Sex-specific modulation of cardiac fibrosis and lipid metabolism by B-vitamins in heart failure with reduced ejection fraction in mice.

Abstract

Despite significant advancements in therapies, heart failure (HF) remains a major health challenge. Women, who are underrepresented in HF research, are particularly in need of effective treatments. B-vitamins are a promising and cost-effective option for improving cardiac function. Our study aimed to investigate the sex-specific effects of B-vitamin supplementation on HF with reduced ejection fraction in mice. Male and female mice underwent transverse aortic constriction (TAC) to induce pressure overload. Four weeks post-TAC, mice were randomized to receive either a standard or a vitamin B-enriched (VitB) diet. We found that in females, but not in males, VitB 1) extended survival, 2) slowed down the decrease in ejection fraction (EF), and 3) improved left ventricular morphology. The observed benefits in females were associated with evidence of improved cardiac and lung fibrosis and lower inflammation. In contrast, in males, VitB treatment did not reduce cardiac and lung fibrosis, whereas inflammation remained active in the myocardium. Regarding the circulating lipidome, disturbances were normalized in females with a specific enrichment in long-chain and polyunsaturated triglycerides (TGs) in response to VitB. Conversely, in males, lipidomic alterations remained under VitB treatment and were characterized by the accumulation of shorter and saturated TG in the circulation and myocardium. These data reveal a sex-specific response to VitB supplementation in HF in the context of pressure overload and point to a differential lipidomic remodeling that is only favorable in females.NEW & NOTEWORTHY This study explores the sex-specific effects of B-vitamin supplementation on heart failure with reduced ejection fraction in mice subjected to pressure overload. Our study found that B-vitamins improved survival rates, cardiac function, and reduced fibrosis in female mice, with favorable lipidomic remodeling characterized by an increase in polyunsaturated triglycerides. In contrast, male mice exhibited persistent inflammation, fibrosis, and unfavorable lipidome remodeling despite the B-vitamin supplementation. These findings underscore the sex-specific benefits of B-vitamins in heart failure, suggesting their potential therapeutic value for women, who remain underrepresented in cardiovascular research.