Acute Effects of Myeloperoxidase Inhibition on Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial.

Abstract

Myeloperoxidase (MPO) is a heme peroxidase that scavenges nitric oxide and contributes to microvascular dysfunction. Patients with heart failure and preserved ejection fraction (HFpEF) have microvascular dysfunction that leads to increased pulmonary capillary wedge pressure (PCWP). We sought to investigate whether acute MPO inhibition can reduce exertional PCWP in patients with HFpEF. Between July 1, 2018, and February 24, 2022, participants with HFpEF were recruited. They underwent baseline invasive hemodynamic exercise evaluation and were then randomized, double-blind, to a single dose of the MPO inhibitor mitiperstat at 30 mg or matching placebo, after which they underwent repeated invasive hemodynamic exercise testing. The primary end point was PCWP during 20-W exercise workload. Patients with HFpEF (N=30; mean ± SD age, 70±9 years; 11 female [37%]; body mass index, 34.0 kg/m²) displayed typical hemodynamic responses to exercise prior to treatment, with PCWP increasing from 17±5 to 32±6 mm Hg with exercise and mean pulmonary artery pressure increasing from 28±9 to 49±11 mm Hg. Contrary to our hypothesis, as compared with placebo, mitiperstat treatment resulted in a higher PCWP during the second bout of exercise (-1±3 vs -4±5 mm Hg; P=.04). There was a trend for less reduction in mean pulmonary artery pressure and lower pulmonary artery compliance during exercise with mitiperstat as compared with placebo. There was no effect of mitiperstat on arterial, coronary sinus, or transcardiac uptake/release of O₂, CO₂, and lactate compared with placebo. Acute MPO inhibition with mitiperstat did not reduce exertional hemodynamic congestion in patients with HFpEF.