Department of Chemistry, Tamkang University, Taipei, Taiwan.
J Am Heart Assoc. 2013 Sep 18;2(5):e000231. doi: 10.1161/JAHA.113.000231.
Sudden cardiac death due to malignant ventricular arrhythmia is a devastating manifestation of cardiac hypertrophy. Sarcomere protein myosin binding protein C is functionally related to cardiac diastolic function and hypertrophy. Zebrafish is a better model to study human electrophysiology and arrhythmia than rodents because of the electrophysiological characteristics similar to those of humans.
We established a zebrafish model of cardiac hypertrophy and diastolic dysfunction by genetic knockdown of myosin binding protein C gene (mybpc3) and investigated the electrophysiological phenotypes in this model. We found expression of zebrafish mybpc3 restrictively in the heart and slow muscle, and mybpc3 gene was evolutionally conservative with sequence homology between zebrafish and human mybpc3 genes. Zebrafish with genetic knockdown of mybpc3 by morpholino showed ventricular hypertrophy with increased myocardial wall thickness and diastolic heart failure, manifesting as decreased ventricular diastolic relaxation velocity, pericardial effusion, and dilatation of the atrium. In terms of electrophysiological phenotypes, mybpc3 knockdown fish had a longer ventricular action potential duration and slower ventricular diastolic calcium reuptake, both of which are typical electrophysiological features in human cardiac hypertrophy and heart failure. Impaired calcium reuptake resulted in increased susceptibility to calcium transient alternans and action potential duration alternans, which have been proved to be central to the genesis of malignant ventricular fibrillation and a sensitive marker of sudden cardiac death.
mybpc3 knockdown in zebrafish recapitulated the morphological, mechanical, and electrophysiological phenotypes of human cardiac hypertrophy and diastolic heart failure. Our study also first demonstrated arrhythmogenic cardiac alternans in cardiac hypertrophy.
恶性室性心律失常导致的心脏性猝死是心脏肥大的一种毁灭性表现。肌球蛋白结合蛋白 C 是收缩蛋白，其功能与心脏舒张功能和肥大有关。与啮齿动物相比，斑马鱼在研究人类电生理和心律失常方面是更好的模型，因为其电生理特征与人类相似。
我们通过基因敲低肌球蛋白结合蛋白 C 基因（mybpc3）建立了心肌肥厚和舒张功能障碍的斑马鱼模型，并研究了该模型中的电生理表型。我们发现斑马鱼 mybpc3 的表达局限于心和慢肌，mybpc3 基因在序列上与人类 mybpc3 基因具有同源性，在进化上是保守的。用 morpholino 基因敲低斑马鱼 mybpc3 表现出心室肥厚，心肌壁厚度增加，舒张性心力衰竭，表现为心室舒张松弛速度减慢，心包积液和心房扩张。在电生理表型方面，mybpc3 敲低鱼的心室动作电位持续时间延长，心室舒张钙重摄取速度减慢，这两种都是人类心肌肥厚和心力衰竭的典型电生理特征。钙重摄取受损导致钙瞬变alternans 和动作电位持续时间 alternans 的易感性增加，这已被证明是恶性室性颤动发生的核心，也是心脏性猝死的敏感标志物。
斑马鱼 mybpc3 敲低重现了人类心肌肥厚和舒张性心力衰竭的形态、力学和电生理表型。我们的研究还首次证明了心脏肥厚中的心律失常性心脏 alternans。
