Disease modeling of cardiac arrhythmias using human induced pluripotent stem cells

ABSTRACT

Introduction: Inherited arrhythmias are an uncommon, but malignant family of cardiac diseases that result from genetic abnormalities in the ion channels and/or structural proteins within cardiomyocytes. Given the inherent differences between species and the limited reproducibility of in vitro heterologous cell models, progress in understanding the mechanisms underlying these malignant diseases has always languished far behind the clinical science and need. The ability to study human induced pluripotent stem cells (iPSCs) derived cardiomyocytes promises to change this paradigm as patient cells have the potential to become testing platforms for disease phenotyping or therapeutic discovery.

Areas covered: This review will outline methods developed to genetically reprogram adult cells into iPSCs, differentiate iPSCs into ex vivo models of adult cardiac tissue and iPSCs-based progress in exploring the mechanisms underlying pro-arrhythmic disease phenotypes.

Expert opinion: Despite being discovered less than 15 years ago, several studies have successfully leveraged iPSCs-derived cardiomyocytes to study malignant arrhythmogenic diseases. These models promise to increase our understanding of the pathophysiology underlying these complex diseases and may identify personalized approaches to treatment.

KEYWORDS:

• Induced pluripotent stem cell
• cell model
• cardiac arrhythmia
• sudden death
• genetics
• cardiac electrophysiology

Article highlights

• Therapeutic advances in the field of inherited cardiac arrhythmias are currently leveraged on broad generalizations between disease phenotypes with rare input from individual mutations.

• Techniques to stimulate the transition of blood or skin cells into cardiomyocytes promises to make patient cells testing platforms for disease phenotyping or therapeutic discovery.

• Albeit promising, the ability of reprogrammed cells to faithfully recapitulate adult cardiomyopathies is still challenged by the extent of cardiomyogenesis, breadth of cardiac cell subtypes and relative maturity of cells in culture.

• Despite these limitations, an emerging body of evidence has shown patient-derived cardiomyocytes recapitulate many the key defects that cause the disease permitting mechanistic validation and diagnosis for variants of unknown significance.

• In the future, this work will undoubtedly facilitate therapeutic development and early identification of cardiotoxic or ineffective candidates.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Canadian Institutes of Health Research under Grant MC2-121291.