P337Ranolazine reverses unfavourable electrophysiological remodeling associated with hypertrophic cardiomyopathy: an in vitro study on human cardiomyocytes

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Abstract

Hypertrophic cardiomyopathy (HCM), the most frequent genetic cardiomyopathy, purports increased arrhythmic risk. Whether disease-specific electrophysiological (EP) remodeling at the cardiomyocyte level may occur in HCM, and be influenced by pharmacological treatment, is still unknown. Aim of this study was to characterize in vitro EP profiles of human HCM cardiomyocytes, and to assess the effects of the late sodium current blocker ranolazine. Patch clamp studies and intracellular Ca2+ recordings were performed in isolated myocytes from surgical myectomy samples of 26 obstructive HCM patients. Six patients with normal left ventricular thickness undergoing surgery for aortic regurgitation, were used as controls. HCM cardiomyocytes exhibited marked electrophysiological remodeling compared to controls, including prolonged action potential (duration: 915 ± 89ms vs. 507 ± 61ms, p < 0.01), increased prevalence of EADs, decreased repolarizing K+ currents such as Ito and Ik1, increased Ca2+ currents (maximal density: 6.5 ± 0.2pA/pF vs. 5.2 ± 0.4pA/pF, p < 0.01), prolonged intracellular calcium transients (duration: 1035 ± 111ms vs. 599 ± 55ms, p < 0.01) with higher diastolic Ca2+. Ranolazine 10μM reversed most of these electrophysiological abnormalities by reducing action potential duration (by 23 ± 3%), shortening calcium transient (by 21 ± 2%) and preventing intracellular diastolic calcium overload (diastolic fluorescence -20 ± 2%), the latter reflecting into improved diastolic properties of isolated trabeculae; all these effects were negligible in control cardiomyocytes. In patients with HCM, cardiomyocytes are characterized by severe EP remodeling both at the membrane and intracellular level. At therapeutic concentrations, ranolazine exerts a potent reversal of these abnormalities, resulting in multifactorial improvement in EP and mechanical function. These observations suggest a potentially favorable effect of ranolazine in the management of arrhythmias and diastolic dysfunction associated with HCM, providing a strong rationale for clinical investigation.

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