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.