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+ (Ca2+i) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na+ (INaL) and Ca2+ (ICaL) currents and decreased repolarizing K+ currents, increased occurrence of cellular arrhythmias, prolonged Ca2+i transients, and higher diastolic Ca2+i. 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 a...