Department of Emergency Medicine, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Department of Cardiovascular Disease, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Cardiovasc Res. 2021 Jan 1;117(1):137-148. doi: 10.1093/cvr/cvaa018.
Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF.
Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats.
Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.
心脏交感神经过度激活是慢性心力衰竭（CHF）患者室性心律失常的一个重要触发因素。我们之前的研究表明，CHF 中心脏交感节后神经元（CSP）中的 N 型钙（Cav2.2）电流增加。本研究旨在探讨 Cav2.2 通道在 CHF 中心脏交感神经过度激活和室性心律失常发生中的作用。
通过手术结扎左冠状动脉诱导大鼠 CHF。慢病毒 Cav2.2-α shRNA 或乱序 shRNA 在体内转染 CHF 大鼠的星状神经节（SG）。在冠状动脉结扎后 14 周进行最终实验。实时聚合酶链反应和 Western blot 数据显示，体内转染 Cav2.2-α shRNA 可降低 CHF 大鼠 SG 中 Cav2.2-α mRNA 和蛋白的表达。Cav2.2-α shRNA 还降低了 CSP 神经元的 Cav2.2 电流和细胞兴奋性，并减弱了 CHF 大鼠的心脏交感神经活动（CSNA）。心率变异性（HRV）的功率谱分析进一步表明，SG 中转染 Cav2.2-α shRNA 可使 CHF 引起的清醒大鼠心脏交感神经过度激活正常化。24 小时连续遥测心电图记录显示，这种 Cav2.2-α shRNA 不仅降低了室性心动过速/心室颤动的发生率和持续时间，而且改善了清醒 CHF 大鼠心脏电活动的不均一性。Cav2.2-α shRNA 还降低了麻醉 CHF 大鼠对室性心律失常的易感性。然而，Cav2.2-α shRNA 未能改善 CHF 引起的心脏收缩功能障碍。乱序 shRNA 不影响 CHF 大鼠 CSP 神经元的 Cav2.2 电流和细胞兴奋性、CSNA、HRV 和室性心律失常的发生。
CSP 神经元中 Cav2.2 通道的过度激活导致 CHF 中心脏交感神经过度激活和室性心律失常的发生。这表明，发现纯选择性和有效力的小分子 Cav2.2 通道阻滞剂可能是减少 CHF 中致命性室性心律失常的一种潜在治疗策略。
