Sex-specific association between obesity and sympathetic nerve activity in HFpEF

Background: Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women than in men, and most patients with HFpEF are overweight or obese in the United States. However, whether the impact of obesity on autonomic dysregulation and inflammation differs by sex in HFpEF remains unknown. We investigated sex-specific associations between obesity, inflammation, and muscle sympathetic nerve activity (MSNA) in patients with HFpEF. Methods: In 57 HFpEF patients (mean±SD; 71±7 years; 37 women, 20 men) and 69 non-HFpEF controls (70±6 years; 43 women, 26 men), body mass index (BMI), MSNA, and C-reactive protein (CRP) were measured during supine rest. Results: A significant sex-by–BMI interaction was observed for the association between BMI and MSNA (Pinteraction=0.047), as well as BMI and CRP (Pinteraction=0.012). The slopes of these associations were steeper in women than men. Women with HFpEF had greater MSNA than men with HFpEF and control women (P<0.05); however, MSNA was not different between men with HFpEF and control men (P=0.727). The association between CRP and MSNA demonstrated a consistent trend toward sex-specificity (Pinteraction=0.060). In sex-stratified subgroup analyses of patients, MSNA and CRP were higher in women with high body fat assessed by DEXA than those with low body fat, but not in men. Conclusions: These findings identify a sex-specific association between obesity, inflammation, and sympathetic neural activity in HFpEF, characterized by a stronger obesity-related sympathetic activation in women. This pattern provides insight into the role of obesity-related inflammation as a key feature of disease expression in women with HFpEF.