Contraction and electrophysiological abnormalities in myofilament mutation-positive and mutation-negative human HCM myocardium

Myofilament mutation-positive and mutation-negative hypertrophic cardiomyopathy (HCM) patients show different prognosis and arrhythmic burden that are likely related to the different pathogenesis. For instance, post-translational activation of CaMKII pathway is a specific biomarker of myofilament mutation-positive HCM while depressed sarcoplasmic reticulum calcium uptake is present in both groups. However, the functional consequences of a mutation-driven pathogenesis is still not completely understood. In the last 15 years, we analyzed in vitro a large number of myomectomy samples collected in the Florence referral centre for HCM trying to dissect differences in contraction and electrophysiological properties of myofilament-positive (myo+) and myofilament-negative (myo-) human myocardium. Tension was measured isometrically in 48 HCM patient intact multicellular preparations and compared with those from two reference group: i) non-failing non-hypertrophic and ii) secondary hypertrophy myocardium. Twitch contraction was prolonged in overall HCM trabeculae compared to both reference group but when HCM muscles were discerned into myo+ (i.e. carrying MHY7 or MYBPC mutations) and myo-, only the latter showed prolonged contractions, similarly to what observed in secondary hypertrophy. In myo+ myocardium, twitch duration was comparable to non-failing non-hypertrophic patients. Despite the apparently normal twitch contraction kinetics, myo+ patients showed major prolongation of action potential duration and higher rates of cellular arrythmias (both EADs and DADs) compared to both reference groups. In silico studies of myocardium carrying MHY7 or MYBPC mutations demonstrated that despite faster cross-bridge cycling, twitch contraction duration may be normal due to the prolonged calcium transient and action potential duration. In myo+ human myocardium carrying MHY7 and MYBPC mutations, the time course of twitch contractions is not prolonged but calcium-handling and membrane electrical abnormalities are more pronounced compared to myo- exposing patients to a more severe arrhythmic risk