Human iPSC models of cardiac electrophysiology and arrhythmia

Cardiac arrhythmias and sudden cardiac death are a major cause of death worldwide. Defined as irregularities in heart rate or rhythm, arrhythmias can be caused by a variety of mechanisms, including abnormal automaticity, triggered activity, and reentry. Over the past decade, efforts allowing differentiation of cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from both healthy donors and those with cardiac disease have enabled invitro models of the human myocardium capable of recapitulating key functional, structural, and electrophysiological features of native tissue. Advances in these models have led to the generation of increasingly complex and physiologically relevant platforms, moving beyond the study of individual cells toward multidimensional networks of hiPSC-CMs that allow modeling of cardiac tissue as a functional syncytium. Though many hiPSC-derived myocardial models have been used to investigate cardiac electrophysiology and disease, few have explored the complex mechanisms of tissue-level arrhythmias and their contribution to myocardial pathogenesis. This chapter outlines existing single cell and multidimensional hiPSC-CM models of cardiac electrophysiology in the context of how they contribute to our understanding of tissue-level arrhythmia mechanisms in diseased states. We discuss not only the limitations but also the emerging uses of these models, and of hiPSC-CM technology more generally, in the context of modeling arrhythmia mechanisms. We also propose several design considerations for multicellular hiPSC-CM models so that they are better suited to investigate arrhythmogenic mechanisms on the tissue scale. We conclude with a brief discussion of broader relationships between tissue-level arrhythmias and other pathophysiologic mechanisms, such as metabolic disorders and inflammation.