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

Abstract

Background and PurposeIn 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 low efficacy and tolerability. We assessed the potential of late sodium current (INaL)‐inhibitors to treat inducible obstruction in HCM.Experimental ApproachThe electrophysiological and mechanical responses to β‐adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of INaL‐inhibitors (ranolazine and GS‐967) in HCM samples were investigated under conditions simulating rest and exercise.Key ResultsIn cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective INaL‐inhibitor GS‐967 (0.5 μM) hastened twitch kinetics, decreased diastolic [Ca2+] and shortened action potentials, matching the effects of ranolazine (10μM). Mechanical responses to isoprenaline (inotropic and lusitropic) were comparable in HCM and control myocardium. However, isoprenaline prolonged action potentials in HCM myocardium, while it shortened them in controls. Unlike disopyramide, neither GS‐967 nor ranolazine reduced force at rest. However, in the presence of isoprenaline, 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 isoprenaline.Conclusions and ImplicationsRanolazine and GS‐967 reduced 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.

Altered Ca2+ and Na+ Homeostasis in Human Hypertrophic Cardiomyopathy: Implications for Arrhythmogenesis

“…Most of the results presented in the figures were previously published in Coppini et al (2013) and in Ferrantini et al (2018) . Previously unpublished results are presented in Figures 3 , 4 .…”

“…Previously unpublished results are presented in Figures 3 , 4 . Cardiomyocytes and intact trabeculae were freshly isolated as previously described ( Coppini et al, 2013 ; Ferrantini et al, 2018 ), using surgical upper inter-ventricular septum samples excised from HCM patients who underwent myectomy operation for the relief of severe symptoms due to obstruction of the LV outflow tract. Notably, all recruited patients had preserved systolic function but impaired diastole and most of them have a history of documented non-sustained ventricular tachycardia at Holter monitoring.…”

“…Hypertrophic cardiomyopathy (HCM) cellular pathophysiology is characterized by the interplay between primary alterations (direct consequences of causal sarcomeric mutations altering myofilament function) and a large number of secondary myocardial modifications, comprising cellular electrophysiological remodeling (changes in transmembrane currents) and alterations of intracellular Ca 2+ handling [Ca 2+ transients and diastolic (Ca 2+ )] ( Coppini et al, 2013 ; Coppini et al, 2017 ; Ferrantini et al, 2017 ; Ferrantini et al, 2018 ). Due to the profound electrophysiological differences between mouse and human cardiomyocytes, studies conducted on transgenic rodent models did not help to identify the features if ion-current remodeling occurring in HCM myocardium ( van der Velden et al, 2015 ).…”

“…Therefore, arrhythmias in HCM cannot be the sole consequence of the substrate for re-entry circuits at tissue level. On the contrary, the main determinants of arrhythmogenesis in HCM are to be found within the affected cardiomyocytes, a consequence of the alterations of ion currents and intracellular Ca 2+ handling that occur as a part of HCM-related ventricular cardiomyocyte remodeling ( Coppini et al, 2013 ; Coppini et al, 2017 ; Ferrantini et al, 2017 ; Ferrantini et al, 2018 ). Indeed, from a pathophysiological standpoint, the vast majority of ventricular tachycardia episodes begin with one or more premature ectopic ventricular beats ( Ulus et al, 2013 ).…”

Interplay Between Sub-Cellular Alterations of Calcium Release and T-Tubular Defects in Cardiac Diseases

“…In fact, recent studies in failing human hearts agree on the reduction of t-tubule density, which was two to three times lower in failing ventricular myocytes from HF patients with different aetiologies than in healthy donors ( Cannell et al, 2006 ; Lyon et al, 2009 ). Loss of t-tubules have been also described in patients with genetic-based cardiomyopathies ( Maron et al, 1975 ; Kaprielian et al, 2000 ; Ferrantini et al, 2018 ). We believe that our studies on rodent models of HF and congenital cardiac diseases could (qualitatively) reflect the spatio-temporal variability of Ca 2+ release that may occur in human cardiomyocytes.…”