MECHANISMS OF SEX DIFFERENCES IN RIGHT (-SIDED) HEART FAILURE: ROLE OF ANGIOGENESIS

Abstract

Female sex is associated with better right ventricular (RV) adaptation and survival in patients with elevated RV afterload. Understanding the mechanisms responsible for sex differences in RV adaptation and development of right (-sided) heart failure (RHF) may uncover novel therapeutic targets for treatment of RHF patients. Therefore, this thesis investigated mechanisms of sex differences in RHF using Fischer CDF rats and the pulmonary artery banding (PAB) model.

Male and female Fischer CDF rats aged 5-7 weeks were subjected to pulmonary artery banding (PAB) or sham surgery; a subset was ovariectomized (OVX). Echocardiography and catheterization were performed at 1-, 2- and 4-weeks post-PAB to evaluate RV structure and function. Histological analyses were used to quantify sex differences in cardiomyocyte cross sectional area (CSA), and endothelial cell markers. A focused PCR array was performed to assess the expression of angiogenic genes in heart tissue. Primary right ventricular endothelial cells were isolated and effect of estradiol on angiogenic gene expression and network growth was assessed using RT-qPCR and Matrigel assay experiments, respectively.

At 1- and 2-weeks post-PAB, RV systolic pressure (RVSP) and RV hypertrophy (RVH) were significantly elevated in PAB rats compared to sham controls; however, no significant differences were observed between male and female rats. At 2-weeks post-PAB, male rats had a significant increase in the RV cardiomyocyte CSA (330 m2 vs 234 m2, p<0.05). RV internal diameter in diastole was also increased in male rats compared to female rats (3.33 mm vs 2.05 mm; p<0.05). Female rats had a higher cardiac index compared to male rats 2-weeks post-PAB. At 2-weeks post-PAB, the up-regulation of 24 angiogenic genes was observed in the RV of female rats compared to male rats.

In response to PAB, female Fischer CDF rats develop adaptive RV remodelling with better preserved RV function compared to maladaptive remodelling in male rats up to the 2-week timepoint. These sex differences are associated with a better RV angiogenic response in the female RV. Specific mechanisms for this effect are yet to be elucidated.