Exercise-induced pulmonary hypertension in HFpEF and HFrEF: Different pathophysiologic mechanism behind similar functional impairment

Pathophysiological mechanisms behind cardio-pulmonary impairment in heart failure (HF) with reduced (HFrEF) and preserved (HFpEF) ejection fraction are likely different. We analysed them using combined cardiopulmonary-exercise stress echocardiography (CPET-ESE). Methods: We matched 1:1 subjects with HFrEF (n = 90) and HFpEF (n = 90) for age, sex, body mass index (BMI), peak oxygen consumption, and minute ventilation/carbon dioxide production slope. All patients underwent a symptom-limited graded ramp bicycle CPET-ESE compared with 40 age-, sex- and BMI-matched healthy controls. Results: During a median follow-up of 25 months, we observed 22 deaths and 80 HF hospitalisations, with similar distribution between HFpEF and HFrEF. Compared with HFrEF, HFpEF had a higher prevalence of metabolic syndrome (p = 0.02) with higher levels of high-sensitivity C-reactive protein and uric acid (p < 0.01). The multipoint mean pulmonary artery pressure/cardiac output (mPAP/CO) slope showed equally increased values in HFrEF and HFpEF (3.5 ± 1.8 and 3.7 ± 1.5 mmHg/L/min) compared with controls (1.8 ± 1.1 mmHg/L/min; p < 0.0001). During exercise, HFpEF displayed more adverse interaction of right ventricle-pulmonary artery (RV- PA; tricuspid annular plane systolic excursion/systolic pulmonary artery pressure: 0.40 ± 0.2 vs 0.47 ± 0.2 mm/ mmHg in HFrEF; p < 0.01) and left atrium-left ventricle (LA-LV; LA reservoir strain/LV global longitudinal strain: 1.5 ± 0.8 vs 2.2 ± 1.1 in HFrEF; p < 0.01). The latter were independent predictors of mPAP/CO slope, along with hs-CRP (adjusted R2: 0.21; p < 0.0001). Conclusion: Despite similar disease severity, HFpEF and HFrEF show different pathophysiological mechanisms. HFpEF is characterised by a worse LA-LV and RV-PA interaction than HFrEF, with more prevalent low-grade systemic inflammation. In HFpEF, these features may have a role in exercise-induced pulmonary hypertensio