The Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Cardiovasc Res. 2021 Jul 7;117(8):1891-1907. doi: 10.1093/cvr/cvaa238.
In mammalian ventricles, electrical gradients establish electrical heterogeneities as essential tissue mechanisms to optimize mechanical efficiency and safeguard electrical stability. Electrical gradients shape mammalian electrocardiographic patterns; disturbance of electrical gradients is proarrhythmic. The zebrafish heart is a popular surrogate model for human cardiac electrophysiology thanks to its remarkable recapitulation of human electrocardiogram and ventricular action potential features. Yet, zebrafish ventricular electrical gradients are largely unexplored. The goal of this study is to define the zebrafish ventricular electrical gradients that shape the QRS complex and T wave patterns at baseline and under oxidative stress.
We performed in vivo electrocardiography and ex vivo voltage-sensitive fluorescent epicardial and transmural optical mapping of adult zebrafish hearts at baseline and during acute H2O2 exposure. At baseline, apicobasal activation and basoapical repolarization gradients accounted for the polarity concordance between the QRS complex and T wave. During H2O2 exposure, differential regional impairment of activation and repolarization at the apex and base disrupted prior to baseline electrical gradients, resulting in either reversal or loss of polarity concordance between the QRS complex and T wave. KN-93, a specific calcium/calmodulin-dependent protein kinase II inhibitor (CaMKII), protected zebrafish hearts from H2O2 disruption of electrical gradients. The protection was complete if administered prior to oxidative stress exposure.
Despite remarkable apparent similarities, zebrafish and human ventricular electrocardiographic patterns are mirror images supported by opposite electrical gradients. Like mammalian ventricles, zebrafish ventricles are also susceptible to H2O2 proarrhythmic perturbation via CaMKII activation. Our findings suggest that the adult zebrafish heart may constitute a clinically relevant model to investigate ventricular arrhythmias induced by oxidative stress. However, the fundamental ventricular activation and repolarization differences between the two species that we demonstrated in this study highlight the potential limitations when extrapolating results from zebrafish experiments to human cardiac electrophysiology, arrhythmias, and drug toxicities.
在哺乳动物心室中，电梯度构成了电异质性，是优化机械效率和保障电稳定性的重要组织机制。电梯度塑造了哺乳动物心电图模式；电梯度的紊乱可引发心律失常。由于其出色地重现了人类心电图和心室动作电位特征，斑马鱼心脏成为了人类心脏电生理学的热门替代模型。然而，斑马鱼心室的电梯度在很大程度上尚未被探索。本研究旨在确定塑造斑马鱼心室电梯度的因素，这些电梯度会在基线状态和氧化应激下塑造 QRS 波群和 T 波的形态。
我们在成年斑马鱼心脏的体内心电图和体外电压敏感荧光心外膜和透壁光学标测中，分别在基线状态和急性 H2O2 暴露期间进行了研究。在基线状态下，心尖到基底的激活和基底到心尖的复极梯度解释了 QRS 波群和 T 波极性的一致性。在 H2O2 暴露期间，心尖和基底的激活和复极的区域性差异损害会先于基线电梯度发生，导致 QRS 波群和 T 波之间的极性一致性发生反转或丧失。KN-93，一种特定的钙/钙调蛋白依赖性蛋白激酶 II 抑制剂（CaMKII），可保护斑马鱼心脏免受 H2O2 对电梯度的破坏。如果在氧化应激暴露之前给药，保护作用是完全的。
尽管斑马鱼和人类心室心电图模式存在明显的相似之处，但它们是由相反的电梯度支持的镜像图像。与哺乳动物心室一样，斑马鱼心室也容易受到 H2O2 通过 CaMKII 激活引发的心律失常的影响。我们的研究结果表明，成年斑马鱼心脏可能构成一个具有临床相关性的模型，可用于研究氧化应激诱导的心室心律失常。然而，我们在本研究中发现的两种物种之间基本的心室激活和复极差异，突出了将斑马鱼实验结果外推到人类心脏电生理学、心律失常和药物毒性时存在的潜在局限性。
