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.