Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, Japan 565-8565.
J Cardiovasc Transl Res. 2012 Apr;5(2):170-9. doi: 10.1007/s12265-012-9348-9. Epub 2012 Jan 21.
Heart failure (HF) is associated with anatomic and functional remodeling of cardiac tissues in both animal models and humans, which alters Ca(2+) homeostasis, protein phosphorylation, excitation-contraction coupling, results in arrhythmias. Indeed, the electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the dyssynchronously contracting heart. Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous left ventricular (LV) contraction (DHF), but the electrophysiological consequences of CRT are not fully understood. We demonstrated the molecular and cellular basis of excitability, conduction, and electrical remodeling in DHF and its restoration by CRT using a canine tachypacing HF model. CRT partially reversed the DHF-induced downregulation of K(+) current and improved Na(+) channel gating and abbreviated persistent (late) Na(+) current. CRT reduced Ca(2+)/calmodulin protein kinase II activity and restored transverse tubular system and spatial distribution of ryanodine receptor, thus it significantly improved Ca(2+) homeostasis especially in myocytes from late-activated, lateral wall and restored the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD and suppressed the development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca(2+) homeostasis, blunted β-adrenergic response, and regional heterogeneity of APD, thus it may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.
心力衰竭（HF）与动物模型和人类中心脏组织的解剖和功能重塑有关，这会改变 Ca（2+）稳态、蛋白磷酸化、兴奋-收缩偶联，导致心律失常。事实上，从衰竭心脏中分离的细胞和组织的电生理特征是动作电位时程（APD）延长和传导减慢。细胞和组织功能的变化在区域上是不均匀的，特别是在不同步收缩的心脏中。心脏再同步治疗（CRT）广泛应用于心力衰竭和左心室（LV）收缩不同步（DHF）的患者，但 CRT 的电生理后果尚未完全了解。我们使用犬快速起搏 HF 模型，证明了 DHF 中的兴奋性、传导和电重构的分子和细胞基础，以及 CRT 对其的恢复。CRT 部分逆转了 DHF 诱导的 K（+）电流下调，并改善了 Na（+）通道门控和缩短持续（晚期）Na（+）电流。CRT 降低了 Ca（2+）/钙调蛋白蛋白激酶 II 活性，并恢复了横管系统和兰尼碱受体的空间分布，从而显著改善了 Ca（2+）稳态，特别是在晚期激活的、侧壁的心肌细胞中，并恢复了 DHF 诱导的β-肾上腺素能受体反应性减弱。CRT 缩短了 DHF 诱导的侧壁心肌细胞 APD 延长，并降低了 LV 区域 APD 梯度，并抑制了早期后除极的发展。总之，CRT 部分恢复了 DHF 诱导的离子通道重塑、异常的 Ca（2+）稳态、β-肾上腺素能反应减弱和 APD 的区域异质性，因此它可能抑制室性心律失常，并有助于 CRT 的死亡率获益以及改善心脏的机械性能。
