Altered Ca2+ and Na+ Homeostasis in Human Hypertrophic Cardiomyopathy: Implications for Arrhythmogenesis
Altered Ca2+ and Na+ Homeostasis in Human Hypertrophic Cardiomyopathy: Implications for Arrhythmogenesis
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DOI：
10.3389/fphys.2018.01391
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发表时间：
2018-10-16
影响因子：
4
通讯作者：
Cerbai, Elisabetta
中科院分区：
文献类型：
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作者：
Coppini, Raffaele;Ferrantini, Cecilia;Cerbai, Elisabetta
肥厚型心肌病（HCM）是最常见的孟德尔心脏病，患病率为1/500。HCM是猝死的主要原因，这是由于室性快速性心律失常的风险增加，通常发生在年轻的无症状患者中。由于舒张功能的恶化，HCM可以缓慢地进展为心力衰竭，射血分数保持或降低。心肌内纤维化和替代瘢痕的积累是心力衰竭进展的基础，也是终末期患者持续性心律失常的基础。然而，心律失常和机械异常可能发生在很少或没有纤维化的心脏中，提示功能性病理机制。通过研究从患有症状性梗阻的非衰竭HCM患者接受肌切除术的室间隔样本中分离的存活心肌细胞和小梁，我们发现细胞内Ca 2+处理的特定异常与细胞心律失常和舒张功能障碍的增加相关。在HCM心肌细胞中，舒张期Ca 2+浓度在胞质溶胶和肌浆网中均增加，并且Ca 2+瞬时衰减的速率较慢，而Ca 2+释放的幅度保持不变。Ca 2+过载是通过L型Ca 2+电流增加的Ca 2+进入[由于动作电位（AP）平台延长]，结合通过Na+/Ca 2+交换器的Ca 2+挤出速率降低[由于细胞溶质（Na+）增加]和SERCA表达降低的结果。增加的晚期Na+电流（I-NaL）起主要作用，因为它导致AP延长和Na+过载。细胞内Ca 2+超载决定了更高频率的Ca 2+波，导致延迟后除极（DAD）和过早收缩，但也与HCM心肌舒张张力增加和舒张较慢有关。细胞内[Ca 2 +]的持续增加与Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）的活化增加及其靶点（包括Ca 2+处理蛋白）的磷酸化增强密切相关。在转基因HCM小鼠模型中，我们发现Ca 2+超载，CaMKII和增加的INaL从疾病的最早阶段开始驱动心肌重塑，并成为肥大，舒张功能障碍和致炎底物发展的基础。总之，HCM心肌舒张功能障碍和血管生成是由细胞和分子水平的功能改变驱动的，这可能是创新治疗的靶点。
Hypertrophic cardiomyopathy (HCM) is the most common mendelian heart disease, with a prevalence of 1/500. HCM is a primary cause of sudden death, due to an heightened risk of ventricular tachyarrhythmias that often occur in young asymptomatic patients. HCM can slowly progress toward heart failure, either with preserved or reduced ejection fraction, due to worsening of diastolic function. Accumulation of intra-myocardial fibrosis and replacement scars underlies heart failure progression and represents a substrate for sustained arrhythmias in end-stage patients. However, arrhythmias and mechanical abnormalities may occur in hearts with little or no fibrosis, prompting toward functional pathomechanisms. By studying viable cardiomyocytes and trabeculae isolated from inter-ventricular septum samples of non-failing HCM patients with symptomatic obstruction who underwent myectomy operations, we identified that specific abnormalities of intracellular Ca2+ handling are associated with increased cellular arrhytmogenesis and diastolic dysfunction. In HCM cardiomyocytes, diastolic Ca2+ concentration is increased both in the cytosol and in the sarcoplasmic reticulum and the rate of Ca2+ transient decay is slower, while the amplitude of Ca2+-release is preserved. Ca2+ overload is the consequence of an increased Ca2+ entry via L-type Ca2+-current [due to prolongation the action potential (AP) plateau], combined with a reduced rate of Ca2+-extrusion through the Na+/Ca2+ exchanger [due to increased cytosolic (Na+)] and a lower expression of SERCA. Increased late Na+ current (I-NaL) plays a major role, as it causes both AP prolongation and Na+ overload. Intracellular Ca2+ overload determines an higher frequency of Ca2+ waves leading to delayed-afterdepolarizations (DADs) and premature contractions, but is also linked with the increased diastolic tension and slower relaxation of HCM myocardium. Sustained increase of intracellular [Ca2+] goes hand-in-hand with the increased activation of Ca2+/calmodulin-dependent protein-kinase-II (CaMKII) and augmented phosphorylation of its targets, including Ca2+ handling proteins. In transgenic HCM mouse models, we found that Ca2+ overload, CaMKII and increased INaL drive myocardial remodeling since the earliest stages of disease and underlie the development of hypertrophy, diastolic dysfunction and the arrhythmogenic substrate. In conclusion, diastolic dysfunction and arrhythmogenesis in human HCM myocardium are driven by functional alterations at cellular and molecular level that may be targets of innovative therapies.