Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Abstract

Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

Inspiration from heart development: Biomimetic development of functional human cardiac organoids

“…Despite immature characteristics of cardiac organoids compared to adult ventricular tissue, the presence of fundamental physiological cardiac functions provided a basis for exploring critical pathways involved in cardiac pathologies, supported by recent progress using hiPSC-CMs for cardiac pathophysiology insights (12, 86–89). Particularly, cardiac organoids have potential to serve as an in vitro cardiac model for ischemic heart failure, which makes up the majority of cardiovascular-related disorders (90).…”

Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

“…To investigate the role of chromatin dynamics in cardiac laminopathy, we took advantage of hiPSCs 155 bearing a heterozygous nonsense mutation in LMNA predicted to cause premature truncation of both 156 lamin A and lamin C splicing isoforms (c.672C>T, resulting in p.Arg225*, which we will refer to as R225X; 157 It is well established that variability among hiPSC lines can profoundly influence both molecular and 164 cellular phenotypes (Ortmann and Vallier, 2017), which is particularly evident when assessing the 165 complex electrophysiology and contractile properties of hiPSC-CMs (Sala et al, 2017). Thus, we decided 166 to generate isogenic control hiPSCs by correcting the R225X mutation back to the wild-type allele, a 167 strategy currently considered the gold standard to determine the association between genotype and 168 phenotype in hiPSC-CMs (Bellin et al, 2013;Kodo et al, 2016;Mosqueira et al, 2018).…”

Drug‐induced Proarrhythmia and Torsade de Pointes: A Primer for Students and Practitioners of Medicine and Pharmacy

“…Additional references are provided. [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82]…”