Abstract 18906: Congenital Right Ventricular Hypertrophy Compensation is Characterized by Sustained Angiogenesis
The right ventricle (RV) is hypertrophied at birth and in the neonatal period. The RV regresses to a normal phenotype in the first month of life correlated with a concomitant drop PVR over that time. The RV may remain hypertrophied and compensated in response to maintained afterload in patients with congenital heart disease (CHD) for decades; whereas the hypertrophied RV acquired in adulthood from pulmonary arterial hypertension (PAH) quickly transitions to failure, and remains their primary determinant of mortality in PAH. Potentially, the transition from RV compensation to failure has been attributed to ischemia from deficient capillary density from inadequate angiogenesis in RV hypertrophy. Angiogenesis is largely regulated by the transcription factor hypoxia-inducible factor 1a (HIF1a), which governs the transcription of proangiogenic signaling effectors. Two such effectors strongly promoting angiogenesis under HIF1a regulation are vascular endothelial growth factor (VEGF) and stromal derived factor 1 (SDF1), which promote endothelial cell survival/proliferation and recruitment of CXCR4+ stem cells, respectively. We hypothesized that sustained HIF1a-driven angiogenesis maintains adequate RV vascularity in hypertrophy, thus preventing the transition from RV compensation to failure in CHD patients. The free walls of neonatal rat RVs had elevated levels of HIF1a (immunoblot and nuclear localization) compared to those of adult RVs, adult LVs, and neonatal LVs. This was associated with increased VEGF and SDF1 expression (Immunoblot and ELISA), which correlated with increased angiogenesis (matrigel assay) and CXCR4+ stem cell recruitment (Boyden chamber migration assay). Neonatal RVs had elevated expression vascular density (CD31 expression) and tissue perfusion (Lectin) compared to adult RVs, further supporting proangiogenic signaling. Human compensated RV hypertrophy myocardium from CHD patients had elevated SDF1 and CXCR4 expression compared to normal adult RV and LV myocardium (immunoblot), suggesting HIF1a driven angiogenic pathways are maintained in CHD tissues. Therapies that maintain HIF1a signaling may delay the transition from compensation to failure in adults with acquired PAH.
- © 2012 by American Heart Association, Inc.