Endothelin-1 and peak oxygen consumption in patients with heart failure with preserved ejection fraction

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.

To explore the association between plasma ET-1 levels and maximal oxygen consumption (pVO2), and their changes over 24 weeks in HFpEF.

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).

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.

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.