SEX DIFFERENCES IN RIGHT (-SIDED) HEART FAILURE IN PULMONARY ARTERY BANDING MODEL ARE ASSOCIATED WITH DIFFERENTIAL RIGHT VENTRICULAR ANGIOGENESIS

Abstract

BACKGROUND Female sex has been associated with better right ventricular (RV) adaptation and survival in patients with elevated RV afterload. Understanding the mechanisms of sex differences in RV adaptation and development of right (-sided) heart failure (RHF) may uncover novel therapeutic targets for the treatment of RHF patients. Therefore, in this study, we investigated the mechanisms underlying sex differences in the development of RHF using the rat pulmonary artery banding (PAB) model. METHODS AND RESULTS Adult male and female Fischer CDF rats were subjected to PAB or sham surgery and echocardiography were performed at 1- or 2-weeks post-PAB to evaluate RV structure and function. RV systolic pressure (RVSP) was measured using a pressure catheter and Fulton Index (RV/ left ventricle + septum) was measured to evaluate RV hypertrophy (RVH). Masson's Trichrome stain and Hematoxylin and Eosin stain were used to quantify fibrosis and cardiomyocyte surface area, respectively. At 1-week post-PAB, RVSP and RVH were significantly elevated in PAB rats compared to control rats; however, no differences were observed between male and female rats. Interestingly, at a 2-week time-point, a trend towards an increase in RVH was observed in male rats compared to female rats (0.48 vs 0.41; p=0.07). Consistent with RVH, cardiomyocyte surface area (330 vs 234 μm2, p < 0.05) and fibrosis (6.96 vs 4.58%, p < 0.05) were both significantly higher in male compared to female rats. RV end-diastolic diameter was also increased in male rats compared to female rats (3.33 vs 2.05 mm; p < 0.05). On the contrary, RV function was preserved in female rats as indicated by higher cardiac index and fractional area change compared to male rats. Immunohistochemistry, using an antibody against von Willebrand Factor, was performed to quantify endothelial cells (EC) in the right ventricle. Female rats, at 2-weeks post-PAB, had a significant increase in RV EC count compared to control rats (345 vs 230 cells/mm2), while there was no significant change in the male rats (199 vs 188 cells/mm2). To explore the mechanisms, a focused PCR array was performed to assess the expression of angiogenic genes in the RV of male and female rats subjected to sham or PAB procedures. Up-regulation of 24 angiogenic genes was observed in the RV of female rats compared to male rats at 2 weeks post-PAB. CONCLUSION Female Fischer CDF rats develop adaptive RV remodeling in response to PAB compared to mal-adaptive RV remodeling in male rats. Moreover, the better RV adaptation in female rats involves increased RV angiogenesis. Female sex has been associated with better right ventricular (RV) adaptation and survival in patients with elevated RV afterload. Understanding the mechanisms of sex differences in RV adaptation and development of right (-sided) heart failure (RHF) may uncover novel therapeutic targets for the treatment of RHF patients. Therefore, in this study, we investigated the mechanisms underlying sex differences in the development of RHF using the rat pulmonary artery banding (PAB) model. Adult male and female Fischer CDF rats were subjected to PAB or sham surgery and echocardiography were performed at 1- or 2-weeks post-PAB to evaluate RV structure and function. RV systolic pressure (RVSP) was measured using a pressure catheter and Fulton Index (RV/ left ventricle + septum) was measured to evaluate RV hypertrophy (RVH). Masson's Trichrome stain and Hematoxylin and Eosin stain were used to quantify fibrosis and cardiomyocyte surface area, respectively. At 1-week post-PAB, RVSP and RVH were significantly elevated in PAB rats compared to control rats; however, no differences were observed between male and female rats. Interestingly, at a 2-week time-point, a trend towards an increase in RVH was observed in male rats compared to female rats (0.48 vs 0.41; p=0.07). Consistent with RVH, cardiomyocyte surface area (330 vs 234 μm2, p < 0.05) and fibrosis (6.96 vs 4.58%, p < 0.05) were both significantly higher in male compared to female rats. RV end-diastolic diameter was also increased in male rats compared to female rats (3.33 vs 2.05 mm; p < 0.05). On the contrary, RV function was preserved in female rats as indicated by higher cardiac index and fractional area change compared to male rats. Immunohistochemistry, using an antibody against von Willebrand Factor, was performed to quantify endothelial cells (EC) in the right ventricle. Female rats, at 2-weeks post-PAB, had a significant increase in RV EC count compared to control rats (345 vs 230 cells/mm2), while there was no significant change in the male rats (199 vs 188 cells/mm2). To explore the mechanisms, a focused PCR array was performed to assess the expression of angiogenic genes in the RV of male and female rats subjected to sham or PAB procedures. Up-regulation of 24 angiogenic genes was observed in the RV of female rats compared to male rats at 2 weeks post-PAB. Female Fischer CDF rats develop adaptive RV remodeling in response to PAB compared to mal-adaptive RV remodeling in male rats. Moreover, the better RV adaptation in female rats involves increased RV angiogenesis.