Abstract
Background: Rest or exercise obstruction is present in two thirds of patients with hypertrophic cardiomyopathy (HCM) and is a major determinant of symptoms and disability. Hypercontractile upper septum is the main pathophysiological determinant of obstruction, thus negative inotropic interventions such as dysopiramide or beta-blockers are the only available options to pharmacologically treat obstruction, commonly with partial efficacy. We have previously demonstrated that ranolazine ameliorates diastolic function in trabeculae from septal samples of obstructive HCM patients undergoing myectomy (Coppini et al, Circulation 2013). Methods: 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. Myocardial specimens from non-failing non-hypertrophic patients or patients with secondary hypertrophy were used as controls. Results: Dysopiramide (Dys) reduced twitch tension in a dose dependent manner and 5µM Dys accelerated contraction kinetics in HCM trabeculae. Isoproterenol 10−7 mol/L (Iso) determined a significant potentiation of twitch amplitude and an accelleration of contraction kinetics (both time to peak and relaxation). Changes induced by Iso in control trabeculae were similar. Interestingly, Iso caused APD prolongation in HCM cardiomyocytes instead of the shortening observed in control cells. This was likely related to the unbalance between depolarizing and repolarizing currents, including increased Late-Na+ current (INaL). The INaL blocker Ranolazine 10 µM (Ran) applied on top of Iso (Iso+Ran) markedly reduced isometric twitch tension of HCM trabeculae, while Ran alone showed no negative inotropic effect. Contraction kinetics in Iso+Ran were still significantly faster compared to baseline. Conclusions: Beta adrenergic stimulation may enhance septal contractility and determine obstruction in HCM. Ranolazine, by reducing septal tension at peak exercise but not at rest, may represent a safe therapeutic option for obstruction.
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