Vitamin Deficiency and Heart Health: How Strong Is the Link

A deficiency of some B vitamins, in particular folate, B12 or B6, raises homocysteine levels in the blood. Homocysteine is an intermediate product of the metabolism of methionine, an essential amino acid obtained from food. The body converts most homocysteine back into methionine, and it is this conversion that requires the vitamins. Observational data consistently link higher homocysteine levels with a higher frequency of cardiovascular events (D'Elia et al., J. Cardiovasc. Dev. Dis., 2025).

A common simplification rests on this mechanism: if B vitamins lower homocysteine levels, they should also reduce the frequency of cardiovascular events. This assumption has been tested in dozens of randomized trials, and it has been confirmed only in part (Ghattas Hasbun et al., BMC Nutr., 2025). The result differed by outcome and depended on baseline vitamin status.

Vitamin Deficiency and Vascular Health

A shortage of vitamins affects blood vessels in several ways, and these have been studied unequally. The metabolism of homocysteine, whose concentration is linked to cardiovascular risk, is described most fully. Alongside homocysteine metabolism, the effect of vitamin D has been studied, and the mechanisms there are different: its status is assessed by the blood concentration of 25-hydroxyvitamin D.

A high homocysteine level does not in itself prove a vitamin shortage. It is affected by reduced kidney function, age, lifestyle, the use of certain medications, including metformin and proton pump inhibitors, and inherited features of folate metabolism, so the marker is read together with these factors (D'Elia et al., J. Cardiovasc. Dev. Dis., 2025).

B Vitamins and Homocysteine Metabolism

Homocysteine is metabolized by two pathways: remethylation returns it to methionine, while transsulfuration converts it to cysteine. Both pathways require cofactors that are formed from B vitamins, and for this reason the supply of these vitamins affects the concentration of homocysteine. In these reactions the vitamins perform different functions:

• folate (vitamin B9) supplies one-carbon groups for remethylation;
• vitamin B12 in the form of methylcobalamin is a cofactor of methionine synthase;
• vitamin B6 in the form of pyridoxal-5′-phosphate is a cofactor of transsulfuration enzymes.

Remethylation also has an alternative pathway: betaine-homocysteine methyltransferase uses betaine as a methyl group donor. Riboflavin (vitamin B2) acts indirectly: its derivative FAD is a cofactor of methylenetetrahydrofolate reductase. This enzyme is encoded by the gene MTHFR (methylenetetrahydrofolate reductase) and produces 5-methyltetrahydrofolate, the form of folate that takes part in the remethylation of homocysteine.

For more on homocysteine metabolism and the role of B vitamins, see the article B Vitamins and Homocysteine: What a Standard Test Will Not Show.

What Observational and Genetic Studies of Homocysteine Show

Observational data consistently show an association between a higher homocysteine level and cardiovascular risk. According to meta-analyses, a 5 µmol/L increase in homocysteine concentration is accompanied by an increase in the risk of coronary heart disease of about 20–30%. However, such an association does not in itself prove that homocysteine is what causes the event: its level depends, among other things, on age and kidney function, which are independently linked to cardiovascular risk (D'Elia et al., J. Cardiovasc. Dev. Dis., 2025).

To check whether these observations are consistent with a causal hypothesis, Mendelian randomization is used. The method compares groups of people whose genetic variants are associated with a higher or lower level of a trait. Since variants are distributed at random at conception, this split works much like a draw in a clinical trial. In one such study, a higher genetically predicted homocysteine level was associated with a higher probability of stroke overall and of ischemic stroke: the odds ratio was 1.11 (95% confidence interval 1.03–1.21) (Yuan et al., BMC Med., 2021). For subarachnoid hemorrhage the estimate was higher, at 1.26 (1.05–1.51). No association was found with other studied cardiovascular conditions, including coronary heart disease. The authors themselves describe the associations found as tentative: their p values do not reach the conservative Bonferroni threshold of 0.001 applied in the study (Yuan et al., BMC Med., 2021).

A 2025 systematic review of Mendelian randomization studies also found evidence supporting a link between homocysteine and several types of stroke, including small vessel stroke (Zhu et al., Nutr. Metab., 2025). These estimates cannot be transferred directly to the effect of lowering homocysteine in adulthood: Mendelian randomization estimates a difference associated with lifelong exposure to genetic variants (Burgess & Gill, Eur. Heart J., 2022), whereas supplements are used during a specific period and under specific conditions. Interpretation also depends on which genetic variants were chosen for the analysis.

Thus, observational and genetic data support a link of homocysteine primarily with stroke. Genetic data do not confirm the observational association with coronary heart disease, so there is no basis for interpreting the value of the marker in the same way for all cardiovascular diseases. Whether intervening in homocysteine metabolism changes the frequency of clinical complaints, is assessed separately.

What Randomized Trials of Folic Acid Show

Randomized studies test the result of a specific intervention, not the causal role of homocysteine. A meta-analysis of 45 randomized controlled trials involving 96,962 people showed that taking folic acid was associated with a 15% reduction in the relative risk of stroke (RR 0.85; 95% CI 0.76–0.96). For cardiovascular diseases overall, the effect was smaller: relative risk 0.95 (95% CI 0.90–0.99). For coronary heart disease (RR 0.98; 95% CI 0.91–1.06) and mortality (RR 0.98; 95% CI 0.93–1.02), no statistically convincing effect was found (Ghattas Hasbun et al., BMC Nutr., 2025).

A negative result for coronary heart disease does not negate the biological role of folate: the biochemical role of a nutrient does not automatically determine the clinical effect of additional intake of it. The heterogeneity of results in the 2025 review is explained by differences between trials: baseline folate status, initial homocysteine level, genetic background, including the MTHFR genotype, dosage and duration of follow-up (D'Elia et al., J. Cardiovasc. Dev. Dis., 2025).

In the conclusions of the meta-analysis, the benefit is described as most noticeable in people with a higher homocysteine level, lower folate status and no history of cardiovascular disease (Ghattas Hasbun et al., BMC Nutr., 2025). Correction of a confirmed deficiency and additional vitamin intake when status is adequate remain different situations from the standpoint of interpreting the evidence.

The authors of the review conclude that the available evidence does not support routine intervention in unselected populations, and they frame it as an open question: whether homocysteine is an independent participant in vascular damage or merely a passive indicator of existing pathology (D’Elia et al., J. Cardiovasc. Dev. Dis., 2025).

Vitamin D and Blood Vessels: Observational Data and Intervention Results

In a meta-analysis of 79 observational studies that covered 46,713 cases of cardiovascular disease among 1,397,831 participants, the lowest category of 25-hydroxyvitamin D compared with the highest was associated with a higher probability of developing cardiovascular disease (RR 1.34; 95% CI 1.26–1.43) and of recurrent events (RR 1.86; 95% CI 1.46–2.36) (Jani et al., Nutr. Metab. Cardiovasc. Dis., 2021).

In the randomized D-Health trial, 21,315 people aged 60–84 received vitamin D monthly or placebo. The risk ratio for major cardiovascular events was 0.91 (95% CI 0.81–1.01), for myocardial infarction 0.81 (95% CI 0.67–0.98), and for stroke 0.99 (95% CI 0.80–1.23). In absolute terms over five years, this is 5.8 fewer events per 1,000 participants, and the confidence interval spans values from 12.2 fewer events to 0.5 more events, and the authors describe it as compatible with no effect (Thompson et al., BMJ, 2023).

The distribution of outcomes here differs from that for homocysteine: the effect is noticeable for myocardial infarction, whereas for stroke there is none.

For more on individual differences in vitamin D absorption, see the article Vitamin D: Why There Is No Universal Working Dose.

Genetic Features of Homocysteine Metabolism and Interpretation of the Marker

Part of the interindividual difference in homocysteine level is explained by inherited features of folate cycle enzymes. The C677T variant in the gene MTHFR reduces the activity of methylenetetrahydrofolate reductase. Methionine synthase is encoded by the gene MTR (5-methyltetrahydrofolate-homocysteine methyltransferase), and the gene MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) encodes its reductase, which returns the cofactor to its active form.

A gene–nutrient interaction has been described for riboflavin. In an observational study, 242 adults with the MTHFR 677TT genotype were compared with a group of the same age without this genotype. The TT genotype and low riboflavin status were independently associated with hypertension, and the blood pressure difference between genotypes was more pronounced among women; riboflavin status did not differ between the groups (Rooney et al., J. Hum. Nutr. Diet., 2022).

Laboratory and genetic data address different questions. Homocysteine concentration shows the current biochemical state. A genetic variant characterizes an inherited feature of an enzyme and establishes neither a deficiency nor the current level of the marker. In the 2025 review, routine genetic testing of the MTHFR gene is not recommended for cardiovascular decisions, while measuring homocysteine is described as a way to assess the marker when the goal is its correction (D’Elia et al., J. Cardiovasc. Dev. Dis., 2025).

The Apixmed Prism genetic report works exactly at this level: inherited features of homocysteine metabolism fall under the “Vitamins and Micronutrients” and “Amino Acids” areas. The current homocysteine level and vitamin status are determined by laboratory tests.

For more on what genetic analysis adds to the assessment of cardiovascular risk, see the article Cardiovascular Risk and DNA: What a Genetic Test Shows and What a Blood Test Does Not.

What Is Known Today About the Link Between Vitamins and the Heart

Folate, vitamins B12 and B6 are needed for homocysteine metabolism, and this role of theirs is well established. A different question remains open: whether influencing the marker itself changes the course of disease.

A higher homocysteine level is associated with a higher probability of certain cardiovascular events, primarily stroke. For coronary heart disease, genetic data do not confirm such a link. Folic acid trials showed a lower probability of stroke and showed no effect for coronary heart disease or mortality. For vitamin D the picture is the same: the association of a low level with events is pronounced, while the confidence interval for the effect of the intervention remains compatible with no effect.

The homocysteine level itself does not explain the reason for its rise and does not confirm a shortage of a specific vitamin, so the marker is not interpreted in isolation. Genetic data add inherited metabolic features to the picture but do not replace measuring the current state.

Genetic test results are not a diagnosis and not a substitute for consulting a doctor. The Apixmed Prism report provides genetic context that complements examination results and helps in making decisions together with a doctor.

References

1. D'Elia, S., Morello, M., Titolo, G., Caso, V. M., Solimene, A., Luisi, E., Serpico, C., Morello, A., La Mura, L., Loffredo, F. S., Natale, F., Golino, P., Cimmino, G. (2025). Homocysteine in the Cardiovascular Setting: What to Know, What to Do, and What Not to Do. Journal of Cardiovascular Development and Disease, 12(10), 383. https://doi.org/10.3390/jcdd12100383

2. Ghattas Hasbun, P., Calderon Martinez, E., Arvelaez Pascucci, J., Livier Castillo, J., Alonso-Ramírez, A., Giron De Marza, M. M., Martinez Illan, J., Sosaya Zuñiga, B., Camacho Davila, K., Flores Monar, G., Sanchez Cruz, C. (2025). Efficacy of folic acid supplementation in the prevention of cardiovascular disease - a systematic review and meta-analysis of randomized controlled trials. BMC Nutrition, 11(1), 203. https://doi.org/10.1186/s40795-025-01178-z

3. Yuan, S., Mason, A. M., Carter, P., Burgess, S., Larsson, S. C. (2021). Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study. BMC Medicine, 19(1), 97. https://doi.org/10.1186/s12916-021-01977-8

4. Zhu, X., Wei, J., Li, J., Zuo, S., Wang, J., Liu, N. (2025). The causal role of homocysteine in multiple diseases: a systematic review of Mendelian randomization studies. Nutrition & Metabolism, 22(1), 45. https://doi.org/10.1186/s12986-025-00933-0

5. Burgess, S., Gill, D. (2022). Genetic evidence for vitamin D and cardiovascular disease: choice of variants is critical. European Heart Journal, 43(18), 1740–1742. https://doi.org/10.1093/eurheartj/ehab870

6. Jani, R., Mhaskar, K., Tsiampalis, T., Kassaw, N. A., Gonzalez, A. M., Panagiotakos, D. B. (2021). Circulating 25-hydroxy-vitamin D and the risk of cardiovascular diseases. Systematic review and meta-analysis of prospective cohort studies. Nutrition, Metabolism and Cardiovascular Diseases, 31(12), 3282–3304. https://doi.org/10.1016/j.numecd.2021.09.003

7. Thompson, B., Waterhouse, M., English, D. R., McLeod, D. S., Armstrong, B. K., Baxter, C., Duarte Romero, B., Ebeling, P. R., Hartel, G., Kimlin, M. G., Rahman, S. T., van der Pols, J. C., Venn, A. J., Webb, P. M., Whiteman, D. C., Neale, R. E. (2023). Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial. BMJ, 381, e075230. https://doi.org/10.1136/bmj-2023-075230

8. Rooney, M., Hughes, C. F., Strain, J. J., Clements, M., McNulty, H., Ward, M. (2022). Impact of the MTHFR C677T polymorphism on blood pressure and related central haemodynamic parameters in healthy adults. Journal of Human Nutrition and Dietetics, 35(4), 689–700. https://doi.org/10.1111/jhn.13061