ORCID Profile
0000-0003-0322-6147
Current Organisation
James Cook University
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Publisher: Elsevier BV
Date: 2018
Publisher: Bentham Science Publishers Ltd.
Date: 05-2011
DOI: 10.2174/157016111795495503
Abstract: Vascular endothelial growth factor (VEGF) is an endogenous polypeptide that modulates angiogenesis in normal physiological conditions as well as in cancer. During angiogenesis, VEGF interacts with several other angiogenic factors, playing an important role in cell proliferation, differentiation, migration, cell survival, nitric oxide (NO) production, release of other growth factors and sympathetic innervation. Based on these mechanisms of action, several anti-VEGF drugs have been developed for cancer treatment. This review discusses the physiology and interactions of VEGF, its mechanisms of action and role in modulating vascular homeostasis. It also discusses the adverse cardiovascular effects of recently developed anti-VEGF drugs for the treatment of various types of cancer. A critical appraisal of the human studies on these drugs is provided. Furthermore, putative mechanisms for the onset of hypertension, the most common adverse cardiovascular effect, are discussed.
Publisher: Research Square Platform LLC
Date: 07-07-2021
DOI: 10.21203/RS.3.RS-656782/V1
Abstract: Introduction Gout is a systemic inflammatory disease which has been associated with an increased risk of cardiovascular events but its association with abdominal aortic aneurysm (AAA) progression is unknown. The aim of this study was to investigate the association of gout with growth of small AAA. Methods Patients with initial AAA diameter measuring 30-54mm were recruited from surveillance programs at four Australian centres. Maximum AAA diameter was measured with a standardised and reproducible protocol to monitor AAA growth. Presence of gout was defined by clinical diagnosis by clinician or prescription of medications used to treat gout. Linear mixed effects modelling was performed to examine the independent association of gout with AAA growth. Results A total of 637 participants, including 66 (10.3%) diagnosed with gout, received a median of 4 (Inter-quartile range (IQR): 3, 6) scans over a median follow-up of 1.8 (IQR: 1.0, 3.0) years. In unadjusted analyses, participants with diagnosis of gout had a slower mean annual AAA growth of -0.3 mm/year (95% CI: -0.7, 0.2 p=0.25) than those without gout. After adjusting for potential confounders including initial AAA diameter, body mass index, prior stroke and anti-hypertensive medication prescription, gout was not significantly associated with AAA growth (-0.3 mm/year 95% CI: -0.7, 0.2 p=0.24). Sensitivity analyses investigating the impact of initial AAA diameter on the association of gout with AAA growth found no interaction. Conclusion This study suggests diagnosis of gout is not associated with growth of small AAA.
Publisher: MDPI AG
Date: 21-10-2022
DOI: 10.3390/S22208070
Abstract: Background: This study aimed to investigate whether home exercise programs informed by wearable activity monitors improved walking ability of patients with peripheral artery disease (PAD). Methods: A systematic literature search was performed to identify randomised controlled trials (RCT) testing home exercise that were or were not informed by wearable activity monitors. The primary outcome was the change in walking distance measured by a six-minute walking test or treadmill test over the course of the trial. Network meta-analysis (NMA) was performed using the gemtc R statistical package. The risk of bias was assessed using Cochrane tool for assessing risk of bias in RCTs (RoB 2.0). Results: A total of 14 RCTs involving 1544 participants were included. Nine trials used wearable activity monitors to inform the home exercise program tested, while five trials did not use wearable activity monitors to inform the home exercise program tested. Overall quality assessment showed 12 trials to be at low risk of bias and two trials at high risk of bias. Home exercise programs informed by wearable activity monitors significantly improved walking distance compared to non-exercise controls (Mean difference, MD: 32.8 m [95% credible interval, CrI: 6.1, 71.0]) but not compared to home exercise programs not informed by wearable activity monitors (MD: 4.7 m [95% CrI: −38.5, 55.4]). Conclusions: Home exercise informed by wearable activity monitors improve walking ability of patients with PAD. It is, however, unclear if activity monitoring informed exercise programs are more effective than exercise programs not using activity monitors.
Publisher: Oxford University Press (OUP)
Date: 10-2019
DOI: 10.1093/EURHEARTJ/EHZ748.0192
Abstract: Obesity-mediated epicardial adipose tissue (EAT) expansion drives fat cell infiltration which forms the unique substrate for atrial fibrillation (AF). The LEGACY study showed the benefits of weight loss but an attenuated response with weight fluctuation. How fluxes in weight impacts the atrial substrate in not known. To investigate EAT and the atrial substrates due to weight fluctuation, with comparison to stable obesity. We studied 24 sheep in 3 equal groups over 80 weeks: 1. Obesity induced by high calorie diet fed ad libitum 2. Weight fluctuation induced by 20-week cycle of weight gain/loss (20:20:20:20) and 3. Lean controls fed quality hay to maintain baseline weight. All sheep underwent: daily weight measurement haemodynamic and imaging assessments (cardiac MRI dual-energy X-ray absorptiometry and matrix assisted laser desorption infrared lipid imaging) electrophysiological studies and electroanatomic mapping histological and structural analysis. Evaluations included: atrial voltage, conduction velocity, and refractoriness (7 sites, 2 cycle lengths), electrogram fractionation, EAT volume, fibro-fatty infiltration, myolysis of myocytes, and spatial distribution of intra-atrial lipids. The Table shows the group differences. Compared to reference controls, obesity demonstrated: Increased atrial volume and pressure, abnormal atrial electrical properties, expanded EAT and ensuing fibro-fatty infiltrations, and myolysis of myocytes. Despite comparable weight and EAT with controls, weight fluctuation resulted in extensive and severe fibro-fatty infiltrations, and twofold greater myolysis that persisted. Moreover, characteristic profiles and abundance of lipid species in the atrial myocardium were noted on further evaluation. More importantly, EAT and fibro-fatty infiltrates strongly correlated with increased atrial volume and pressure with only fibro-fatty infiltrates correlating with fractionated electrograms (r=0.71, p .001) and conduction slowing (r=−0.59, p=0.006). Similarly, atrial myolysis exhibited significant correlations with atrial enlargement and haemodynamics, and electrical substrates (p .05 for all). Obesity induces fibro-fatty replacement of atrial myocytes and deterioration of contractile units, which may drive impaired electrical remodeling. Despite final weight loss, weight fluctuation demonstrates residual electro-structural, fibro-fatty and contractile substrates.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.EJVS.2021.12.038
Abstract: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models 131 of the 210 participants recruited to TEDY were included. In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.
Publisher: MDPI AG
Date: 11-10-2021
DOI: 10.3390/BIOMEDICINES9101442
Abstract: Background: The aim of this systematic review was to pool evidence from studies testing if pentagalloyl glucose (PGG) limited aortic expansion in animal models of abdominal aortic aneurysm (AAA). Methods: The review was conducted according to the PRISMA guidelines and registered with PROSPERO. The primary outcome was aortic expansion assessed by direct measurement. Secondary outcomes included aortic expansion measured by ultrasound and aortic diameter at study completion. Sub analyses examined the effect of PGG delivery in specific forms (nanoparticles, periadventitial or intraluminal), and at different times (from the start of AAA induction or when AAA was established), and tested in different animals (pigs, rats and mice) and AAA models (calcium chloride, periadventitial, intraluminal elastase or angiotensin II). Meta-analyses were performed using Mantel-Haenszel’s methods with random effect models and reported as mean difference (MD) and 95% confidence intervals (CIs). Risk of bias was assessed with a customized tool. Results: Eleven studies reported in eight publications involving 214 animals were included. PGG significantly reduced aortic expansion measured by direct observation (MD: −66.35% 95% CI: −108.44, −24.27 p = 0.002) but not ultrasound (MD: −32.91% 95% CI: −75.16, 9.33 p = 0.127). PGG delivered intravenously within nanoparticles significantly reduced aortic expansion, measured by both direct observation (MD: −116.41% 95% CI: −132.20, −100.62 p 0.001) and ultrasound (MD: −98.40% 95% CI: −113.99, −82.81 p 0.001). In studies measuring aortic expansion by direct observation, PGG administered topically to the adventitia of the aorta (MD: −28.41% 95% CI −46.57, −10.25 p = 0.002), studied in rats (MD: −56.61% 95% CI: −101.76, −11.46 p = 0.014), within the calcium chloride model (MD: −56.61% 95% CI: −101.76, −11.46 p = 0.014) and tested in established AAAs (MD: −90.36 95% CI: −135.82, −44.89 p 0.001), significantly reduced aortic expansion. The findings of other analyses were not significant. The risk of bias of all studies was high. Conclusion: There is inconsistent low-quality evidence that PGG inhibits aortic expansion in animal models.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2021
DOI: 10.1038/S41598-021-91855-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Oxford University Press (OUP)
Date: 03-2018
Publisher: Elsevier BV
Date: 08-2016
Publisher: BMJ
Date: 08-2020
DOI: 10.1136/BMJDRC-2020-001676
Abstract: The aims of this systematic review were to assess the clinical relevance and quality of previously published animal models of ischemic ulceration and examine the available evidence for interventions improving ulcer healing in these models. Publicly available databases were searched for original studies investigating the effect of limb ischemia on wound healing in animal models. The quality of studies was assessed using two tools based on the Animal research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the clinical relevance of the models. A total of 640 wounds (ischemic=314 non-ischemic=326) were assessed in 252 animals (92 mice, 140 rats, 20 rabbits) from 7 studies. Meta-analyses showed that wound healing was consistently delayed by ischemia at all time-points examined (day-7 standard median difference (SMD) 5.36, 95% CI 3.67 to 7.05 day-14 SMD 4.50, 95% CI 2.90 to 6.10 and day-21 SMD 2.53, 95% CI 1.25 to 3.80). No significant difference in wound healing was observed between 32 diabetic and 32 non-diabetic animals with ischemic wounds. Many studies lacked methods to reduce bias, such as outcome assessors blinded to group allocation and s le size calculations and clinically relevant model characteristics, such as use of older animals and a peripheral location of the wound. Five different interventions were reported to improve wound healing in these models. The impaired wound healing associated with limb ischemia can be modeled in a variety of different animals. Improvements in study design could increase clinical relevance, reduce bias and aid the discovery of translatable therapies.
Publisher: Elsevier BV
Date: 2015
Publisher: Elsevier BV
Date: 2015
Publisher: MDPI AG
Date: 26-09-2022
DOI: 10.3390/BIOMEDICINES10102409
Abstract: Inflammation is strongly implicated in the pathogenesis of abdominal aortic aneurysms (AAA). This review examined the potential role of biologic disease-modifying anti-rheumatic drugs (bDMARDs) as repurposed drugs for treating AAA. Published evidence from clinical and preclinical studies was examined. Findings from animal models suggested that a deficiency or inhibition of tumour necrosis factor-α (TNF-α) (standard mean difference (SMD): −8.37, 95% confidence interval (CI): −9.92, −6.82), interleukin (IL)-6 (SMD: −1.44, 95% CI: −2.85, −0.04) and IL-17 (SMD: −3.36, 95% CI: −4.21, −2.50) led to a significantly smaller AAA diameter compared to controls. Human AAA tissue s les had significantly increased TNF-α (SMD: 1.68, 95% CI: 0.87, 2.49), IL-1β (SMD: 1.93, 95% CI: 1.08, 2.79), IL-6 (SMD: 2.56, 95% CI: 1.79, 3.33) and IL-17 (SMD: 6.28, 95% CI: 3.57, 8.99) levels compared to non-AAA controls. In human serum, TNF-α (SMD: 1.11, 95% CI: 0.25, 1.97) and IL-6 (SMD: 1.42, 95% CI: 0.91, 1.92) levels were significantly elevated compared to non-AAA controls. These findings implicate TNF-α, IL-17 and IL-6 in AAA pathogenesis. Randomised controlled trials testing the value of bDMARDs in limiting AAA growth may be warranted.
Publisher: Elsevier BV
Date: 2013
Publisher: Elsevier BV
Date: 2013
Publisher: Elsevier BV
Date: 11-2021
Publisher: Wiley
Date: 29-04-2021
DOI: 10.1111/DME.14585
Abstract: Topical oxygen therapy (TOT) has been suggested as a treatment for diabetes‐related foot ulcer (DFU) but no prior meta‐analyses of randomised clinical trials (RCT) have been reported. This systematic review and meta‐analysis examined the randomised evidence for the benefit of TOT in healing DFU. Publicly available databases were searched for RCTs investigating the effect of TOT on wound healing in participants with a DFU. The primary outcome was ulcer healing defined as full epithelialisation. Meta‐analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using a modified version of the Cochrane Collaboration's tool and funnel plots, respectively. Six RCTs involving 530 participants with a DFU testing TOT were included. Meta‐analysis suggested that TOT significantly increased the likelihood of ulcer healing compared to controls (Risk ratio [RR] 1.94 95% CI 1.19, 3.17 I 2 = 57% NNT = 5.33) and findings were robust in sensitivity analyses. Risk of bias was high, moderate and low in two, one and three studies, respectively. Analysis of the three trials judged to be at low risk of bias suggested that TOT increased the likelihood of ulcer healing compared to controls (RR 2.37 95% CI 1.52, 3.68 I 2 = 0%). Funnel plots suggested the possibility of publication bias. Data on utation were too limited for meta‐analysis. This meta‐analysis suggests that TOT improves the likelihood of DFU healing however, its effect on utation and cost‐effectiveness are unclear.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Hindawi Limited
Date: 30-09-2022
DOI: 10.1155/2022/5299370
Abstract: Background and Aims. The nacht domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is upregulated in human abdominal aortic aneurysm (AAA), but its pathogenic role is unclear. The aims of this study were firstly to examine whether the inflammasome was upregulated in a mouse model of AAA and secondly to test whether the inflammasome inhibitor colchicine limited AAA growth. Methods. AAA was induced in eight-week-old male C57BL6/J mice with topical application of elastase to the infrarenal aorta and oral 3-aminopropionitrile (E-BAPN). For aim one, inflammasome activation, abdominal aortic diameter, and rupture were compared between mice with AAA and sham controls. For aim two, 3 weeks after AAA induction, mice were randomly allocated to receive colchicine ( n = 28 , 0.2 mg/kg/d) or vehicle control ( n = 29 ). The primary outcome was the rate of maximum aortic diameter increase measured by ultrasound over 13 weeks. Results. There was upregulation of NLRP3 markers interleukin- (IL-) 1β (median, IQR 15.67, 7.11-22.60 pg/mg protein versus 6.87, 4.54-11.60 pg/mg protein, p = .048 ) and caspase-1 (109, 83-155 relative luminosity units (RLU) versus 45, 38-65 RLU, p .001 ) in AAA s les compared to controls. Aortic diameter increase over 80 days (mean difference, MD, 4.3 mm, 95% CI 3.3, 5.3, p .001 ) was significantly greater in mice in which aneurysms were induced compared to sham controls. Colchicine did not significantly limit aortic diameter increase over 80 days (MD -0.1 mm, 95% CI -1.1, 0.86, p = .922 ). Conclusions. The inflammasome was activated in this mouse model of AAA however, daily oral administration of colchicine did not limit AAA growth.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2022
DOI: 10.1161/ATVBAHA.122.317635
Abstract: Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin’s role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83–1.57] P =0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53–1.59] P =0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.
Publisher: Informa UK Limited
Date: 02-12-2021
Publisher: Wiley
Date: 27-07-2017
Publisher: Public Library of Science (PLoS)
Date: 27-08-2013
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.JELECTROCARD.2018.11.014
Abstract: The potential utility of entropy (En) for atrial fibrillation (AF) mapping has been demonstrated in previous studies by multiple groups, where an association between high bipolar electrogram (EGM) entropy and the pivot of rotors has been shown. Though En is potentially attractive new approach to ablation, no studies have examined its temporal stability and specificity, which are critical to the application of entropy to clinical ablation. In the current study, we sought to objectively measure the temporal stability and specificity of bipolar EGM entropy in medium to long term recordings using three studies: i) a human basket catheter AF study, ii) a tachypaced sheep AF study and iii) a computer simulation study. To characterize the temporal dynamics and specificity of Approximate, S le and Shannon entropy (ApEn/S En/ShEn) in human (H), sheep (S), and computer simulated AF. 64-electrode basket bi-atria sustained AF recordings (H:15 min S:40 min) were separated into 5 s segments. ShEn/ApEn/S En were computed, and co-registered with NavX 3D maps. Temporal stability was determined in terms of: (i) global pattern stability of En and (ii) the relative stability the top 10% of En regions. To provide mechanistic insights into underlying mechanisms, stability characteristics were compared to models depicting various propagation patterns. To verify these results, cross-validation was performed across multiple En algorithms, across species, and compared with dominant frequency (DF) temporal characteristics. The specificity of En was also determined by looking at the association of En to rotors and areas of wave cross propagation. Episodes of AF were analysed (H:26 epochs, 6040 s S:15 epochs, 14,160 s). The global pattern of En was temporally unstable (CV- H:13.42% ± 4.58% S:14.13% ± 8.13% Friedman- H: p > 0.001 S: p > 0.001). However, within this dynamic flux, the top 10% of ApEn/S En/ShEn regions were relatively temporally stable (Kappa >0.6) whilst the top 10% of DF regions were unstable (Kappa <0.06). In simulated AF scenarios, the experimental data were optimally reproduced in the context of an AF pattern with stable rotating waves surrounded by wavelet breakup (Kappa: 0.610 p < 0.0001). En shows global temporal instability, however within this dynamic flux, the top 10% regions exhibited relative temporal stability. This suggests that high En regions may be an appealing ablation target. Despite this, high En was associated with not just the pivot of rotors but also with areas of cross propagation, which suggests the need for future work before clinical application is possible.
Publisher: Wiley
Date: 05-06-2023
DOI: 10.1002/DMRR.3670
Abstract: This study examined the relative efficacy of growth factor therapies in healing diabetes‐related foot ulcers (DFU). PubMed and Cochrane databases were searched for randomized controlled trials testing growth factor therapies for treating DFU. The primary outcome was complete wound closure. Results were reported as relative risk (RR) ± 95% credible intervals (CrI). The risk of bias was assessed using Cochrane's RoB‐2 tool. A total of 31 RCTs involving 2174 participants were included. Only 13 of the trials ( n = 924) reported on the aetiology of the ulcers (85.4% neuropathic and 14.6% ischaemic). Epidermal growth factor (RR 3.83 95% CrI 1.81, 9.10), plasma‐rich protein (PRP) (RR 3.36 95% CrI 1.66, 8.03) and platelet‐derived growth factor (PDGF) (RR 2.47 95% CrI 1.23, 5.17) significantly improved the likelihood of complete ulcer healing compared to control. Sub‐analyses suggested that PRP (3 trials ‐ RR 9.69 95% CrI 1.37, 103.37) and PDGF (6 trials ‐ RR 2.22 95% CrI 1.12, 5.19) significantly improved the likelihood of wound closure amongst trial mainly recruiting participants with neuropathic ulcers. Eleven trials had a low risk of bias, 9 had some concerns and 11 had a high risk of bias. Sub‐analysis of trials with a low risk of bias suggested that none of the growth factors significantly improved ulcer healing compared with control. This network meta‐analysis found low‐quality evidence that Epidermal growth factor, PRP and PDGF therapy improved DFU healing likelihood compared with control. Larger well‐designed trials are needed.
Publisher: Frontiers Media SA
Date: 15-03-2021
DOI: 10.3389/FENDO.2021.618434
Abstract: Improved understanding of abdominal aortic aneurysms (AAA) pathogenesis is required to identify treatment targets. This systematic review summarized evidence from animal studies and clinical research examining the role of adipokines and perivascular adipose tissue (PVAT) in AAA pathogenesis. Meta-analyses suggested that leptin (Standardized mean difference [SMD]: 0.50 [95% confidence interval (CI): −1.62, 2.61]) and adiponectin (SMD: −3.16 [95% CI: −7.59, 1.28]) upregulation did not significantly affect AAA severity within animal models. There were inconsistent findings and limited studies investigating the effect of resistin-like molecule-beta (RELMβ) and PVAT in animal models of AAA. Clinical studies suggested that circulating leptin (SMD: 0.32 [95% CI: 0.19, 0.45]) and resistin (SMD: 0.63 [95% CI 0.50, 0.76]) concentrations and PVAT to abdominal adipose tissue ratio (SMD: 0.56 [95% CI 0.33, 0.79]) were significantly greater in people diagnosed with AAA compared to controls. Serum adiponectin levels were not associated with AAA diagnosis (SMD: −0.62 [95% CI −1.76, 0.52]). One, eight, and one animal studies and two, two, and four human studies had low, moderate, and high risk-of-bias respectively. These findings suggest that AAA is associated with higher circulating concentrations of leptin and resistin and greater amounts of PVAT than controls but whether this plays a role in aneurysm pathogenesis is unclear.
Publisher: Elsevier BV
Date: 2012
Publisher: Elsevier BV
Date: 2011
Publisher: Oxford University Press (OUP)
Date: 04-2018
Publisher: Informa UK Limited
Date: 08-03-2017
DOI: 10.1080/14779072.2017.1299005
Abstract: Recent research has unravelled an increasing list of cardiac conditions and risk factors that may be responsible for the abnormal underlying atrial substrate that predisposes to atrial fibrillation (AF). Atrial fibrosis has been demonstrated as the pivotal structural abnormality underpinning conduction disturbances that promote AF in different disease models. Despite the advancement in our discoveries of the molecular mechanisms involved in the profibrotic milieu, targeted therapeutics against atrial fibrosis remain lacking. Areas covered: This review is focused on detailing the key molecular signalling pathways that contribute to atrial fibrosis including: angiotensin II, transforming growth factor (TGF- ß1), connective tissue growth factor (CTGF) and endothelin-1. We also discussed the potential therapeutic options that may be useful in modulating the abnormal atrial substrate. In addition, we examined the new paradigm of AF care in lifestyle and risk factor management that has been shown to arrest and reverse the atrial remodelling process leading to improved AF outcomes. Expert commentary: The future of AF care is likely to require an integrated approach consisting of aggressive risk factor management in addition to the established paradigm of rate and rhythm management and anticoagulation. Translational studies on molecular therapeutics to combat atrial fibrosis is urgently needed.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 2019
Publisher: Elsevier BV
Date: 2018
Publisher: Elsevier BV
Date: 2012
Publisher: Elsevier BV
Date: 2013
Publisher: Elsevier BV
Date: 2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
DOI: 10.1161/CIRCEP.112.976654
Abstract: The pivot is critical to rotors postulated to maintain atrial fibrillation (AF). We reasoned that wavefronts circling the pivot should broaden the litude distribution of bipolar electrograms because of directional information encoded in these signals. We aimed to determine whether Shannon entropy (ShEn), a measure of signal litude distribution, could differentiate the pivot from surrounding peripheral regions and thereby assist clinical rotor mapping. Bipolar electrogram recordings were studied in 4 systems: (1) computer simulations of rotors in a 2-dimensional atrial sheet (2) isolated rat atria recorded with a multi-electrode array (n=12) (3) epicardial plaque recordings of induced AF in hypertensive sheep (n=11) and (4) persistent AF patients (n=10). In the model systems, rotation episodes were identified, and ShEn calculated as an index of litude distribution. In humans, ShEn distribution was analyzed at AF termination sites and with respect to complex fractionated electrogram mean. We analyzed rotation episodes in simulations (4 cycles) and animals (rats: 14 rotors, duration 80±81 cycles sheep: 13 rotors, 4.2±1.5 cycles). The maximum ShEn bipole was consistently colocated with the pivot zone. ShEn was negatively associated with distance from the pivot zone in simulated spiral waves, rats, and sheep. ShEn was modestly inversely associated with complex fractionated electrogram however, there was no relationship at the sites of highest ShEn. ShEn is a mechanistically based tool that may assist AF rotor mapping.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2021
DOI: 10.1161/ATVBAHA.121.315942
Abstract: There are no current effective abdominal aortic aneurysm (AAA) drug therapies. An important limitation of most preclinical studies is that they test the effect of drugs on AAA formation rather than AAA progression. The aim of this study was to systematically review AAA mouse model studies that have tested the effect of interventions in limiting the progression of preestablished AAA. The literature search identified 35 studies meeting eligibility, and 30 (n=935 mice) contributed to the meta-analyses. AAAs were induced with angiotensin II (n=745 mice), calcium chloride (n=91 mice), or elastase (n=99 mice). Anti-inflammatory drugs (standardized mean difference [SMD], 1.62 [95% CI, 0.93–2.30]), protease inhibitors (SMD, 1.23 [95% CI, 0.52–1.95]), stem cells (SMD, 1.64 [95% CI, 1.05–2.24]), antiplatelet or anticoagulant drugs (SMD, 0.93 [95% CI, 0.63–1.22]), and renin-angiotensin system inhibitors (SMD, 1.45 [95% CI, 0.58–2.33]) reduced AAA diameter. Interventions initiated soon after model induction commenced were more likely to reduce AAA diameter (R 2 , 16% P =0.007). Funnel plots suggested possible publication bias. Most studies did not report blinding or s le size calculations, and the risk of bias was considered medium or high in 20 (57%) of the 35 studies. There is low-quality evidence that a range of drugs are effective in limiting AAA progression when administered early after AAA induction in mouse models. Some of these drugs, such as antiplatelet and renin-angiotensin system inhibitors, have been reported to be ineffective in clinical trials.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.AVSG.2021.06.038
Abstract: Depression is associated with an increased risk of cardiovascular events but its association with abdominal aortic aneurysm (AAA) progression is unknown. This study examined if a diagnosis of depression was association with more rapid AAA growth. Patients with small AAA measuring between 30 and 50 mm were recruited from surveillance programs at 4 Australian centres. Maximum AAA diameter was measured by ultrasound imaging using a standardised and reproducible protocol to monitor AAA growth. Depression was defined from medical records of treatment for depression at recruitment. Linear mixed effects modelling was performed to examine the independent association of depression with AAA growth. A propensity matched sub-analysis was performed. A total of 574 participants were included of whom 73 (12.7%) were diagnosed with depression. Participants were followed with a median of 3 (Inter-quartile range (IQR): 2, 5) ultrasound scans for a median of 2.1 (IQR: 1.1, 3.5) years. The unadjusted model suggested that annual AAA growth was non-significantly reduced (mean difference: -0.3 mm/year 95% confidence interval (CI): -0.7, 0.2 P = 0.26) in participants with a diagnosis of depression compared to other participants. After adjustment for covariates, depression was not significantly associated with AAA growth (mean difference: -0.3 mm/year 95% CI: -0.8, 0.2 P = 0.27). Findings were similar in the propensity matched sub-analysis. Sensitivity analyses investigating the impact of initial AAA diameter and follow up on the association of depression with AAA growth found no interaction. This study suggested that depression was not associated with faster AAA growth.
Publisher: MDPI AG
Date: 14-04-2023
DOI: 10.3390/BIOMEDICINES11041178
Abstract: Major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke and cardiovascular death, cause substantial morbidity and mortality. This review assessed the incidence rate of MACE and the association with modifiable risk factors (diabetes, hypertension) and medication use (aspirin, statins) in patients with unrepaired abdominal aortic aneurysm (AAA). Electronic databases were searched systematically for observational studies reporting the incidence of MI, stroke or cardiovascular death in patients with unrepaired AAAs. The primary outcome was cardiovascular death reported as an incidence rate (events per 100 person-years (PY)). Fourteen studies, including 69,579 participants with a mean follow-up time of 5.4 years, were included. Meta-analysis revealed the overall incidence of cardiovascular death, MI and stroke of 2.31 per 100 PY (95% CI, 1.63–3.26 I2 = 98%), 1.65 per 100 PY (95% CI, 1.01–2.69, I2 = 88%) and 0.89 per 100 PY (95% CI, 0.53–1.48, I2 = 87.0%), respectively. The mean rates of statin and aspirin prescriptions were 58.1% and 53.5%, respectively. In conclusion, there is a substantial incidence of MACE in patients with unrepaired AAA, but the prescription of preventative medication is suboptimal. Greater emphasis should be placed on secondary prevention in this population.
Publisher: Wiley
Date: 10-08-2023
DOI: 10.1002/DMRR.3703
Abstract: Diabetes is a key risk factor for ischaemic foot disease, which causes pain, tissue loss, hospital admission, and major utation. Currently, treatment focuses on revascularisation, but many patients are unsuitable for surgery and revascularisation is frequently unsuccessful. The authors describe recent research in animal models and clinical trials investigating novel medical targets for ischaemia, including theories about impaired wound healing, animal models for limb ischaemia and recent randomised controlled trials testing novel medical therapies. Novel targets identified in animal models included stimulating mobilisation of CD34+ progenitor cells through upregulating oncostatin M or microRNA‐181, downregulating tumour necrosis factor superfamily member 14, or activating the Wingless pathway. Within the ischaemic limb vasculature, upregulation of apolipoprotein L domain containing 1, microRNA‐130b or long noncoding RNA that enhances endothelial nitric oxide synthase expression promoted limb blood supply recovery, angiogenesis, and arteriogenesis. Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3‐ketoacyl‐CoA thiolase inhibitor trimetazidine promoted blood flow recovery. Translating pre‐clinical findings to patients has been challenging, mainly due to limitations in clinically translatable animal models of human disease. Promising results have been reported for administering plasmids encoding hepatocyte growth factor or intra‐arterial injection of bone marrow derived cells in small clinical trials. It remains to be seen whether these high resource therapies can be developed to be widely applicable. In conclusion, an ever‐expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes.
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.PBIOMOLBIO.2017.07.010
Abstract: Atrial fibrillation (AF) is the most common sustained arrhythmia and across the developed nations, it contributes to increasing hospitalizations and healthcare burden. Several comorbidities and risk factors including hypertension, heart failure, obstructive sleep apnoea and obesity are known to play an important role in the initiation and perpetuation of AF and atrial stretch or dilatation may play a central mechanistic role. The impact of atrial stretch in the development of AF can vary dependent on the underlying disease. This review focuses on understanding the substrate for AF in conditions of acute and chronic stretch and in the presence of common co-morbidities or risk factors through the review of findings in both animal and human studies. Additionally, the reversibility of atrial remodeling following stretch release will also be discussed. Identification of clinical conditions associated with increased atrial stretch as well as the treatment or prevention of these conditions may help to prevent AF progression and improve sinus rhythm maintenance.
Publisher: Elsevier BV
Date: 11-2021
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2010
Publisher: Elsevier BV
Date: 08-2021
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.JVS.2021.07.248
Abstract: This review aimed to systematically pool evidence from randomized clinical trials on the efficacy of interventions in assisting smoking cessation in participants with peripheral artery disease (PAD). Publicly available databases were searched for randomized clinical trials testing the effect of interventional programs in achieving smoking cessation in participants with PAD who were current smokers. The primary outcome was smoking cessation at the end of follow-up. Meta-analyses were performed using random effect models and reported as risk ratios and 95% confidence intervals. Risk of bias and publication bias were assessed using a modified version of the Cochrane Collaboration's tool and funnel plots, respectively. Six randomized clinical trials testing smoking cessation programs comprising physician advice, behavioral counselling from an expert delivered in-person or over the telephone, and the provision of nicotine replacement therapy and/or varenicline in 558 smokers with PAD were included. A meta-analysis suggested that, overall, these interventions did not significantly increase the chance of quitting smoking (risk ratio, 1.48 95% confidence interval, 0.84-2.61), with low heterogeneity between studies (I Overall, previously tested smoking cessation interventions have not been effective in achieving smoking cessation in people with PAD. Further research is needed to develop and test interventions that can effectively help current smokers with PAD to quit.
Publisher: Elsevier BV
Date: 2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-2021
Abstract: No network meta‐analysis has considered the relative efficacy of cilostazol, home exercise therapy, supervised exercise therapy (SET), endovascular revascularization (ER), and ER plus SET (ER+SET) in improving maximum walking distance (MWD) over short‐ ( year), moderate‐ (1 to years), and long‐term (≥2 years) follow‐up in people with intermittent claudication. A systematic literature search was performed to identify randomized controlled trials testing 1 or more of these 5 treatments according to Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. The primary outcome was improvement in MWD assessed by a standardized treadmill test. Secondary outcomes were adverse events and health‐related quality of life. Network meta‐analysis was performed using the gemtc R statistical package. The Cochrane collaborative tool was used to assess risk of bias. Forty‐six trials involving 4256 patients were included. At short‐term follow‐up, home exercise therapy (mean difference [MD], 89.4 m 95% credible interval [CrI], 20.9–157.7), SET (MD, 186.8 m 95% CrI, 136.4–237.6), and ER+SET (MD, 326.3 m 95% CrI, 222.6–430.6), but not ER (MD, 82.5 m 95% CrI, −2.4 to 168.2) and cilostazol (MD, 71.1 m 95% CrI, −24.6 to 167.9), significantly improved MWD (in meters) compared with controls. At moderate‐term follow‐up, SET (MD, 201.1 95% CrI, 89.8–318.3) and ER+SET (MD, 368.5 95% CrI, 195.3–546.9), but not home exercise therapy (MD, 99.4 95% CrI, −174.0 to 374.9) or ER (MD, 84.2 95% CrI, −35.3 to 206.4), significantly improved MWD (in meters) compared to controls. At long‐term follow‐up, none of the tested treatments significantly improved MWD compared to controls. Adverse events and quality of life were reported inconsistently and could not be meta‐analyzed. Risk of bias was low, moderate, and high in 4, 24, and 18 trials respectively. This network meta‐analysis suggested that SET and ER+SET are effective at improving MWD over the moderate term ( year) but not beyond this. Durable treatments for intermittent claudication are needed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-03-2020
Abstract: The aim of this study was to assess the relationship between serum lipoprotein (a) (Lp[a]) concentration and the requirement for peripheral artery disease ( PAD ) operations or incidence of major adverse cardiovascular events. A total of 1472 people with PAD presenting with intermittent claudication (n=355), abdominal aortic aneurysm (n=989) or critical limb ischemia (n=128) were prospectively recruited from 4 outpatient clinics in Australia. Lp(a) was measured in serum s les collected at recruitment using an immunoassay. Participants were followed for a median (interquartile range) of 2.4 (0.1–6.1) years to record requirement for any PAD operation, defined to include any open or endovascular PAD intervention (lower limb peripheral revascularization, abdominal aortic aneurysm repair, other aneurysm repair, or carotid artery revascularization). Myocardial infarctions, strokes, and deaths were also recorded. The association of Lp(a) with events was assessed using Cox proportional hazard analysis adjusting for traditional risk factors. Participants with Lp(a) ≥30 mg/dL had a greater requirement for any PAD operation (hazard ratio, 1.20, 95% CI , 1.02–1.41) and lower limb peripheral revascularization alone ( hazard ratio 1.33, 95% CI , 1.06–1.66) but no increased risk of major adverse cardiovascular events or all‐cause mortality. Lp(a) ≥50 mg/dL and a 40 mg/dL increase in Lp(a) were also associated with an increased risk of lower limb peripheral revascularization alone but not with other outcomes. In participants with PAD referred for hospital management those with high Lp(a) had greater requirement for lower limb peripheral revascularization but Lp(a) was not consistently associated with other clinical events.
Publisher: Elsevier BV
Date: 08-2016
Publisher: MDPI AG
Date: 28-06-2021
DOI: 10.3390/IJMS22136941
Abstract: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study subsequent histological analyses and plasma s les were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.JACC.2015.04.058
Abstract: Obesity and atrial fibrillation (AF) are public health issues with significant consequences. This study sought to delineate the development of global electrophysiological and structural substrate for AF in sustained obesity. Ten sheep fed ad libitum calorie-dense diet to induce obesity over 36 weeks were maintained in this state for another 36 weeks 10 lean sheep with carefully controlled weight served as controls. All sheep underwent electrophysiological and electroanatomic mapping hemodynamic and imaging assessment (echocardiography and dual-energy x-ray absorptiometry) and histology and molecular evaluation. Evaluation included atrial voltage, conduction velocity (CV), and refractoriness (7 sites, 2 cycle lengths), vulnerability for AF, fatty infiltration, atrial fibrosis, and atrial transforming growth factor (TGF)-β1 expression. Compared with age-matched controls, chronically obese sheep demonstrated greater total body fat (p < 0.001) LA volume (p < 0.001) LA pressure (p < 0.001), and PA pressures (p < 0.001) reduced atrial CV (LA p < 0.001) with increased conduction heterogeneity (p < 0.001) increased fractionated electrograms (p < 0.001) decreased posterior LA voltage (p < 0.001) and increased voltage heterogeneity (p 0.8) or ERP heterogeneity (p > 0.3). Obesity was associated with more episodes (p = 0.02), prolongation (p = 0.01), and greater cumulative duration (p = 0.02) of AF. Epicardial fat infiltrated the posterior LA in the obese group (p < 0.001), consistent with reduced endocardial voltage in this region. Atrial fibrosis (p = 0.03) and TGF-β1 protein (p = 0.002) were increased in the obese group. Sustained obesity results in global biatrial endocardial remodeling characterized by LA enlargement, conduction abnormalities, fractionated electrograms, increased profibrotic TGF-β1 expression, interstitial atrial fibrosis, and increased propensity for AF. Obesity was associated with reduced posterior LA endocardial voltage and infiltration of contiguous posterior LA muscle by epicardial fat, representing a unique substrate for AF.
Publisher: Springer Science and Business Media LLC
Date: 13-11-1971
DOI: 10.1038/S41598-021-86128-Y
Abstract: Disease modifying anti-rheumatic drugs (DMARDs) were developed to treat joint inflammation. There is growing evidence that anti-inflammatory drugs prevent major cardiovascular events (MACE). The aim of this systematic review and meta-analysis was to examine whether DMARDs reduce the risk of MACE. A systematic literature search was performed to identify randomized controlled trials (RCTs) testing the effect of DMARDs on cardiovascular events. The primary outcome was MACE defined as the first occurrence of non-fatal myocardial infarction (MI), non-fatal stroke or cardiovascular death. Secondary outcomes were myocardial infarction or stroke alone and all-cause mortality. Safety was assessed by fatal or life threatening infection. Meta-analyses were performed using random effect models and reported as risk ratios (RR) and 95% confidence intervals (CI). Study quality and publication bias were assessed using the Cochrane Collaboration’s tool for assessing risk of bias and funnel plots. Twelve RCTs involving 18,056 participants testing three different DMARDs subclasses (Tumor Necrosis Factor inhibitors—4 trials Janus Kinase inhibitors—5 trials Interleukin inhibitors—3 trials) were included. Meta-analysis suggested that none of the DMARD subclasses had any effect on MACE, MI alone, stroke alone, risk of fatal or life threatening infection or death. Risk of bias was high, low and unclear in five, six and one studies respectively. Funnel plots suggested a low possibility of publication bias. This meta-analysis suggests that DMARDs do not affect the incidence of MACE. More trials are needed for firm conclusions.
No related grants have been discovered for Shivshankar Thanigaimani.