T lymphopenia in ischemic heart failure - myocardial infarction (MI)-induced heart failure is the leading cause of morbidity and mortality in the united states

About one in four MI patients will progress to develop chronic heart failure, which has a 5-year mortality rate of 40%. IT is highly urgent to improve long-term outcomes of MI patients. Lymphopenia, a reduction in peripheral blood lymphocyte count (primarily due to t-cell loss), has consistently been shown to correlate with worse cardiac function and poor outcome in MI patients and is an independent marker to predict the prognosis. Unfortunately, how t lymphopenia occurs following MI and whether targeting t lymphopenia has therapeutic potential are largely unknown. Using the mouse MI-induced ischemic heart failure model, our preliminary data showed that MI-induced t lymphopenia may involve blood t-cell redistribution to the bone marrow and t cell development impairment. CD4+ t-cell activation is known to improve wound healing post-MI. Thus, persistent CD4+ t lymphopenia may reduce protective CD4+ t-cell response and compromise myocardial repair after MI. The goals of this proposal are: 1) to elucidate the underlying mechanisms that cause t lymphopenia following MI; and 2) to investigate whether inhibiting CD4+ t lymphopenia can serve as a therapeutic strategy. We hypothesize that MI induces t lymphopenia by both stimulating t-cell trafficking from blood to the bone marrow and impairing t lymphopoiesis; inhibiting CD4+ t lymphopenia improves post-MI cardiac repair. Three specific aims will address this novel hypothesis in a mouse ischemic heart failure model that combines multidisciplinary approaches. Specific aim 1 will examine the mechanisms of blood t-cell trafficking to the bone marrow and alterations of distinct t-cell phenotypes and functions after MI. Specific aim 2 will determine the mechanisms by which MI impairs t lymphopoiesis. Specific aim 3 will examine the hypothesis that inhibiting CD4+ t lymphopenia would improve post-MI cardiac repair. Accomplishment of this proposal will provide new insights into t lymphopenia mechanisms in ischemic heart failure and may offer potential intervention strategies to improve the prognosis of heart failure patients.