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Top Things to Know:
Use of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes in Preclinical Cancer Drug Cardiotoxicity Testing

  1. Many lifesaving oncology drugs may adversely affect the heart and CV system, causing irreversible cardiac injury that can result in reduced quality of life.
  2. The emergence of human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) as an in vitro research tool holds great promise for understanding drug-induced cardiotoxicity.
  3. This statement reviews the current challenges of cardio-oncology, strengths and limitations of using hiPSC-CMs to represent clinical findings in the non-clinical research space, and future directions for their further use.
  4. Molecular and cellular mechanisms of cardiotoxicity are diverse and complex, reflecting the interactions of drug effects, diverse pathways, and underlying pathologies of the CV system.
  5. Rigorous analysis of cardiotoxicity of oncological drugs is needed to inform patient care and benchmark the utility of hiPSC-CM models and biomarkers for the early detection of cardiotoxicity.
  6. Preparation and generation of hiPSC-CMs of different levels of complexity and maturation, and the use of standardized protocols, will enable a best practice for cardiotoxicity assays to be developed with universal applications.
  7. Genome editing of hiPSC-CMs is valuable to delineate the pathogenicity of variants of uncertain significance in patients with suspected cardiomyopathy and channelopathy.
  8. Clinical studies evaluating the use of biomarkers for the early detection of cardiotoxicity are continuing and will provide guidance for non-clinical in vitro studies of cardiotoxicity using hiPSC-CMs.
  9. Work is still needed to ensure reproducibility and define standards of myocyte-based preparations and experimental protocols to avoid incorrect decisions guiding personalized patient care.
  10. Although the application of hiPSC-CMs for prediction of cardiotoxicity is in the early stage, they provide a novel approach to individualized cardiotoxicity testing that may prove better at protecting patients and promoting future drug development efforts.

Citation

Gintant G, Burridge P, Gepstein L, Harding S, Herron T, Hong C, Jalife J, Wu JC, on behalf of the American Heart Association Council on Basic Cardiovascular Sciences. Use of human induced pluripotent stem cell–derived cardiomyocytes in preclinical cancer drug cardiotoxicity testing: a scientific statement from the American Heart Association [published online ahead of print September 19, 2019]. Circ Res. doi: 10.1161/RES.0000000000000291.