The study of inherited human cardiovascular diseases has been hampered by limited access to cardiac tissue from patients harboring specific mutations, which are thought to be causal. The ability of the human induced pluripotent stem cells (hiPSCs) to differentiate to any cell type including cardiomyocytes, while carrying patients’ complex genetic backgrounds, has made them a promising and powerful tool for drug screening, assessing the cardiotoxicity of chemotherapeutic agents, and studying inherited cardiac diseases in vitro by recapitulating their cellular phenotypes. In Chapter 3, I used human pluripotent stem cell (hPSC)-derived ventricular and atrial cells to study the toxicity of ibrutinib, a novel Bruton’s tyrosine kinase (BTK) inhibitor, which has demonstrated benefit in B cell cancers, but is associated with atrial fibrillation. I showed that ibrutinib has a dramatic impact on the cardiac electrophysiology of hPSC-derived atrial cardiomyocytes, without affecting hPSC-derived ventricular cardiomyocytes. In Chapter 4, I investigated the arrhythmogenic role of a novel TNNI1 mutation (R37C TNNI1) in the death of “autopsy negative” sudden infant deaths (SIDs) victims. Specifically, I generated R37C+/- TNNI1 hiPSC-CMs using the genome-editing technology CRISPR/Cas9 and monitored voltage- and Ca2+ transients through optical mapping. Unlike the isogenic control cell line, irregular voltage- and Ca2+ transients and arrhythmic activities were observed in the presence higher rates of stimulation or β-adrenergic agonists in monolayer of R37C+/- TNNI1 hiPSC-CMs. Chapter 5 focused on the familial hypertrophic cardiomyopathy (FHC)-associated mutations found in patients, I79N TNNT2, which I generated using CRISPR/Cas9 in hiPSC-CMs. Compared to other FHC-associated mutations found in patients, I79N TNNT2 often results in significantly less ventricular hypertrophy and a higher incidence of sudden cardiac death. Unlike control hiPSC-CMs, the mutant hiPSC-CMs developed irregular and arrhythmogenic voltage- and Ca2+ transients at high stimulation rates and in the presence of β-adrenergic agonists. In sum, hiPSC-CMs have been successfully used to model a growing number of arrhythmogenic disorders, thereby enabling prediction of high-risk populations’ susceptibilities to drug-induced cardiotoxicity as a form of personalized medicine. Besides disease modeling and drug screening, hiPSC-CMs have emerged as a powerful platform for studying the cardiotoxicity of chemotherapeutic agents.
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Thesis advisor: Tibbits, Glen
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