Obesity-Related Biomarkers Linked to Exercise Intolerance, Heart Failure

Inflammation and insulin resistance underlay the association between obesity and heart failure with preserve ejection fraction.

Obesity-related biomarkers such as inflammation, adipokine pathways, and insulin resistance are associated with exercise intolerance underlying heart failure with preserved ejection fraction (HFpEF), according to study findings published in Circulation

Previous research has identified obesity and its associated metabolic risk factors as contributors to the development of HFpEF. However, the underlying mechanisms of this relationship remain unclear.

To better understand the association between obesity-related biomarkers and cardiovascular dysfunction in HFpEF, researchers at Massachusetts General Hospital conducted a retrospective cohort study of participants with preserved ejection fraction and chronic dyspnea who underwent cardiopulmonary exercise tests from 2006 to 2017.

A history and physical examination, including overnight fasting phlebotomy at the time of exercise tests, were conducted for each participant. Obesity was defined as a body mass index (BMI) greater than 30 kg/m2. From blood samples, the researchers measured high-sensitivity C-reactive protein (CRP), adiponectin, interleukin-6, leptin (IL-6), resistin, and insulin resistance (HOMA-IR).

Participants underwent right heart catheterization prior to exercise testing. Hemodynamic parameters were obtained at rest and during exercise. Overall exercise capacity was measured by peak oxygen consumption (VO2). The researchers defined HFpEF on the basis of elevated left ventricular filling pressures at rest or during exercise.

The association between obesity-related biomarkers and exercise parameters was evaluated with multivariable linear regression. The researchers used Cox proportional hazard analyses to assess the association between the biomarkers and clinical outcomes. 

The study included 509 participants, of whom 228 (49%) met the clinical criteria for HFpEF. Compared with participants without HFpEF, those with HFpEF were more likely to have obesity, hypertension, and diabetes. Participants with HFpEF were also more likely to have higher baseline levels of CRP, IL-6, HOMA-IR, and leptin in addition to lower VO2

[S]pecific obesity-related pathways including inflammation, adipokine signaling, and insulin resistance may underlie the association of obesity with HFpEF and exercise intolerance.

The researchers found that obesity-related biomarkers were associated with overall exercise capacity (≤.002 for all). Higher biomarker levels were associated with worse fitness, although higher levels of adiponectin were associated with better peak VO2. The largest effect size was seen with leptin (β, -2.35; SD, 0.19; P <.001). 

CRP, IL-6, and resistin were associated with chronotropic response (P ≤.001 for all), whereas worse HOMA-IR, lower adiponectin, and higher leptin levels were associated with greater blood pressure response (P ≤.002 for all). 

In secondary analyses, increased risk for HFpEF was significantly associated with:

  • Obesity (odds ratio [OR], 1.96; 95% CI, 1.30–2.96);
  • Diabetes (OR, 1.89; 95% CI, 1.04–3.41);
  • Higher leptin levels (OR, 1.35; 95% CI, 1.09-1.70); and,
  • Higher CRP levels (OR, 1.25; 95% CI, 1.03-1.52).

Study limitations include a lack of generalizability due to potential referral bias, the potential of confounding comorbid conditions, limited power to examine the association between the explored biomarkers and a purely obese-HFpEF phenotype, and limited associations with clinical outcomes due to sample sizes. 

The researchers concluded, “[S]pecific obesity-related pathways including inflammation, adipokine signaling, and insulin resistance may underlie the association of obesity with HFpEF and exercise intolerance.” 

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Endocrinology Advisor


Ramirez MF, Lau ES, Parekh JK, et al. Obesity-related biomarkers are associated with exercise intolerance and HFpEF. Circulation. Published online September 13, 2023. doi:10.1161/CIRCHEARTFAILURE.123.010618