Myocardial structure, function and ischaemic tolerance in a rodent model of obesity with insulin resistance
Authors: Wensley I. , Salaveria K. , Bulmer A. C. , Donner D. G. , du Toit E. F. 
Published: July 2013

New findings

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.

Obesity and its comorbidities (dyslipidaemia, insulin resistance and hypertension) that together constitute the metabolic syndrome are all risk factors for ischaemic heart disease. Although obesity has been reported to be an independent risk factor for congestive heart failure, whether obesity‐induced heart failure develops in the absence of increased afterload (induced by hypertension) is not clear. We have previously shown that obesity with insulin resistance decreases myocardial tolerance to ischaemia–reperfusion, but the mechanism for this decreased tolerance remains unclear. We hypothesize that obesity with insulin resistance induces adverse cardiac remodelling and pump dysfunction, as well as adverse changes in myocardial prosurvival reperfusion injury salvage kinase (RISK) pathway signalling to reduce myocardial tolerance to ischaemia–reperfusion. Wistar rats were fed an obesogenic (obese group) or a standard rat chow diet (control group) for 32 weeks. Echocardiography was performed over the 32 weeks before isolated Langendorff‐perfused hearts were subjected to 40 min coronary artery ligation followed by reperfusion, and functional recovery (rate–pressure product), infarct size and RISK pathway function were assessed (Western blot analysis). Obesity with insulin resistance increased myocardial lipid accumulation but had no effect on in vivo or ex vivo left ventricular structure/function. Hearts from obese rats had lower reperfusion rate–pressure products (13115 ± 562 beats min−1 mmHg for obese rats versus 17781 ± 1109 beats min−1 mmHg for control rats, P < 0.05) and larger infarcts (36.3 ± 5.6% of area at risk in obese rats versus 14.1 ± 2.8% of area at risk in control rats, P < 0.01) compared with control hearts. These changes were associated with reductions in RISK pathway function, with 30–50 and 40–60% reductions in Akt and glycogen synthase kinase 3 beta (GSK‐3β) expression and phosphorylation, respectively, in obese rat hearts compared with control hearts. Total endothelial nitric oxide synthase expression was reduced by 25% in obese rats. We conclude that obesity with insulin resistance had no effect on basal cardiac structure or function but decreased myocardial tolerance to ischaemia–reperfusion. This reduction in ischaemic tolerance was likely to be due to compromised RISK pathway function in obese, insulin‐resistant animals.