Adverse structural and mechanical remodelling of main pulmonary artery in experimental pulmonary arterial hypertension is associated with impaired right ventricle-pulmonary artery coupling and function

Abstract

RationaleCoupling between right ventricular function and the pulmonary vasculature determines outcomes in pulmonary arterial hypertension. The mechanics of the main pulmonary artery is an important but understudied determinant of right ventricular-pulmonary artery coupling. ObjectivesTo investigate the histology and mechanics of the pulmonary artery in relationship to right ventricular remodeling, mechanics, hemodynamics and coupling in experimental pulmonary arterial hypertension. MethodsIn a sugen+hypoxia rat model of pulmonary arterial hypertension, right ventricular hemodynamics were assessed by conductance catheters. Active tension-strain curves were generated using echocardiography. Main pulmonary artery and right ventricle free-wall were harvested to determine their macro- and micro-structure, composition, and mechanical properties. Comprehensive multivariate analyses elucidated relationships between pulmonary artery and right ventricle mechanics, structure and coupling. Measurements and Main ResultsPulmonary hypertensive main pulmonary arteries developed fibrosis relative to healthy controls, as did right ventricles, which also hypertrophied, with re-orientation of muscle fibres toward a tri-layer architecture reminiscent of normal left ventricular architecture. Increased glycosaminoglycan deposition and increased collagen-to-elastin ratio in the pulmonary artery; and increased collagen, as well as hypertrophy and reorganization of myofibers in the right ventricle, led to increased stiffness. This increase in stiffness was more pronounced in the longitudinal direction in the high- and low-strain regime for the pulmonary artery and right ventricle, respectively, causing increased mechanical anisotropy. Main pulmonary artery stiffening correlated significantly with right ventricular tissue mechanical remodelling and reduced systolic performance, cardiac output and right ventricle-pulmonary artery coupling. ConclusionsCompositional, structural, and mechanical changes in the main pulmonary artery correlate with adverse right ventricular remodeling, mechanics, function and coupling in pulmonary arterial hypertension. Therefore, increasing mechanical compliance of the large pulmonary arteries may be an important and novel therapeutic strategy for mitigating right ventricular failure.