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.