Mechanisms of exercise limitation in heart failure with preserved ejection fraction and obesity: a case of engine-chassis mismatch

Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF), but its impact on limitations in peak oxygen uptake (V̇o_2peak) and its Fick determinants remains unclear. We assessed these factors in patients with obesity and patients without obesity with HFpEF, and non-HFpEF controls. Patients with HFpEF were subgrouped by body mass index [body mass index (BMI) ≥ 30 or < 30 kg/m²] into HFpEF with (HFpEF_Obese, <i>n</i> = 139) or without obesity (HFpEF_Nonobese, <i>n</i> = 317), and non-HFpEF controls (CON, <i>n</i> = 270). Cardiopulmonary exercise testing with simultaneous echocardiography assessed V̇o_2peak, cardiac output (CO), stroke volume (SV), heart rate (HR), mean pulmonary artery pressure (mPAP) dynamics, and arterio-venous oxygen difference (a-vO₂diff). HFpEF_Obese tended to have higher absolute V̇o_2peak (+7%, <i>P</i> = 0.069), and significantly higher peak exercise CO and SV, with no differences in HR or a-vO₂diff. Resting and exercise mPAP and mPAP/CO slopes did not differ between HFpEF obesity phenotypes. In contrast, bodyweight-indexed V̇o_2peak was markedly lower in HFpEF_Obese (-23%) despite comparable indexed peak CO and SV. Regardless of HFpEF subgroup, V̇o_2peak, central (CO, HR, mPAP) and peripheral factors (a-vO₂diff) were markedly impaired in HFpEF versus CON (<i>P</i> < 0.05 for all). Therefore, although patients with HFpEF_Obese have preserved absolute V̇o_2peak and cardiac reserve, bodyweight-indexing reveals that these adaptations are insufficient for the heightened metabolic and functional demands induced by obesity. Alternatively, several physiological HFpEF features are not exacerbated by obesity. This highlights the importance of incorporating weight loss alongside multicomponent therapeutic strategies to address exercise intolerance in HFpEF.<b>NEW & NOTEWORTHY</b> Patients with obesity with heart failure with preserved ejection fraction (HFpEF) have larger hearts and preserved cardiac reserve, but this was insufficient to maintain bodyweight-indexed V̇o_2peak at comparable levels to patients without obesity. Obesity did not exacerbate other HFpEF impairments, such as decreased oxygen extraction or elevated pulmonary pressures. This suggests weight loss may help to improve exercise intolerance in obese patients with HFpEF, but should be combined with other treatments to target all of the features that contribute to exercise intolerance in HFpEF.