Veterans have 2-times higher risk of developing cardiovascular disease compared to non-veterans. For veterans who have a heart attacked (myocardial infarction; MI), 1 in 3 will not survive 1 year after the event compared to 1 in 10 in the general population. The goal of my project is to understand how the wound healing response after MI can promote the development of heart failure. My focus is the innate immune response, specifically the role of CD8+ T-cells. My central hypothesis is that CD8+ effector T- cells regulate PMN physiology through MMP-9 to induce adverse remodeling post-MI.
Aim 1 will determine the role of CD8+ T-cells on the neutrophil physiology using cellular proteomics coupled with ex vivo experiments.
Aim 2 will determine the role CD8+ T-cells in vivo focusing on how CD8+ T-cell effector subtypes and the secretion of MMP-9 effect long term cardiac function and survival post-MI. This is the first proposal to integrate multidisciplinary approaches to evaluate CD8+ T-cells in the MI setting. This study will add to our understanding of critical mechanisms underlying adverse effects of the adaptive immune response and wound healing after MI. The proposed study aligns with the mission of the VA Healthcare System by providing molecular knowledge to clinical practices so that the VA Healthcare System can continue to provide exceptional health care that improves Veteran health and well-being.
Development of heart failure after a heart attack is the number one reason for admission among those in the Veterans' Health Care System. Chronic diseases effect Veterans more than the rest of the population, implicating chronic inflammation as an underlying source for the higher rates of cardiovascular disease in Veterans. Chronic inflammation is associated with activation of T-cells. Patients who have elevated CD8+ T-cell counts have 2-fold higher chance of mortality after a heart attack; the mechanism however is unclear. Focusing on the adverse effects of CD8+ T-cells and cardiac wound healing will provide potential intervention targets to prevent, slow, or reverse progression to heart failure in heart attack patients. Decreasing incidence of heart failure after a heart attacks aligns with the mission of the VA Healthcare System.
