Abstract 16200: Chronic Central Nervous System Actions of Leptin Protect Against Myocardial Ischemia/reperfusion Injury

Abstract

While myocardial reperfusion is the most effective therapy to reduce mortality after myocardial infarction, it can paradoxically exacerbate ischemic injury. We recently showed that leptin, via its actions on the central nervous system (CNS), improved left ventricular function in a model of heart failure induced by permanent ligation of the left anterior coronary artery (LAD). To investigate whether leptin also protects the heart against ischemia/reperfusion (I/R) injury via its actions in the CNS, we instrumented female Wistar rats (15 weeks of age) with an intracerebroventricular (ICV) cannula into the lateral ventricle, and after 7 days of recovery and baseline assessment of cardiac function by echocardiography (VisualSonics VEVO-3100®), myocardial I/R was induced by temporary LAD ligation (60 min). Vehicle (saline, 0.5 μL/hr, n=6) or leptin (15 μg/day, n=7) were infused ICV for 28 consecutive days starting 20 min after reperfusion using osmotic minipump connected to the ICV cannula. Echocardiographic assessment of cardiac function was performed every week and at the end of the 4 th week of treatment, the heart was collected and processed for protein analysis and histological evaluation of infarct size and collagen deposition. Compared to vehicle treatment, chronic ICV leptin infusion significantly reduced infarcted area (21±2 vs. 37±4 %), septal collagen deposition (2.2±0.2 vs. 4.0±0.7 %), and markedly attenuated systolic dysfunction as evidenced by increased ejection fraction 4 weeks post I/R (59±1 vs. 30±2%), stroke volume (296±19 vs. 159±8 μL) and cardiac output (108±5 vs.63±4 μL/min). ICV leptin infusion also prevented the increase in left atrium to aorta diameter ratio (1.5±0.1 vs. 2±0.1 mm), an index of cardiac congestion. In addition, we found a 2-fold increase in the ratio of phospho-acetyl-CoA carboxylase (p-ACC) to total ACC protein expression, a marker of fatty acid oxidation, in hearts of leptin-treated rats compared with vehicle infusion. These results indicate that leptin exerts powerful beneficial CNS-mediated effects on the heart that improve systolic function and protect the myocardium against I/R injury. Our results also suggest that these beneficial actions may involve improved myocardial bioenergetics.