Heart failure with preserved ejection fraction (HFpEF) currently represents half of the ~6 million heart failure patients in the United States. Population studies have repeatedly found HFpEF to disproportionally effect women over the age of 65 at a rate of 2:1 compared to men. The prevalence of HFpEF sharply increases in women after menopause concomitant with higher morbidity and mortality rates. The pathological mechanisms underlying HFpEF, as well as the causes of the unequal distribution among sex, remain controversial and poorly understood. Underrepresentation of women in human and animal studies may be a primary reason for the uncertainty. While evidence suggests that sex hormones may protect the premenopausal heart against cardiovascular disease, the specific mechanisms involved remain elusive. Moreover, the protective role of estrogens against cardiovascular disease, and specifically HFpEF, continues to be controversial. The general purpose of this proposal is to assess if female sex hormones play a protective role on cardiac function in disease, and if their loss exacerbates the development of HFpEF. The specific aims of the proposal are: 1) Determine if the development of HFpEF is delayed in aortic-banded female miniature swine compared to aortic-banded males; and 2) Determine if female sex hormones influence the development of HFpEF. To examine these issues, we will extend our male aortic- banded mini-swine model of HFpEF, which displays key clinical features of the disease, into intact and ovariectomized female mini-swine. I will use an integrated approach to comprehensively evaluate in vivo whole heart cardiac function (pressure-volume loops, ultrasound, myocardial blood flow & oxygen consumption) and pathological remodeling (hypertrophy, fibrosis) alongside in vitro cardiomyocyte calcium handling and contractile function. In summary, this investigation will use a translational large animal model displaying clinical features of HFpEF to elucidate novel mechanisms contributing to the increased susceptibility of post-menopausal women to developing HFpEF.