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

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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.