Abstract 207: Molecular Signatures of Sex Differences in Heart Failure with Preserved Ejection Fraction

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome involving diastolic dysfunction and metabolic disorders. Women are twice as likely to develop HFpEF as compared to men and present with a greater symptom burden. However, the sex-specific biology of HFpEF is unknown. This study aims to dissect sex-specific molecular signatures of diastolic dysfunction in HFpEF. Methods: We developed a ‘two-hit’ HFpEF model with HFD and l-NAME (Nω-nitrol-arginine methyl ester) in C57BL/6J male and female mice. RNA-seq for heart tissue from mice under HFpEF versus Chow condition was performed and results were integrated with multi-omics datasets including hybrid mouse diversity panel (HMDP, a panel of more than 100 inbred strains of mice) and human heart failure cohort to dissect novel gene-by-sex interactions in the heart. Results: HFD and l-NAME induced diastolic heart failure phenotypes in both male and female mice. We observed higher E/A (1.68 ± 0.09 vs. 1.40 ± 0.04, p < 0.05 under chow diet), E/E’ (35.82 ± 2.05 vs. 26.13±1.11, p < 0.05 under chow diet; 53.78 ± 3.94 vs. 43.92±2.08, p < 0.05 after HFpEF) and lung weight (wet/dry ratio, 4.51 ± 0.09 vs. 4.15 ± 0.09, p < 0.05 after HFpEF) in females compared to males. Pathway analysis revealed that compared with male mice, female mice exhibited a greater decrease in fatty acid metabolism, insulin signaling, heart development and an enhanced increase in cell cycle, inflammation, cholesterol efflux and serine synthesis upon HFpEF. Together with our high fat/high sucrose diet-induced metabolic disorder HMDP cohort and isoproterenol-induced heart failure HMDP cohort, HFpEF mice revealed that female hearts contained reduced mtDNA copy number relative to males (3102.56 ± 85.70 vs. 3770.43 ± 77.44, p = 4.51E-08). Cardiac mtDNA was inversely correlated with diastolic dysfunction (bicor = -0.307, p = 0.005) and was regulated by gonadal hormones. Conclusions: We utilize our systems genetics approach that integrates multi-omics datasets and dissect novel gene-by-sex interactions in the heart. Females exhibit more severe metabolic disorders and mitochondrial dysfunction relative to males, which are responsible for greater diastolic dysfunction of HFpEF.