| Autor: |
Ambade AS; Division of Pulmonary and Critical Care Medicine., Naranjo M; Department of Thoracic Medicine and Surgery, Temple University, Philadelphia, Pennsylvania., Tuhy T; Division of Pulmonary and Critical Care Medicine., Yu R; Division of Pulmonary Medicine, Johns Hopkins Community Physicians, Columbia, Maryland., Marimoutou M; Institute for In Vitro Sciences, Gaithersburg, Maryland; and., Everett AD; Division of Pediatric Cardiology, Department of Pediatrics., Shimoda LA; Division of Pulmonary and Critical Care Medicine., Zimmerman SL; Department of Radiology and Radiological Science, and., Cubero Salazar IM; Division of Cardiology, Department of Medicine., Simpson CE; Division of Pulmonary and Critical Care Medicine., Tedford RJ; Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina., Hsu S; Division of Cardiology, Department of Medicine., Hassoun PM; Division of Pulmonary and Critical Care Medicine., Damico RL; Division of Pulmonary and Critical Care Medicine.; Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. |
| Abstrakt: |
Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII α 1 chain and encoded by COL18A1 , is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1 /ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure-volume loops in patients with PAH to assess RV-pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV-pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1 /ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1 /ES increases early in disease development in the RV and implicates COL18A1 /ES in pathologic RV dysfunction in PAH. |
