Impact of Adaptive Immune System on Cardiac Electrophysiology

Heart diseases, including myocardial infarction (MI), heart failure (HF) and cardiac arrhythmias are the leading causes of morbidity and mortality within developed nations. However, our limited understanding of the mechanisms leading to cardiac dysfunction in HF has hampered the development of effective treatment strategies for these patients. Activation of CD4+ T-cells post-MI promote wound-healing and scar formation. However, we have shown that by 8 weeks post-MI, CD4+ T-cells undergo a temporal phenotypic switch that promotes pathological left-ventricular (LV) remodeling and the development of ischemic HF. Importantly, we have shown that during HF, splenic CD4+ T-cells are enriched with antigen-experienced and central memory T- cells, and their adoptive transfer (AT) to naïve mice induce cardiac dysfunction and LV-remodeling, suggesting that CD4+ T-cells contribute to cardiac dysfunction in HF. However, the mechanisms by which HF-activated CD4+ T-cells induce cardiomyocyte (and cardiac) dysfunction are unknown. Our preliminary data show that upon AT, significantly higher numbers of HF-activated CD4+ T-cells (compared to sham T-cells) infiltrate the myocardium of naïve mice (almost 80-85% of all CD4+ T-cells), and induce significant cardiac dysfunction, arrhythmic events, myocyte hypertrophy and LV remodeling in naïve mice. Importantly, co-culture of adult mouse cardiomyocytes with HF-activated T-cells alter electrophysiological function of cardiac myocytes through pro-arrhythmic changes in cardiac currents. Notably, HF-activated T-cells form functional connexin43 gap junctions (Cx43 GJs) with cardiomyocytes and, we demonstrated that changes in currents induced by HF-activated T-cells are contact- dependent. This, contact-dependent alteration of cellular electrophysiology and overall cardiac dysfunction induced by pathological CD4+ T-cells represent a heretofore-unappreciated mechanism contributing to HF and arrhythmias . Thus, we will test the overall hypothesis that HF-activated T-cells promote LV remodeling, cardiac dysfunction and arrhythmias during chronic HF through Cx43 mediated contact with cardiomyocytes. We will test this hypothesis using the following aims: 1. To delineate the pathophysiological role of ischemic HF (IHF) activated CD4+ T-cells on cardiac dysfunction. 2. To determine electrophysiological changes in cardiomyocytes resulting from HF T-cells. 3. To delineate the role of gap junctions in mediating pathological effects of T-cells on cardiomyocyte/cardiac function. These studies will identify mechanisms that mediate contact-dependent pathological effects of HF-activated T-cells on cardiomyocyte electrophysiology and overall cardiac dysfunction, thereby furthering our understanding of the cellular basis for inflammation in this disease. PIs are trained scientists in cardiomyocyte electrophysiology and cardiovascular T-cell biology, and we are collaborating with experts in gap junctions, computational modeling and arrhythmia mechanisms, making us an exceptional team to conduct these studies. Project Number: 1R01HL174473-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Isabelle Deschenes (+1 co-PI) | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $741,112 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology B Study Section[MPPB] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17447301A1