Abstract Body: BACKGROUND:
The prevalence of heart failure with preserved ejection fraction (HFpEF) is higher in older women. Concurrently, the incidence of risk factors for HFpEF, like obesity, hypertension, diabetes, and atrial fibrillation, rises significantly after menopause, impacting HFpEF rates. The role of sex chromosomes and sex hormones in HFpEF is incompletely understood.

METHODS:
We used the 2-hit (high-fat-diet [HFD]+L-NAME) HFpEF model in combination with Four Core Genotype (FCG) mice as well as gonadectomized female mice to investigate the role of sex chromosomes and sex hormones in HFpEF. FCG mice uncouple gonadal and chromosomal sex by moving SRY (the Y chromosome testis determining gene) to an autosome. Phenotypic sex is determined by SRY inheritance, thus generating male (M) and female (F) mice that can be either XX or XY.

RESULTS:
6-7-month-old male and female wildtype mice treated with 15 weeks of HFD+L-NAME both developed HFpEF. While both sexes gained weight (1.35-fold in males, 1.52-fold in females, P<0.001, N=6-12), female mice had greater fat mass than male mice (2.19-fold in males, 2.80-fold in females, P<0.001, N=6-12). Cardiac mass also increased more in female than male mice. Female WT gonadectomized mice with long-term low sex hormones had worse diastolic dysfunction (DD) after 15 weeks on HFD+L-NAME. In the FCG mouse model, left ventricular mass (LVM) was greater in male (XX-M and XY-M) mice than in female (XX-F and XY-F) mice at baseline. However, within each sex, XX mice had greater LVM than the corresponding XY mice ( XX-M vs. XY-M, 1.15-fold, P=0.004, N=21-20; XX-F vs. XY-F, 1.17-fold, P=0.039, N=16). XX mice of both sexes (XX-F and XX-M) also manifest greater body mass than the corresponding XY mice after 15 weeks of HFD+L-NAME treatment. A second X chromosome (XX-F, XX-M) also exacerbated diastolic dysfunction (MV E/E’: XX-F vs. XY-F, 1.35-fold, P<0.001, N=10-7) and LVM compared with XY-mice with the same gonadal sex female mice (XX-F vs. XY-F, 1.26-fold, P=0.021, N=10-7).

CONCLUSIONS:
Together, our studies show that sex chromosomes and sex hormones each contribute to HFpEF, with predominantly protective effects from female sex hormones but deleterious effects of a second X-chromosome. RNAseq data implicating potential mechanistic pathways will be reviewed. These results may help explain why older females have a higher risk of diastolic dysfunction and HFpEF.