COBRE Abstract 1
Patients suffering from chronic myocardial ischemia due to coronary artery disease have few treatment options beyond pharmaceutical drugs to stop, reduce, or slow cardiac remodeling. In a large subset of these patients, cardiac function continues to decline over months to years and will progress to heart failure, where the end stage disease requires assist devices or heart transplant to prolong life. Therefore, there is a critical need to develop novel therapies beyond pharmaceuticals to treat patients with ischemic heart disease. The long-term goals of this research is to revolutionize treatment with a dual revascularization-remuscularization therapy to restore myocardial perfusion and function. The main objective of this pilot project proposal is to examine functional changes in myocardial contractility as a result of improved perfusion when implanting novel engineered human myocardium containing hiPSC-derived cardiomyocytes and patterned vascular channels with an angiogenic factor-releasing biomaterial film on the epicardial surface of the chronic ischemic heart in a translationally relevant large animal porcine model of chronic myocardial ischemia. Aim 1 is to enhance perfusion in the ventricular myocardium and engineered tissue implant using patterned engineered vessels within hiPSC-cardiac tissue with localized angiogenic therapy. Aim 2 is to remuscularize the ventricular wall to unload the host myocardium and promote systolic function. The engineered therapy will be implanted four weeks after ischemia onset (by surgical ameroid constrictor placement over a coronary artery) and perfusion and revascularization will be assessed by angiography, microbead perfusion, and immunohistochemistry after four weeks. Functional changes will be captured by 2D echocardiography to assess left ventricular function and regional ventricular wall strain prior to ischemia, prior to implant, and after four weeks. Results will demonstrate feasibility of the project and efficacy of the dual revascularization-remuscularization therapy.

COBRE Abstract 2
Omega-3 fatty acids have long been recognized for their cardiovascular benefits, with extensive evidence demonstrating their role in reducing atherosclerotic cardiovascular events and sudden cardiac death. However, recent clinical trials, including JELIS, REDUCE-IT, and RESPECT-EPA, suggest that EPA (eicosapentaenoic acid), but not DHA (docosahexaenoic acid), provides significant cardiovascular protection. While EPA reduces major cardiovascular events, it has also been consistently linked to an increased risk of atrial fibrillation (AFib), as seen in large-scale studies such as the UK Biobank. At the same time, omega-3 fatty acids, particularly EPA, have been shown to reduce ventricular arrhythmias and sudden cardiac death. The reason for this chamber-specific discrepancy remains unclear. This study aims to investigate the mechanistic basis of omega-3 fatty acid-induced arrhythmogenesis using human induced pluripotent stem cell (hiPSC)-derived cardiac microtissues, which provide a physiologically relevant in vitro model for atrial and ventricular electrophysiology. Using these chamber-specific models, we will determine how EPA promotes pro-arrhythmic electrical remodeling in atrial cells while exerting protective effects in ventricular cells and whether DHA exerts distinct or protective effects in AFib susceptibility. We propose three specific aims: Aim 1: Examine the electrophysiological effects of EPA and DHA on hiPSC-derived atrial and ventricular cardiac microtissues using optical mapping and calcium transient imaging to assess changes in action potential duration, conduction velocity, and arrhythmic susceptibility. Aim 2: Investigate mitochondrial dysfunction and oxidative stress as a mechanism of EPA-induced atrial dysregulation using Seahorse XF assays, mitochondrial membrane potential imaging, and reactive oxygen species (ROS) detection. Aim 3: Identify bioactive lipid-mediated signaling pathways involved in EPA-induced atrial remodeling using mass spectrometry-based lipidomics and metabolomics to profile changes in lipid signaling and metabolic pathways. This study will provide critical mechanistic insights into EPA-induced AFib while addressing the paradox of EPA’s protective effects against ventricular arrhythmias. By clarifying the differential electrophysiological effects of EPA and DHA in atrial vs. ventricular cardiomyocytes, this project will establish the foundation for personalized omega-3 supplementation strategies that maximize cardiovascular benefits while minimizing arrhythmic risks.