Abstract 14306: Sex Differences in GC1-cGMP Related Cardioprotective Mechanism for Right Heart Failure in Mice Subjected to Right Ventricular Pressure Overload

Abstract

Introduction: Right ventricular dysfunction and failure are independently associated with worse clinical outcomes, regardless of left ventricular EF. The molecular pathophysiology of right ventricular failure and its sex differences are poorly understood. The recent success of cGMP enhancing drugs in HF clinical trials indicated potential right heart benefits by activating cGMP signaling. However, details how myocardial cGMP signaling regulates right heart failure remain to be elucidated. Hypothesis: GC1α-cGMP signaling confers anti-remodeling benefits to RV with improvement of LV diastolic function after RV pressure overload. Method: Adult male and female constitutive GC1α knockout mice (GC1α KO) were subjected to pulmonary artery banding (PAB, 25G needle) and serial echocardiography were performed at 3- and 6-weeks post-surgery. Age and sex-matched wild type C57B6/J mice were used as controls. Results: Survival at 6wks post-PAB was worse in GC1αKO compared to WT controls (100 % of WT vs 38.5 % of GC1αKO, p<0.05; Gehan-Breslow-Wilcoxon-test) indicating the exacerbated heart failure by GC1α ablation. RV systolic function at 3 weeks post-surgery was deteriorated in GC1αKO male, assessed with RV FAC (%) (WT vs GC1αKO: 58.0 vs 35.6 p<0.05; t-test) and TAPSE (mm) (WT vs GC1αKO: 0.94 vs 0.64 p<0.05; t-test). Female showed limited RV systolic dysfunction and worse LV diastolic dysfunction at 3 weeks post-surgery compared to male, assessed with TAPSE (mm) (WT vs GC1αKO: 0.85 vs 0.63, p<0.05; t-test) and mitral IVS E/E’ (WT vs GC1αKO: 18.3 vs 29.3, p<0.05; t-test). Interestingly, the impact of GC1α ablation to RV systolic function is bigger in male, but that to LV diastolic function is bigger in female, indicating sex differences of GC1-cGMP regulated cardio-protective effects to right heart failure. The fetal gene expressions( nppb and Myh7 ) in right heart also showed worse right heart remodeling by GC1α ablation especially in male at 6 weeks post-surgery. Conclusions: Inactivation of GC1α-cGMP signaling induced right heart remodeling after PAB. Female mice showed LV diastolic dysfunction with limited right heart remodeling compared to age-matched male, indicating sex differences in GC1-cGMP related right heart protective mechanism.