Sexual Dimorphism in Response to Vitamins B3, B9 and B12, Used in Combination, in a Mice Model of Heart Failure Induced by Pressure Overload

Abstract

IntroductionHeart failure (HF) is still a major cause of mortality worldwide. HF pathogenesis involves disturbances in cardiac energy metabolism. Studies have shown that preventive treatment with a diet supplemented with vitamins B3 or B9/B12 in experimental models of HF, exhibits beneficial effects on cardiac and mitochondrial functions and improves survival. Therefore, the overall objective of our pilot study is to evaluate the curative benefit of a synthetic diet enriched with vitamins B3 (nicotinamide riboside), B9 and B12 (BVit) in a mouse model of HF based on the hypothesis that this enriched diet is beneficial for cardiac function via an improvement of cardiac metabolism.MethodPressure overload was induced by transverse aortic constriction (TAC) in 8‐week‐old male and female C57Bl6/N mice. Four weeks post‐TAC and according to their cardiac function evaluated by echocardiography, mice were randomised to a BVit‐enriched diet or not and compared to SHAM animals. The criteria of selection for randomisation were as follows: 10% decrease in ejection fraction (EF), 30% increase in left ventricular (LV) mass and an average pressure gradient of 60mmHg. Mice survival was evaluated and cardiac function was assessed by echocardiography every 4 weeks. Blood samples were taken at 8 weeks of treatment in fasted mice (5 hours) for non‐targeted lipidomics mass spectrometry‐based analysis.ResultsOur pilot study show that survival is not improved in males while mortality is reduced in females from 12 weeks of treatment. In males, the reduced EF in the TAC group is not improved by BVit treatment and myocardial hypertrophy, as illustrated by the left ventricular mass (+20% in TAC), is exacerbated with BVit treatment. In contrast, in females, both EF and cardiac hypertrophy were improved (+20% and ‐13% respectively) after 12 weeks of BVit treatment. To better understand the sexual dimorphism in the response of BVit, non‐targeted lipidomics was used on plasma from mice following 8 weeks of treatment. In TAC‐females, compared to their SHAM controls, a decrease in triglycerides (TG) and an increase in choline phospholipids were observed while the lipid profile was normalized with BVit treatment. In TAC‐males vs SHAM, however, TGs were significantly increased and the treatment with BVit exacerbated the lipidomic profile both in terms of TGs and additional lipid species (identification in progress).ConclusionOur pilot study suggests a sexual dimorphism in the response to BVit treatment in experimental HF. Indeed, the benefit of BVit treatment is only shown in females with a delay in the mortality rate associated with improved cardiac function and normalisation of lipid disturbances. To explore and understand the mechanisms underlying this sexual dimorphism, the lipid profile hypothesis appears as a relevant avenue to explore in the future.