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

摘要 从生物标志物研究、动物模型和人体组织学来看，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心力衰竭发生和进展中的重要性。但是 人类的先天性和适应性免疫细胞是否也是心血管健康和心血管健康的积极推动者 病理学仍然是一个很大程度上未经检验的假设。心力衰竭是一种复杂的综合征，其特征是无法 心脏充分满足由于心输出量减少、充盈压升高或 两者都有。尽管存在一些重叠，但这两种主要类型包括 (1) 射血分数保留的 HF (HFpEF)，通常与高血压 (HTN)、糖尿病 (DM) 和肥胖相关，以及 (2) HF 降低 射血分数（HFrEF），通常与动脉粥样硬化和心肌梗塞（MI）相关。在设置中 心肌细胞损伤或细胞死亡，心力衰竭的发生可能取决于心肌细胞损伤或细胞死亡的类型和强度 免疫细胞激活。很大程度上基于动物模型实验（第 3a 节），我们假设 高密度的促炎免疫细胞是心力衰竭（尤其是HFrEF）发生的危险因素；那个 高密度的促纤维化免疫细胞也是心力衰竭（尤其是HFpEF）发生的危险因素；和 控制炎症和纤维化的高密度调节性免疫细胞可以降低这两种疾病的风险 HFpEF 和 HFrEF。随着技术进步的出现，采集外周血单个核细胞 1998-1999 年心血管健康研究和 2000-2002 年动脉粥样硬化多种族研究 并从那时起冷冻保存在-140°C，提供了在人类中进行纵向研究的独特机会 研究先天免疫细胞和适应性免疫细胞的密度作为心力衰竭（HFrEF）发病危险因素的研究 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，并将包括更多内容 超过 800 起 HF 事件加上每个队列中的随机样本，2 个队列中总共有约 4200 名参与者 研究。我们将使用流式细胞术对基线的冷冻细胞进行检测，检测 17 种免疫细胞亚群。 主要目的是前瞻性评估它们与 HF 事件及其两种主要类型 HFpEF 的关联 和 HFrEF。第二个目标包括分析免疫细胞亚群作为疾病发生的危险因素。 其他结果，如糖尿病、高血压和心房颤动。该修订后的申请包括来自以下机构的初步数据： 正在进行的 MI 研究，对相隔五年的 MESA 样本进行的分析比较，以及一项新的 复制工作，使 HF 事件总数超过 1000 个。拟议的研究很好 供电。尽管针对免疫系统的治疗已经改善了多种疾病的治疗选择 癌症、预防心力衰竭的免疫相关疗法的开发和使用还有待进一步发现 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.