Late Sodium Current Inhibition Reverses Electromechanical Dysfunction in Human Hypertrophic Cardiomyopathy

Abstract

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 Ca 2+ (Ca 2+ i ) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na + ( I NaL ) and Ca 2+ ( I CaL ) currents and decreased repolarizing K + currents, increased occurrence of cellular arrhythmias, prolonged Ca 2+ i transients, and higher diastolic Ca 2+ i . Such changes were related to enhanced Ca 2+ /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 2+ i transients and the lower diastolic Ca 2+ i , 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 2+ i handling proteins changes identified, an enhanced I NaL seems to be a major contributor to the electrophysiological and Ca 2+ i dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of I NaL inhibition.