Assessment of Cardiotoxicity With Stem Cell-based Strategies

TY - JOUR

T1 - Assessment of Cardiotoxicity With Stem Cell-based Strategies

AU - Stoter, Aaltje Maria Stella Sterre

AU - Hirt, Marc N

AU - Stenzig, Justus

AU - Weinberger, Florian

N1 - Copyright © 2020 Elsevier Inc. All rights reserved.

PY - 2020/10

Y1 - 2020/10

N2 - PURPOSE: Adverse cardiovascular drug effects pose a substantial medical risk and represent a common cause of drug withdrawal from the market. Thus, current in vitro assays and in vivo animal models still have shortcomings in assessing cardiotoxicity. A human model for more accurate preclinical cardiotoxicity assessment is highly desirable. Current differentiation protocols allow for the generation of human pluripotent stem cell-derived cardiomyocytes in basically unlimited numbers and offer the opportunity to study drug effects on human cardiomyocytes. The purpose of this review is to provide a brief overview of the current approaches to translate studies with pluripotent stem cell-derived cardiomyocytes from basic science to preclinical risk assessment.METHODS: A review of the literature was performed to gather data on the pathophysiology of cardiotoxicity, the current cardiotoxicity screening assays, stem cell-derived cardiomyocytes, and their application in cardiotoxicity screening.FINDINGS: There is increasing evidence that stem cell-derived cardiomyocytes predict arrhythmogenicity with high accuracy. Cardiomyocyte immaturity represents the major limitation so far. However, strategies are being developed to overcome this hurdle, such as tissue engineering. In addition, stem cell-based strategies offer the possibility to assess structural drug toxicity (eg, by anticancer drugs) on complex models that more closely mirror the structure of the heart and contain endothelial cells and fibroblasts.IMPLICATIONS: Pluripotent stem cell-derived cardiomyocytes have the potential to substantially change how preclinical cardiotoxicity screening is performed. To which extent they will replace or complement current approaches is being evaluated.

AB - PURPOSE: Adverse cardiovascular drug effects pose a substantial medical risk and represent a common cause of drug withdrawal from the market. Thus, current in vitro assays and in vivo animal models still have shortcomings in assessing cardiotoxicity. A human model for more accurate preclinical cardiotoxicity assessment is highly desirable. Current differentiation protocols allow for the generation of human pluripotent stem cell-derived cardiomyocytes in basically unlimited numbers and offer the opportunity to study drug effects on human cardiomyocytes. The purpose of this review is to provide a brief overview of the current approaches to translate studies with pluripotent stem cell-derived cardiomyocytes from basic science to preclinical risk assessment.METHODS: A review of the literature was performed to gather data on the pathophysiology of cardiotoxicity, the current cardiotoxicity screening assays, stem cell-derived cardiomyocytes, and their application in cardiotoxicity screening.FINDINGS: There is increasing evidence that stem cell-derived cardiomyocytes predict arrhythmogenicity with high accuracy. Cardiomyocyte immaturity represents the major limitation so far. However, strategies are being developed to overcome this hurdle, such as tissue engineering. In addition, stem cell-based strategies offer the possibility to assess structural drug toxicity (eg, by anticancer drugs) on complex models that more closely mirror the structure of the heart and contain endothelial cells and fibroblasts.IMPLICATIONS: Pluripotent stem cell-derived cardiomyocytes have the potential to substantially change how preclinical cardiotoxicity screening is performed. To which extent they will replace or complement current approaches is being evaluated.

U2 - 10.1016/j.clinthera.2020.08.012

DO - 10.1016/j.clinthera.2020.08.012

M3 - SCORING: Review article

C2 - 32938533

VL - 42

SP - 1892

EP - 1910

JO - CLIN THER

JF - CLIN THER

SN - 0149-2918

IS - 10

ER -