410 Patients With Congenital Heart Disease Have Compensated Right Ventricular Hypertrophy (RVH) from Sustained Increased Levels of Angiogenesis: Implications for Treatment of Acquired RVH

Abstract

At birth, the neonatal right ventricle (RV) is hypertrophied, which regresses after a decrease in pulmonary vascular resistance over the first 3 weeks of life. Patients with congenital heart disease (CHD) often have sustained RV hypertrophy (RVH) secondary to a maintained increased RV afterload, which can remain compensated for decades. In contrast, acquired RVH in adults quickly transitions to failure, representing a major determinant of mortality in a variety of diseases. The transition between RVH and RV failure has been attributed to ischemia. Angiogenesis is largely mediated by transcription factor hypoxia-inducible factor-1á (HIF1á). HIF1á represents a major defense mechanism against hypoxia, triggering a shift towards anaerobic glycolysis (decrease O2-demand) and increased angiogenesis (increased O2-supply). Two main targets of HIF1á, vascular endothelial growth factor (VEGF) and stromal derived factor 1 (SDF1), promote endothelial cell proliferation and recruitment of CXCR4+ stem cells, respectively, strongly facilitating angiogenesis. We hypothesize that patients with CHD maintain compensated RV hypertrophy, despite ongoing exposure to increased afterload, due to sustained HIF1á driven production of VEGF and SDF1 and adequate angiogenesis. Hearts from neonatal and adult rats were split into RV and LV free walls. Ventricular samples were analyzed for secretion of VEGF and SDF1. Functional cell migration assays were performed with CXCR4+ bone marrow-derived mesenchymal stem cells. Angiogenesis was assessed by ventricle tissue culture on a matrigel containing endothelial cells. Tubule formation was assessed at 24, 48 ad 72 hours. Human RV samples were derived from normal adult RVs (RV; 2) normal adult left ventricles (LV; 2), and congenital RVH (6). Neonatal RVs had elevated HIF1á protein levels (immunoblot) and activation (nuclear localization), increased levels of VEGF and SDF-1 (immunoblot, ELISA), and increased stem cell recruitment (migration assay) compared to adult RVs. The neonatal RVs also had greater SDF1 levels and increased stem cell recruitment compared to the neonatal LV. Ex-vivo, neonatal RVs stimulated tubule formation more than normal RV samples, further supporting activation of angiogenic signaling. These results were supported by human data from RVH myocardium of patients with CHD showing elevated SDF1 and CXCR4 cell recruitment compared to normal adult RV or LV. Our results support sustained increased angiogenesis through HIF1á signaling in human RVs with congenital heart disease and subsequent RVH. Therapies targeted at maintaining HIF1á activation may help patients with acquired RVH from pulmonary hypertension maintain RV compensation delaying the transition to RV failure.