Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
Pathology Sciences, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
Sci Rep. 2018 Jul 5;8(1):10160. doi: 10.1038/s41598-018-28393-y.
Pharmaceutical agents despite their efficacy to treat disease can cause additional unwanted cardiovascular side effects. Cardiotoxicity is characterized by changes in either the function and/or structure of the myocardium. Over recent years, functional cardiotoxicity has received much attention, however morphological damage to the myocardium and/or loss of viability still requires improved detection and mechanistic insights. A human 3D cardiac microtissue containing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblasts was used to assess their suitability to detect drug induced changes in cardiac structure. Histology and clinical pathology confirmed these cardiac microtissues were morphologically intact, lacked a necrotic/apoptotic core and contained all relevant cell constituents. High-throughput methods to assess mitochondrial membrane potential, endoplasmic reticulum integrity and cellular viability were developed and 15 FDA approved structural cardiotoxins and 14 FDA approved non-structural cardiotoxins were evaluated. We report that cardiac microtissues provide a high-throughput experimental model that is both able to detect changes in cardiac structure at clinically relevant concentrations and provide insights into the phenotypic mechanisms of this liability.
尽管药物在治疗疾病方面具有疗效，但它们也可能引起额外的心血管不良副作用。心脏毒性的特征是心肌的功能和/或结构发生变化。近年来，功能性心脏毒性受到了广泛关注，然而，心肌的形态损伤和/或活力丧失仍需要更好的检测和机制洞察力。一种包含人诱导多能干细胞衍生的心肌细胞（hiPS-CMs）、心脏内皮细胞和心脏成纤维细胞的人 3D 心脏微组织被用于评估其检测药物引起的心脏结构变化的适用性。组织学和临床病理学证实，这些心脏微组织形态完整，没有坏死/凋亡核心，并且包含所有相关的细胞成分。开发了高通量方法来评估线粒体膜电位、内质网完整性和细胞活力，并评估了 15 种 FDA 批准的结构性心脏毒素和 14 种 FDA 批准的非结构性心脏毒素。我们报告称，心脏微组织提供了一种高通量的实验模型，既能在临床相关浓度下检测到心脏结构的变化，又能深入了解这种不良反应的表型机制。
