Experimental right ventricular failure is associated with dysregulation of genes involved in dilated cardiomyopathy

Purpose: We aimed to identify pathways involved in experimental right ventricular failure (RVF) due to chronic pressure overload. Methods: Wistar rats were subjected to pulmonary artery banding (PAB) (1.1mm, n=12) or sham surgery (CON, n=7) and then daily checked for clinical signs of RVF (inactivity, ruffled fur, dyspnea, ascites). At the onset of clinical RVF (necessitating termination) pressure-volume analysis was performed in the rats with RVF and in randomly selected PAB rats without clinical signs of RVF (RVDysfunction, RVD) at the same time points. Gene micro array was performed on RV tissue using GeneChip Rat Gene 1.1 ST (Affymetrics). Quality control and normalization (RMA) were performed according to international standards. False discovery rate was set to 1.3 in RVF vs. RVD. Micro array data were analyzed using gene-set enrichment analysis (GSEA), gene ontology mapping (biological processes) (ErmineJ) and pathway analysis (DAVID). Results: All rats with PAB had RV dysfunction, but clinical RVF ensued in only 5 rats, after a period of 52±5 days. RVF rats had pericardial effusion, liver congestion, and widely dilated right atria, in contrast to RVD rats. RVF rats also had significantly lower cardiac index (0.10±0.04 vs. 0.19±0.04 mL/min/g, RVF vs. RVD, p<0.05). In RVF contractility was preserved (end systolic elastance 269±173 vs. 101±44mmHg/mL, ns), but diastolic function deteriorated (end diastolic elastance 32±21 vs. 11±4mmHg/mL; end diastolic pressure 6±3 vs. 3±1mmHg, RVF vs. RVD, p<0.05). We identified 9 pathways that were differentially regulated in RVF vs. RVD. Among these, the dilated cardiomyopathy (DCM) KEGG-pathway was negatively enriched in RVF compared to RVD (normalized enrichment score= -1.94, p<0.05). Gene ontology mapping supported the dysregulation of the DCM pathway in RVF; 10 ontology categories overlapping with the DCM pathway were strongly decreased in RVF vs. RVD (p<1.00E-10 for all categories). Further pathway analysis and comparison to CON, revealed that within the DCM pathway, the dysregulation involved transforming growth factor beta (TGFβ) 2 (Rank Metric Score: -4.316 RVF vs. RVD), TGFβ 3 (RMS: -3.840) and specific calcium channel-subunits: CACNA2D2 (RMS: -2.429), CACNA2D3 (RMS: -1.754), CACNA1D (RMS: -1.730) and CACNB3 (RMS: -2.429). Conclusions: We identified novel pathways involved in experimental RVF. RVF is associated with dysregulation of specific parts of the dilated cardiomyopathy pathway. New studies should explore whether an imbalance in TGFβ activation or alterations in calcium cycling are central in the pathobiology of RVF.