Cameron Breanne A, Baumeister Peter A, Lawen Tarek, Rafferty Sara A, Taeb Behzad, Stoyek Matthew R, Greiner Joachim, Uzelac Ilija, Fenton Flavio H, Peyronnet Rémi, Kohl Peter, Quinn T Alexander
Department of Physiology and Biophysics (B.A.C., P.A.B., T.L., S.A.R., B.T., M.R.S., T.A.Q.), Dalhousie University, Halifax, Nova Scotia, Canada.
Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen and Faculty of Medicine (B.A.C., J.G., R.P., P.K.), University of Freiburg, Germany.
Circ Res. 2025 Jul 18;137(3):363-382. doi: 10.1161/CIRCRESAHA.124.326057. Epub 2025 Jun 2.
The heart's mechanical state feeds back to its electrical activity, potentially contributing to arrhythmias. Mechano-arrhythmogenesis has been mechanistically explained during electrical diastole, when cardiomyocytes are at their resting membrane potential. During electrical systole, cardiomyocytes are refractory right after the onset of depolarization, while during repolarization in physiological conditions, they seem to be protected from systolic mechano-arrhythmogenesis by near-simultaneous restoration of resting membrane potential and cytosolic calcium concentration ([Ca]): repolarization-relaxation coupling (RRC). Yet, late-systolic mechano-arrhythmogenesis has been reported in ischemic myocardium, with unclear underlying mechanisms. We hypothesize that ischemia-induced alteration of RRC gives rise to a vulnerable period for mechano-arrhythmogenesis.
Acute left ventricular regional ischemia was induced by coronary artery ligation in Langendorff-perfused rabbit hearts, with mechanical load controlled by an intraventricular balloon. Mechanical activity was assessed by echocardiography and arrhythmia incidence by ECG. Single left ventricular cardiomyocytes were exposed to simulated ischemia or pinacidil (ATP-sensitive potassium channel opener). Stretch was applied in diastole or late systole using carbon fibers. Stretch characteristics and arrhythmia incidence were assessed by sarcomere length measurement. In both models, RRC was assessed by simultaneous voltage-[Ca] fluorescence imaging and mechano-arrhythmogenesis mechanisms were pharmacologically tested.
In whole hearts, acute regional ischemia leads to systolic stretch and disturbed RRC at the ischemic border. These electro-mechanical changes were associated with waves of arrhythmias, which could be reduced by mechanical unloading, electro-mechanical uncoupling, or buffering of [Ca]. In left ventricular cardiomyocytes, physiological RRC is associated with a low incidence of systolic mechano-arrhythmogenesis, while a vulnerable period emerged by prolonged RRC during ischemia. The increase in systolic mechano-arrhythmogenesis was reduced by restoring RRC, chelating [Ca], blocking mechano-sensitive TRPA1 (transient receptor potential ankyrin 1) channels, or buffering reactive oxygen species levels.
Prolonged RRC allows for late-systolic mechano-arrhythmogenesis in acute ischemia, involving contributions of elevated [Ca], TRPA1 activity, and reactive oxygen species, which represent potential antiarrhythmic targets.
心脏的机械状态会反馈至其电活动，这可能是心律失常的成因之一。机械性心律失常的发生机制已在电舒张期得到解释，此时心肌细胞处于静息膜电位。在电收缩期，心肌细胞在去极化开始后即进入不应期，而在生理条件下的复极化过程中，静息膜电位和胞质钙浓度（[Ca]）近乎同时恢复，即复极化 - 舒张偶联（RRC），这似乎能保护心肌细胞免受收缩期机械性心律失常的影响。然而，已有报道称在缺血心肌中会发生收缩晚期机械性心律失常，但其潜在机制尚不清楚。我们推测，缺血诱导的RRC改变会引发机械性心律失常的易损期。
在Langendorff灌注的兔心脏中通过冠状动脉结扎诱导急性左心室局部缺血，通过心室内球囊控制机械负荷。通过超声心动图评估机械活动，通过心电图评估心律失常发生率。将单个左心室心肌细胞暴露于模拟缺血或吡那地尔（ATP敏感性钾通道开放剂）中。在舒张期或收缩晚期使用碳纤维施加拉伸。通过肌节长度测量评估拉伸特征和心律失常发生率。在两个模型中，通过同步电压 - [Ca]荧光成像评估RRC，并对机械性心律失常的发生机制进行药理学测试。
在完整心脏中，急性局部缺血会导致缺血边界处的收缩期拉伸和RRC紊乱。这些电 - 机械变化与心律失常波相关，通过机械卸载、电 - 机械解偶联或[Ca]缓冲可减少心律失常。在左心室心肌细胞中，生理性RRC与收缩期机械性心律失常的低发生率相关，而在缺血期间RRC延长会出现一个易损期。通过恢复RRC、螯合[Ca]、阻断机械敏感的TRPA1（瞬时受体电位锚蛋白1）通道或缓冲活性氧水平，可降低收缩期机械性心律失常的增加。
在急性缺血中，RRC延长会导致收缩晚期机械性心律失常，涉及升高的[Ca]、TRPA1活性和活性氧的作用，这些代表了潜在的抗心律失常靶点。
