0298: The early mineralocorticoid receptor antagonism mitigates the metabolic syndrome symptoms and transition to heart failure in the SHHF rat model

Mineralocorticoid Receptor Antagonists (MRA) have proven their cardioprotective effects in individuals with chronic heart failure (CHF) by minimizing the cardiovascular damages caused by the excessive aldosterone production observed in those patients. Metabolic syndrome (MetS) that represents one of the major risk factors for CHF has been also reported to be associated with increased aldosterone levels and MR activation and may contribute in that way to the pathogenesis of HF. Thus, we hypothesized that targeting the MetS by the early antagonism of the MR may prevent or delay the subsequent transition to CHF in a rat model of HF associated or not with a MetS. MRA Eplerenone (100 mg/kg/day) or placebo was administrated to 1.5 month-old obese and lean Spontaneously Hypertensive Heart Failure male rats (SHHF cp/cp and SHHF +/+ respectively) for a period of 11 months. Animal metabolic and cardiac parameters were regularly monitored during the protocol. When compared to the SHHF +/+ , MetS rats induces of mortality of 30% in SHHF cp/cp group that was completely prevented by the preventive treatment with Eplerenone. Indeed, SHHF cp/cp developed over time a massive obesity, dyslipidemia and insulin resistance. Echocardiograms showed an accelerated transition to cardiac dysfunction evidenced by left ventricular hypertrophy (LVH), a decreased relaxation and contractile properties of the myocardium as well as LV dilatation. MRA, prevented rats’ body weight gain (–10%), dyslipidemia (–50%) and enhanced adiponectinemia (+50%). Independently of a blood pressure decrease, cardiac parameters of Eple-SHHF cp/cp rats were preserved compared to SHHF cp/cp : LV diameter (9.9±0.14 vs 11.4±0.13 mm, respectively), LV mass (1760±72 vs 2195±73 mg), ejection fraction (70±1 vs 59±1%), isovolumic relaxation time (30±1 vs 22±1 ms) and E/A ratio (1.7±0.1 vs 3±0.3). Altogether, our data demonstrated that administration of eplerenone at the very early stages of MetS delayed their progression to CHF and prevented mortality. The beneficial cardioprotective effects were obtained via a mechanism independent of blood pressure lowering.