Abstract

BACKGROUND: Mechanisms of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) are not well understood. Pulmonary hypertension, a common accompaniment in patients with HFpEF, is associated with poor outcomes. While Endothelin -1 (ET-1) plays a mechanistic role in pulmonary hypertension, its role in exercise intolerance in HFpEF is not well established. OBJECTIVE: To explore the association between plasma ET-1 levels and maximal oxygen consumption (pVO2), and their changes over 24 weeks in HFpEF. METHODS: This is a post-hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. We performed linear regressions to assess the relationship between plasma ET-1 and pVO2. We also used linear regressions to determine whether ET-1 was associated with change in peak VO2 (ΔpVO₂). RESULTS: A total of 210 patients were included. Baseline plasma ET-1 levels were associated with older age, higher NT-proBNP levels, higher serum creatinine levels, and higher prevalence of atrial fibrillation. Patients with higher ET1 levels also had higher plasma galectin-3 and CITP levels. After multiple adjustments, baseline ET1 levels were associated with lower pVO₂ (β -0.927, SE 0.196, p < 0.001). Over 24 weeks, the change in ET1 levels was associated with the change in pVO2 (multivariable adjusted β -0.415, SE 0.115, p = 0.018). Baseline ET1 levels did not modify the effect of sildenafil on change in peak VO₂. CONCLUSIONS: Plasma ET1 levels are significantly associated with lower exercise oxygen consumption both at baseline and longitudinally over 24 weeks. Future studies should explore Endothelin-1 antagonism to improve exercise tolerance in HFpEF.