Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiology Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan 646000, China.
Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
Oxid Med Cell Longev. 2022 Mar 28;2022:8538296. doi: 10.1155/2022/8538296. eCollection 2022.
Ageing is one of the risk factors associated with cardiovascular diseases including cardiac arrhythmias and heart failure. Ageing-related cardiac dysfunction involves a complicated pathophysiological progress. Abnormal membrane voltage and Ca dynamics in aged cardiomyocytes contribute to ageing-related arrhythmias. However, its underlying mechanisms have not been well clarified.
Young and old rats or mice were included in this study. Cardiac electrophysiological properties and functions were assessed by ECG, echocardiography, and ex vivo heart voltage and Ca optical mapping. Proteomics, phosphor-proteomics, Western blotting, Masson staining, and ROS measurement were used to investigate the underlying mechanisms.
Ageing increased the incidence of cardiac hypertrophy and fibrosis in rats. Moreover, ageing increased the occurrence of ventricular tachycardia or ventricular fibrillation induced by rapid pacing and during isoprenaline (ISO) (1 mg/kg i.p.) challenge in mice . Optical mapping with dual dyes (membrane voltage ( ) dye and intracellular Ca dye) simultaneously recording revealed that ageing increased the action potential duration (APD) and Ca transient duration (CaTD) and slowed the ventricular conduction with the Langendorff-perfused mouse heart. More importantly, ageing increased the ISO-induced (1 M) changes of APD (APD80) and CaTD (CaTD50). Ageing also delayed the decay of Ca transient by extending the decay time constant from 30% to 90% ( ). In addition, ageing decreased the / latency which represented the coupling of / including between the midpoint of AP depolarization and Ca upstroke, peak transmembrane voltage and peak cytosolic calcium, and time to 50% voltage repolarization and extrusion of cytosolic calcium. Optical mapping also revealed that ageing increased the ISO-induced arrhythmia incidence and occurrence of the excitation rotor. Proteomics and phosphor-proteomics assays from rat hearts demonstrated ageing-induced protein and phosphor-protein changes, suggesting that CaMKII was involved in ageing-induced change. Ageing increased the level of ROS and the expression of NOX4, oxidative CaMKII (ox-CaMKII), phosphorated CaMKII (p-CaMKII), and periostin.
Ageing accelerates cardiac remodelling and increases the susceptibility to ventricular arrhythmias through NOX4/ROS/CaMKII pathway-mediated abnormal membrane voltage and intracellular Ca handling and / coupling.
衰老与心血管疾病（包括心律失常和心力衰竭）有关，是其风险因素之一。与衰老相关的心脏功能障碍涉及复杂的病理生理过程。衰老心肌细胞的膜电压和钙动力学异常导致与衰老相关的心律失常。然而，其潜在机制尚未得到很好的阐明。
本研究纳入了年轻和老年大鼠或小鼠。通过心电图、超声心动图和离体心脏电压和钙光学映射评估心脏电生理特性和功能。蛋白质组学、磷酸化蛋白质组学、Western blot、Masson 染色和 ROS 测量用于研究潜在机制。
衰老使大鼠心脏肥大和纤维化的发生率增加。此外，衰老增加了快速起搏和异丙肾上腺素（ISO）（1mg/kg，腹腔注射）刺激下诱导的心室性心动过速或心室颤动的发生在小鼠中。用双染料（膜电压（）染料和细胞内钙染料）同时记录的光学映射显示，衰老增加了动作电位时程（APD）和钙瞬变时程（CaTD），并使 Langendorff 灌流小鼠心脏的心室传导速度减慢。更重要的是，衰老增加了 ISO 诱导的 APD（APD80）和 CaTD（CaTD50）变化。衰老还通过延长从 30%到 90%的钙瞬变衰减时间常数（）来延迟钙瞬变的衰减。此外，衰老降低了代表 AP 去极化和 Ca 内流中点与跨膜电压峰值和细胞溶质钙峰值以及 50%电压复极化和细胞溶质钙排出之间偶联的 / 潜伏期。光学映射还显示，衰老增加了 ISO 诱导的心律失常发生率和兴奋转子的发生。从大鼠心脏进行蛋白质组学和磷酸化蛋白质组学检测表明，衰老诱导了蛋白质和磷酸化蛋白质的变化，提示 CaMKII 参与了衰老诱导的变化。衰老增加了 ROS 水平和 NOX4、氧化型 CaMKII（ox-CaMKII）、磷酸化 CaMKII（p-CaMKII）和 periostin 的表达。
衰老通过 NOX4/ROS/CaMKII 通路介导的异常膜电压和细胞内钙处理以及 / 偶联加速心脏重塑，并增加心室性心律失常的易感性。
