Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.
Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.
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DOI：
10.1093/cvr/cvaa018
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发表时间：
2020-01
影响因子：
10.8
通讯作者：
Dongze Zhang;H. Tu;Chaojun Wang;Liang Cao;Wenfeng Hu;Bryan T. Hackfort;R. Muelleman;M. Wadman;Yu-Long Li
中科院分区：
文献类型：
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作者：
Dongze Zhang;H. Tu;Chaojun Wang;Liang Cao;Wenfeng Hu;Bryan T. Hackfort;R. Muelleman;M. Wadman;Yu-Long Li
目的 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重要触发因素。我们之前的研究表明，CHF 患者心脏交感神经节后 (CSP) 神经元中的 N 型钙 (Cav2.2) 电流增加。本研究调查了 Cav2.2 通道在 CHF 心脏交感神经过度激活和室性心律失常发生中的作用。方法与结果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 在体内转染到 CHF 大鼠的星状神经节 (SG) 中。最终实验在冠状动脉结扎后14周进行。实时PCR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 CHF 大鼠的 Cav2.2 电流和 CSP 神经元的细胞兴奋性，并减弱了心脏交感神经活动 (CSNA)。心率变异性 (HRV) 的功率谱分析进一步表明，在 SG 中转染 Cav2.2-α shRNA 可使 CHF 正常化，导致清醒大鼠的心脏交感神经过度激活。 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/颤动 (VT/VF) 的发生率和持续时间，而且还改善了清醒 CHF 大鼠中由 CHF 诱导的心室电活动的异质性。 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 诱导的心脏收缩功能障碍。乱序 shRNA 不影响 CHF 大鼠的 Cav2.2 电流和 CSP 神经元的细胞兴奋性、CSNA、HRV 和室性心律失常发生。结论 CSP 神经元中 Cav2.2 通道的过度激活导致 CHF 患者心脏交感神经过度激活和室性心律失常发生。这表明发现纯选择性且有效的小分子 Cav2.2 通道阻滞剂可能是减少 CHF 致命性室性心律失常的潜在治疗策略。翻译视角我们目前的研究表明，抑制 CSP 神经元中的 N 型 Ca2+ 通道可以减轻 CHF 诱导的心脏交感神经过度激活和室性心律失常。这项研究的临床意义是为治疗CHF患者致命性室性心律失常开辟一条新途径。 CSP 神经元中的 N 型 Ca2+ 通道可能成为 CHF 中心脏交感神经过度激活和室性心律失常的新治疗靶点。探索具有局部靶向给药系统的特异性小分子 N 型 Ca2+ 通道阻滞剂可以转化为改善 CHF 患者预后的临床试验和应用。
AIMS 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 postganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. METHODS AND RESULTS 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 PCR 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 ECG recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/fibrillation (VT/VF), 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 anesthetized 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. CONCLUSIONS 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. TRANSLATIONAL PERSPECTIVES Our present study demonstrates that inhibition of N-type Ca2+ channels in CSP neurons attenuates CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias. The clinical significance of this study is to open a new avenue in therapeutics working against lethal ventricular arrhythmias in patients with CHF. N-type Ca2+ channels in CSP neurons could be a new therapeutic target for cardiac sympathetic overactivation and ventricular arrhythmias in CHF. Exploring specific, small-molecule N-type Ca2+ channel blockers with local targeting drug delivery system could translate to clinical trials and applications that improve outcomes for patients with CHF.