Abstract 11636: Right Ventricle Lymphatic Vessel Insufficiency Contributes to Interstitial Fluid Stasis, Inflammation, Fibrosis, and Failure in Pulmonary Hypertension
Introduction: Pulmonary hypertension (PH) is characterized by cardiopulmonary remodeling. The ensuing right ventricular (RV) hypertrophy and failure contribute to significant mortality. Pericardial effusion worsens the prognosis for PH patients, yet no mechanistic data are available.
Hypothesis: We hypothesized that lymphatic vessels in rat models of PH would be decreased and dysfunctional compared to controls.
Methods: We used the Sugen 5416-hypoxia (Su-Hx) and monocrotaline (MCT) models of PH. To assess the degree of cardiac lymphatic vascularity, identify cell types, and to evaluate cell junction complexes in PH rats vs. controls, we used flow cytomtery, qPCR, immunofluorescence, and immunoblot. To assess myocardial edema, we used wet-to-dry weight ratios, echocardiography, and magnetic resonance imaging (MRI). In patients, we used echocardiography and magnetic resonance imaging to quantify RV edema and pericardial effusion.
Results: We found that the presence of pericardial effusion by either MRI or echocardiography correlated with lower cardiac output in patients with PH (n =6). We found decreased lymphatics in RVs of rats with PH due to either Su-Hx or MCT, compared to controls (n= 5 per group). In the heart, AQP-1+/vWF-/KDR- lymphatic vessels co-expressed podoplanin and were distributed throughout the RV in controls and much less so in PH rats. Lymphatics appeared unchanged in size or number in the left ventricle of all rats. We found increases in myocardial fluid in RVs of PH rats vs. controls, which correlated positively with fibrosis and negatively to cardiac output. The presence of excess myocardial fluid coincided with collagen deposition but without increases in CD68, CD11b, CD11c, or CD163 macrophage infiltration. We observed disturbed connexin-43 and claudin-5 junctional complexes around alpha-actinin+ myocytes and TCF21+ cardiac fibroblasts in PH RVs compared to controls.
Conclusions: In severe PH, RV function is likely impaired by insufficient lymphatic-mediated fluid clearance and the presence of dysfunctional cell junctions. A clearer understanding of how the cardiac lymphatic system impacts the pathobiology of PH may lead to novel therapy.
Author Disclosures: K.L. Colvin: None. O. Lohani: None. S.M. Williams: None. D.D. Ivy: None. K.R. Stenmark: None. M.E. Yeager: None.
- © 2014 by American Heart Association, Inc.