Cardiac myosin motor deficits are associated with left ventricular dysfunction in human ischemic heart failure

During ischemic heart failure (IHF), cardiac muscle contraction is typically impaired while the molecular changes within the myocardium are not fully understood. Thus, we aimed to characterize the biophysical properties of cardiac myosin in IHF. Cardiac tissue was harvested from ten age-matched males, either with a history of IHF or non-failing (NF) controls that had no history of structural or functional cardiac abnormalities. Clinical measures prior to cardiac biopsy demonstrated significant differences in measures of ejection fraction and left ventricular dimensions. Myofibrils and myosin were extracted from left ventricular free wall cardiac samples. There were no changes in myofibrillar ATPase activity or calcium sensitivity between groups. Using isolated myosin, we found a 15% reduction in the IHF group in actin sliding velocity in the in vitro motility assay, which was observed in the absence of a myosin isoform shift. Oxidative damage (carbonylation) of isolated myosin was compared, in which there were no significant differences between groups. Synthetic thick filaments were formed from purified myosin and the ATPase activity was similar in both basal and actin-activated conditions (20µM actin). Correlation analysis and Deming linear regression were performed between all studied parameters, in which we found statistically significant correlations between clinical measures of contractility with molecular measures of sliding velocity and ELC carbonylation. Our data indicate that subtle deficits in myosin mechanochemical properties are associated with reduced contractile function and pathological remodeling of the heart, suggesting the myosin motor may be an effective pharmacologic intervention in ischemia.