Abstract 285: Glycogen Receptor Antagonism Ameliorates Progression of Heart Failure

Abstract

Glucagon is an important hormone for glycemic control with counter-balancing function vs. insulin, and treatment of glucagon receptor antibody is shown to be efficacious for type I and type II diabetes. It was reported recently that systemic treatment of glucagon aggravated myocardial injury and pathological remodeling in heart in a glucagon receptor dependent manner, while cardiomyocyte specific inactivation of glucagon receptor protected heart from ischemic injury and remodeling, implicating the therapeutic potential of targeting glucagon receptor for heart failure. In this report, we investigated the functional outcome of glucagon receptor antagonist treatment in mice following myocardial infarction (MI) and pressure-overload using a humanized monoclonal glucagon receptor antagonist antibody REMD2.59. Mice treated with REMD2.59 after myocardial infarction showed significantly reduced scar sizes, blunted cardiac hypertrophy and fibrotic remodeling, and attenuated contractile dysfunction at four weeks after myocardial infarction comparing to mice treated with vehicle as controls. In contrast, treatment of glucagon aggravated these pathological manifestations triggered by myocardial infarction. Furthermore, treatment with REMD2.59 at the onset of pressure-overload significantly suppressed the development of cardiac hypertrophy and chamber dilation with marked preservation of cardiac systolic and diastolic function. More remarkably, initiation of REMD2.59 treatment two weeks after pressure-overload significantly blunted the progression of cardiac pathology with remarkable recovery of hypertrophic gene induction. These results provide the first in vivo proof-of-concept evidence that glucagon receptor antagonism is a potentially efficacious therapy to block both onset and progression of heart failure.