Abstract 545: Sex Difference in Right Ventricular Response to Pressure Overload is Associated With Differential Fibrotic Remodeling and Cyclic Guanosine Monophosphate Signaling

Abstract

Background: In HFpEF and PAH, men are more likely than women to develop right ventricular dysfunction (RVD) and die. Mechanisms underlying these sex differences are not well understood. In advanced HF patients, RVD is associated with RV fibrosis. Sex differences in cGMP anti-fibrotic cardioprotection have been reported. Hypothesis: Sex differences in RV response to pressure overload may be due to differential anti-fibrotic cGMP signaling in the RV. Methods: Adult male and female C57BL6/J mice underwent pulmonary artery banding (PAB, 25g) vs. thoracotomy (Sham). RV remodeling was assessed by echocardiography, pressure-volume loop recordings, morphometrics, and histology. Expression of transcripts encoding various cGMP signaling proteins ( Nppa, Nppb, Npr1, Npr2, Npr3, Gucy1a3, Gucy1b3, Pde5, Pde9a, Pkg1a ), the fetal gene program, tissue fibrosis and ECM remodeling ( Ace, Tgfβs, Smads, Ctgf, αSma, Postn, Col1α1, Lum, Igfbp5, Mmp2-3, Timp1-2) were assessed at 9wks. Results: Post-PAB survival rate did not differ between sexes (log-rank HR 1.02, 95% CI 0.30-3.48, P=NS), but median time-to-death was 20 days (IQR 15-32) for M-PAB vs. 35.5 days (IQR 10.8-41.5) for F-PAB. PAB increased RV mass in both sexes (Fulton’s index 0.45±0.07 M-PAB vs 0.21±0.01 M-Sham, P<0.01; 0.49±0.06 F-PAB vs 0.22±0.01 F-Sham, P<0.01). RV myocyte hypertrophy was greater in M-PAB (cardiomyocyte area 592.7±6μm 2 vs 397.7±21.6μm 2 F-PAB, P<0.01). RV dilation and decreased TAPSE and RV S’ were present in all PAB mice. Only M-PAB had depressed RV FAC (29.9±1.9% vs. 38.1±2.4% F-PAB, P=0.02). M-PAB had worse diastolic function than F-PAB (Tau 32.8±2.9ms M-PAB vs 14.2±2.1ms M-Sham, P<0.01; 25.6±5.3ms F-PAB vs 15.0±2.1ms M-Sham, P=NS). In male but not female mice, PAB induced upregulation of Nppa, Nppb, Npr1, Npr2, Npr3, Gucy1a3, Gucy1b3, Pde5 and Pkg1a in the RV. RV transcript levels of Ace, Col1α1, Ctgf, Igfbp5, Mmp2, and Timp2 were also higher in M-PAB than F-PAB. Conclusions: Males have worse RV functional response to PAB than do females. This sex difference was also associated with increased mRNA levels of cGMP signaling mediators and upregulation of pro-hypertrophic and pro-fibrotic genes in male PAB mice. Further studies are needed to elucidate sex-dependent regulation of RV remodeling.