Pulmonary congestion in heart failure with preserved ejection fraction: impact on respiratory mechanics

Heart failure with preserved ejection fraction (HFpEF) is a growing health problem worldwide. Among several pathophysiological hallmarks, pulmonary congestion in HFpEF has been shown to be closely linked to poor outcomes. The mechanisms underpinning the increases in extravascular lung water content in HFpEF are not fully understood. However, acute increases in hemodynamic load during routine daily activities has been pointed out as one major contributor to the development of pulmonary congestion in HFpEF. Despite, the long-term consequences of pulmonary congestion on respiratory mechanics have not been thoroughly studied. Accordingly, we aimed to determine the impact of pulmonary congestion on respiratory function in mice with HFpEF. Adult (P90) male and female mice were fed with a high fat diet (60% Kcal from fat) and L-Name (0.75 mg/L) in the tap water for 16 weeks to induced HFpEF. Aged-matched control mice received normal chow diet and tap water. At the end of the 16-week period, blood pressure was measured in non-anesthetized conditions followed by 2D echocardiography. Then, animals were deeply anesthetized with urethane/a-chloralose (80/800 mg/kg i.p.) and connected to a fully automated mechanical ventilator through an endotracheal tube. Once ventilated, pancuronium (1mg/kg) was injected i.p. before assessing pulmonary mechanics using pressure-volume loops. Compared to control healthy mice, we found that both male and female HFpEF mice showed significant (p<0.05) increases in body weight (♀: 28.3±3.5 vs 47.3±7.0 g; ♂: 32.7±0.7 vs 47.8±2.4 g, Control vs HFpEF), systolic blood pressure (♀:102.3±8.2 vs 120.0±6.3 mmHg; ♂: 100.3±6.9 vs 127±4.6 mmHg, Control vs HFpEF) and cardiac stiffness, evidenced by larger E/e’ (♀: 10.9±2.0 vs 23.2±2.4; ♂: 8.8±1.8 vs 25.0±3.1, Control vs HFpEF). In addition, a 1.4 and 1.6-fold increase in the wet-to-dry lung weight ratio was found in male and female HFpEF mice compared to healthy controls. We found no effects of pulmonary congestion on inspiratory capacity in both males and females with HFpEF. Contrarily, we found decreases in respiratory system resistance (Rrs) and elastance (Ers) in HFpEF. Indeed, changes in Ers in HFpEF were associated with decreases in lung but not in airway resistance since tissue damping (G) was markedly reduced in both male and female HFpEF mice compared to control (♀: 3.7±0.4 vs 2.9±0.3 cmH 2 O/ml; ♂: 3.6±0.6 vs 2.7±0.2 cmH 2 O/ml, Control vs HFpEF) without affecting airway resistance. Furthermore, we found that changes in Ers were associated with decreases in lung tissue elasticity (H) in mice with HFpEF. Indeed, both male and female HFpEF mice showed decreases in H compared to healthy mice (♀: 22.4±1.7 vs 19.9±1.2 cmH 2 O/ml; ♂: 19.5±1.2 vs 18.7±0.7 cmH 2 O/ml, Control vs HFpEF). No changes in static compliance were found between groups. Our results showed long-term alterations in respiratory mechanics in rodents with pulmonary congestion secondary to HFpEF. Importantly, these alterations appear not to be linked to biological sex in HFpEF. Whether the changes in respiratory system resistance and elastance in HFpEF negatively impact gas exchange during daily activities in the setting of HFpEF remains to be determined. Supported by Fondecyt 1220950 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.