Advanced Cardiovascular Toxicity Screening: Integrating Human iPSC-Derived Cardiomyocytes with 2D In Silico Models.

IF 3.7 3区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Toxicology Pub Date : 2025-05-01 Epub Date: 2025-03-28 DOI:10.1007/s12012-025-09987-1

Anastasiya Sinitsyna, Andrey Berezhnoy, Ivan Semidetnov, Vadim Naumov, Tatyana Sergeeva, Sergey Bakumenko, Mikhail Slotvitsky, Valeriya Tsvelaya, Konstantin Agladze

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Abstract

The pharmaceutical industry is evolving with the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT-interval prolongation as a main arrhythmogenicity marker is being challenged. In addition, the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as a more comprehensive approach for arrhythmogenicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess the potential arrhythmogenic effect of drug-induced impact on ionic currents and electrophysiological intercellular coupling. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modeling. We show, using the examples of lidocaine (100-300 μM) and Cyclophosphamide (639, 852 μM), that with the use of an integrative experimental and computer platform, it is possible to correctly display the clinical manifestations of side effects in advance.

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先进的心血管毒性筛选：整合人类ipsc衍生的心肌细胞与二维硅模型。

随着人类诱导多能干细胞衍生心肌细胞（hiPSC-CM）用于体外心脏安全性筛选，制药行业正在发展。传统上依赖qt间期延长作为心律失常的主要标志正在受到挑战。此外，综合体外心律失常原测定（CiPA）倡议建议使用计算机建模和计算机平台作为结合hiPSC-CM体外筛选的更全面的致心律失常性检测方法。我们的研究提出了一个创新的平台，将体外hiPSC-CM繁殖试验与硅模型相结合，以评估药物诱导的对离子电流和电生理细胞间偶联的潜在致心律失常作用。利用hiPSC-CM的电生理和形态学特征，我们通过计算机建模对潜在的药物性心脏风险进行了全面评估。我们以利多卡因（100-300 μM）和环磷酰胺（639,852 μM）为例，通过实验和计算机集成平台，可以提前正确显示副作用的临床表现。

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来源期刊

Cardiovascular Toxicology 医学-毒理学

CiteScore

6.60

自引率

3.10%

发文量

审稿时长

>12 weeks

期刊介绍： Cardiovascular Toxicology is the only journal dedicated to publishing contemporary issues, timely reviews, and experimental and clinical data on toxicological aspects of cardiovascular disease. CT publishes papers that will elucidate the effects, molecular mechanisms, and signaling pathways of environmental toxicants on the cardiovascular system. Also covered are the detrimental effects of new cardiovascular drugs, and cardiovascular effects of non-cardiovascular drugs, anti-cancer chemotherapy, and gene therapy. In addition, Cardiovascular Toxicology reports safety and toxicological data on new cardiovascular and non-cardiovascular drugs.