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

先天性和适应性免疫细胞密度是心力衰竭的危险因素

• 批准号: 10226411
• 负责人: Bruce M Psaty
• 金额: $ 67.73万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226411
• 关键词: Adoptive Transfer; Age; Animal Model; Atherosclerosis; Atrial Fibrillation; Biological Assay; Biological Markers; Biological Products; Blood; Cardiac Myocytes; Cardiac Output; Cardiovascular Pathology; Cardiovascular system; Cell Death; Cell Density; Cells; Cohort Studies; Complex; Congestive Heart Failure; Coronary; Coronary heart disease; Cryopreservation; Cryopreserved Cell; Data; Dendritic Cells; Development; Diabetes Mellitus; EFRAC; Etiology; Event; Experimental Animal Model; Fibrosis; Flow Cytometry; Functional disorder; Heart; Heart Injuries; Heart failure; Histology; Home; Human; Hypertension; Immune; Immune Targeting; Immune system; Incidence; Inflammation; Inflammatory; Injury; Left; Left Ventricular Dysfunction; Ligation; Longitudinal Studies; Lymphocyte Subset; Malignant Neoplasms; Mediating; Medicine; Metabolic; Multi-Ethnic Study of Atherosclerosis; Mus; Myocardial Infarction; Obesity; Operative Surgical Procedures; Outcome; Participant; Pathologic; Peripheral Blood Mononuclear Cell; Play; Process; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Specimen; Splenectomy; Splenocyte; Study Subject; Syndrome; Therapeutic; Ventricular; base; cardiogenesis; cardiovascular health; cohort; density; design; experimental study; healing; histological studies; immune activation; improved; monocyte; myocardial injury; novel; novel therapeutic intervention; population based; preservation; pressure; prevent; prospective; protein biomarkers; repaired; response; sex; targeted treatment

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.

抽象的 根据生物标志物研究，动物模型和人类组织学，心力衰竭的发生（HF）是 越来越被认为是炎症过程。动物模型中精心设计的实验具有 确定了先天性和适应性免疫球在HF的发展和发展中的重要性。但 人类的先天和适应性免疫能力是否也是心血管健康的活跃作者 病理仍然是一个未经测试的假设。 HF是一种复杂综合征，其特征是 由于心脏输出降低，填充压力升高或 尽管存在一些重叠，但两种主要类型包括（1）HF，保留射血分数 （HFPEF），通常与高血压（HTN），糖尿病（DM）和肥胖有关，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）有关。在 心肌细胞损伤或细胞死亡，HF的发展可能取决于 免疫细胞激活。在很大程度上是基于动物模型的实验（第3A节），我们假设 高密度促炎性免疫细胞是HF事件，尤其是HFREF的危险因素。 高密度的促纤维免疫细胞也是HF事件，尤其是HFPEF的风险因素。和 控制注射和纤维化的高密度调节免疫细胞降低了两者的风险 HFPEF和HFREF。随着技术进步的冒险，收集的外周血单核细胞 1998 - 1999年的心血管健康研究和2000 - 2002年的动脉粥样硬化研究 从那时起，在-140°C以来，为人类提供了独特的机会，以提供独特的机会 研究先天性和适应性免疫小球作为HF事件的危险因素的研究，均为HFREF 和HFPEF。拟议的病例研究研究为正在进行的MI案例研究研究增加了HF，并将包括更多 超过800个HF事件以及每个队列中的随机样本，总共约4200名参与者 研究。使用基线的冷冻保存细胞上的流式细胞仪，我们将主张17个免疫细胞子集。 主要目的是前瞻性地评估他们的关联及其两种主要类型HFPEF 和hfref。次要目的包括对免疫细胞亚集的分析作为事件的风险因素 其他结果，例如DM，HTN和心房颤动。此修订的应用程序包括来自 正在进行的MI研究，对台面标本进行的测定相距五年的比较，还有一个新的 复制工作，将HF事件的总数带到了1000多个。拟议的研究很好 尽管针对免疫系统的治疗方法改善了几种治疗方法 癌症，与免疫相关疗法的开发和使用，以防止HF等待进一步发现 免疫细胞在HF中的潜在作用。

项目成果

Nonclassical Monocytes (CD14dimCD16+) Are Associated With Carotid Intima-Media Thickness Progression for Men but Not Women: The Multi-Ethnic Study of Atherosclerosis-Brief Report.

• DOI: 10.1161/atvbaha.120.315886
• 发表时间: 2021-05-05
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Feinstein MJ;Doyle MF;Stein JH;Sitlani CM;Fohner AE;Huber SA;Landay AL;Heckbert SR;Rice K;Kronmal RA;Hedrick C;Manichaikul A;McNamara C;Rich S;Tracy RP;Olson NC;Psaty BM;Delaney JAC
• 通讯作者: Delaney JAC

Association of Peripheral Lymphocyte Subsets with Cognitive Decline and Dementia: The Cardiovascular Health Study.

• DOI: 10.3233/jad-220091
• 发表时间: 2022
• 期刊: JOURNAL OF ALZHEIMERS DISEASE
• 影响因子: 4
• 作者: Fohner, Alison E.;Sitlani, Colleen M.;Buzkova, Petra;Doyle, Margaret F.;Liu, Xiaojuan;Bis, Joshua C.;Fitzpatrick, Annette;Heckbert, Susan R.;Huber, Sally A.;Kuller, Lewis;Longstreth, William T.;Feinstein, Matthew J.;Freiberg, Matthew;Olson, Nels C.;Seshadri, Sudha;Lopez, Oscar;Odden, Michelle C.;Tracy, Russell P.;Psaty, Bruce M.;Delaney, Joseph A.;Floyd, James S.
• 通讯作者: Floyd, James S.