Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.
Br J Pharmacol. 2018 Jul;175(13):2635-2652. doi: 10.1111/bph.14223. Epub 2018 May 3.
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 )-inhibitors to treat inducible obstruction in HCM.
The electrophysiological and mechanical responses to β-adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of I -inhibitors (ranolazine and GS-967) in HCM samples were investigated under conditions simulating rest and exercise.
In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective I -inhibitor GS-967 (0.5 μM) hastened twitch kinetics, decreased diastolic [Ca ] 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 Ca -transient amplitude and twitch tension, while the acceleration of relaxation was maintained. I -inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, I -inhibitors abolished arrhythmias induced by isoprenaline.
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 β-blockers.
在 30-40%的肥厚型心肌病（HCM）患者中，由于儿茶酚胺诱导的左心室（LV）过度收缩（可诱导性梗阻），仅在运动期间才会出现有症状的 LV 流出道梯度。负性肌力药物的选择仅限于β受体阻滞剂或双异丙吡胺，但疗效和耐受性均较低。我们评估了晚期钠电流（I ）抑制剂治疗 HCM 中可诱导性梗阻的潜力。
研究了β-肾上腺素能受体刺激对 HCM 和对照患者心肌的电生理和机械反应。在模拟休息和运动的条件下，研究了 I -抑制剂（雷诺嗪和 GS-967）在 HCM 样本中的作用。
在梗阻 18 例外科室间隔样本的心肌细胞和小梁中，选择性 I -抑制剂 GS-967（0.5μM）加速了抽搐动力学，降低了舒张[Ca ]，缩短了动作电位，与雷诺嗪（10μM）的作用相匹配。异丙肾上腺素（正性肌力和正性松弛）对 HCM 和对照心肌的机械反应相似。然而，异丙肾上腺素延长了 HCM 心肌中的动作电位，而在对照组中则缩短了动作电位。与双异丙吡胺不同，GS-967 和雷诺嗪均不降低静息时的力。然而，在异丙肾上腺素存在的情况下，它们降低了 Ca 瞬变幅度和抽搐张力，而松弛的加速得以维持。与双异丙吡胺相比，I -抑制剂在模拟运动时更有效地降低收缩力。最后，I -抑制剂消除了异丙肾上腺素诱导的心律失常。
雷诺嗪和 GS-967 在体外模拟运动时降低了间隔心肌的张力，因此有可能改善 HCM 患者中由可诱导性梗阻引起的症状，与双异丙吡胺和β受体阻滞剂相比具有一些优势。
