Segal Sofia, Arbel-Ganon Limor, Mazgaoker Savyon, Davoodi Moran, Yaniv Yael
Laboratory of Bioenergetic and Bioelectric Systems, Faculty of Biomedical Engineering, Technion-IIT, Haifa, Israel.
Front Physiol. 2022 May 11;13:839140. doi: 10.3389/fphys.2022.839140. eCollection 2022.
Bradycardia or tachycardia are known side effects of drugs that limit their clinical use. The heart pacemaker function which control the heart rate under normal conditions is determined by coupled clock system. Thus, interfering with specific clock mechanism will affect other clock mechanisms through changes in interconnected signaling and can lead to rhythm disturbance. However, upregulation of a different clock components can compensate for this change. We focus here on hydroxychloroquine (HCQ), which has been shown effective in treating COVID-19 patients, however its bradycardic side effect limits its clinical use. We aim to decipher the mechanisms underlying the effect of HCQ on pacemaker automaticity, to identify a potential drug that will eliminate the bradycardia. We used isolated rabbit sinoatrial node (SAN) cells, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and mouse SAN cells residing in SAN tissue. Further, we employed SAN cell computational model to suggest mechanistic insights of the effect of HCQ on pacemaker function. HCQ increased mean spontaneous beat interval and variability in all three models in parallel to slower intracellular kinetics. The computational model suggested that HCQ affects the pacemaker (funny) current (I), L-type Ca current (I), transient outward potassium (I) and due to changes in Ca kinetics, the sodium-calcium exchanger current (I). Co-application of 3'-isobutylmethylxanthine (IBMX) and HCQ prevented the increase in beat interval and variability in all three experimental models. The HCQ-induced increase in rabbit and mice SAN cell and hiPSC-CM spontaneous beat interval, can be prevented by a phosphodiester inhibitor that restores automaticity due to slower intracellular Ca kinetics.
心动过缓或心动过速是已知的药物副作用，这限制了它们的临床应用。在正常情况下控制心率的心脏起搏器功能由耦合时钟系统决定。因此，干扰特定的时钟机制会通过相互连接的信号变化影响其他时钟机制，并可能导致节律紊乱。然而，上调不同的时钟组件可以补偿这种变化。我们在此聚焦于羟氯喹（HCQ），它已被证明对治疗新冠肺炎患者有效，但其心动过缓的副作用限制了其临床应用。我们旨在破解HCQ对起搏器自律性影响的潜在机制，以确定一种能消除心动过缓的潜在药物。我们使用了分离的兔窦房结（SAN）细胞、人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）以及位于SAN组织中的小鼠SAN细胞。此外，我们采用了SAN细胞计算模型来揭示HCQ对起搏器功能影响的机制性见解。在所有三种模型中，HCQ均增加了平均自发搏动间隔和变异性，同时细胞内动力学变慢。计算模型表明，HCQ影响起搏（起搏）电流（I）、L型钙电流（I）、瞬时外向钾电流（I），并且由于钙动力学的变化，还影响钠钙交换电流（I）。联合应用3'-异丁基甲基黄嘌呤（IBMX）和HCQ可防止所有三种实验模型中的搏动间隔和变异性增加。磷酸二酯酶抑制剂可恢复因细胞内钙动力学变慢而导致的自律性，从而防止HCQ引起的兔和小鼠SAN细胞以及hiPSC-CM自发搏动间隔增加。
