TeBay Clifford, McArthur Jeffrey R, Mangala Melissa, Kerr Nicholas, Heitmann Stewart, Perry Matthew D, Windley Monique J, Vandenberg Jamie I, Hill Adam P
Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia.
Br J Pharmacol. 2022 Jun;179(11):2631-2646. doi: 10.1111/bph.15757. Epub 2022 Jan 27.
Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat coronavirus disease 2019 (COVID-19). While concern already existed around their proarrhythmic potential, there are little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles.
Potency of human ether-à-go-go related gene (hERG) block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals.
Chloroquine and hydroxychloroquine blocked hERG with IC of 1.47 ± 0.07 and 3.78 ± 0.17 μM, respectively, indicating proarrhythmic risk at concentrations effective against severe acute respiratory syndrome-coronovirus-2 (SARS-CoV-2) in vitro. Hypokalaemia and hypermagnesaemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure and identified specific genetic backgrounds associated with emergence of arrhythmia.
Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations, can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.
羟氯喹、氯喹和阿奇霉素是三种被提议用于治疗2019冠状病毒病（COVID-19）的药物。尽管人们已经对它们的促心律失常潜力有所担忧，但关于发热状态、电解质失衡或酸中毒等患者所经历的生理状态改变如何可能改变其风险特征的数据却很少。
在存在可变环境因素的情况下，使用高通量电生理学测量人醚-à-去相关基因（hERG）阻断的效力。这些效力为预测群体风险特征的模拟提供了依据。在来自多个个体的人诱导多能干细胞衍生的心肌细胞中验证了对心脏复极化的影响。
氯喹和羟氯喹分别以1.47±0.07和3.78±0.17μM的半数抑制浓度（IC）阻断hERG，表明在体外对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）有效的浓度下存在促心律失常风险。低钾血症和高镁血症增加了氯喹和羟氯喹的效力，表明促心律失常风险增加。酸中毒显著降低了所有药物的效力，而温度升高降低了氯喹和羟氯喹对hERG的效力，但增加了阿奇霉素的效力。计算机模拟表明，女性性别、低钾血症和心力衰竭会增加促心律失常风险，并确定了与心律失常出现相关的特定遗传背景。
我们的研究表明代谢变化和既有疾病如何可能加剧促心律失常风险。更广泛地说，该研究为高通量体外筛选与计算机模拟相结合如何有助于指导与具有延长复极化潜力药物相关的患者的临床前筛选和临床管理提供了蓝图。
