Chronic Central Leptin Infusion Improves Cardiac Function in Diabetic Rats With Heart Failure

Abstract

Myocardial infarction (MI) is a major cause of mortality and morbity and the leading cause of heart failure (HF) worldwide. We previously demonstrated that leptin, a peptide hormone produced by adipocytes, exerts powerful antidiabetic effects via activation of its receptors in the central nervous system (CNS). We also showed that chronic central leptin infusion restores intrinsic heart rate, cardiac sympathetic‐vagal balance and baroreflex sensitivity in uncontrolled diabetes. Therefore, in this study we examined if chronic intracerebroventricular infusion of leptin improves cardiac function in rats with HF induced by MI. Wistar Munich rats (275–300 g, n=4–5/group) were submitted to MI by ligation of the left descending coronary artery. Diabetes was induced one week later by a single injection of streptozotocin (STZ, 35 mg/kg, i.p.). Seven days later, rats were instrumented with an intracerebroventricular (ICV) cannula into the lateral ventricle for continuous infusion of leptin (0.62 μg/h, 0.5 μL/h, n=5) or vehicle (0.5 μL/h, n=4), for 4 weeks using osmotic pumps (Alzet, model 2002). Cardiac function was evaluated 6 days after MI surgery and on days 14 and 28 of ICV leptin or vehicle infusion using the echocardiograph VEVO 2100 (VisualSonics, Canada). STZ caused severe hyperglycemia in both groups (ranging from 472±17 to 477±14 mg/dl) which was completely normalized by chronic ICV leptin infusion (120±8 mg/dl). Compared to vehicle group, leptin infusion for 4 weeks also markedly ameliorated cardiac function as evidenced by lower left atrium/aorta ratio (1.73±0.07 vs. 2.63±0.23 mm) and higher cardiac output (113.8±27.6 vs. 69.5±10.0 ml/min) and ejection fraction (36.7±2.3 vs. 30.7±8.7 %). These results suggest that in addition to its powerful CNS‐mediated antidiabetic effects, leptin attenuates the progression of HF after MI in diabetic rats by improving cardiac function.Support or Funding InformationNHLBI‐PO1HL51971, NIGMS‐P20GM104357, FAPESP, CNPq