the brain.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2000
DOI: 10.1097/00004872-200018060-00009
Abstract: Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release. Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions. At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05). This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JACC.2013.10.084
Abstract: The purpose of this study was to use cardiac magnetic resonance (CMR) imaging and invasive left ventricular (LV) pressure-volume (PV) measurements to explore the relationship between diffuse myocardial fibrosis and indexes of diastolic performance in a cohort of cardiac transplant recipients. The precise mechanism of LV diastolic dysfunction in the presence of myocardial fibrosis has not previously been established. We performed CMR with T1 mapping and obtained invasive LV PV measurements via a conductance catheter in 20 cardiac transplant recipients at the time of clinically-indicated coronary angiography. Both post-contrast myocardial T1 time and extracellular volume fraction correlated with β, the load-independent passive LV stiffness constant (r = -0.71, p = 0.001, and r = 0.58, p = 0.04, respectively). After multivariate analysis, post-contrast myocardial T1 time remained the only independent predictor of β. No significant associations were observed between myocardial T1 time and τ, the active LV relaxation constant, or other load-dependent parameters of diastolic function. Diffuse myocardial fibrosis, assessed by post-contrast myocardial T1 time, correlates with invasively-demonstrated LV stiffness in cardiac transplant recipients. In patients with increased diffuse myocardial fibrosis, abnormal passive ventricular stiffness is therefore likely to be a major contributor to diastolic dysfunction.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
DOI: 10.1161/CIRCHEARTFAILURE.113.000665
Abstract: In hypertrophic cardiomyopathy (HCM), accumulation of myocardial collagen may play a central role in the pathogenesis of diastolic dysfunction and arrhythmia. Previous studies have suggested that peripheral levels of byproducts of collagen synthesis are reflective of myocardial extracellular matrix metabolism, although this has not been validated in detail. Given the potential clinical utility of such biomarkers, we sought to validate the assumed relationship between peripheral markers and myocardial fibrosis in HCM. Fifty patients with HCM and 25 healthy controls underwent peripheral venous s ling to determine plasma concentrations of key collagen precursors (procollagen I and III N-terminal propeptides [PINP, PIIINP]). Contrast-enhanced cardiac magnetic resonance imaging was performed to quantify regional (by late-gadolinium enhancement) and diffuse (by T 1 mapping) myocardial fibrosis. Nineteen subjects also underwent simultaneous arterial and coronary sinus blood s ling (to derive transcardiac concentration gradients of PINP, PIIINP, and C-terminal telopeptide of type I collagen) and right heart catheterization. Despite cardiac magnetic resonance evidence of regional (late-gadolinium enhancement quantity, 6.4±8.0%) and diffuse (T 1 time, 478±79 ms) myocardial fibrosis in patients with HCM, peripheral levels of collagen precursors were similar compared with control subjects (PINP, 45.9±22.9 versus 53.4±25.9 μg/L P =0.21 PIIINP, 4.8±1.7 versus 4.4±1.1 μg/L P =0.26). No significant net positive transcardiac concentration gradient was detected for either biomarker of collagen synthesis. The cardiac contribution to peripheral levels of byproducts of collagen synthesis in patients with HCM is insignificant. Furthermore, peripheral levels of these biomarkers do not accurately reflect myocardial collagen content in these patients.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Springer Science and Business Media LLC
Date: 21-10-2020
DOI: 10.1038/S41598-020-73614-Y
Abstract: Increasing evidence supports a role for the gut microbiota in the development of cardiovascular diseases such as hypertension and its progression to heart failure (HF). Dietary fibre has emerged as a modulator of the gut microbiota, resulting in the release of gut metabolites called short-chain fatty acids (SCFAs), such as acetate. We have shown previously that fibre or acetate can protect against hypertension and heart disease in certain models. HF is also commonly caused by genetic disorders. In this study we investigated whether the intake of fibre or direct supplementation with acetate could attenuate the development of HF in a genetic model of dilated cardiomyopathy (DCM) due to overexpression of the cardiac specific mammalian sterile 20-like kinase (Mst1). Seven-week-old male mice DCM mice and littermate controls (wild-type, C57BL/6) were fed a control diet (with or without supplementation with 200 mM magnesium acetate in drinking water), or a high fibre diet for 7 weeks. We obtained hemodynamic, morphological, flow cytometric and gene expression data. The gut microbiome was characterised by 16S rRNA licon sequencing. Fibre intake was associated with a significant shift in the gut microbiome irrespective of mouse genotype. However, neither fibre or supplementation with acetate were able to attenuate cardiac remodelling or cardiomyocyte apoptosis in Mst1 mice. Furthermore, fibre and acetate did not improve echocardiographic or hemodynamic parameters in DCM mice. These data suggest that although fibre modulates the gut microbiome, neither fibre nor acetate can override a strong genetic contribution to the development of heart failure in the Mst1 model.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-04-2014
DOI: 10.1161/CIRCRESAHA.114.302530
Abstract: Cardiac fibroblasts are critical to proper heart function through multiple interactions with the myocardial compartment, but appreciation of their contribution has suffered from incomplete characterization and lack of cell-specific markers. To generate an unbiased comparative gene expression profile of the cardiac fibroblast pool, identify and characterize the role of key genes in cardiac fibroblast function, and determine their contribution to myocardial development and regeneration. High-throughput cell surface and intracellular profiling of cardiac and tail fibroblasts identified canonical mesenchymal stem cell and a surprising number of cardiogenic genes, some expressed at higher levels than in whole heart. While genetically marked fibroblasts contributed heterogeneously to interstitial but not cardiomyocyte compartments in infarcted hearts, fibroblast-restricted depletion of one highly expressed cardiogenic marker, T-box 20, caused marked myocardial dysmorphology and perturbations in scar formation on myocardial infarction. The surprising transcriptional identity of cardiac fibroblasts, the adoption of cardiogenic gene programs, and direct contribution to cardiac development and repair provoke alternative interpretations for studies on more specialized cardiac progenitors, offering a novel perspective for reinterpreting cardiac regenerative therapies.
Publisher: Elsevier BV
Date: 09-2012
No related grants have been discovered for David Kaye.