Electrophysiology Scientific Core 2

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SC2 PROJECT SUMMARY Atrial fibrillation (AF) is the most common arrhythmia and a major risk factor for cardiovascular mortality and stroke. Incidence of AF is further increasing due to the rise in obesity and age of the population, factors closely related to AF risk and progression. Despite significant advances in AF diagnosis and management, treatment and clinical outcomes remain poor and more than a decade has passed since the last AF drug discovery. The overall goal of this PPG application is to use genetic/genomic findings to identify preventative and therapeutic strategies for AF and develop them towards clinical application. Our central hypothesis is that increasing the understanding of molecular mechanisms involved in genetic, metabolic and structural changes in the atria will allow us to pinpoint possible targets for safer and more effective therapeutic strategies. Scientific Core 2 (SC2): Electrophysiology Core will support the overall goal of the PPG and test program hypotheses as follows: Aim 1. Routine and reliable acquisition of ECG data for serial assessment of AF progression and burden, Aim 2: Optical mapping of mice atria and engineered heart tissue (EHT) for linking cellular pathophysiology with mechanisms of AF, Aim 3: Enzymatic isolation of mouse atrial myocytes for electrophysiologic, ion channel and Ca2+ cycling studies. Collectively, the isolated myocyte studies combined with optical mapping will provide important mechanistic links between cellular pathophysiology, AF in situ, and the progresion of AF in serial ECGs. We will leverage the capabilities and expertise of this Core to allow Project investigators to systematically integrate electrophysiological and cellular findings with genetic observations. This allows an assessment of differences in susceptibility of the atria to metabolic or other stressors that Projects will be studying as important contributors to AF initiation and progression. Importantly, use of the Core for the acquisition and analysis of ECGs, optical mapping (mouse atria and EHTs), and characterization of Ca2+, action potential, and ion channel dynamics in isolated myocytes ensures uniform methodology that will strengthen the individual Projects of this PPG. Furthermore, metabolic dynamics measured in an electrophysiological context herein, will complement the same measured in a metabolic context (Scientific Core 1). This Core will provide in-depth intellectual input to support Projects with experimental design, execution and coordination of experiments, and centralization for data gathering, thereby promoting interaction and integration between Projects beyond merely providing a service. Finally, this core eliminates duplication of effort and optimizes the use of personnel, equipment, and supplies, which enables all Projects on this PPG to achieve their scientific goals in an organized and cost-efficient manner. In sum, the services provide by this core to the Projects will help advance the understanding of the pathophysiology of AF, thereby supporting the main goal of this PPG to identify preventive and therapeutic strategies for AF and advance them towards clinical application.