ORCID Profile
0000-0001-8016-5128
Current Organisations
University of Sydney
,
TU Dresden
,
Royal Prince Alfred Hospital
,
Heart Research Institute
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Plant Biology | Plant Physiology | Natural Products Chemistry | Systems Biology
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.IJCARD.2016.09.016
Abstract: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of all mediators of atherosclerosis, and some reports have suggested increased levels in coronary artery disease (CAD) and acute myocardial infarction (AMI). However, the potential of miRNAs as biomarkers or predictors of disease remains to be established. We designed a study comprising 150 patients (50 Control, 50 Stable CAD, and 50 ST Elevation Myocardial Infarction (STEMI)), and measured plasma miRNAs in each. We then determined the ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) risk factors, to discriminate between CAD vs Control, and STEMI vs Control. Three miRNAs (miR15a-5p, miR16-5p, and miR93-5p) were significantly increased in Stable CAD vs Control groups and one (miR146a-5p) was significantly decreased in Stable CAD vs Control. One miRNA - miR499a-5p - was significantly increased in the STEMI group compared to Controls. After adjustment for FHS risk factors, miR93-5p levels remained an independent predictor of the presence of CAD (Odds Ratio [OR]=8.76, P=0.002). All 4 miRNAs improved discriminatory power for CAD over FHS alone in ROC analysis. Similarly, after adjustment for risk factors miR499-5p remained an independent predictor of STEMI (OR=3.03, P=0.001) and improved discriminatory power for STEMI in ROC analyses. We identified 4 miRNAs that were differentially expressed among stable CAD and control patients, and 1 miRNA that was elevated in STEMI patients vs controls. MiR93-5p was the strongest predictor of CAD after adjustment for traditional risk factors, suggesting potential diagnostic utility.
Publisher: Oxford University Press (OUP)
Date: 20-09-2007
DOI: 10.1016/J.EUJE.2007.07.012
Abstract: The following is an account of a 58-year-old lady who presented to our institution with two episodes of acute limb ischemia: one upper, which required embolectomy and one lower, which required a below knee utation. We subsequently performed transesophageal echocardiography (TOE), which revealed very large mobile echogenic masses adherent to the wall of her aortic arch, described below.
Publisher: BMJ
Date: 17-06-2018
DOI: 10.1136/BJSPORTS-2016-096197
Abstract: Exercise training has been shown to have beneficial effects on liver function in adults overweight or with fatty liver disease. To establish which exercise programme characteristics were likely to elicit optimal improvements. Systematic review and meta-analysis of randomised, controlled trials. PubMed, CINAHL and Cochrane controlled trials registry searched (1966 to 2 October 2015). Exercise intervention, with or without dietary intervention, versus usual care in adults undertaking, exercise training, who were overweight, obese or exhibited fatty liver disease (non-alcoholic fatty liver disease or non-alcoholic steatohepatitis). We included 21 randomised controlled trials, totalling 1530 participants. Exercise intervention studies with total exercise programme workload 000 kcal produced significant improvements in intrahepatic fat, −3.46% (95% CI −5.20% to −1.73%), p .0001, I 2 =73% effect size (standardised mean difference, SMD) −1.77 (−3.11 to −0.42), p=0.01, I 2 =77%. When data from only exercise studies were pooled, there was a reduction in fasting free fatty acids (FFAs) −74.15 µmol/L (95% CI −118.47 to −29.84), p=0.001, I 2 =67% with a large effect size (SMD) −0.94 (−1.36 to −0.52), p .0001, I 2 =0%. When data from only exercise studies were pooled, there was a significant reduction in insulin MD −1.88 UL (95% CI −3.43 to −0.34), p=0.02, I 2 =31%. The liver enzymes, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase, were not significantly altered with exercise. Exercise training reduces intrahepatic fat and FFAs while increasing cardiorespiratory fitness. An aggregate exercise programme energy expenditure ( 000 kcal) may be required to promote reductions in intrahepatic fat.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.STEM.2017.01.010
Abstract: Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but functional analysis remains a challenge. Here we describe an approach to functionally validate identified variants through differentiation of induced pluripotent stem cells (iPSCs) to study cellular pathophysiology. We collected peripheral blood cells from Framingham Heart Study participants and reprogrammed them to iPSCs. We then differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the effect of the 1p13 rs12740374 variant on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures. We observed a clear association between rs12740374 and lipid accumulation and gene expression in differentiated hepatocytes, in particular, expression of SORT1, CELSR2, and PSRC1, consistent with previous analyses of this variant using other approaches. Initial investigation of additional SNPs also highlighted correlations with gene expression. These findings suggest that iPSC-based population studies hold promise as tools for the functional validation of GWAS variants.
Publisher: Elsevier BV
Date: 06-2017
Publisher: Oxford University Press (OUP)
Date: 04-2020
DOI: 10.1093/CVR/CVAA051
Abstract: To examine the metabolic adaptation to an 80-day exercise intervention in healthy young male adults where lifestyle factors such as diet, sleep, and physical activities are controlled. This study involved cross-sectional analysis before and after an 80-day aerobic and strength exercise intervention in 52 young, adult, male, newly enlisted soldiers in 2015. Plasma metabolomic analyses were performed using liquid chromatography, tandem mass spectrometry. Data analyses were performed between March and August 2019. We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation. For statistical analyses, a paired t-test was used and Bonferroni-adjusted P-value of & .0004 was considered to be statistically significant. The metabolite dimethylguanidino valeric acid (DMGV) (recently shown to predict lack of metabolic response to exercise) tracked maladaptive metabolic changes to exercise those with increases in DMGV levels had increases in several cardiovascular risk factors changes in DMGV levels were significantly positively correlated with increases in body fat (P = 0.049), total and LDL cholesterol (P = 0.003 and P = 0.007), and systolic blood pressure (P = 0.006). This study was approved by the Departments of Defence and Veterans’ Affairs Human Research Ethics Committee and written informed consent was obtained from each subject. For the first time, the true magnitude and extent of metabolic adaptation to chronic exercise training are revealed in this carefully designed study, which can be leveraged for novel therapeutic strategies in cardiometabolic disease. Extending the recent report of DMGV’s predictive utility in sedentary, overweight in iduals, we found that it is also a useful marker of poor metabolic response to exercise in young, healthy, fit males.
Publisher: Wiley
Date: 08-10-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2013
DOI: 10.1161/CIRCGENETICS.113.000191
Abstract: Association between the C677T polymorphism of the methylene tetrahydrofolate reductase ( MTHFR ) gene and congenital heart disease (CHD) is contentious. We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87–1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03–1.51] P =0.022) but with substantial heterogeneity among contributing studies (I 2 =64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR .05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91–1.03]) without significant heterogeneity (I 2 =0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87–1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2020
DOI: 10.1038/S41514-020-0046-6
Abstract: There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.
Publisher: Elsevier BV
Date: 12-2016
Publisher: Wiley
Date: 29-01-2021
DOI: 10.1113/JP280825
Publisher: Frontiers Media SA
Date: 14-05-2019
Publisher: Elsevier BV
Date: 08-2020
Publisher: Oxford University Press (OUP)
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 07-06-2022
DOI: 10.1038/S41598-022-13169-2
Abstract: Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 . qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency . This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2019
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.PATHOL.2022.01.008
Abstract: Asymmetric dimethylguanidino valeric acid (ADGV), asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are three arginine metabolites which have utility in the assessment of cardiovascular disease, renal disease and non-alcoholic fatty liver disease (NAFLD). Translation of these research metabolomic markers into routine clinical use requires the development of robust assays with appropriately assessed preanalytical variables and traceable clinical reference intervals. A hydrophilic interaction liquid chromatography (HILIC) tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ADGV, ADMA and SDMA was developed. S le stability and collection conditions were scrutinised to determine any preanalytical factors that could affect quantification under routine laboratory conditions. Patient s les from 120 males and 120 females were used to derive preliminary reference intervals. All three analytes were quantifiable in human plasma using unique MS/MS transitions. The analytes were stable for up to a week once separated from red cells, though reduced stability was observed upon extraction of the analytes from plasma. The assay was linear for concentration of ADGV between 1.6 nmol/L and 200 nmol/L and for ADMA and SDMA between 0.1 μmol/L and 4.0 μmol/L. The accuracy for all analytes was 97-103% and interday and intraday imprecisions (coefficients of variation) were less than 10%. ADGV concentrations were noted to be lower in the female reference population when compared to males. The analytical method shows excellent performance and is sufficiently robust to be used in the clinical investigation of cardiovascular disease and NAFLD.
Publisher: American Physiological Society
Date: 09-2020
DOI: 10.1152/AJPENDO.00207.2020
Abstract: Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.
Publisher: American Society for Clinical Investigation
Date: 16-09-2013
DOI: 10.1172/JCI64801
Publisher: Springer Science and Business Media LLC
Date: 14-07-2021
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JACC.2017.12.049
Abstract: When comparing effects of on- versus off-pump coronary artery bypass grafting (CABG), it is important to assess the long-term clinical outcomes. However, most research conducted thus far has concentrated on short-term outcomes and ignored the long-term clinical outcomes, especially the 5-year outcomes of the largest randomized controlled trials. The aim of this systematic review and meta-analysis was to investigate the long-term clinical outcomes of on- versus off-pump CABG. To identify potential studies systematic searches were carried out using various databases. The search strategy included the key concepts of cardiopulmonary bypass AND off-pump AND long term OR 5-year outcomes. This was followed by a meta-analysis investigating mortality, incidence of myocardial infarction, incidence of angina, need for revascularization, and incidence of stroke. Six studies totaling 8,145 participants were analyzed. In the on-pump group mortality was 12.3%, compared with 13.9% in the off-pump group. The odds ratio (OR) for this comparison was 1.16 (95% confidence interval [CI]: 1.02 to 1.32 p = 0.03 13.9% vs. 12.3%). In contrast, there were no differences in the incidence of myocardial infarction (OR: 1.06: 95% CI: 0.91 to 1.25 p = 0.45 8.4% vs. 7.9%), incidence of angina (OR: 1.09 95% CI: 0.75 to 1.57 p = 0.65 2.3% vs. 2.1%), need for revascularization (OR: 1.15 95% CI: 0.95 to 1.40 p = 0.16 5.9% vs. 5.1%), and the incidence of stroke (OR: 0.78 95% CI: 0.56 to 1.10 p = 0.16 2.2% vs. 2.8%). Statistically, on-pump CABG appeared to offer superior long-term survival, although the clinical significance of this may be more uncertain.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.IJCARD.2016.08.250
Abstract: To reduce complications during coronary artery bypass grafting (CABG) off-pump CABG was introduced however, results have been mixed. The aim of this work was to conduct a systematic review and meta-analysis of off-pump vs. on-pump CABG. To identify potential studies systematic searches were carried out using various databases. The search strategy included the key concepts of "cardiopulmonary bypass" AND "coronary artery bypass grafting" AND "off pump". This was followed by a meta-analysis investigating post-operative atrial fibrillation, myocardial infarction, ≤30day mortality, stroke, ventilation time, intensive care unit (ICU) stay and hospital stay. Fifty four studies (59 intervention groups), totalling 16,261 participants were analysed. Off pump CABG led to a significantly lower incidence of post-operative atrial fibrillation odds ratio (OR) 0.87 (95% confidence interval [CI] 0.78 to 0.97, p=0.01), but no differences in either myocardial infarction OR 0.98 (95% CI 0.82 to 1.15, p=0.77) or ≤30day mortality OR 0.85 (95% CI 0.68 to 1.06, p=0.16). There was a strong trend towards a reduced incidence of stroke OR 0.77 (95% CI 0.59 to 1.00, p=0.05) however this did not quite reach significance. Ventilation time mean difference (MD) -3.78h (95% CI -4.75 to -2.82, p<0.00001) ICU stay MD -0.34days (95% CI -0.50 to -0.17, p<0.0001) and hospital stay MD -0.9days (95% CI -1.25 to -0.56, p<0.00001) were all significantly shorter in the off-pump group. Off-pump CABG has some benefits over on-pump CABG, particularly in relation to post-operative atrial fibrillation.
Publisher: Elsevier BV
Date: 2013
Publisher: Wiley
Date: 17-10-2021
DOI: 10.1002/EHF2.13631
Abstract: Sleep apnoea and congestive heart failure (CHF) commonly co‐exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome. We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively. We used linear and Cox regression to relate plasma concentrations of metabolites and lipids to echocardiographic parameters CHF and its subtypes heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and sleep indices. Adenine dinucleotide phosphate (ADP) associated with left ventricular (LV) fractional shortening phosphocreatine with LV wall thickness lysosomal storage molecule sphingomyelin 18:2 with LV mass and nicotine metabolite cotinine with time spent with an oxygen saturation less than 90% ( β = 2.3 min, P = 2.3 × 10 −5 ). Pro‐hypertrophic metabolite hydroxyglutarate partly mediated the association between LV wall thickness and HFpEF. Central sleep apnoea was significantly associated with HFpEF ( P = 0.03) but not HFrEF ( P = 0.5). There were three significant metabolite canonical variates, one of which conferred protection from cardiovascular death [hazard ratio = 0.3 (0.11, 0.81), P = 0.02]. Energetic metabolites were associated with cardiac function energy‐ and lipid‐storage metabolites with LV wall thickness and mass plasma levels of nicotine metabolite cotinine were associated with increased time spent with a sleep oxygen saturation less than 90%, a clinically significant marker of outcome, indicating a significant hazard for smokers who have sleep apnoea.
Publisher: Bentham Science Publishers Ltd.
Date: 31-01-2014
DOI: 10.2174/22115366113026660018
Abstract: The pathogenesis of atherosclerosis involves the interplay of inflammation, altered cellular activity, angiogenesis, and neointima formation. The main cellular participants in atherosclerosis include vascular endothelial cells, smooth muscle cells, and monocytes. The recent discovery of small, non-coding RNAs, microRNAs (miRNAs), and their influence on these processes has provided a greater molecular insight into atherosclerosis. This in turn has led to increase focus on the potential utility of miRNA subtypes as biomarkers for coronary artery disease. Furthermore miRNAs could potentially provide therapeutic targets for the treatment of atherosclerosis and its complications. In this review, we discuss the experimental and clinical evidence for the role of miRNAs in the pathogenesis of coronary artery disease, the limitations of the data and challenges facing the field.
Publisher: Elsevier BV
Date: 05-2019
Publisher: Springer Netherlands
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 08-01-2021
DOI: 10.1038/S41467-020-20422-7
Abstract: The gut microbiota is reported to modulate the immune response in hepatocellular carcinoma (HCC). Here, we employ metagenomic and metabolomic studies to characterise gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) related cirrhosis, with or without HCC, and evaluate its effect on the peripheral immune response in an ex vivo model. We find that dysbiosis characterises the microbiota of patients with NAFLD-cirrhosis, with compositional and functional shifts occurring with HCC development. Gene function of the microbiota in NAFLD-HCC supports short chain fatty acid production, and this is confirmed by metabolomic studies. Ex vivo studies show that bacterial extracts from the NAFLD-HCC microbiota, but not from the control groups, elicit a T cell immunosuppressive phenotype, characterised by expansion of regulatory T cells and attenuation of CD8 + T cells. Our study suggest that the gut microbiota in NAFLD-HCC is characterised by a distinctive microbiome/metabolomic profile, and can modulate the peripheral immune response.
Publisher: Elsevier BV
Date: 03-2020
Publisher: Oxford University Press (OUP)
Date: 08-2007
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.TEM.2019.07.013
Abstract: Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disorder worldwide. Specifically, nonalcoholic steatohepatitis (NASH) and fibrosis pose an enormous burden for patients and health-care systems. In the absence of approved pharmacological therapies, effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training, are currently the therapeutic strategies of choice. This review covers the influence of macronutrient quality and quantity (i.e., low-carbohydrate and high-protein diets), for successful reduction of intrahepatocellular lipids (IHL). Moreover, we discuss the effectiveness of different modalities of physical exercising with and without weight loss. These lifestyle modifications not only provide strategies to reduce IHL but may also hold a still underestimated potential to induce improvement and/or even remission of NAFLD.
Publisher: American Society for Clinical Investigation
Date: 04-05-2017
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.JACC.2010.09.029
Abstract: Vascular smooth muscle cells (VSMCs), which make up the arterial medial layer, possess a phenotype switching capability. This modulation of VSMCs is important in the development of atherosclerotic vascular disease. It has been recognized that VSMCs may also have a stabilizing role in advanced atherosclerotic plaques. Moreover, reduction of the proliferative capacity of these cells may be of benefit in reducing neointimal hyperplasia following therapeutic percutaneous intervention. The biology of microribonucleic acids (miRNAs) and their ability to modify smooth muscle biology has recently emerged in a number of investigations. These studies elucidated the key role of miRNAs, miR-143 and miR-145, in particular, in the regulation of SMC homeostasis in vitro, in murine models of targeted gene deletion, and also in human vascular pathology. This review places this burgeoning knowledge within the wider context of atherosclerosis and restenosis and explores the therapeutic potential of miRNAs to change the fate of VSMCs within the plaque.
Publisher: MDPI AG
Date: 13-08-2019
DOI: 10.3390/NU11081882
Abstract: Protein and branched-chain amino acid (BCAA) intake are associated with changes in circulating BCAAs and influence metabolic health in humans and rodents. However, the relationship between BCAAs and body composition in both species is unclear, with many studies questioning the translatability of preclinical findings to humans. Here, we assessed and directly compared the relationship between circulating BCAAs, body composition, and intake in older mice and men. Body weight and body fat were positively associated with circulating BCAA levels in both mouse and human, which remained significant after adjustments for age, physical activity, number of morbidities, smoking status, and source of income in the human cohort. Macronutrient intakes were similarly associated with circulating BCAA levels however, the relationship between protein intake and BCAAs were more pronounced in the mice. These findings indicate that the relationship between circulating BCAAs, body composition, and intakes are comparable in both species, suggesting that the mouse is an effective model for examining the effects of BCAAs on body composition in older humans.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2015
Publisher: SAGE Publications
Date: 2004
DOI: 10.1177/153857440403800105
Abstract: Ruptured abdominal aortic aneurysm (RAAA) is a demanding vascular surgical problem and the cause of significant morbidity and mortality. The aim of this study was to identify prognostic factors that influence outcome. Over 6 years, 42 ruptured abdominal aortic aneurysms were operated on with a mean diameter of 7.2 cm. RAAA was defined as free intraperitoneal rupture. Data were collected retrospectively from hospital medical records. The male:female ratio was 8:1 and the mean age was 74 years (range 55–89). Fifteen were in hypovolemic shock and 27 patients were clinically stable. The perioperative mortality rate for the 15 shocked patients was 60% (9 patients) and the 1-year cumulative survival rate was 33%. The perioperative mortality rate for the 27 clinically stable patients was 40% (11 patients) and the 1-year cumulative survival rate was 56%. Survival curves were constructed for these groups to compare male versus female, age =70 versus age , shocked versus stable, and preoperative hemoglobin (Hb) =10 vs . No patient with preoperative cardiac arrest survived more than 24 hours. With VassarStats, the confidence interval for age, gender, hemodynamic status, and preoperative Hb were calculated. The standard weighted mean analysis by ANOVA gave a p value of .001. The overall 30-day mortality rate was 47% (20 of 42) and the 1-year mortality rate was 52% (22 of 42). Male patients over 70 years with RAAA in hypovolemic shock with low Hb have a higher 30-day mortality rate and few survive more than 1 year. The study suggests that each of these 4 parameters separately was not a strong prognostic indicator. Collectively, however, they strongly influence the prognosis of patients with RAAA. These findings strengthen the case for selective treatment for RAAA.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10623320600659997
Abstract: Recent studies implicate hyperglycemia as an important cause of macrovascular and ocular complications in diabetes mellitus. In this study, the authors examined the effect of high glucose on macrovascular and microvascular endothelial cell viability and apoptosis in culture. Human aortic endothelial cells (HAECs) and human retinal endothelial cells (HRECs) were exposed to normal-glucose conditions (NG) and high-glucose conditions (NG supplemented with 25 mM D-glucose) for 72 h in vitro. D-Mannitol was used as an osmotic control. Cell viability was assessed by methlythiazolydiphenyltetrazolium bromide (MTT) assay, and induction of apoptosis was assessed by Hoechst staining. Statistics were analyzed by paired t tests. In HAECs, cell viability was decreased by 12.9% in high-glucose conditions, and apoptotic cells were significantly increased by 77%. However, in HRECs, cell viability was increased by 14.9% in high-glucose conditions, and apoptotic cells were significantly decreased by 33.3%. Mannitol did not show any effect on cell survival or apoptosis ruling out an osmotic effect. High-glucose conditions reduce cell viability and induce apoptosis in HAECs, which may contribute to macrovascular complications associated with diabetes. In contrast, high-glucose increases viability in HRECs and inhibits apoptosis, which may contribute to the development of diabetic retinopathy.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2021
DOI: 10.1038/S41467-021-25210-5
Abstract: Liquid chromatography-mass spectrometry-based metabolomics studies are increasingly applied to large population cohorts, which run for several weeks or even years in data acquisition. This inevitably introduces unwanted intra- and inter-batch variations over time that can overshadow true biological signals and thus hinder potential biological discoveries. To date, normalisation approaches have struggled to mitigate the variability introduced by technical factors whilst preserving biological variance, especially for protracted acquisitions. Here, we propose a study design framework with an arrangement for embedding biological s le replicates to quantify variance within and between batches and a workflow that uses these replicates to remove unwanted variation in a hierarchical manner (hRUV). We use this design to produce a dataset of more than 1000 human plasma s les run over an extended period of time. We demonstrate significant improvement of hRUV over existing methods in preserving biological signals whilst removing unwanted variation for large scale metabolomics studies. Our tools not only provide a strategy for large scale data normalisation, but also provides guidance on the design strategy for large omics studies.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.IJCARD.2016.08.227
Abstract: Minimally invasive (MI) cardiac surgery was introduced to reduce problems associated with a full sternotomy. This meta-analysis aimed to investigate the effects of minimally invasive cardiac surgery on a range of clinical outcomes. To identify potential studies (randomised rospective clinical trials) systematic searches were carried out. The search strategy included the concepts of "minimally invasive" OR "MIDCAB" AND "coronary artery bypass grafting" OR "cardiac surgery". This was followed by a meta-analysis investigating cross-cl time, cardiopulmonary bypass (CPB) time, operation time, ventilation time, intensive care unit (ICU) stay, hospital stay, incidence of myocardial infarction and of stroke/neurologic complications. Eight studies (9 intervention groups), totalling 596 participants were analysed. MI cardiac surgery was associated with a shorter ICU stay mean difference (MD) -0.7days (95% confidence interval (CI) -1.23 to -0.18, p=0.009) and longer cross-cl MD 6.7min (95% CI 1.24 to 12.17, p=0.02), CPB MD 26.68min (95% CI 10.31 to 43.05, p=0.001), and operation times MD 55.03min (95% CI 22.76 to 87.31, p=0.0008). However no differences were found in the ventilation time MD -3.94h (95% CI -8.09 to 0.21, p=0.06), length of hospital stay MD -1.14days (95% CI -3.11 to 0.83, p=0.26) and in the incidence of myocardial infarction odds ratio (OR) 1.97 (95% CI 0.49 to 7.9, p=0.34) or stroke/neurologic complications OR 0.67 (95% CI 0.11 to 4.05, p=0.66). Minimally invasive cardiac surgery is as safe as conventional surgery and could reduce costs due to a shorter period spent in ICU.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.IJCARD.2022.06.049
Abstract: To identify biomarkers of cardiomyopathy in patients with type 2 diabetes mellitus (T2DM) using cardiovascular magnetic resonance (CMR) and to identify associations between functional status, metabolomic profile and myocardial fibrosis. In this prospective case control study, patients (n = 49) with T2DM without significant coronary artery disease, and matched controls (n = 18) underwent CMR, cardiopulmonary exercise testing, and plasma metabolomic analyses. Patients with T2DM (n = 49, median [interquartile range] age 61 [56-63] years, 61% male, diabetes duration 11 [7-20] years), historical HbA1c 7.6% (60 mmol/mol) (6.9-8.6) and matched controls (n = 18) were examined. Study patients had increased myocardial extracellular volume (ECV) (26.9 [23.8-30.0] vs 23.4 [22.4-25.5) %, p < 0.001). Increased ECV was associated with male sex (p = 0.04), time with T2DM (p = 0.02), reduced peak VO Patients with well-controlled T2DM without significant coronary disease exhibit focal and diffuse myocardial fibrosis and diffuse myocardial fibrosis is associated with reduced exercise tolerance and metabolites. Plasma metabolites may provide mechanistic insights into diffuse myocardial fibrosis, and cardiopulmonary fitness.
Publisher: Elsevier BV
Date: 09-2012
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.YJMCC.2021.11.009
Abstract: The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic β-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, in idual HFD- or STZ-treatments and the combined HFD + STZ approach were used to generate ventricular s les (n = 9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in β-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, γ-aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete β-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess β-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2011
Publisher: Oxford University Press (OUP)
Date: 15-12-2013
Abstract: We have previously reported the cardioprotective effects of endothelial progenitor cell (EPC)-conditioned media (CM) therapy post-myocardial infarction (MI). In the present study, we have determined the insulin-like growth factor-1 (IGF-1) contribution to EPC CM effects on cardiomyocyte survival, contractility, and angiogenesis in vivo. Conditioned media from porcine EPC were administered intracoronary in the presence and absence of specific neutralizing antibodies to IGF-1 or control IgG in a porcine model of MI. X-vivo (non-conditioned) medium was used as a control. Functional, histological, and biochemical parameters were evaluated at 24 h and 8-week post-therapy. Conditioned media therapy significantly abrogated infarct zone (IZ) apoptosis, hypocontractility, and impaired left ventricular (LV) relaxation observed in control infarcts acutely (24 h post-MI). At 8 weeks following treatment, CM therapy augmented LV contractility and relaxation, IZ angiogenesis and inhibited infarct size expansion, wall expansion, and wall thinning. All of these acute and chronic beneficial effects of CM therapy were vitiated by neutralizing antibodies to IGF-1 but not by control IgG. Moreover, the addition of neutralizing IGF-1 antibody to control medium had no effect on these structural or functional changes in the heart post-treatment. Insulin-like growth factor-1 within the EPC CM mediates potent acute myocardial repair and chronic remodelling effects post-MI. These findings may provide a rationale for comparative trials of specific growth factors vs. current progenitor cell strategies.
Publisher: American Institute of Mathematical Sciences (AIMS)
Date: 2016
Publisher: Oxford University Press (OUP)
Date: 04-06-2015
DOI: 10.1002/STEM.2050
Abstract: Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 106 MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI. Stem Cells 2015 :2726–2737
Publisher: Wiley
Date: 02-08-2021
DOI: 10.1002/EHF2.13504
Abstract: There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell‐derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three‐dimensional ‘organoids’ incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter‐relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra‐thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S42255-021-00393-9
Abstract: Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.
Publisher: Wiley
Date: 29-03-2019
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.IJCARD.2007.12.101
Abstract: A 52 year old gentleman presented with chest pain, after a long distance flight from India he had made long haul flights every 2 weeks over the last 5 years as part of his job. His ECG revealed T wave inversion in leads V1-3. Cardiac biomarkers including troponin were negative we proceeded to exercise stress testing (EST). This revealed 2 mm ST depression at 2 min of the standard Bruce protocol, associated with chest pain. He was taken immediately to the coronary catheterization laboratory engagement of the left main caused pressure d ing with 6 French, then 5 French diagnostic Judkins left 4 catheters. An ostial left main stenosis was seen the right and left coronary trees otherwise had no significant stenoses. He had normal LV function. He underwent inpatient CABG 7 days later.
Publisher: Wiley
Date: 02-12-2009
Publisher: Cambridge University Press (CUP)
Date: 27-10-2010
DOI: 10.1017/S1047951110001447
Abstract: Patients with repaired tetralogy of Fallot may develop symptomatic and haemodynamic deterioration for many reasons such as arrhythmia, pulmonary regurgitation, and impairment in ventricular function. We describe a consecutive group of patients whose main clinical problem was atrial tachyarrhythmias. To describe the clinical outcome of atrial tachyarrhythmias occurring late after surgical repair of tetralogy of Fallot to define the circuits/foci responsible for these atrial tachyarrhythmias to evaluate the outcome of computer-assisted mapping and catheter ablation in this patient group. Consecutive patients with surgically repaired tetralogy of Fallot and atrial tachyarrhythmias, who underwent catheter ablation between January, 2001 and June, 2007, were identified retrospectively from case records. Computer-assisted mapping was performed in all using either EnSite ® (St Jude Medical Inc.) arrhythmia mapping and intra-cardiac catheter guidance system or CARTO™ (Biosense Webster Inc.) electroanatomical mapping systems. Ten patients (four males) with a median age of 39 plus or minus 8 years were studied. The total number of atrial tachyarrhythmias identified was 22 (six macro-reentrant, 16 micro-reentrant/focal). In nine patients, catheter ablation led to improvement in arrhythmia episodes and/or symptoms during follow-up of 41 plus or minus 20 months. Following ablation(s), five patients required pacing for pre-existing conduction disease and five needed further surgery for haemodynamic indications. All patients remained on anti-arrhythmic drugs. Patients with surgically repaired tetralogy of Fallot and atrial tachyarrhythmias typically have multiple arrhythmic circuits/foci arising from a scarred right atrium. Catheter ablation reduces arrhythmia frequency and improves symptoms. However, hybrid management is often required, comprising drugs, pacing, and further surgery tailored to the in idual.
Publisher: Public Library of Science (PLoS)
Date: 16-06-2014
Publisher: Elsevier BV
Date: 02-2019
Publisher: BMJ
Date: 02-2019
DOI: 10.1136/HEARTASIA-2018-011134
Abstract: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of multiple phases of atherothrombosis, and some reports have suggested altered levels in coronary artery in-stent restenosis (ISR). We recently demonstrated that miR-93-5 p was able to discriminate between patients with stable coronary artery disease (CAD) and those with no CAD, after adjusting for traditional risk factors (RFs). Thus, we wanted to determine if circulating miRNAs could predict coronary ISR. To determine if circulating miRNAs have diagnostic capability for determining ISR in a cohort of matched patients with and without ISR. To determine if miRNA plasma levels are elevated in coronary ISR, we conducted a study comprising 78 patients (39 with no ISR and 39 with ISR) and measured plasma miRNAs in each. We then determined the predictive ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) RFs, and stent length and diameter, to discriminate between ISR and no ISR. After correction for multiple testing, two miRNAs—miR425-5p and miR-93-5 p—were differential between patients with ISR and patients without ISR. Only miR-93-5 p remained a strong independent predictor of ISR after correction for FHS RFs (OR 6.30, p=0.008) and FHS RFs plus stent length and diameter (OR 4.80, p=0.02) and improved discriminatory power for ISR over FHS RFs alone in receiver operator characteristic curve analysis. This novel finding that miR-93-5 p independently predicts ISR extends our recent observation that miR-93-5 p predicted CAD after adjustment for traditional CAD RFs. These data suggest further potential diagnostic utility.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2012
DOI: 10.1161/CIRCGENETICS.111.962035
Abstract: Tetralogy of Fallot (TOF) is the commonest cyanotic form of congenital heart disease. In 80% of cases, TOF behaves as a complex genetic condition exhibiting significant heritability. As yet, no common genetic variants influencing TOF risk have been robustly identified. Two hundred and seven haplotype-tagging single nucleotide polymorphisms in 22 candidate genes were genotyped in a test cohort comprising 362 nonsyndromic British white patients with TOF together with 717 unaffected parents of patients and 183 unrelated healthy controls. Single nucleotide polymorphisms with suggestive evidence of association in the test cohort ( P .01) were taken forward for genotyping in an independent replication cohort comprising 392 cases of TOF, 218 unaffected parents of patients, and 1319 controls. Significant association was observed for 1 single nucleotide polymorphism, rs11066320 in the PTPN11 gene, in both the test and the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.34 (95% confidence interval [CI], 1.19 to 1.52 P =2.9×10 −6 ) in the total cohort of TOF cases and controls this remained highly significant after Bonferroni correction for 207 analyses (corrected P =0.00061). Genotype at rs11066320 was responsible for a population-attributable risk of TOF of approximately 10%. Common variation in the linkage disequilibrium block including the PTPN11 gene contributes to the risk of nonsyndromic TOF. Rare mutations in PTPN11 are known to cause the autosomal dominant condition Noonan syndrome, which includes congenital heart disease, by upregulating Ras/mitogen-activated protein kinase (MAPK) signaling. Our results suggest a role for milder perturbations in PTPN11 function in sporadic, nonsyndromic congenital heart disease.
Publisher: MDPI AG
Date: 28-02-2019
DOI: 10.3390/NU11030524
Abstract: The prevalence and incidence of metabolic syndrome is reaching pandemic proportions worldwide, thus warranting an intensive search for novel preventive and treatment strategies. Recent studies have identified a number of soluble factors secreted by adipocytes and myocytes (adipo-/myokines), which link sedentary life style, abdominal obesity, and impairments in carbohydrate and lipid metabolism. In this review, we discuss the metabolic roles of the recently discovered myokine β-aminoisobutyric acid (BAIBA), which is produced by skeletal muscle during physical activity. In addition to physical activity, the circulating levels of BAIBA are controlled by the mitochondrial enzyme alanine: glyoxylate aminotransferase 2 (AGXT2), which is primarily expressed in the liver and kidneys. Recent studies have shown that BAIBA can protect from diet-induced obesity in animal models. It induces transition of white adipose tissue to a “beige” phenotype, which induces fatty acids oxidation and increases insulin sensitivity. While the exact mechanisms of BAIBA-induced metabolic effects are still not well understood, we discuss some of the proposed pathways. The reviewed data provide new insights into the connection between physical activity and energy metabolism and suggest that BAIBA might be a potential novel drug for treatment of the metabolic syndrome and its cardiovascular complications.
Publisher: Elsevier BV
Date: 03-2022
Publisher: Wiley
Date: 11-06-2019
DOI: 10.1002/EJHF.1479
Publisher: Springer Science and Business Media LLC
Date: 14-07-2015
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000438582
Abstract: Background/Aims: Hyperhomocysteinaemia is recognised as a strong independent risk factor for developing cardiovascular disease. This study investigated how an acute homocysteine dose affected cardiac performance during ischaemia reperfusion and cardiomyocyte contractility and morphology under normal conditions and during oxidative stress. Methods: Cardiac function was measured in isolated and perfused rat hearts before and after 40 minutes' global normothermic ischaemia. Where used, 0.1 mM L-homocysteine was present prior to, and throughout ischaemia, before wash out after 10 minutes' reperfusion. Calcium transients under normal conditions and changes in contractile synchronicity during oxidative stress (exposure to 0.2 mM H2O2) were measured in freshly isolated rat cardiomyocytes incubated for 60 minutes ± 0.1 mM L-homocysteine. Results: During ischaemia reperfusion 0.1 mM L-homocysteine significantly reduced the rate pressure product during reperfusion (10,038 ± 749 vs. 5955 ± 567 mmHg bpm, p 0.001), but did not affect time to ischaemic contracture. Incubation of freshly isolated cardiomyocytes with 0.1 mM L-homocysteine significantly decreased the litude of the calcium transient and slowed the time to half relaxation. Conclusions: These findings suggest that homocysteine exposure affected myocardial recovery from ischaemia and contractile homeostasis although the exact mechanisms for these changes remain to be determined.
Publisher: MDPI AG
Date: 22-04-2021
Abstract: Despite effective prevention programs targeting cardiovascular risk factors, coronary artery disease (CAD) remains the leading cause of death. Novel biomarkers are needed for improved risk stratification and primary prevention. To assess for independent associations between plasma metabolites and specific CAD plaque phenotypes we performed liquid chromatography mass-spectrometry on plasma from 1002 patients in the BioHEART-CT study. Four metabolites were examined as candidate biomarkers. Dimethylguanidino valerate (DMGV) was associated with presence and amount of CAD (OR) 1.41 (95% Confidence Interval [CI] 1.12–1.79, p = 0.004), calcified plaque, and obstructive CAD (p 0.05 for both). The association with amount of plaque remained after adjustment for traditional risk factors, ß-coefficient 0.17 (95% CI 0.02–0.32, p = 0.026). Glutamate was associated with the presence of non-calcified plaque, OR 1.48 (95% CI 1.09–2.01, p = 0.011). Phenylalanine was associated with amount of CAD, ß-coefficient 0.33 (95% CI 0.04–0.62, p = 0.025), amount of calcified plaque, (ß-coefficient 0.88, 95% CI 0.23–1.53, p = 0.008), and obstructive CAD, OR 1.84 (95% CI 1.01–3.31, p = 0.046). Trimethylamine N-oxide was negatively associated non-calcified plaque OR 0.72 (95% CI 0.53–0.97, p = 0.029) and the association remained when adjusted for traditional risk factors. In targeted metabolomic analyses including 53 known metabolites and controlling for a 5% false discovery rate, DMGV was strongly associated with the presence of calcified plaque, OR 1.59 (95% CI 1.26–2.01, p = 0.006), obstructive CAD, OR 2.33 (95% CI 1.59–3.43, p = 0.0009), and amount of CAD, ß-coefficient 0.3 (95% CI 0.14–0.45, p = 0.014). In multivariate analyses the lipid and nucleotide metabolic pathways were both associated with the presence of CAD, after adjustment for traditional risk factors. We report novel associations between CAD plaque phenotypes and four metabolites previously associated with CAD. We also identified two metabolic pathways strongly associated with CAD, independent of traditional risk factors. These pathways warrant further investigation at both a biomarker and mechanistic level.
Publisher: Springer Science and Business Media LLC
Date: 07-05-2015
DOI: 10.1007/S00726-015-1997-Y
Abstract: The amino acids glycine and glutamine have been implicated in myocardial protection of the much studied young adult heart. This study aimed to determine whether such protection could be enhanced using the dipeptide, L-glycyl-L-glutamine (gly-gln) in both young hearts and in middle-aged hearts representative of a more clinically relevant age group. Hearts from 8-week-old and 36-week-old rats were perfused in the Langendorff mode for 20 min, before 40 min global normothermic ischaemia and 30 min reperfusion. Where present, 0.5, 2, or 5 mM gly-gln was added 10 min into baseline perfusion, was present throughout ischaemia and was washed out after 10 min reperfusion. Reperfusion damage was assessed from the release of lactate dehydrogenase. Metabolic fitness was assessed from the time to ischaemic contracture and the accumulation of lactate and thiobarbituric acid reactive substances during ischaemia. The presence of 5 mM gly-gln significantly improved the post-ischaemic rate pressure product (RPP) and decreased reperfusion damage in both the 8 (RPP in control on reperfusion 5527 ± 957 vs. 10,320 ± 795 mmHg beat min(-1) in 5 mM gly-gln, n = 6 ± SE, p < 0.05) and 36-week-old (RPP in control on reperfusion 1964.33 ± 876.3 vs. 4008 ± 675 mmHg beat min(-1), n = 6 ± SE, p < 0.01) hearts. Five mM gly-gln also increased the time to ischaemic contracture and was able to protect against the rise in lactate that occurred in the controls during ischaemia. These results suggest that gly-gln has good potential as a combatant against ischaemia-reperfusion injury in both the young adult and middle-aged populations.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2015
DOI: 10.1038/NCB3205
Publisher: Frontiers Media SA
Date: 20-02-2017
Publisher: MDPI AG
Date: 15-12-2022
Abstract: The liver, skeletal muscle, and adipose tissue are major insulin target tissues and key players in glucose homeostasis. We and others have described erse insulin resistance (IR) phenotypes in people at risk of developing type 2 diabetes. It is postulated that identifying the IR phenotype in a patient may guide the treatment or the prevention strategy for better health outcomes in populations at risk. Here, we performed plasma metabolomics and lipidomics in a cohort of men and women living with obesity not complicated by diabetes (mean [SD] BMI 36.0 [4.5] kg/m2, n = 62) to identify plasma signatures of metabolites and lipids that align with phenotypes of IR (muscle, liver, or adipose tissue) and abdominal fat depots. We used 2-step hyperinsulinemic-euglycemic cl with deuterated glucose, oral glucose tolerance test, dual-energy X-ray absorptiometry and abdominal magnetic resonance imaging to assess muscle-, liver- and adipose tissue- IR, beta cell function, body composition, abdominal fat distribution and liver fat, respectively. Spearman’s rank correlation analyses that passed the Benjamini–Hochberg statistical correction revealed that cytidine, gamma-aminobutyric acid, anandamide, and citrate corresponded uniquely with muscle IR, tryptophan, cAMP and phosphocholine corresponded uniquely with liver IR and phenylpyruvate and hydroxy-isocaproic acid corresponded uniquely with adipose tissue IR (p 7.2 × 10−4). Plasma cholesteryl sulfate (p = 0.00029) and guanidinoacetic acid (p = 0.0001) differentiated between visceral and subcutaneous adiposity, while homogentisate correlated uniquely with liver fat (p = 0.00035). Our findings may help identify erse insulin resistance and adiposity phenotypes and enable targeted treatments in people living with obesity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 31-07-2009
DOI: 10.1161/CIRCRESAHA.109.199984
Abstract: Rationale: Smooth muscle precursor cells have previously been reported to reside in bone marrow and in the circulation, but little is currently known regarding the proximate stimuli for smooth muscle cell differentiation of these putative progenitors. Objective: Because local thrombin generation occurs as an initial response to vascular injury, we hypothesized that thrombin may influence the differentiation of circulating smooth muscle progenitor cells. Methods and Results: Peripheral blood mononuclear cells were cultured on type I collagen using a protocol optimized to stimulate smooth muscle cell outgrowth. Thrombin-stimulated upregulation of the transcription factor myocardin and smooth muscle myosin heavy chain, and both were inhibited by hirudin or the RhoA inhibitor Y27632. After 10 days of culture, smooth muscle outgrowth colonies formed, which stained positive for α-smooth muscle actin, smooth muscle myosin heavy chain, and calponin, in addition to having a contractile response to 100 nmol/L angiotensin II. Coincubation of peripheral blood mononuclear cells with thrombin, 10 μmol/L protease-activated receptor-1, but not protease-activated receptor-4 activating peptide significantly increased the number of smooth muscle outgrowth colonies formed. Thrombin-induced enhancement of smooth muscle outgrowth colony formation was inhibited by hirudin, Y27632, and an antibody against protease-activated receptor-1. Conclusions: These data illustrate a novel thrombin-induced pathway for smooth muscle differentiation from putative smooth muscle progenitors in peripheral blood.
Publisher: Springer Singapore
Date: 2019
Publisher: BMJ
Date: 09-2019
DOI: 10.1136/BMJOPEN-2018-028649
Abstract: Coronary artery disease (CAD) persists as a major cause of morbidity and mortality worldwide despite intensive identification and treatment of traditional risk factors. Data emerging over the past decade show a quarter of patients have disease in the absence of any known risk factor, and half have only one risk factor. Improvements in quantification and characterisation of coronary atherosclerosis by CT coronary angiography (CTCA) can provide quantitative measures of subclinical atherosclerosis—enhancing the power of unbiased ‘omics’ studies to unravel the missing biology of personal susceptibility, identify new biomarkers for early diagnosis and to suggest new targeted therapeutics. BioHEART-CT is a longitudinal, prospective cohort study, aiming to recruit 5000 adult patients undergoing clinically indicated CTCA. After informed consent, patient data, blood s les and CTCA imaging data are recorded. Follow-up for all patients is conducted 1 month after recruitment, and then annually for the life of the study. CTCA data provide volumetric quantification of total calcified and non-calcified plaque, which will be assessed using established and novel scoring systems. Comprehensive molecular phenotyping will be performed using state-of-the-art genomics, metabolomics, proteomics and immunophenotyping. Complex network and machine learning approaches will be applied to biological and clinical datasets to identify novel pathophysiological pathways and to prioritise new biomarkers. Discovery analysis will be performed in the first 1000 patients of BioHEART-CT, with validation analysis in the following 4000 patients. Outcome data will be used to build improved risk models for CAD. The study protocol has been approved by the human research ethics committee of North Shore Local Health District in Sydney, Australia. All findings will be published in peer-reviewed journals or at scientific conferences. ACTRN12618001322224.
Publisher: American Society for Clinical Investigation
Date: 30-10-2017
DOI: 10.1172/JCI95995
Publisher: Oxford University Press (OUP)
Date: 13-07-2017
Abstract: Aims Identification and management of the Standard Modifiable Cardiovascular Risk Factors (SMuRFs hypercholesterolaemia, hypertension, diabetes and smoking) has substantially improved cardiovascular disease outcomes. However, cardiovascular disease remains the leading cause of death worldwide. Suspecting an evolving pattern of risk factor profiles in the ST elevation myocardial infarction (STEMI) population with the improvements in primary care, we hypothesized that the proportion of 'SMuRFless' STEMI patients may have increased. Methods/results We performed a single centre retrospective study of consecutive STEMI patients presenting from January 2006 to December 2014. Over the study period 132/695 (25%) STEMI patients had 0 SMuRFs, a proportion that did not significantly change with age, gender or family history. The proportion of STEMI patients who were SMuRFless in 2006 was 11%, which increased to 27% by 2014 (odds ratio 1.12 per year, 95% confidence interval: 1.04-1.22). The proportion of patients with hypercholesterolaemia decreased (odds ratio 0.92, 95% confidence interval 0.86-0.98), as did the proportion of current smokers (odds ratio 0.93, 95% confidence interval 0.86-0.99), with no significant change in the proportion of patients with diabetes and hypertension. SMuRF status was not associated with extent of coronary disease in-hospital outcomes, or discharge prescribing patterns. Conclusion The proportion of STEMI patients with STEMI poorly explained by SMuRFs is high, and is significantly increasing. This highlights the need for bold approaches to discover new mechanisms and markers for early identification of these patients, as well as to understand the outcomes and develop new targeted therapies.
Publisher: Elsevier BV
Date: 2014
Publisher: Informa UK Limited
Date: 12-2009
DOI: 10.2147/SCCAA.S6210
Publisher: Frontiers Media SA
Date: 02-07-2019
Publisher: Oxford University Press (OUP)
Date: 17-05-2017
DOI: 10.1093/HMG/DDX140
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-02-2019
DOI: 10.1161/CIRCRESAHA.118.313250
Abstract: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4 , surpassed thresholds for genome-wide significance (assigned as P ×10 −8 ) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5% 95% CI, 3.2%–6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%–3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1 , FLT4 and the well-established TOF gene, TBX1 , we identified potential association with variants in several other candidates, including RYR1 , ZFPM1 , CAMTA2 , DLX6 , and PCM1 . The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4 . Together, variants in these genes are found in almost 7% of TOF patients.
Publisher: MDPI AG
Date: 27-09-2022
Abstract: Diet, exercise and the gut microbiome are all factors recognised to be significant contributors to cardiometabolic health. However, diet and exercise interventions to modify the gut microbiota to improve health are limited by poor understanding of the interactions between them. In this pilot study, we explored diet–exercise–microbiome dynamics in bodybuilders as they represent a distinctive group that typically employ well-defined dietary strategies and exercise regimes to alter their body composition. We performed longitudinal characterisation of diet, exercise, the faecal microbial community composition and serum metabolites in five bodybuilders during competition preparation and post-competition. All participants reduced fat mass while conserving lean mass during competition preparation, corresponding with dietary energy intake and exercise load, respectively. There was in idual variability in food choices that aligned to in idualised gut microbial community compositions throughout the study. However, there was a common shift from a high protein, low carbohydrate diet during pre-competition to a more macronutrient-balanced diet post-competition, which was associated with similar changes in the gut microbial ersity across participants. The circulating metabolite profiles also reflected in iduality, but a subset of metabolites relating to lipid metabolism distinguished between pre- and post-competition. Changes in the gut microbiome and circulating metabolome were distinct for each in idual, but showed common patterns. We conclude that further longitudinal studies will have greater potential than cross-sectional studies in informing personalisation of diet and exercise regimes to enhance exercise outcomes and improve health.
Publisher: Springer Science and Business Media LLC
Date: 07-2021
DOI: 10.1038/S42003-021-02279-8
Abstract: Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that loss of Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2011
DOI: 10.1161/CIRCINTERVENTIONS.110.960765
Abstract: Insulin-like growth factor-1 (IGF-1) is recognized as an important regulator of cardiac structure and cardiomyocyte homeostasis. The prosurvival and antiapoptotic effects of IGF-1 have been investigated in vitro and in rodent models of myocardial infarction (MI). However, the clinical application of IGF-1 has been h ered by dose-dependent side effects both acutely and during chronic administration. We hypothesized that single, low-dose IGF-1 (LD-IGF-1) administered locally and early in the reperfusion phase after acute MI in a large animal model would avoid significant side effects but would have prosurvival effects that would manifest in long-term structural and functional improvement after MI treatment. Forty-four female Landrace pigs underwent intracoronary administration of LD-IGF-1 or saline 2 hours into the reperfusion phase of acute left anterior descending artery occlusion MI. In the area of infarction, IGF-1 receptor and signaling responses were activated at 30 minutes and cardiomyocyte cell death attenuated at 24 hours after LD-IGF-1 but not saline treatment. Hemodynamic and structural studies using pressure-volume loop, CT, and triphenyltetrazolium chloride analysis 2 months post-MI confirmed a marked reduction in infarct size, attenuation of wall thinning, and augmentation of wall motion in the LD-IGF-1-treated but not in the saline-treated animals. These regional structural benefits were associated with global reductions in left ventricular volumes and significant improvement in left ventricular systolic and diastolic function. One-time LD-IGF-1 effects potent acute myocardial salvage in a preclinical model of left anterior descending artery occlusive MI, extending to long-term benefits in MI size, wall structure, and function and underscoring its potential as an adjunctive therapeutic agent.
Publisher: Portland Press Ltd.
Date: 1988
DOI: 10.1042/BJ2490191
Abstract: The synthesis of very long chain (C24 to C36) polyunsaturated (four, five and six double bonds) fatty acids (VLCPUFA) is investigated in bovine retina using [14C]acetate. Saturates on the one hand (mainly palmitate), and polyenes on the other (mainly VLCPUFA), incorporate most of the label found in lipids. Phosphatidylcholine (PC) is the most highly labelled lipid class, since both types of 14C-labelled fatty acids, but especially this novel series of VLCPUFA, are concentrated in this phospholipid. Radioactivity from [14C]acetate is found in very long chain tetra, penta and hexaenoic fatty acids of PC. The labelling of 20:4(n − 6), 20:5(n − 3), 22:5(n − 6) and 22:6(n − 3) is much lower than that of longer polyenes of each of these series, indicating that VLCPUFA are synthesized in situ by successive elongations of the above polyenes, pre-existing in retina lipids. In various subcellular fractions isolated from retinas after incubations with [14C]acetate (including cytosol, microsomes, mitochondria and photoreceptor membranes), the labelling of the VLCPUFA of PC is very high, even at relatively short intervals of incubation. The results suggest that not only the synthesis but also the intracellular traffic among membranes of VLCPUFA-containing species of PC are very active processes in the retina.
Publisher: MDPI AG
Date: 21-05-2020
DOI: 10.3390/NU12051505
Abstract: The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models—the diacylglycerol (DAG) model and the ceramide model—have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.
Publisher: Wiley
Date: 23-07-2018
DOI: 10.1111/MICC.12488
Abstract: Identification of the four standard modifiable cardiovascular risk factors (SMuRFs)-diabetes mellitus, hyperlipidaemia, hypertension, and cigarette smoking-has allowed the development of risk scores. These have been used in conjunction with primary and secondary prevention strategies targeting SMuRFs to reduce the burden of CAD. Recent studies show that up to 25% of ACS patients do not have any SMuRFs. Thus, SMuRFs do not explain the entire burden of CAD. There appears to be variation at the in idual level rendering some in iduals relatively susceptible or resilient to developing atherosclerosis. Important disease pathways remain to be discovered, and there is renewed enthusiasm to discover novel biomarkers, biological mechanisms, and therapeutic targets for atherosclerosis. Two broad approaches are being taken: traditional approaches investigating known candidate pathways and unbiased omics approaches. We review recent progress in the field and discuss opportunities made possible by technological and data science advances. Developments in network analytics and machine learning algorithms used in conjunction with large-scale multi-omic platforms have the potential to uncover biological networks that may not have been identifiable using traditional approaches. These approaches are useful for both biomedical research and precision medicine strategies.
Publisher: Springer Science and Business Media LLC
Date: 02-06-2020
DOI: 10.1038/S41467-020-16584-Z
Abstract: Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) s les from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes and provide an interactive online application as a publicly-available resource.
Publisher: Wiley
Date: 21-12-2021
DOI: 10.1002/EHF2.13768
Abstract: Biobanking in health care has evolved over the last few decades from simple biological s le repositories to complex and dynamic units with multi‐organizational infrastructure networks and has become an essential tool for modern medical research. Cardiovascular tissue biobanking provides a unique opportunity to utilize cardiac and vascular s les for translational research into heart failure and other related pathologies. Current techniques for diagnosis, classification, and treatment monitoring of cardiac disease relies primarily on interpretation of clinical signs, imaging, and blood biomarkers. Further research at the disease source (i.e. myocardium and blood vessels) has been limited by a relative lack of access to quality human cardiac tissue and the inherent shortcomings of most animal models of heart disease. In this review, we describe a model for cardiovascular tissue biobanking and databasing, and its potential to facilitate basic and translational research. We share techniques to procure endocardial s les from patients with hypertrophic cardiomyopathy, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction, in addition to aortic disease s les. We discuss some of the issues with respect to data collection, privacy, biobank consent, and the governance of tissue biobanking. The development of tissue biobanks as described here has significant scope to improve and facilitate translational research in multi‐omic fields such as genomics, transcriptomics, proteomics, and metabolomics. This research heralds an era of precision medicine, in which patients with cardiovascular pathology can be provided with optimized and personalized medical care for the treatment of their in idual phenotype.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.YMGME.2019.10.002
Abstract: A small minority ( 400,000 subjects in UK Biobank - with metabolites. We conducted these analyses in three community-based cohorts: the Framingham Heart Study (FHS) Offspring Cohort, FHS Generation 3, and the KORA F4 cohort. We identified 19 new low-frequency or rare (minor allele frequency (MAF) 5%) pLOF variant-metabolite associations. Rare pLOF variants in the genes BTN3A2, ENPEP, and GEM that have been associated with blood pressure in UK Biobank, were associated with vasoactive metabolites indoxyl sulfate, asymmetric dimethylarginine (ADMA), and with niacinamide, respectively. A common pLOF variant in gene CCHCR1, associated with asthma in UK Biobank, was associated with histamine and niacinamide in FHS Generation 3, both reported to play a role in this disease. Common variants in olfactory receptor gene OX4C11 that associated with blood pressure in UK Biobank were associated with the nicotine metabolite cotinine, suggesting an interaction between altered olfaction, smoking behaviour, and blood pressure. These findings provide biological validity for pLOF variant-disease associations, and point to the effector roles of common metabolites. Such an approach may provide novel disease markers and therapeutic targets.
Publisher: Springer Science and Business Media LLC
Date: 07-10-2017
DOI: 10.1007/S00232-017-9990-X
Abstract: Tri- and dipeptides are transported in the kidney by PEPT1 and PEPT2 isoforms. The aim of this study was to investigate differences in transport kinetics between renal brush border (BBMV) and outer medulla (OMMV) membrane vesicles (where PEPT1 and PEPT2 are sequentially available) for a range of di- and tripeptides and peptidomimetic drugs. This was accomplished through the use of the potential-sensitive fluorescent dye 3,3'-dipropylthiacarbocyanine iodide [DiS-C
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-07-2016
DOI: 10.1161/CIRCULATIONAHA.116.021803
Abstract: Single-stranded DNA aptamers are oligonucleotides of ≈50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low s le throughput, which have hindered proteomic analyses of large cohorts. To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood s les were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform’s ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait. We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15 P .70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15 P .30E-4) % were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P =1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P =1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46 P .05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (β=0.3386, P =2.54E-22) and trigger factor 2 (β=0.2846, P =5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity. Our results highlight an emerging proteomics tool capable of profiling low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well.
Start Date: 04-2019
End Date: 12-2021
Amount: $489,045.00
Funder: Australian Research Council
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