Out of breath and looking for options: Understanding pulmonary contributions to exercise intolerance in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases, and the prevalence of HFpEF is growing (Reddy & Borlaug, 2016). Dyspnoea on exertion and exercise intolerance are hallmark symptoms in patients with HFpEF (Reddy & Borlaug, 2016), and although the focus has traditionally been on understanding the impaired cardiovascular response in these patients, there is emerging evidence that patients with HFpEF have altered pulmonary responses to exercise, such as exercise-induced arterial hypoxaemia (EIAH), which may contribute to dyspnoea and exercise intolerance. Leahy et al. (2025) sought to characterize the occurrence of EIAH in patients with HFpEF and to examine whether EIAH was associated with lower peak oxygen uptake, augmented cardiac filling pressure and greater dyspnoea. The authors found that 42% of patients with HFpEF developed EIAH, which was related to greater dyspnoea on exertion, but that EIAH was not associated with more severe exercise impairment or augmented cardiac filling/pulmonary vascular pressures. The study by Leahy et al. (2025) is an outstanding example of clinical integrated physiology conducted at the highest level. What truly sets this paper apart is the simultaneous evaluation during upright exercise of cardiovascular haemodynamics, including pulmonary artery (PAP) and pulmonary artery wedge (PAWP) pressures, respiratory responses, dyspnoea, and direct arterial and mixed venous blood sampling in a large sample of patients with HFpEF. The data presented within the manuscript provide tremendous insight into the pathophysiology of HFpEF, while also expanding our understanding of fundamental pulmonary physiology. Firstly, dyspnoea was shown to be greater in HFpEF with EIAH (EIAH+) in comparison to HFpEF without EIAH (EIAH−). Given that dyspnoea is a defining feature of HFpEF and greatly influences quality of life (Obokata et al., 2018), this finding highlights the clinical significance of EIAH in HFpEF. High filling pressures are widely considered to be the primary cause of dyspnoea in HFpEF, secondary to pressure-induced stimulation of pulmonary J-receptors (Obokata et al., 2018). Interestingly, Leahy et al. (2025) observed greater dyspnoea in the EIAH+ group, despite no difference in PAP/PAWP pressures between EIAH+ and EIAH− groups, suggesting that high pulmonary vascular pressures alone would not explain the greater dyspnoea in the EIAH+ group. Importantly, there were no between-group differences in end-expiratory/end-inspiratory lung volume, tidal volume, breathing frequency, minute ventilation and breathing reserve that would suggest alterations in lung mechanics or ventilatory drive that would explain the greater dyspnoea in the EIAH+ group (Stickland et al., 2022). These observations suggest that other factors likely contribute to dyspnoea in HFpEF, which warrant further investigation. In health, EIAH is most common in elite endurance athletes exercising close to maximal oxygen consumption and occurs because of a substantial impairment in gas exchange (as demonstrated by an alveolar-to-arterial O2 pressure difference of >25 mmHg) and a blunted hyperventilatory response to exercise that fails to increase alveolar P O 2 ${P_{{\mathrm{O}}_2}}$ . Interestingly, EIAH+ patients also demonstrated a somewhat blunted hyperventilatory response to exercise relative to the EIAH− patients, for reasons that are not easily explained by lung mechanics. Classically, an increase in alveolar-to-arterial O2 pressure difference occurs with ventilation–perfusion mismatch, diffusion limitation or shunt (Stickland & Hopkins, 2025). The current theories explaining the increased alveolar-to-arterial O2 pressure difference during exercise in health include ventilation–perfusion mismatch as a result of subclinical interstitial oedema and a diffusion limitation from reduced pulmonary capillary transit time (see recent review by Stickland & Hopkins, 2025). Considering that patients with HFpEF have baseline elevations in PAWP, it would be logical that HFpEF patients would develop oedema and ventilation–perfusion mismatch with exercise because of the elevated PAWP and the corresponding elevation in pulmonary capillary pressure. And yet, Leahy et al. (2025) found that PAP and PAWP were virtually identical between EIAH+ and EIAH− groups, suggesting that high pulmonary vascular pressures might not be the primary mechanism for the significant impairment of gas exchange observed in EIAH+ patients. A diffusion limitation for O2 can be evaluated using the equilibration index (DL/βQ̇); broadly, a diffusion limitation occurs when there is a mismatch between diffusing capacity (DL) and pulmonary capillary blood flow (Q̇) (Stickland & Hopkins, 2025). The coefficient β is the effective solubility of O2, which varies based on mixed-venous P O 2 ${P_{{\mathrm{O}}_2}}$ (i.e. where mixed-venous P O 2 ${P_{{\mathrm{O}}_2}}$ sits within the slope of the O2 dissociation curve). In comparing EIAH+ and EIAH− patient groups, both Q̇ and mixed venous O2 content at peak exercise were similar between groups, the latter indicating no between-group differences in β. Thus, any potential diffusion limitation in EIAH+ patients would be explained by a lower exercise diffusing capacity. Importantly, resting carbon monoxide diffusing capacity (an estimate of DLO2) was lower than predicted in both groups, with EIAH+ patients having a lower DLCO in comparison to EIAH− patients. It remains to be determined whether diffusing capacity increases appropriately with exercise in HFpEF or whether a diffusion limitation occurs in some HFpEF patients that would contribute to EIAH. Leahy et al. (2025) should be commended on completing a challenging integrative physiological study that greatly advances our understanding of pulmonary gas exchange in HFpEF. As with any great physiological study that presents a wealth of data, their fascinating work generates as many questions as answers. The data presented form part of a larger programme examining exercise intolerance in HFpEF, and we look forward to further work from the investigators examining mechanism(s) and, potentially, treatments for dyspnoea and the pulmonary consequences of HFpEF. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. Sole author. M.K.S. is funded by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. Owing to restriction in the number of articles that can be cited in this perspective, not all relevant literature is cited.