B005 Dietary-induced insulin resistance associated with dyslipidemia induces progressive cardiac dysfunction in rats as evidenced by echocardiography

BackgroundA major complication of diabetes is the development of cardiac dysfunction in absence of vascular disease. Metabolic disorders such as insulin resistance (IR) and dyslipidemia (DL) might contribute to the induction of diabetic cardiomyopathy (DCM). However, few relevant animal models are currently available for studying the time-course of DCM and evaluating experimental therapeutics. We developed a rodent model of dietary-induced IR combined or not with DL in order to investigate the impact of chronic IR and DL on in vivo myocardial function.Methods & ResultsMale Sprague-Dawley rats were fed a western-type diet (65 % fat ; 15 % fructose ; WD: n=12). DL was induced by combining the western diet with i.p. injections of a nonionic surface-active agent (P-407 ; 0.2mg/kg, 3 times/wk ; WD-P407 n=9). A chow diet was used as control (Chow: n=9). At 6, 11 and 14 wks, cardiac function was assessed by echocardiography. After 6 wks, plasma insulin was significantly increased in both WD and WD-P407 groups (P<0.05 vs. Chow). Fasting blood glucose increased in WD group while plasma lipids markedly accumulated in WD-P407-treated rats (P<0.05 and P<0.01 vs. Chow, respectively). Pulse-wave Doppler indicated impaired diastolic function at 14 wks (E/A wave ratio: WD-P407: 1.42±0.06 vs. Chow: 1.65±0.11). M-mode imaging showed no significant differences in cardiac function and geometry under basal conditions. However, fractional shortening (FS) was significantly depressed under dobutamine stress in WD group at 14 wks (FS in % of baseline: 151±9 % vs 196±7 % ; P<0.05) whereas systolic dysfunction appeared as early as 11 wks and worsened at 14 wks in WD-P407 animals (P<0.05 and P<0.01 vs. Chow, respectively). Finally, compared to Chow, myocardial lipid tissue content were significantly higher in WD and WD-P407 groups, the cardiac lipid accumulation being more pronounced in the later.ConclusionsDL exacerbated cardiac lipotoxicity and functional complications associated with IR. This experimental model of combined IR and DL closely mimics the main clinical manifestations of DCM and might therefore constitute a useful tool for the evaluation of pharmacological treatments

Inhibition of cardiac leptin expression after infarction reduces subsequent dysfunction.

International audienceLeptin is known to exert cardiodepressive effects and to induce left ventricular (LV) remodelling. Nevertheless, the autocrine and/or paracrine activities of this adipokine in the context of post-infarct dysfunction and remodelling have not yet been elucidated. Therefore, we have investigated the evolution of myocardial leptin expression following myocardial infarction (MI) and evaluated the consequences of specific cardiac leptin inhibition on subsequent LV dysfunction. Anaesthetized rats were subjected to temporary coronary occlusion. An antisense oligodesoxynucleotide (AS ODN) directed against leptin mRNA was injected intramyocardially along the border of the infarct 5 days after surgery. Cardiac morphometry and function were monitored by echocardiography over 11 weeks following MI. Production of myocardial leptin and pro-inflammatory cytokines interleukin (IL)-1β and IL-6 were assessed by ELISA. Our results show that (1) cardiac leptin level peaks 7 days after reperfused MI; (2) intramyocardial injection of leptin-AS ODN reduces early IL-1β and IL-6 overexpression and markedly protects contractile function. In conclusion, our findings demonstrate that cardiac leptin expression after MI could contribute to the evolution towards heart failure through autocrine and/or paracrine actions. The detrimental effect of leptin could be mediated by pro-inflammatory cytokines such as IL-1β and IL-6. Our data could constitute the basis of new therapeutic approaches aimed to improve post-MI outcome