Abstract
BACKGROUND: Obesity and adiposity are associated with an increased risk of heart failure with preserved ejection fraction (HFpEF); yet, specific underlying mechanisms remain unclear. We sought to examine the association of obesity-related biomarkers including adipokines (leptin, resistin, adiponectin), inflammatory markers (CRP [C-reactive protein], IL-6 [interleukin-6]), and insulin resistance (HOMA-IR) with HFpEF status, exercise capacity, and cardiovascular outcomes. METHODS: We studied 509 consecutive patients with left ventricular ejection fraction ≥50% and chronic dyspnea, who underwent clinically indicated cardiopulmonary exercise test with invasive hemodynamic monitoring between 2006 and 2017. We defined HFpEF based on the presence of elevated left ventricular filling pressures at rest or during exercise. Fasting blood samples collected at the time of the cardiopulmonary exercise test were used to assay obesity-related biomarkers. We examined the association of log-transformed biomarkers with HFpEF status and exercise traits using multivariable-adjusted logistic regression models. RESULTS: We observed associations of obesity-related biomarkers with measures of impaired exercise capacity including peak VO(2) (P≤0.002 for all biomarkers). The largest effect size was seen with leptin, where a 1-SD higher leptin was associated with a 2.35 mL/kg per min lower peak VO(2) (β, -2.35±0.19; P<0.001). In addition, specific biomarkers were associated with distinct measures of exercise reserve including blood pressure (homeostatic model assessment of insulin resistance, leptin, adiponectin; P≤0.002 for all), and chronotropic response (CRP, IL-6, homeostatic model assessment of insulin resistance, leptin, and resistin; P<0.05 for all). Our findings suggest that among the obesity-related biomarkers studied, higher levels of leptin and CRP are independently associated with increased odds of HFpEF, with odds ratios of 1.36 (95% CI, 1.09-1.70) and 1.25 (95% CI, 1.03-1.52), respectively. CONCLUSIONS: Specific obesity-related pathways including inflammation, adipokine signaling, and insulin resistance may underlie the association of obesity with HFpEF and exercise intolerance.