Abstract 3129: Molecular and Physiologic Characterization of RV Remodeling and Failure in a Murine Model of Mild, Moderate and Severe Pulmonary Stenosis
RV dysfunction is a long-term complication in patients after repair of congenital heart disease involving RV outflow obstruction. Despite considerable data on the molecular events of LV remodeling, little is known about the RV. We have developed and characterized a murine model of varying degrees of RV hypertrophy and failure, including the effects of RV-LV interaction. Pulmonary artery banding was performed in 86 mice, categorized into mild, moderate and severe groups based on RV-PA pressure gradient and degree of shift of the interventricular septum (IVS). Mice with mild PS develop stable hypertrophy with 100% survival; moderate PS develop slow RV failure (100% mortality by 90 d, survival half-time 51 d); severe PS develop generalized edema, RBBB, TR and more rapid RV failure (100% mortality by 50 d, survival half-time 19.6 d). RVEDP increases 6 h after PAC (p<0.01 vs pre) but recovers by 24 h. By 10 d, RVEDP is slightly increased in mild (5.8±1.0 mmHg) and moderate PS (6.4±0.9), but markedly increased in severe PS (12.6±2.6, p<0.01). Serial measurements of RV free wall fractional shortening (RVFS) show RV dysfunction at all time points in severe PS (p<0.001). In moderate PS, RVFS is initially normal, decreasing by 4 wks (p<0.01). There is excellent correlation (r=0.83, p<0.0001) between echo-derived RVFS and Millar catheter-derived dP/dtmax, indicating that RVFS is a good non-invasive surrogate for RV dP/dt. Tissue Doppler imaging demonstrates septal dyssynchrony and deleterious RV-LV interaction (decreased cardiac output) only in severe PS. RV myocyte area is increased in moderate PS vs control (341±21 μm2 vs 203±6 μm2, p<0.01) and greatest in severe PS (455±10 μm2, p<0.01). Gene microarray analysis shows 196 genes with increased expression after 10 d of PS. Although most are similar to the afterloaded LV (10 d after aortic banding), several transcripts are differentially increased in the afterloaded RV vs. LV, including Clusterin/ApoJ, Nbl1, Dkk3, Sfrp2, Fnbp4, Annexin A7, and LOX. Thus, we have developed a murine model of RV afterload stress with many of the characteristics of both acute and chronic RV failure encountered in clinical settings, and demonstrated both similar and differential gene expression changes in the RV vs LV in response to afterload stress.