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. 2023 Nov;16(11):e010618.
doi: 10.1161/CIRCHEARTFAILURE.123.010618. Epub 2023 Sep 13.

Obesity-Related Biomarkers Are Associated With Exercise Intolerance and HFpEF

Mariana F Ramirez  1 , Emily S Lau  2 , Juhi K Parekh  1 , Abigail S Pan  1 , Ndidi Owunna  1 , Dongyu Wang  1   3 , Jenna N McNeill  2   4 , Rajeev Malhotra  2 , Matthew Nayor  5 , Gregory D Lewis  2 , Jennifer E Ho  1
Affiliations

Obesity-Related Biomarkers Are Associated With Exercise Intolerance and HFpEF

Mariana F Ramirez et al. Circ Heart Fail. 2023 Nov.

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 VO2 (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 VO2 (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.

Keywords: adiposity; biomarker; heart failure; inflammation; obesity.

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Conflict of interest statement

Disclosures Dr Ho has received past research funding from Bayer AG. Dr Lau reports modest honoraria from Roche Diagnostics. Dr Nayor has received modest honoraria from Cytokinetics. Dr Malhotra receives research funding from Angea Biotherapeutics and Amgen and serves as a consultant for Myokardia/BMS, Renovacor, Epizon Pharma, and Third Pole. The other authors report no conflicts.

Figures

Figure 1.
Figure 1.. Study design and approach to explore the associations of obesity-related biomarkers with exercise intolerance and HFpEF.
Diagram shows assessment of adiposity-related biomarkers representing adipokines, inflammation and insulin resistance to explore possible mechanistic pathways in which obesity may associate with HFpEF and exercise intolerance.
Figure 2.
Figure 2.. Differences in obesity-related biomarkers in participants with HFpEF vs. without HFpEF.
Violin plots displays between group differences in baseline values for biomarkers in participants with (red) and without HFpEF (blue). * Indicates p ≤ 0.0.5 via Mann-Whitney test. HOMA-IR levels calculated only in patients without diabetes. Lower detection limit for CRP is <0.15 mg/L and for IL-6 is <1.38 pg/mL.
Figure 3.
Figure 3.. Association of obesity related biomarkers with HFpEF.
Forest plot shows odds ratio per 1-SD unit change in log-transformed biomarker with HFpEF using a multivariable model adjusted for age, sex, hypertension, diabetes, smoking, and previous MI. Abbreviations: OR = Odds ratio (point estimate and 95% CI) of HFpEF.
See this image and copyright information in PMC

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