Modeling sarcomeric cardiomyopathies with human cardiomyocytes derived from induced pluripotent stem cells.

Cardiomyocytes derived from human induced pluripotent stem cells (iPSCs) provide a unique opportunity to understand the pathophysiological effects of genetic cardiomyopathy mutations. In particular, these cells hold the potential to unmask the effects of mutations on contractile behavior in vitro, providing new insights into genotype-phenotype relationships. With this goal in mind, several groups have established iPSC lines that contain sarcomeric gene mutations linked to cardiomyopathy in patient populations. Their studies have employed diverse systems and methods for performing mechanical measurements of contractility, ranging from single cell techniques to multicellular tissue-like constructs. Here, we review published results to date within the growing field of iPSC-based sarcomeric cardiomyopathy disease models. We devote special attention to the methods of mechanical characterization selected in each case, and how these relate to the paradigms of classical muscle mechanics. An appreciation of these somewhat subtle paradigms can inform efforts to compare the results of different studies and possibly reconcile discrepancies. Although more work remains to be done to improve and possibly standardize methods for producing, maturing, and mechanically interrogating iPSC-derived cardiomyocytes, the initial results indicate that this approach to modeling cardiomyopathies will continue to provide critical insights into these devastating diseases. In this review, we describe current progress in the field of modeling sarcomeric cardiomyopathies using induced pluripotent stem cell-derived cardiomyocytes. In many cases, these models have been developed for the purpose of characterizing the contractile phenotype that underlies disease. We discuss the various methods that have been employed to measure contractile behavior of iPSC-derived cardiomyocytes and provide an overview of the phenotypic data that is accumulating from these studies.2 This article is protected by copyright. All rights reserved.