Effects of myosin heavy chain manipulation in experimental heart failure

Abstract

The myosin heavy chain (MHC) isoforms, α- and β-MHC, are expressed in developmental- and chamber-specific patterns. Healthy human ventricle contains ∼2–10% α-MHC and these levels are reduced even further in the failing ventricle. While down-regulation of α-MHC in failing myocardium is considered compensatory, we previously demonstrated that persistent transgenic (TG) α-MHC expression in the cardiomyocytes is cardioprotective in rabbits with tachycardia-induced cardiomyopathy (TIC). We sought to determine if this benefit extends to other types of experimental heart failure and focused on two models relevant to human heart failure: myocardial infarction (MI) and left ventricular pressure overload. TG and nontransgenic rabbits underwent either coronary artery ligation at 8 months or aortic banding at 10 days of age. The effects of α-MHC expression were assessed at molecular, histological and organ levels. In the MI experiments, we unexpectedly found modest functional advantages to α-MHC expression. In contrast, despite subtle benefits in TG rabbits subjected to aortic banding, cardiac function was minimally affected. We conclude that the benefits of persistent α-MHC expression depend upon the mechanism of heart failure. Importantly, in none of the scenarios studied did we find any detrimental effects associated with persistent α-MHC expression. Thus manipulation of MHC composition may be beneficial in certain types of heart failure and does not appear to compromise heart function in others. Future considerations of myosin isoform manipulation as a therapeutic strategy should consider the underlying etiology of cardiac dysfunction.