D. Donner

Myocardial structure, function and ischaemic tolerance in a rodent model of obesity with insulin resistance

•  What is the central question of this study? Does obesity with insulin resistance decrease left ventricular pump function and/or myocardial tolerance to ischaemia in a rodent model of metabolic syndrome, and what mechanisms are involved in these changes? •  What is the main finding and its importance? These data suggest that although left ventricular pump function may be maintained with obesity and insulin resistance, the hearts from these animals are more prone to ischaemia–reperfusion injury, which is in part due to changes in the functionality of the myocardial reperfusion injury salvage kinase (RISK) pathway. Interventions/therapies aimed at normalizing RISK pathway function have the potential to normalize myocardial tolerance to ischaemia–reperfusion in patients with the metabolic syndrome.

Trenbolone Improves Cardiometabolic Risk Factors and Myocardial Tolerance to Ischemia-Reperfusion in Male Rats With Testosterone-Deficient Metabolic Syndrome

The increasing prevalence of obesity adds another dimension to the pathophysiology of testosterone (TEST) deficiency (TD) and potentially impairs the therapeutic efficacy of classical TEST replacement therapy. We investigated the therapeutic effects of selective androgen receptor modulation with trenbolone (TREN) in a model of TD with the metabolic syndrome (MetS). Male Wistar rats (n=50) were fed either a control standard rat chow (CTRL) or a high-fat/high-sucrose (HF/HS) diet. After 8 weeks of feeding, rats underwent sham surgery or an orchiectomy (ORX). Alzet miniosmotic pumps containing either vehicle, 2-mg/kg·d TEST or 2-mg/kg·d TREN were implanted in HF/HS+ORX rats. Body composition, fat distribution, lipid profile, and insulin sensitivity were assessed. Infarct size was quantified to assess myocardial damage after in vivo ischaemia reperfusion, before cardiac and prostate histology was performed. The HF/HS+ORX animals had increased sc and visceral adiposity; circulating triglycerides, cholesterol, and insulin; and myocardial damage, with low circulating TEST compared with CTRLs. Both TEST and TREN protected HF/HS+ORX animals against sc fat accumulation, hypercholesterolaemia, and myocardial damage. However, only TREN protected against visceral fat accumulation, hypertriglyceridaemia, and hyperinsulinaemia and reduced myocardial damage relative to CTRLs. TEST caused widespread cardiac fibrosis and prostate hyperplasia, which were less pronounced with TREN. We propose that TEST replacement therapy may have contraindications for males with TD and obesity-related MetS. TREN treatment may be more effective in restoring androgen status and reducing cardiovascular risk in males with TD and MetS.

Impact of Diet-Induced Obesity and Testosterone Deficiency on the Cardiovascular System: A Novel Rodent Model Representative of Males with Testosterone-Deficient Metabolic Syndrome (TDMetS)

Introduction Current models of obesity utilise normogonadic animals and neglect the strong relationships between obesity-associated metabolic syndrome (MetS) and male testosterone deficiency (TD). The joint presentation of these conditions has complex implications for the cardiovascular system that are not well understood. We have characterised and investigated three models in male rats: one of diet-induced obesity with the MetS; a second using orchiectomised rats mimicking TD; and a third combining MetS with TD which we propose is representative of males with testosterone deficiency and the metabolic syndrome (TDMetS). Methods Male Wistar rats (n = 24) were randomly assigned to two groups and provided ad libitum access to normal rat chow (CTRL) or a high fat/high sugar/low protein “obesogenic” diet (OGD) for 28 weeks (n = 12/group). These groups were further sub-divided into sham-operated or orchiectomised (ORX) animals to mimic hypogonadism, with and without diet-induced obesity (n = 6/group). Serum lipids, glucose, insulin and sex hormone concentrations were determined. Body composition, cardiovascular structure and function; and myocardial tolerance to ischemia-reperfusion were assessed. Results OGD-fed animals had 72% greater fat mass; 2.4-fold greater serum cholesterol; 2.3-fold greater serum triglycerides and 3-fold greater fasting glucose (indicative of diabetes mellitus) compared to CTRLs (all p<0.05). The ORX animals had reduced serum testosterone and left ventricle mass (p<0.05). In addition to the combined differences observed in each of the isolated models, the OGD, ORX and OGD+ORX models each had greater CK-MB levels following in vivo cardiac ischemia-reperfusion insult compared to CTRLs (p<0.05). Conclusion Our findings provide evidence to support that the MetS and TD independently impair myocardial tolerance to ischemia-reperfusion. The combined OGD+ORX phenotype described in this study is a novel animal model with associated cardiovascular risk factors and complex myocardial pathology which may be representative of male patients presenting with TDMetS.

Pravastatin improves risk factors but not ischaemic tolerance in obese rats

&NA; Statins are effective in management of dyslipidaemia, and a cornerstone of CVD prevention strategies. However, the impacts of their pleiotropic effects on other cardiovascular risk factors and myocardial responses to infarction are not well characterised. We hypothesised that pravastatin treatment in obesity improves lipid profiles, insulin‐resistance and myocardial resistance to ischaemia/reperfusion (I/R) injury. Wistar rats were fed a control (C) chow or high carbohydrate and fat diet (HCFD) for 16 weeks with vehicle or pravastatin (prava 7.5 mg/kg/day) treatment for 8 weeks. At 16 weeks HOMAs were performed, blood samples collected and hearts excised for Langendorff perfusions/biochemical analyses. Anti‐oxidant activity and proteins regulating mitochondrial fission/fusion and apoptosis were assessed. The HCFD increased body weight (736±15 vs. 655±12 g for C; P<0.001), serum triglycerides (2.91±0.52 vs. 1.64±0.26 mmol/L for C; P<0.001) and insulin‐resistance (HOMA‐ 6.9±0.8 vs. 4.2±0.5 for C; P<0.05) while prava prevented diet induced changes and paradoxically increased lipid peroxidation. The HCFD increased infarct size (34.1±3.1% vs. 18.8±3.0% of AAR for C; P<0.05), which was unchanged by prava in C and HCFD animals. The HCFD decreased cardiac TxR activity and mitochondrial MFN‐1 and increased mitochondrial DRP‐1 (reducing MFN‐1:DRP‐1 ratio) and Bax expression, with the latter changes prevented by prava. While unaltered by diet, cytosolic levels of Bax and caspase‐3 were reduced by prava in C and HCFD hearts (without changes in cleaved caspase‐3). We conclude that obesity, hyper‐triglyceridemia and impaired glycemic control in HCFD rats are countered by prava. Despite improved risk factors, prava did not reduce myocardial infarct size, potentially reflecting its complex pleiotropic impacts on cardiac GPX activity and MFN‐1, DRP‐1, caspase‐3 and Bcl‐2 proteins.