Elucidating the Role of Adipokines in Mediating and Predicting HF Associated with Obesity

阐明脂肪因子在调节和预测肥胖相关心力衰竭中的作用

• 批准号: 9883039
• 负责人: Chiadi E Ndumele
• 金额: $ 80.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883039
• 关键词: APLN gene; Adipocytes; Adipose tissue; Age; Algorithms; Atherosclerosis Risk in Communities; Biological Assay; Biological Markers; Body Weight decreased; Brain natriuretic peptide; Cardiac; Cardiomyopathies; Clinical; Clinical Research; Cohort Studies; Complement; Data; Demographic Factors; Diabetes Mellitus; Disease; EFRAC; Echocardiography; Epidemiology; Evaluation; Event; Fibrosis; Future; Galectin 3; Guidelines; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertension; Individual; Inflammation; Institutes; Laboratories; Laboratory Study; Left Ventricular Remodeling; Leptin; Link; Measures; Mediating; Mentors; Metabolic; Methods; Molecular; Morbidity - disease rate; Myocardial; Myocardial dysfunction; N-terminal; Obesity; Participant; Pathogenesis; Pathway interactions; Patients; Pattern; Physical activity; Play; Population; Prevalence; Prevention; Proteins; Public Health; Recording of previous events; Registries; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Serum; Structure; Time; Troponin T; Visceral; Visit; Weight; adipokines; adiponectin; adjudication; bariatric surgery; base; cohort; demographics; epidemiologic data; epidemiology study; healthy weight; heart function; improved; middle age; mortality; multidisciplinary; novel; novel strategies; physical inactivity; prediction algorithm; preservation; prevent; resistin

Heart failure is a major clinical and public health challenge, with marked associated morbidity and mortality. Obesity is strongly linked to myocardial dysfunction and subsequent heart failure (HF), but this association is poorly explained by traditional risk factors, and standard HF risk prediction algorithms perform relatively poorly in obesity. Despite increasing focus in guidelines on averting HF onset, strategies to predict and prevent HF in obesity are limited. Adipokines are molecules secreted by adipose tissue that likely mediate many of the clinical consequences of obesity. Laboratory data suggest effects of several adipokines on cardiac structure and function. While some clinical studies suggest a role of established adipokines (leptin, resistin, adiponectin) in mediating the obesity-HF association, clinical findings have been inconsistent, and risk associations for novel adipokines (visfatin, apelin) are not defined. Despite increasing recognition of the predominance of HF with preserved ejection fraction (vs reduced ejection fraction; HFpEF vs HFrEF) in obesity, adipokine studies to date have not separately described risk for these pathophysiologically distinct conditions. Additionally, there is need to understand the association of adipokines with subclinical cardiac biomarkers linked to HF risk in obesity, the clinical implications of longitudinal changes in adipokines, and the impact of weight loss on these risk associations. This project will combine serum assays of a carefully selected panel of established and novel adipokines and new adjudication of HFpEF and HFrEF cases in the well established ARIC study with adipose tissue adipokine expression studies among bariatric surgery patients in the Geisinger Obesity Institute Registry, to fully characterize the role of adipokines in mediating and predicting HF related to obesity. We propose: Aim 1: To relate established and novel adipokines in 11,656 ARIC participants to (A) demographics, weight history and physical activity, and B) subclinical and (C) clinical HF (~2200 events); Aim 2: To relate longitudinal trajectories of adipokines from late midlife to older age in a sample of 1,000 ARIC participants selected on cardiac function, to cardiac remodeling by echocardiogram, cardiac biomarkers and incident HF; and Aim 3: To assess (A) the associations of adipokine expression in visceral adipocytes with circulating adipokine concentrations and cardiac biomarkers in 300 bariatric surgery patients, and (B) the association of adipokine trajectories after bariatric surgery with changes in cardiac biomarker levels. This proposal will advance our understanding of the link of obesity to myocardial dysfunction and HF, and will be executed by a strong interdisciplinary team, including Dr. Ndumele who is transitioning from productive mentored research to independent investigator status.

心力衰竭是一项重大的临床和公共卫生挑战，具有显着的相关发病率和死亡率。 肥胖与心肌功能障碍和随后的心力衰竭 (HF) 密切相关，但这种关联是 传统的风险因素很难解释，标准的心力衰竭风险预测算法表现相对较差 在肥胖中。尽管人们越来越关注避免心力衰竭发作的指南，但预测和预防心力衰竭的策略 肥胖是有限的。脂肪因子是由脂肪组织分泌的分子，可能介导许多 肥胖的临床后果。实验室数据表明几种脂肪因子对心脏结构的影响 和功能。虽然一些临床研究表明已确定的脂肪因子（瘦素、抵抗素、脂联素）的作用 在介导肥胖与心力衰竭之间的关联时，临床研究结果并不一致，并且与肥胖和心力衰竭的风险关联 新型脂肪因子（visfatin、apelin）尚未定义。尽管人们越来越认识到 HF 的主导地位 射血分数保留（对比射血分数降低；HFpEF 对比 HFrEF）的肥胖症，脂肪因子研究 迄今为止尚未单独描述这些病理生理学不同病症的风险。此外，还有 需要了解脂肪因子与与心力衰竭风险相关的亚临床心脏生物标志物之间的关系 肥胖、脂肪因子纵向变化的临床意义以及减肥对这些的影响 风险关联。该项目将结合精心挑选的一组已建立的和新颖的血清测定 脂肪因子以及在完善的 ARIC 脂肪研究中对 HFpEF 和 HFrEF 病例的新裁决 盖辛格肥胖研究所减肥手术患者的组织脂肪因子表达研究 注册，以充分表征脂肪因子在介导和预测与肥胖相关的心力衰竭中的作用。我们 建议：目标 1：将 11,656 名 ARIC 参与者中已确定的和新型的脂肪因子与 (A) 联系起来 人口统计数据、体重史和体力活动，以及 B) 亚临床和 (C) 临床心力衰竭 (~2200 事件）；目标 2：将脂肪因子从中年晚期到老年的纵向轨迹联系起来 1,000 名 ARIC 参与者的样本根据心脏功能、心脏重塑进行选择 超声心动图、心脏生物标志物和心力衰竭事件；目标 3：评估 (A) 的关联 内脏脂肪细胞中脂肪因子的表达与循环脂肪因子浓度和心脏的关系 300 名减肥手术患者的生物标志物，以及 (B) 术后脂肪因子轨迹的关联 减肥手术会改变心脏生物标志物水平。该提案将增进我们的理解 肥胖与心肌功能障碍和心力衰竭之间的联系，并将由强大的跨学科团队执行， 包括 Ndumele 博士，他正在从富有成效的指导研究转变为独立研究者 地位。