Abstract 266: Sex Differences in Survival and Pathological Responses of Hearts, Cardiac Myocytes and Fibroblasts

Abstract

Introduction: Biological sex is an important modifier of cardiovascular disease (CVD). However, women and female animals have traditionally been excluded from clinical trials and most preclinical research studies, resulting in therapeutics that are not as effective, or with different side effects, in women relative to men. Methods and Results: We show here that expression of α- and β-adrenergic receptors, cardiac stiffness, myofibroblast proliferation, and expression of fibrotic markers are sexually dimorphic at baseline. To determine whether pathogenesis was different between the sexes, the β-adrenergic agonist, isoproterenol (ISO), was administered to rats. In response to 7-days of ISO treatment, female animals were more likely to survive than their male counterparts (percent survival: 44% in males versus 77% in females). Both sexes developed significant cardiac hypertrophy, activation of cardiac fetal genes (ANF and β-MHC) compared to vehicle controls. Cardiac myocytes from ISO treated animals took less time to reach peak shortening and displayed increased departure velocity; however, only male ISO treated cells exhibited reduced relaxation times and increased return velocities. Importantly, ISO treated animals developed significant fibrosis prompting us to analyze isolated cardiac fibroblasts at baseline and in response to ISO. We observed significantly increased expression of α-SMA and Col1a, two indicators of myofibroblast activation, only in fibroblasts isolated from ISO treated males. Both ISO treated male and female fibroblasts showed significant increases in periostin and decreases in TCF21, indicative of increases in myofibroblasts and decreases in quiescent fibroblasts, respectively. In addition, both sexes revealed increased fibroblast proliferation in vivo , as measured by EdU incorporation, in response to ISO. Conclusions: Chronic in vivo β-adrenergic receptor stimulation revealed dramatic sex differences in mortality, cardiac hypertrophy, myocyte contractility, and cardiac fetal gene expression. Increases in myofibroblast differentiation and fibroblast proliferation should lead to a robust fibrotic response in both male and female ISO treated animals.