Innate and adaptive immune-cell densities as risk factors for heart failure

摘要 从生物标记物研究、动物模型和人类组织学来看，心力衰竭(HF)的发生是 越来越多的人认识到这是一种炎症过程。在动物模型中精心设计的实验已经 确认了先天免疫细胞和获得性免疫细胞在心力衰竭的发生和发展中的重要性。但 无论人类的先天免疫细胞和获得性免疫细胞是否也是心血管健康和 病理学在很大程度上仍是一个未经检验的假说。心力衰竭是一种复杂的综合征，其特征是 心脏因心输出量减少、充盈压升高而充分满足代谢需求 两者都有。虽然有一些重叠，但两种主要类型包括(1)射血分数保留的心衰 通常与高血压(HTN)、糖尿病(DM)和肥胖症有关的(HFpEF)，以及(2)HF伴减少 射血分数(HFrEF)，通常与动脉粥样硬化和心肌梗死(MI)相关。在环境中 心肌细胞损伤或细胞死亡，心力衰竭的发生可能取决于心力衰竭的类型和强度。 免疫细胞激活。在很大程度上基于动物模型的实验(第3a节)，我们假设 高密度的促炎免疫细胞是发生心衰的危险因素，尤其是肝纤维化； 高密度的促纤维化免疫细胞也是发生HF的危险因素，特别是HFpEF；以及 控制炎症和纤维化的高密度调节性免疫细胞降低了两者的风险 HFpEF和HFrEF。随着技术进步的到来，采集的外周血单核细胞 1998-1999年在心血管健康研究和2000-2002年在动脉粥样硬化的多种族研究中 从那时起在-140℃下冷冻保存，为在人体内进行纵向 先天免疫细胞密度和获得性免疫细胞密度作为心力衰竭发病危险因素的研究 和HFpEF。拟议的病例队列研究将心力衰竭添加到正在进行的心肌梗死病例队列研究中，并将包括更多 800多个HF事件加上来自每个队列的随机样本，总共约4200名参与者来自2 学习。用流式细胞术对从基线开始冷冻保存的细胞进行分析，我们将检测17个免疫细胞亚群。 主要目的是前瞻性地评估它们与HF事件及其两种主要类型HFpEF的相关性 和HFrEF。第二个目标包括分析免疫细胞亚群作为风险因素的发病率。 其他结果，如DM、HTN和心房颤动。这份修订后的申请包括来自 正在进行的MI研究，对每隔五年对台地样本进行的分析比较，以及一项新的 复制工作，使HF事件的总数超过1000次。建议的研究是很好的 动力十足。尽管针对免疫系统的治疗已经改善了几个 癌症，免疫相关疗法的开发和使用来预防心力衰竭，有待进一步发现 免疫细胞在心力衰竭中的潜在作用。

Abstract From biomarker studies, animal models and human histology, the occurrence of heart failure (HF) is increasingly recognized as an inflammatory process. Carefully-designed experiments in animal models have identified the importance of innate and adaptive immune cells in the development and progression of HF. But whether innate and adaptive immune cells in humans are also the active authors of cardiovascular health and pathology remains an hypothesis largely untested. HF is a complex syndrome characterized by the inability of the heart to adequately meet metabolic demands due to reduced cardiac output, elevated filling pressures, or both. Although there is some overlap, the two major types include (1) HF with preserved ejection fraction (HFpEF), typically associated with hypertension (HTN), diabetes (DM), and obesity, and (2) HF with reduced ejection fraction (HFrEF), often associated with atherosclerosis and myocardial infarction (MI). In the setting of cardiomyocyte injury or cell death, the development of HF is likely to depend on the type and intensity of immune-cell activation. Largely on the basis of experiments in animal models (section 3a), we hypothesize that high densities of pro-inflammatory immune cells are risk factors for the incidence of HF, especially HFrEF; that high densities of pro-fibrotic immune cells are also risk factors for the incidence of HF, especially HFpEF; and that high-densities of regulatory immune cells that control inflammation and fibrosis reduce the risk of both HFpEF and HFrEF. With the advent of technological advances, peripheral blood mononuclear cells, collected in 1998-1999 in the Cardiovascular Health Study and in 2000-2002 in the Multi-Ethnic Study of Atherosclerosis and cryopreserved since then at -140°C, provide a unique opportunity to conduct, in humans, a longitudinal study of the densities of innate and adaptive immune cells as risk factors for the incidence of HF, both HFrEF and HFpEF. The proposed case-cohort study adds HF to on-going MI case-cohort study and will include more than 800 HF events plus a random sample from each cohort for a total of about 4200 participants from the 2 studies. Using flow cytometry on the cryopreserved cells from baseline, we will assay 17 immune-cell subsets. The primary aim is to evaluate their association prospectively with HF events and its two main types, HFpEF and HFrEF. The secondary aim includes analyses of immune-cell subsets as risk factors for the incidence of other outcomes such as DM, HTN, and atrial fibrillation. This revised application includes preliminary data from the ongoing MI study, comparisons of assays done on MESA specimens five years apart, and a new replication effort, which brings the total number of HF events to more than 1000. The proposed study is well powered. Although treatments targeting the immune system have improved the therapeutic options for several cancers, the development and use of immune-related therapies to prevent HF await further discovery about the potential role of immune cells in HF.