Late sodium current inhibitors to treat exercise induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium.

BACKGROUND AND PURPOSE In 30‐40% of hypertrophic cardiomyopathy (HCM) patients, symptomatic left‐ventricular (LV) outflow gradients develop only during exercise due to catecholamine‐induced LV‐hypercontractility (inducible obstruction). Negative‐inotropic pharmacological options are limited to β‐blockers or disopyramide, with scarce efficacy and tolerability. We assessed the potential use of late Na+‐current (INaL)‐inhibitors to treat inducible obstruction in HCM. EXPERIMENTAL APPROACH The electrophysiological and mechanical responses to β‐adrenergic stimulation were studied in human myocardium from HCM versus control patients. We then investigated the effects of INaL‐inhibitors (ranolazine and GS‐967) in HCM samples under conditions simulating rest and exercise. KEY RESULTS In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective INaL‐inhibitor GS‐967 (0.5μM) hastened twitch kinetics, decreased diastolic [Ca2+] and shortened action potentials, matching the effects of ranolazine at a 20‐times lower concentration. The mechanical response to isoproterenol (inotropic and lusitropic) was comparable in HCM and control myocardium. However, isoproterenol prolonged action potentials in HCM myocardium, while it shortened them in controls. At variance with disopyramide, neither GS‐967 nor ranolazine reduced force at rest; however, in the presence of isoproterenol, they reduced Ca2+‐transient amplitude and twitch tension, while the acceleration of relaxation was maintained. INaL‐inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, INaL‐inhibitors abolished arrhythmias induced by isoproterenol. CONCLUSIONS AND IMPLICATIONS Ranolazine and GS‐967 are effective in reducing septal myocardium tension during simulated exercise in vitro and therefore have the potential to ameliorate symptoms caused by inducible obstruction in HCM patients, with some advantages over disopyramide and β‐blockers.