Mechanical Effects of Late Na-Current Blockers in Human Hypertrophic Cardiomyopathy Myocardium

Abstract

Listen

Translate article

Diastolic dysfunction and left ventricular outflow trait (LVOT) obstruction are major determinants of symptoms and disability in hypertrophic cardiomyopathy (HCM) patients. Disopyramide (Dis), Ranolazine (Ran) and the novel compound GS-967 are late Na-current blockers with progressively increasing selectivity for late vs. peak Na current. Dis is employed in HCM patients as an agent to relieve obstruction, but the cellular basis of its negative inotropic effect remains unknown. We previously showed that Ran ameliorates the diastolic properties of trabeculae from HCM patients, with no effects on baseline systolic force (Coppini et al, Circulation 2013). Here, we aim to study the effects of late Na-current blockers on diastolic function and contractility of HCM myocardium. Patch-clamp studies and intracellular-Ca2+ recordings were performed in isolated myocytes from myectomy samples of obstructive HCM patients; intact trabeculae were used for mechanical measurements. Dis (5µM) reduced twitch tension in a dose dependent manner (EC50: 5.29±1.55µM) and accelerated contraction kinetics in HCM trabeculae. Ran (10µM), despite no significant effect on the amplitude of baseline contraction, significantly reduced isometric twitch tension when applied on top of isoproterenol 10-6M (Iso+Ran). Contraction kinetics in Iso+Ran were still significantly faster than baseline. The late Na-current blocker GS-967 (1µM) did not reduce baseline twitch force but accelerated contraction kinetics, highlighting qualitatively similar effects compared to Ran, albeit at 1/10 concentration. Intracellular Ca2+ measurements and patch clamp studies performed in HCM cardiomyocytes suggest that most of these mechanical effects are mediated by inhibition of the up-regulated INaL via normalization of NCX function and intracellular [Ca2+]. From the clinical perspective: (i)all the three drugs may reduce diastolic dysfunction by speeding up contraction kinetics; (ii)Ran and GS-967 may reduce septal contractility only at peak exercise, representing a safer option to treat obstruction compared to Dis.