Fan Xuehui, Yang Guoqiang, Kowitz Jacqueline, Duru Firat, Saguner Ardan M, Akin Ibrahim, Zhou Xiaobo, El-Battrawy Ibrahim
University of Mannheim, University of Heidelberg, Germany.
Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
Europace. 2022 Mar 2;24(3):481-493. doi: 10.1093/europace/euab214.
Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5-10% of SCDs, mainly in the young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype-phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype-phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.
在发达国家和发展中国家，心血管疾病是心源性猝死（SCD）的主要原因。遗传性心脏离子通道病与5%-10%的心源性猝死有关，主要发生在年轻人中。短QT综合征（SQTS）是一种罕见的遗传性离子通道病，可导致房性和室性快速性心律失常、晕厥，甚至心源性猝死。欧洲心脏病学会国际指南将以下内容列为诊断标准：（i）心电图上QTc≤340毫秒，（ii）QTc≤360毫秒，加上以下之一：存在影响短QT综合征的致病基因突变、短QT综合征家族史、心脏骤停未遂或年轻人心脏骤停家族史。然而，似乎需要对QTc范围进行进一步评估，这可以通过组建大型短QT队列并考虑对新描述的致病突变进行基因筛查来实现。由于短QT综合征心律失常发生的机制尚不清楚，因此仍缺乏针对短QT综合征的最佳治疗方法。该疾病较为罕见，在大量病例中存在不明确的基因型-表型相关性，并且缺乏国际短QT登记处，这限制了对短QT综合征心律失常发生的病理生理机制和治疗的研究。这就导致了研究短QT综合征的实验模型或平台的必要性。在此，我们重点回顾临床前短QT综合征模型和平台，如动物模型、异源表达系统、人诱导多能干细胞衍生的心肌细胞模型、计算机模型以及三维工程心脏组织。我们讨论它们在短QT综合征研究中对于检查基因型-表型关联、揭示疾病机制和测试药物的有用性。这些模型可能有助于为这种离子通道病的确切病理生理机制提供新的见解，并可能为改善短QT综合征患者的诊断和治疗提供机会。
