Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model

Abstract

In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca(2+)-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism.

Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension

“…90 Similarly, in the pig pulmonary vein banding model of pulmonary hypertension, hyperaldosteronism was linked to maladaptive RV remodeling with RV cardiomyocyte hypertrophy and dysfunction as demonstrated by downregulation of SERCA2a. 91 This is not surprising as in other experimental models of hyperaldosteronism, RV and LV cardiomyocytes exhibit heterogeneity in size. This may be attributable to increased cardiomyocyte free Ca 2+ and oxidant stress as well as activation of transforming growth factor-β, tumor necrosis factor-α and insulin signaling, which are all involved in the remodeling process.…”

Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension

“…Aguero et al 27 using a pig model of pulmonary vein banding via thoracotomy similarly found worsened RV longitudinal strain in the pigs with induced pulmonary hypertension. By contrast, our model used hypoxia-induced pulmonary hypertension and avoided confounding traumatic inflammatory responses commonly observed after even minor animal surgery.…”

“…Other large animal models to evaluate RV strain often rely on surgical banding of the pulmonary venous drainage 27 or pulmonary artery banding 28 to induce pulmonary hypertension. Aguero et al 27 using a pig model of pulmonary vein banding via thoracotomy similarly found worsened RV longitudinal strain in the pigs with induced pulmonary hypertension.…”

Advancing knowledge of right ventricular pathophysiology in chronic pressure overload: Insights from experimental studies

“…Impairment of RV-PA coupling is reflected in an Ees/Ea ratio of < 1 in large animals, whereas the normal Ees/Ea ratio ranges from 0.5 to 0.8 in rodents. At the early stage of RV pressure overload, Ees is often increased to compensate for the elevated afterload [27,28]. However, RV-PA coupling may be decreased at that time, without RV dysfunction at rest.…”

“…RV stroke volume and RV ejection fraction decrease. RV dilatation and adverse remodelling then occur, leading to RVF [27,29]. The concept of ventricular-arterial coupling is not commonly used in clinical practice, mainly because it requires invasive and time-consuming measurement.…”