Thick filament proteins and performance in human heart failure

Abstract

Modifications in thick filament protein content and performance are thought to underlie contraction-relaxation dysfunction in human heart failure. It has been found that myofibrillar Mg.ATPase is reduced in failing myocardium, which may be due in part to the reduction in alpha-myosin heavy chain (MHC) isoform content from approximately 5-10% in normal myocardium to <2% in failing myocardium. The physiological importance of this seemingly small amount of alpha-MHC appears substantiated by the development of cardiopathologies in humans with mutated alpha-MHC at normal abundance. Therefore, the replacement of alpha-MHC by beta-MHC (possessing slower actomyosin enzymatic kinetics) may underlie to a significant degree the reduced myocardial shortening velocity and reduced relaxation function in human heart failure. The atrial isoform of myosin essential light chain (ELC) may replace up to 25% of the ventricular isoform in failing ventricles and in so doing promotes myocardial shortening velocity. An elevated accumulation of the higher performing atrial-ELC, unlike the reduced content of the higher performing alpha-MHC, is therefore considered a compensatory response in heart failure. Phosphorylation of the myofilament proteins myosin regulatory light chain and troponin-I are both reduced in heart failure and collectively result in an elevated myofilament sensitivity to calcium activation, which inhibits relaxation function. These and other modifications in thick filament proteins, as discussed in this review, directly affect mechanical power output and relaxation function of the myocardium and thereby may be considered to cause or in some cases to compensate for the otherwise ineffective myocardial performance in heart failure.