Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation

Abstract

Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n=4) or 9 (n=4) weeks after Sugen5416 and hypoxia and 12weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.