Jonathan Hyde, Michael A. Smith, Naveen Swami, John H. Hwang, Yenchun Chao, Jason Boehme,Gary W. Raff, Casper Noah Nilsson, Wenhui Gong, Gail H. Deutsch, Eric G. Johnson, Ting Wang,Stephen M. Black, Sanjeev A. Datar, Emin Maltepe, Jeffrey R. Fineman
University of California, San Francisco. Copenhagen University Hospital. University of Washington. University of California, Davis School of Veterinary Medicine. Florida International University.
United States and Denmark
Comprehensive Physiology
Compr Physiol 2025;
DOI: 10.1002/cph4.70071
Abstract
Background: Pulmonary vascular disease (PVD) in patients with single ventricular heart disease following the partial cavalpulmonary connection (Glenn) is a significant source of morbidity. However, the etiology of pulmonary vascular endothelial cell (EC) dysfunction, an established precursor to PVD, is incompletely understood but may involve abnormal blood flow patterns, hypoxemia, and polycythemia.
Hypothesis: Utilizing an ovine Glenn model, we hypothesized that nonpulsatile pulmonary blood flow (PBF) induces pulmonary vascular EC dysfunction, independent of hypoxemia or polycythemia.
Methods: Seven lambs (6-8 weeks old) underwent a Glenn procedure. Eight weeks later, Glenn and age-matched controls were studied. The response to the endothelium-dependent vasodilator acetylcholine (Ach) was determined in isolated pulmonary arteries (PA). Nitric oxide (NO) and endothelin-1 (ET-1) signaling were determined in right lung tissues. Indices of cell proliferation, angiogenesis, and apoptosis were determined in PA endothelial cells (PAECs). Comparisons were made by unpaired t-test and ANOVA.
Results: There were no differences in age, hemoglobin, or oxygen saturation between groups. Mean PA pressure and left PA flow were higher, and right lung blood flow was lower in Glenn lambs compared to controls (p < 0.05). All other baseline hemodynamics were similar. Glenn PAs had impaired relaxation to Ach. Glenn lung NO metabolite levels (NOx) and eNOS protein were lower, and ET-1 levels and prepro-ET-1 protein were higher than controls (p < 0.05). Glenn PAECs had higher rates of proliferation and angiogenesis, and decreased apoptosis (p < 0.05).
Conclusions: The initiation of nonpulsatile PBF following the Glenn induces early EC dysfunction independent of hypoxemia and polycythemia.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes