Yogesh N V Reddy 1, Robert P Frantz 2, William R Miranda 2, Revati Varma 2, Paul M Hassoun 3, Anna R Hemnes 4, Evelyn Horn 5, Jane A Leopold 6, Franz Rischard 7, Erika B Rosenzweig 8, Nicholas S Hill 9, Serpil C Erzurum 10, Gerald J Beck 11, Samar Farha 12, J Emanuel Finet 12, Christine Jellis 12, Deborah Kwon 12, Stephen Mathai 3, Margaret Park 12, W H Wilson Tang 12, Barry A Borlaug 2; PVDOMICS Study Group
Mayo Clinic. Johns Hopkins University. Vanderbilt University Medical Center. Weill Cornell Medicine. Brigham and Women’s Hospital and Harvard Medical School. University of Arizona. Westchester Medical Center. Tufts Medical Center. Cleveland Clinic.
United States
European Respiratory Journal
Eur Respir J 2026;
DOI: 10.1183/13993003.01871-2025
Abstract
Background: Pulmonary vasodilators increase cardiac output (CO) in group 1 PH and can cause high CO with unclear implications.
Objectives: To describe pathophysiology of high CO in group 1 PH.
Methods: Clinical characteristics were compared among PVDOMICS group 1 PH participants by low (cardiac index (CI) <2.2 L·min-1·m-2),normal, or high output (CO>8 L·min-1 or CI>4 L·min-1·m-2).
Measurements and main results: Of 449 group 1 PH participants, 23%(n=103) had low output, 68%(n=304) had normal CO and 9%(n=42) had high output. Increasing CO was associated with more intensive vasodilator use (triple therapy 11/19/33%,p=0.0008), with progressively lower PVR (p<0.0001). High output was associated with the lowest systemic vascular resistance (p<0.0001), with greater LV and LA enlargement (p<0.001 for all). High flow resulted in increase in LV and RV work at rest, and absolute/relative RV work during exercise (p<0.0001 for all). Despite greater exercise O2 delivery (p<0.0001), peripheral O2 utilization was impaired by O2 extraction ratio (p=0.001) and AVO2 difference (p=0.005), without incremental functional or survival benefit compared to normal output PH. After adjusting for baseline risk, high output had increased risk of death/transplant compared to normal output [adjusted HR 2.1 (95% 1.2-3.7), p=0.007]. In a validation cohort (n=37), 93% had normal CO at diagnosis, with the high output state developing in follow-up after vasodilator initiation.
Conclusions: 1 in 10 patients with group 1 PH has a high output state which is most common in prevalent PH and related to vasodilator intensity, with adverse cardiac remodeling and myocardial workload. Further studies are needed to determine optimal vasodilator dosing with high output, and therapeutic interaction with vasodilator sparing therapies such as sotatercept.
Category
Heart Dysfunction Associated with Pulmonary Vascular Disease (Right and Left)
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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