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

心力衰竭是一个主要的临床和公共卫生挑战，具有显著相关的发病率和死亡率。 肥胖与心肌功能障碍和随后的心力衰竭（HF）密切相关，但这种相关性是不确定的。 传统风险因素解释不佳，标准HF风险预测算法表现相对较差 肥胖症。尽管指南中越来越关注避免HF发作，但预测和预防HF的策略， 肥胖是有限的。脂肪因子是由脂肪组织分泌的分子，其可能介导许多脂肪细胞的凋亡。 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，已建立的脂肪因子（瘦素，瘦素，脂联素）的作用， 在介导肥胖-HF关联方面，临床结果不一致， 没有定义新的脂肪因子（内脂素，爱帕琳）。尽管越来越多的人认识到HF的优势， 与射血分数保留（与射血分数降低; HFpEF与HFrEF）的肥胖，脂肪因子研究， 迄今尚未单独描述这些病理生理学上不同的疾病的风险。此外还有 需要了解脂肪因子与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。 风险协会。该项目将联合收割机血清检测的一个精心挑选的小组建立和新的 脂肪因子和HFpEF和HFrEF病例的新裁定， 在Geisinger肥胖研究所进行的减肥手术患者中的组织脂肪因子表达研究 登记研究，以充分表征脂肪因子在介导和预测肥胖相关HF中的作用。我们 目的1：将11，656名ARIC参与者中已建立的和新的脂肪因子与（A） 人口统计学、体重史和体力活动，以及B）亚临床和（C）临床HF（~2200 目的2：将从中年晚期到老年的脂肪因子的纵向轨迹与一个人的年龄相关。 选择1,000名ARIC参与者进行心脏功能研究， 目标3：评估（A）心脏生物标志物与 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 （B）300名减肥手术患者中的脂肪因子轨迹的相关性， 心脏生物标志物水平变化的减肥手术。这项建议将增进我们对 肥胖与心肌功能障碍和HF之间的联系，并将由一个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过渡到独立研究者 status.

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.