T Lymphopenia in Ischemic Heart Failure

心肌梗死（MI）引起的心力衰竭是美国发病率和死亡率的主要原因。 States.大约四分之一的MI患者将发展为慢性心力衰竭，其具有5年死亡率 率40%。改善心肌梗死患者的长期预后是当务之急。淋巴细胞减少症， 外周血淋巴细胞计数（主要是由于T细胞损失），一直被证明与 MI患者心功能差、预后差，是预测预后的独立指标。 不幸的是，MI后T淋巴细胞减少症是如何发生的，靶向T淋巴细胞减少症是否具有治疗作用， 潜力在很大程度上未知。利用MI诱导的小鼠缺血性心力衰竭模型，我们的初步数据 表明MI诱导的T淋巴细胞减少可能涉及血液T细胞向骨髓和T细胞的再分布， 发育障碍已知CD 4 + T细胞活化可改善MI后的伤口愈合。因此， CD 4 + T淋巴细胞减少可能降低保护性CD 4 + T细胞反应，并损害MI后心肌修复。 本研究的目的是：1）阐明以下引起T淋巴细胞减少症的潜在机制： MI; 2）研究抑制CD 4 + T淋巴细胞减少症是否可以作为一种治疗策略。我们 假设MI通过刺激T细胞从血液向骨髓的运输诱导T淋巴细胞减少症 抑制CD 4 + T淋巴细胞减少改善MI后心脏修复。三个具体 aims将在小鼠缺血性心力衰竭模型中解决这一新的假设， 接近。具体目标1将检查血液T细胞运输到骨髓的机制， MI后不同T细胞表型和功能的改变。具体目标2将通过以下方式确定机制： MI损害T淋巴细胞生成。具体目标3将检验抑制CD 4 + T淋巴细胞减少症 可以改善心肌梗死后的心脏修复该方案的完成将为T 缺血性心力衰竭中淋巴细胞减少的机制，并可能提供潜在的干预策略，以改善缺血性心力衰竭患者的心功能。 心力衰竭患者的预后。

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.