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

心力衰竭是一个重大的临床和公共卫生挑战，伴随着显著的发病率和死亡率。 肥胖与心肌功能障碍和随后的心力衰竭(HF)密切相关，但这种联系 传统风险因素解释不佳，标准的心力衰竭风险预测算法执行相对较差 在肥胖方面。尽管指南越来越注重避免心力衰竭的发作，但预测和预防心力衰竭的战略 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。实验室数据提示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、抵抗素、脂联素)的作用 在调节肥胖与心力衰竭的关联方面，临床结果一直不一致，而且 新的脂肪因子(内脂素、apelin)没有定义。尽管越来越多的人认识到高频的优势 在肥胖症患者中保留射血分数(与减少的射血分数；HFpEF与HFrEF)，脂肪因子研究 日期没有单独描述这些病理生理上不同情况的风险。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，这些生物标志物与心力衰竭的风险有关 肥胖，脂肪因子纵向变化的临床意义，以及减肥对这些因素的影响 风险关联。该项目将结合精心挑选的已建立的和新的小组的血清分析。 脂肪因子与公认的ARIC脂肪研究中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，以充分描述脂肪因子在调节和预测与肥胖相关的心衰中的作用。我们 建议：目标1：在11,656名ARIC参与者中确定和新发现的脂肪因子与(A)有关 人口统计学、体重史和体力活动，以及B)亚临床和(C)临床性心衰(~2200 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，根据心功能、心脏重塑 超声心动图、心脏生物标志物和心力衰竭事件；以及目标3：评估(A) 脂肪因子在内脏脂肪细胞中的表达与循环脂肪因子浓度和心脏 300名减肥手术患者的生物标记物，以及(B)减肥手术后脂肪因子轨迹的相关性 心脏生物标记物水平变化的减肥手术。这项建议将增进我们的了解 肥胖与心肌功能障碍和心力衰竭的联系，并将由一个强大的跨学科团队执行， 包括恩杜梅勒博士，他正在从富有成效的指导研究过渡到独立研究人员 状态。

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.