Differential Cardiac Contractile and Diastolic Responses Underlie Sex Differences in Right Ventricular Response to Pressure Overload

Introduction In HFpEF as well as PAH, men are more likely than women to develop RV dysfunction and die from right heart failure. The pathophysiological mechanisms underlying these sex differences are not well understood. Some animal studies of ischemic left heart disease have suggested that sex differences in NO signaling confer cardioprotection upon females. Others have shown sex differences in left ventricular expression of NP vs NOS systems. Hypothesis We hypothesized that differential NO- vs NP- cGMP signaling within the RV underlie sex differences in its response to pressure overload. Methods Adult male and female C57BL6/J mice were subjected to pulmonary artery banding (PAB, 25gauge) vs thoracotomy (Sham) for 9 wks. Serial echocardiography was performed at 3wk intervals. Histologic and morphometric analyses, as well as RV pressure-volume loop recordings were performed. Right ventricular expression of Nppa, Nppb, Npr1, Npr2, Npr3,Gucy1a3, Gucy1b3 were assessed. Survival analysis was also performed. Results While survival post-PAB were similar between males and females (log-rank HR 2.49, 95% CI 0.488-12.66, p=0.92), time-to-death was 25.5±4.37 days vs 42 days in PAB-M vs PAB-F, respectively. For both sexes, PAB induced increase in RV mass (Fulton's index 0.47±0.03 PAB-M vs 0.29±0.01 Sham-M, p Conclusions Compared to females, males have worse RV contractile and diastolic responses to pressure overload, independent of hypertrophic and fibrotic remodeling. While transcript levels of several cGMP signaling proteins are higher in males, further studies are needed to elucidate the role of these sex differences in RV dysfunction.