Dataset Information

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

ABSTRACT:

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 ?-blockers or disopyramide, with low efficacy and tolerability. We assessed the potential of late sodium current (I_NaL )-inhibitors to treat inducible obstruction in HCM.

Experimental approach

The electrophysiological and mechanical responses to ?-adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of I_NaL -inhibitors (ranolazine and GS-967) in HCM samples were investigated under conditions simulating rest and exercise.

Key results

In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective I_NaL -inhibitor GS-967 (0.5 ?M) hastened twitch kinetics, decreased diastolic [Ca²⁺ ] and shortened action potentials, matching the effects of ranolazine (10?M). 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. I_NaL -inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, I_NaL -inhibitors abolished arrhythmias induced by isoprenaline.

Conclusions and implications

Ranolazine 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 ?-blockers.

SUBMITTER: Ferrantini C

PROVIDER: S-EPMC6003658 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Ferrantini Cecilia C Pioner Josè Manuel JM Pioner Josè Manuel JM Mazzoni Luca L Gentile Francesca F Tosi Benedetta B Rossi Alessandra A Belardinelli Luiz L Tesi Chiara C Palandri Chiara C Matucci Rosanna R Cerbai Elisabetta E Olivotto Iacopo I Poggesi Corrado C Mugelli Alessandro A Coppini Raffaele R

British journal of pharmacology 20180503 13

<h4>Background and purpose</h4>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 low efficacy and tolerability. We assessed the potential of late sodium current (I<sub>NaL</sub> )-inhibitors to treat inducible obstruction in HCM.<h4>Experimental ...[more]

PMID: 29579779

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Project description:ObjectivesA novel transapical beating-heart septal myectomy (TA-BSM) procedure was performed for patients with latent obstruction through the left intercostal incision and without cardiopulmonary bypass. This study aims to demonstrate the experience of the TA-BSM procedure for patients with latent obstruction and compare outcomes to patients with resting obstruction.MethodsWe studied 120 symptomatic hypertrophic obstructive cardiomyopathy patients (33 with latent obstruction and 87 with resting obstruction) who underwent TA-BSM. Demographic profiles, echocardiogram-derived ventricular morphology and haemodynamics and clinical outcomes were analysed.ResultsThere were no important differences in baseline clinical characteristics between patients with latent obstruction and resting obstruction, including age, symptoms, comorbidities and medical history. Patients with latent obstruction had lower basal septum thickness, higher midventricular wall thickness, smaller left atrial chamber size and more frequency of mitral subvalvular anomalies. There was no difference in early (<30 days) deaths (0/33 vs 1/87, P > 0.999) and mid-term survival between patients with latent obstruction and resting obstruction. At 6 months after surgery, 31 (93.9%) patients with latent obstruction and 80 (92.0%) with resting obstruction achieved optimal procedural success, which was defined as a maximal gradient (after provocation) <30 mmHg and mitral regurgitation ≤ grade 1+ without mortality. Maximal left ventricular outflow tract gradient, basal septum thickness, midventricular wall thickness, mitral regurgitation grade and left atrial chamber size were significantly decreased after TA-BSM. In the follow-up, the New York Heart Association class was significantly improved following surgery.ConclusionsTA-BSM preserved favourable gold-standard guideline desired outcomes through real-time echocardiographic-guided resection. Equipoise of outcomes for this procedure regardless of degree of resting left ventricular outflow tract gradients supports operative management with this approach in symptomatic patients with latent obstruction.

Dataset Information

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

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

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

Similar Datasets

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