Late Sodium Current Inhibition Reverses Electromechanical Dysfunction in Human Hypertrophic Cardiomyopathy

Background-Hypertrophic cardiomyopathy (HCM), the most common mendelian heart disorder, remains an orphan of disease-specific pharmacological treatment because of the limited understanding of cellular mechanisms underlying arrhythmogenicity and diastolic dysfunction. Methods and Results-We assessed the electromechanical profile of cardiomyocytes from 26 HCM patients undergoing myectomy compared with those from nonfailing nonhypertrophic surgical patients by performing patch-clamp and intracellular Ca2+ (Ca-i(2+)) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na+ (I-NaL) and Ca2+ (I-CaL) currents and decreased repolarizing K+ currents, increased occurrence of cellular arrhythmias, prolonged Ca-i(2+) transients, and higher diastolic Ca-i(2+). Such changes were related to enhanced Ca2+/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I-NaL inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca-i(2+) transients and the lower diastolic Ca-i(2+), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function. Conclusions-We highlighted a specific set of functional changes in human HCM myocardium that stem from a complex remodeling process involving alterations of CaMKII-dependent signaling, rather than being a direct consequence of the causal sarcomeric mutations. Among the several ion channel and Ca-i(2+) handling proteins changes identified, an enhanced I-NaL seems to be a major contributor to the electrophysiological and Ca-i(2+) dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of I-NaL inhibition. (Circulation. 2013;127:575-584.)