Abstract 13689: Right Ventricular Edema and Pericardial Effusion in Pulmonary Hypertension: Role of Lymphatics

Abstract

Introduction: Pulmonary hypertension (PH), regardless of etiology, is characterized by right ventricular remodeling and eventual failure. Pericardial effusion in the setting of PH is a serious and important clinical problem that portends a grim prognosis. Unfortunately, there are few mechanistic data available to explain its pathogenesis. Hypothesis: We hypothesized that the RV lymphatic vasculature and function would be decreased in PH associated with pericardial effusion. Methods: We examined human RV tissue from patients with PH and from rat models of PH with and without pericardial effusion and RV failure. We evaluated the extent of lymphatic vasculature, the presence of myocardial edema, and degree of pericardial effusion using invasive (immunoblot, immunohistology, RV wet/dry ratios) and non-invasive techniques (MRI, echocardiography, intravital imaging). To investigate whether neo-lymphangiogenesis affected RV function in PH, we treated rats with exogenous recombinant vascular endothelial growth factor C (VEGFC) before and during the development of PH. Results: We found decreased prox1+/podoplanin+ lymphatic vessels in RVs, but not left ventricles, from PH compared to either controls or to individuals with PH that lacked RV failure. The extent of lymphatic vasculature inversely correlated with the presence of myocardial edema, pericardial effusion, and positively correlated with cardiac output. In addition, the presence of increased interstitial fluid preceded development of RV fibrosis and was associated with increased numbers of tcf21+ RV fibroblasts. We found that administration of VEGFC induced a neo-lymphangiogenic response in RVs of rats, reduced myocardial edema, and promoted significant improvement in RV function. Conclusions: Decreased lymphatic vasculature and function likely contribute to myocardial edema and pericardial effusion in severe PH with RV failure. Augmentation of RV neo-lymphangiogenesis in rat models of PH greatly attenuated the edema, effusion, and fibrosis compared to vehicle controls. Collectively, these data raise the possibility that therapies to promote RV lymphangiogenesis and function may have important therapeutic benefit by reducing the high mortality of pericardial effusion in PH.