CONTROL OF MYOFILAMENT ACTIVATION IN HEART-FAILURE

It is now apparent that compared with cardiac myofilaments from normal subjects, cardiac myofilaments from patients in end-stage heart failu re have depressed maximum Ca2+-dependent actomyosin MgATPase activity. We show evidence that confirms these results. This depression cannot be explained by shifts in the population of myosin heavy chain isoform s. The depression could be due to expression of mutant myosins or to l oss of myosin light chain 2. There have also been reports showing that there is a fetal isoform of TnT, the Tm (tropomyosin) binding unit of troponin, expressed in the myopathic myofilaments. In addition, the d epression in actomyosin ATPase may be due to changes in the level of p hosphorylation of sites on TnT or TnI, the inhibitory unit of troponin , associated with myopathy. We discuss how these changes in the thin f ilament might affect activation of the myofilaments by modulating the ability of cross-bridges and/or Ca2+ to reverse thin filament inhibiti on by Tn-Tm. Our discussion emphasizes the role of force-generating cr oss-bridges as determinants of myofilament activation and considers th e possibility that activation by strong cross-bridges could be altered by changes in the thin filament as well as in the thick filament.