Atrial fibrillation (AF) is the most common form of cardiac arrhythmia that causes the irregular and uncoordinated contractions of the atrial chambers. Current first-line pharmacological treatments are limited in efficacy with side effects including ventricular proarrhythmia. Thus, it is imperative to find novel treatments for better management of the disease. However, current preclinical assays such as heterologous expression and animal models do not recapitulate the entirety of human cardiac physiology. As such, the ability to generate hiPSC-derived atrial-like CMs (hiPSC-aCMs) and ventricular-like CMs (hiPSC-vCMs) can provide a more robust physiological system to assess drug effects for AF treatment in vitro. The objective of this thesis is to develop a preclinical assay system using optical mapping technique and human induced pluripotent stem cells (hiPSCs). Here, I characterized the function of hiPSC-aCMs and demonstrated the sensitivity and specificity of the assay system in capturing the effects of atrial-selective compounds.

"Abnormal heart rhythms are a leading cause of mortality worldwide. Tachycardias, which are abnormally fast heart rhythms, can be caused by a circulating wave of excitation referred to as reentry. Patients who previously experienced a myocardial infarction are at a particularly high risk of developing re-entrant rhythms, as scarring can create the requisite pathway. Anatomical cardiac re-entry occurs when an impulse propagates in a circuit around an inexcitable obstacle instead of terminating at the base of the ventricles at the end of the cardiac cycle. In this thesis, I carried out experimental studies using novel techniques in tissue patterning to investigate plausible mechanisms of re-entry formation. The model system consists of a monolayer of human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSCs) and sensitized to light by expression of Channelrhodopsin-2 (ChR2), a light activated channel. By incorporating CHR2, precise short pulses (100 ms) of patterned light could be applied to stimulate the monolayers. By applying long pulses (500 ms) of patterned light to the monolayer, conduction block could be provoked in the illuminated region. The light exposure parameters and patterns can be readily changed anytime during the experiment. These results demonstrate that an all optical dynamical approach is feasible to both stimulate and induce regions of block in the monolayer. This investigation provides a novel strategy for studying the mechanisms of arrhythmia generation in a model system that may lead to insights for treatment options"--

Current Progress in iPSC Disease Modeling, Volume Fourteen in the Advances in Stem Cell Biology series, is a timely and expansive collection of information and new discoveries in the field. This new volume addresses advances in research on how induced pluripotent stem cells are used for the creation of new tissues and organs. The creation of iPSC technology allowed the development of disease-specific human pluripotent stem cells. These cells allow researchers to study questions once impossible for some human diseases. This volume addresses iPSCs for vascular tissue engineering, bioprinting, derived lung organoids for pulmonary disorders, skeletal muscle engineering, human kidney organoids, and more. It is written for researchers and scientists in stem cell therapy, cell biology, regenerative medicine and organ transplantation, and is contributed by world-renowned authors in the field. - Provides an overview of the fast-moving field of stem cell biology and function, regenerative medicine and therapeutics - Covers advances in research on how induced pluripotent stem cells are used to create new tissues/organs - Contributed by world-renowned experts in the field

This book covers the latest information on the anatomic features, underlying physiologic mechanisms, and treatments for diseases of the heart. Key chapters address animal models for cardiac research, cardiac mapping systems, heart-valve disease and genomics-based tools and technology. Once again, a companion of supplementary videos offer unique insights into the working heart that enhance the understanding of key points within the text. Comprehensive and state-of-the art, the Handbook of Cardiac Anatomy, Physiology and Devices, Third Edition provides clinicians and biomedical engineers alike with the authoritative information and background they need to work on and implement tomorrow’s generation of life-saving cardiac devices.

There is a profound need to develop a strategy to predict patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient- specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). A major strength of this approach is that iPSC-CMs contain donor genetic information and therefore capture patient-specific genotype-phenotype relationships. A cited detriment of iPSC-CMs is the cell-to-cell variability observed in electrical activity. We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build in silico cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework to investigate subcellular phenotypic mechanisms in healthy iPSC-CMs. In subsequent studies, this computational framework was utilized to explore genotype-phenotype relationships in control and diseased cases. The computational framework presented utilizes whole-cell models of iPSC-CM comprised of simple model components. We developed models for all major ionic current composed of single exponential voltage-dependent rate constants, parameterized to fit experimental iPSC-CM data. By optimizing ionic current model parameters to multiple experimental datasets, we incorporated experimentally-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs and recapitulates the experimentally observed range of whole-cell behaviors. Additionally, our computational framework was utilized to link molecular mechanisms to known cellular-level iPSC-CM phenotypes, including the mechanisms of immature cardiac behavior in iPSC-CMs. This population-based approach was further expanded to incorporate a panel of genetic mutations related to Long QT Syndrome 1 (LQT1). This allowed us to analyze the severity of each mutation and explore patient-specific susceptibility to LQT1. LQT mutations are known to have vastly different cardiac effects in different patients, and these phenotypic differences are recapitulated in our model population. In the future, the models presented can be readily expanded to include pharmacological interventions to study the mechanisms of rare events, such as arrhythmia triggers.