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

摘要 从生物标志物研究、动物模型和人类组织学来看，心力衰竭（HF）的发生是 越来越多地被认为是一种炎症过程。精心设计的动物模型实验 确定了先天性和适应性免疫细胞在HF发展和进展中的重要性。但 人类的先天性和适应性免疫细胞是否也是心血管健康的积极作者， 病理学仍然是一个基本上未经检验的假设。HF是一种复杂的综合征，其特征在于不能进行 由于心输出量减少、充盈压升高，心脏无法充分满足代谢需求，或 两者虽然有一些重叠，但两种主要类型包括（1）射血分数保留的HF （2）HF pEF，通常与高血压（HTN）、糖尿病（DM）和肥胖相关， 射血分数（HFrEF），通常与动脉粥样硬化和心肌梗死（MI）相关。背景下 心肌细胞损伤或细胞死亡，HF的发展可能取决于心肌细胞损伤的类型和强度。 免疫细胞激活。基于动物模型实验（第3a节），我们假设， 高密度的促炎性免疫细胞是HF发病率的危险因素，尤其是HFrEF; 高密度的促纤维化免疫细胞也是HF发病率的风险因素，尤其是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。随着技术的进步，外周血单个核细胞，收集 1998-1999年参加心血管健康研究，2000-2002年参加动脉粥样硬化多种族研究 并从那时起在-140 ° C冷冻保存，提供了一个独特的机会，在人类中进行纵向 先天性和适应性免疫细胞密度作为HF发病率危险因素的研究，HFrEF 和HFpEF。拟议的病例队列研究将HF添加到正在进行的MI病例队列研究中，并将包括更多 800多例HF事件加上来自每个队列的随机样本，共约4200例参与者，来自2个 问题研究使用流式细胞术对来自基线的冻存细胞进行分析，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。次要目的包括分析免疫细胞亚群作为免疫缺陷发生率的危险因素。 其他结局，如DM、HTN和房颤。这份修订后的申请包括来自以下方面的初步数据： 正在进行的MI研究，对相隔五年的梅萨标本进行的检测进行比较，以及一项新的 复制工作，这使得HF事件的总数超过1000。这项研究建议， 动力十足尽管针对免疫系统的治疗已经改善了几种疾病的治疗选择， 癌症，预防HF的免疫相关疗法的开发和使用有待于进一步发现， 免疫细胞在HF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.