Abstract 10771: Experimental Lung Fibrosis and Pulmonary Hypertension Induces Cardiomyocyte Apoptosis and Right Ventricular Dysfunction
Although right ventricular failure is associated with elevated mortality in pulmonary hypertension (PH) patients, the functional and structural effects of pulmonary fibrosis (PF) and PH on the right ventricle (RV) are unknown. Here, we investigated whether experimental PF and PH impair RV function and structure in a rat model. Our previous work has shown that rats develop significant PH associated with endothelial apoptosis after intratracheal administration of AdTGF-beta1, an adenovirus encoding a mutated TGF-β1 gene. Sprague-Dawley rats received AdTGF-beta1 or AdDL70 (empty control vector) on day 0. Animals were sacrificed at different time points after invasive hemodynamic measurements. RVs and left ventricles (LVs) were snap frozen or formalin fixed. Moderate PH is established in AdTGF-beta1 treated animals, and mean right atrial pressure increased over time, reaching statistical significance at day 21 and further rising to 8.1±1.3 mmHg at day 56. Histologically, the RVs of the AdTGF-β1 rats showed relevant dilatation without obvious hypertrophy or fibrosis. There was only a trend towards reduced capillary density. Interestingly, we detected by TUNEL staining increased apoptosis of cardiomyocytes and other cells (fibroblasts and endothelial cells) peaking early on (day 7 after AdTGF-β1), together with a reduction in the RV/LV ratio of fibroblasts (S100A4+ cells). This was associated with a significant reduction in CTGF mRNA levels in the RV at day 14, whereas there was no change of KLF5 and IGF-1 expression or TGF-beta activity despite of significant PH. We also detected a shift towards a fetal myosin heavy chain gene expression pattern. While a comparison with the SU5416/chronic hypoxia (SuHx) model of severe PH/RV failure showed similarities in the lack of IGF-1 induction in the RV, the hypertrophied RVs of the SU/Hx rats had increased CTGF levels. Our results suggest a close connection between mechanisms of adaptive hypertrophy and fibrosis in the RV following increased afterload. Our data also indicate that RV-specific gene therapy aiming at specific targets within this hypertrophy/fibrosis cluster may be helpful to prevent experimental RV dysfunction or even restore RV function.
- © 2011 by American Heart Association, Inc.