Heart-on-a-Chip Model for Cardiomyopathies

Copyright: Joshi-Mukherjee R© 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Cardiovascular disease is the number one cause of death in the US. According to US Center for Disease Control and Prevention (CDC), about 800,000 American deaths is attributed to cardiovascular disease and each year about hundreds of thousands of people die well before the current life expectancy of 78 years in the US. By 2030, approximately 20% of the population will be aged 65 or older and cardiovascular diseases will be the leading cause of death. Over the past 4 decades, there have been remarkable advances in our understanding and treatment of ischemic heart disease, while our understanding of cardiomyopathies and arrhythmic disorders has lagged behind. Indeed, the realization that many cardiomyopathies and sudden cardiac deaths are in fact related to genetic disorders has heralded a remarkable era for hereditary cardiac disorders. With advances in genetic sequencing methods, more genetic targets are being identified as pathogenic variants of these disorders. Unfortunately, understanding the biology of how these putative genetic variants result in observed phenotypic changes has proven challenging. The patient harbors the mutations from birth but the onset of the development of rhythm disturbances presents much later in life thus indicates the requirement of higher order cardiac model that will encompass patient bio-omics. Genetic variation contributing to complex traits poses numerous barriers in facilitating the development of precision medicine. Classically, various non-human in-vivo models of gainor loss-of-function of a gene have been central to the elucidation of physiological or developmental function. However, increasing number of drugs fail to replicate in human clinical trials posing looming challenges for human disease modeling. A big hurdle to understanding cardiac molecular and cellular physiology is the inability to maintain and study adult human cardiomyocytes in culture. Furthermore, the invasive nature of obtaining primary human cardiac tissue has hindered the field compared with other fields such as hematology or oncology. This leaves scientists to rely on animal models or transfected cell models. Historically, cardiovascular safety testing relied on in vivo models to replicate the integrated nature of cardiovascular physiology. While in vivo models offer good translation for positive findings, they have several limitations namely, 1) the action potential of rodents is significantly shorter and lacks phase-2 plateau; 2) they lack mature β-adrenergic signaling and excitation-contraction (E-C) coupling; and 3) these models for the safety evaluation of candidate drugs are cost-intensive, time-consuming and are often insufficient to predict human relevant cardiotoxicity and arrhythmia. Human induced pluripotent stem cells (hiPSCs) have emerged as a reliable method of producing patient-specific somatic tissue lines via directed differentiation. hiPSC derived beating heart cells from patients’ tissue closely mimic adult heart cells that can be used as a model to study abnormal heart mechanical and electrical function. The model has already proven complementary or superior when compared with transfected cell or animal models of cardiac genetic disorders.