A 3D IN VITRO DISEASE MODEL OF ATRIAL CONDUCTION

PROJECT Summary: The primary goal of this one-year competitive revision is to assess the potential of two novel therapeutics(DS-iKL and DAPT) to mitigate the extrinsic and intrinsic cardiac effects of SARS-CoV-2, respectively. This isimportant because, while acute respiratory distress is a major cause of morbidity and mortality of COVID-19,the clinical disease caused by the SARS-CoV-2 coronavirus, it has more recently become widely evident thatother organ systems are involved including the heart and blood. For example, cardiac arrhythmias are a majorsource of morbidity and mortality (44-60%) associated with COVID-19 disease, especially in individuals withpre-existing cardiovascular disease in ICU settings. Two recent reports have indicated that 20-22% ofhospitalized patients with SARS-Cov-2 experience cardiac injury, and these patients suffer a staggering 50%mortality rate, more than an order of magnitude greater than those patients without cardiac injury. Cardiacarrythmias or myocardial injury are acutely life threatening and can be caused by a host of factors including co-morbidities (e.g., hypertension), drugs, but also viral infection and systemic inflammation. In addition, a stateof hyper coagulation has also been described as a central feature of COVID-19, leading to blood clots that canbe life threatening as pulmonary emboli and right-sided cardiac failure. The specific aims of the project are to:1) Assess the potential of DS-iKL as a novel therapeutic to mitigate the cardiac effects of SARS-CoV-2 initiatedcytokine storm (coagulation and vascular permeability) using a multi-organ microphysiological system of iPS-derived human cardiomyocytes and vascular endothelium; 2) Assess the potential of the Notch signalinginhibitor, DAPT, on viral infectivity and thus intrinsic cardiac effects of SARS-CoV-2, in an organotypic tissueslice model of healthy and predisposed adult human cardiac tissue. We anticipate a rich data set resultingfrom these experiments that should demonstrate the exciting potential of DS-iKL and DAPT to mitigate theextrinsic and intrinsic cardiac effects of SARS-CoV-2. The research plan will also produce a path to in vivohuman studies to accelerate translation. Finally, the potential impact of DS-iKL and DAPT to mitigate theeffects of SARS-CoV-2 are likely to also be applicable to other inflammatory and infectious diseases that sharesimilar disease etiology.