Homocysteine levels are inversely associated with capillary density in men, not in premenopausal women.

BACKGROUND: Homocysteine is an independent predictor of cardiovascular risk. The mechanisms underlying this link are not fully elucidated. Whereas the role of vascular dysfunction in conduit arteries is extensively studied, the role of the microcirculation in this relationship is largely unexplored. We assessed the relationship between homocysteine levels and microvascular structure and function in a healthy, population-based cohort. MATERIALS AND METHODS: We cross-sectionally studied 260 participants (aged 42 years, 47% men) of the Amsterdam Growth and Health Longitudinal Study. Nailfold videocapillaroscopy was used to assess capillary density at baseline, during venous occlusion and during peak reactive hyperaemia. The relationship between tertiles of homocysteine and microvascular outcomes was evaluated using linear regression analyses, with adjustment for BMI and blood pressure. Stratified analyses were performed for men and women. RESULTS: In men, we observed a negative, nonlinear relationship between homocysteine and baseline capillary density, showing a lower capillary density in the highest tertile of homocysteine [adjusted B -8.65 capillaries/mm(2) (95%-CI: -16.05 to -1.25); P = 0.02]. In women, no significant associations were found between homocysteine and microvascular outcomes. CONCLUSIONS: In men, higher homocysteine levels are associated with a reduction in basal perfusion of skin capillaries. This finding provides a novel potential explanation for how homocysteine influences cardiovascular disease risk.

Folic acid supplementation does not reduce intracellular homocysteine, and may disturb intracellular one-carbon metabolism.

BACKGROUND: In randomized trails, folic acid (FA) lowered plasma homocysteine, but failed to reduce cardiovascular risk. We hypothesize this is due to a discrepancy between plasma and intracellular effects of FA. METHODS: In a double-blind trial, 50 volunteers were randomized to received 500 µg FA daily for 8 weeks, or placebo. Plasma and peripheral blood mononuclear cell (PBMC) concentrations of homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine, methionine, cystathionine and 5-methyltetrahydrofolate (bioactive folate) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PBMCs were used as a cellular model since they display the full spectrum of one-carbon (1C) enzymes and reactions. RESULTS: At baseline, plasma concentrations were a poor reflection of intracellular concentrations for most 1C metabolites, except 5-methyltetrahydrofolate (R=0.33, p=0.02), homocysteine (Hcy) (R=0.35, p=0.01), and cystathionine (R=0.45, p=0.001). FA significantly lowered plasma homocysteine (p=0.00), but failed to lower intracellular homocysteine or change the concentrations of any of the other PBMC 1C metabolites. At baseline, PBMC homocysteine concentrations correlated to PBMC SAM. After FA supplementation, PBMC homocysteine no longer correlated with PBMC SAM, suggesting a loss of SAM's regulatory function. In vitro experiments in lymphoblasts confirmed that at higher folate substrate concentrations, physiological concentrations of SAM no longer effectively inhibit the key regulatory enzyme methylenetetrahydrofolate reductase (MTHFR). CONCLUSIONS: FA supplementation does not reduce intracellular concentrations of Hcy or any of its closely related substances. Rather, FA may disturb physiological regulation of intracellular 1C metabolism by interfering with SAM's inhibitory effect on MTHFR activity.