Nutrition: What Grok says about B-12 deficiency as a risk for heart disease

I asked Grok to summarize the potential of B-12 deficiency to be a risk factor for coronary artery disease (blockages due to plaque). The most recent study it identified found a significant association between homocysteine levels (which go up when B-12 is deficient) and coronary artery disease. Another study found that low B-12 tripled the risk of heart disease. In medicine, a tripling of risk is a big deal.

Some other studies found an increased risk of stroke but not heart attacks and some had mixed findings.

In the absence of other risks (a patient that has never smoked, never had alcohol, has normal lipid profiles, is not diabetic or pre-diabetic and so on), vitamin B-12 deficiency might be a significant risk factor. Because nutrition “science” and cardiology have focused on cholesterol (which is easy and cheap to measure), cholesterol became the dominant hypothesis for CVD. And the evidence is convincing that elevated LDL levels are a serious risk factor (also related to how LDL carries homocysteine, apo-B and Lp(a)).

B-12 and other B vitamins have been neglected, even though Dr. McCully established a link between B-12 deficiency, homocysteine and atherosclerosis in 1969 – and which more recent studies have confirmed – there does not seem to be much research on the connection.

Reminder: Meat is our primary dietary source of vitamin B-12. You do not need to be 100% vegetarian to encounter B-12 deficiency – but if you do not eat meat – and do not take B-12 supplements – you will likely become B-12 deficient eventually. Our bodies store about 2-5 years’ worth of B-12 so you need to go meatless for some time before running out of B-12. The overwhelming majority of people who adopt plant-based eating give it up before exhausting their B-12 reserves. Additionally, our ability to absorb B-12 goes down as we get older, plus some medications and autoimmune diseases (such as celiac) interfere with absorption.

Recent Studies on Homocysteine and Heart Disease

Recent research continues to explore the relationship between homocysteine and cardiovascular disease (CVD), with mixed findings on its role as a causal factor versus a marker. Below are key studies from the provided references, published between 2020 and 2024, that shed light on the current understanding:

1. Systematic Review and Meta-Analysis (2024):
   • A 2024 meta-analysis of 59 observational studies found a significant association between homocysteine levels and coronary artery disease (CAD). The pooled standardized mean difference (SMD) in homocysteine levels between CAD cases and controls was 0.73 (95% CI 0.55–0.91), indicating higher homocysteine in CAD patients. Notably, the association was stronger in Asian populations (SMD 0.85) compared to European populations (SMD 0.32). The study also noted that the strength of this association has increased over time (p = 0.048), suggesting evolving risk patterns or improved detection methods. However, high heterogeneity (I² = 94%) and the observational nature of the studies limit causal inferences, and the evidence was rated as low certainty due to potential biases.
2. Mendelian Randomization Study (2021):
   • A 2021 Mendelian randomization study investigated whether genetically predicted homocysteine levels cause CVD. Using 14 single nucleotide polymorphisms (SNPs) associated with homocysteine, the study found a significant link with stroke risk. For each standard deviation increase in genetically predicted homocysteine, the odds ratio (OR) was 1.11 for any stroke (95% CI 1.03–1.21), 1.26 for subarachnoid hemorrhage, and 1.11 for ischemic stroke. However, no significant association was found with coronary heart disease or myocardial infarction, suggesting homocysteine’s role may be more pronounced in cerebrovascular than coronary outcomes. This study supports a potential causal link for stroke but not for all CVD endpoints.
3. Taiwan Community Study (2021):
   • A cross-sectional study in Taiwan involving 396 adults aged 50–85 years examined homocysteine levels and CVD risk using the Framingham Cardiovascular Risk Score (FRS). Homocysteine was identified as an independent risk factor for high CVD risk (FRS ≥ 20%) after adjusting for age, sex, uric acid, creatinine, and BMI. The study highlighted correlations between homocysteine and other cardio-metabolic risk factors, reinforcing its role as a marker in high-risk populations, particularly in Asian cohorts.
4. Vascular Calcification Study (2020):
   • A 2020 study from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort explored homocysteine’s link to vascular calcification, a key feature of atherosclerosis. Elevated homocysteine was associated with increased calcification, but the study noted controversy due to meta-analyses showing no significant effect of MTHFR variants (linked to moderate homocysteine elevation) or folic acid supplementation on coronary heart disease risk. The authors called for further research with direct homocysteine measurements to clarify its role.
5. Mechanistic Insights (2015, updated context):
   • A 2015 review, still referenced in recent discussions, detailed mechanisms by which homocysteine may contribute to CVD, including endothelial dysfunction, oxidative stress, and inflammation via C-reactive protein (CRP) production in vascular smooth muscle cells. However, it noted that homocysteine-lowering interventions (e.g., B-vitamin supplementation) showed no significant reduction in myocardial infarction, stroke, or mortality in randomized trials, suggesting homocysteine may be a bystander rather than a primary driver.

Summary of Recent Studies:

• Observational studies consistently show an association between elevated homocysteine and CVD, particularly in Asian populations and for stroke outcomes.
• Genetic studies (e.g., Mendelian randomization) provide some evidence of causality for stroke but not for coronary heart disease.
• Interventions to lower homocysteine (e.g., B-vitamins) have not consistently reduced CVD risk, raising questions about whether homocysteine is a cause or a marker.
• The role of homocysteine in vascular calcification and inflammation remains biologically plausible but requires further investigation.

Recent Posts on X

Posts on X from April 2025 reflect ongoing public and professional interest in homocysteine as a cardiovascular risk factor, though some express skepticism about its clinical relevance. Below are summarized sentiments and key points from the provided X posts:

1. Public Awareness and Testing Advocacy:
   • Several users advocate for testing homocysteine levels to assess heart disease risk. For example, one post recommends maintaining optimal homocysteine levels (6–7 µmol/L) and suggests that levels ≥10 µmol/L increase stroke risk. It advises limiting alcohol and using methylated B-vitamins to lower homocysteine.
   • Another post links high homocysteine to heart attack and stroke risk, citing Gary Brecka, a health influencer, who emphasizes nutrient deficiencies (e.g., B-vitamins) as a cause of elevated levels.
   • A post encourages routine homocysteine testing, citing its role in heart disease risk assessment.
2. Skepticism from Medical Professionals:
   • Cardiologist@anish_kokaquestions the causal link between homocysteine and heart disease, noting that most cardiologists do not routinely test for it. He cites randomized trials (NORVIT, HOPE-2) showing no reduction in cardiovascular events despite B-vitamin supplementation lowering homocysteine levels.
   • Another user echoes this, stating that interventions to lower homocysteine have not reduced cardiovascular risk, aligning with trial data.
   • A post acknowledges homocysteine as a top-10 cardiac risk factor but notes that B-vitamin treatment showed no clinical benefit in trials from the 2000s, tempering its importance compared to cholesterol or hypertension.
3. Mechanistic and Nutritional Focus:
   • One post highlights homocysteine’s role in vascular inflammation and clot formation, linking elevated levels to deficiencies in glycine, choline, and B-vitamins (B2, B6, B9, B12). It suggests these deficiencies drive inflammation and mitochondrial dysfunction, contributing to CVD.

Summary of X Posts:

• Public-facing posts emphasize homocysteine testing and nutritional interventions (e.g., B-vitamins, dietary changes) to manage levels, often citing stroke and heart attack risks.
• Medical professionals on X are more cautious, pointing to randomized trial data showing no cardiovascular benefit from lowering homocysteine, suggesting it may not be a primary therapeutic target.
• The discourse reflects a divide between integrative health advocates, who prioritize homocysteine management, and conventional cardiologists, who view it as a secondary risk factor.

Synthesis and Current Perspective

Research Insights: Recent studies reinforce that elevated homocysteine is associated with CVD, particularly stroke, and may play a role in vascular calcification and inflammation. However, the lack of benefit from homocysteine-lowering interventions in large trials (e.g., NORVIT, HOPE-2, VITATOPS) suggests it may be a marker of underlying metabolic or vascular dysfunction rather than a direct cause. Genetic studies provide some evidence of causality for stroke, but not for coronary heart disease, indicating context-specific effects. The stronger association in Asian populations may reflect genetic (e.g., MTHFR variants) or dietary factors (e.g., lower folate intake).

X Sentiment: The X posts highlight a public interest in homocysteine as a modifiable risk factor, driven by influencers and integrative health advocates. However, cardiologists on the platform align with trial evidence, downplaying its clinical significance compared to established risk factors like cholesterol or hypertension. This divide mirrors the broader scientific debate.

Critical Perspective: While homocysteine’s biological effects (e.g., endothelial damage, oxidative stress) are well-documented, its clinical relevance is limited by the failure of B-vitamin interventions to reduce CVD events. This suggests that homocysteine may reflect broader metabolic imbalances (e.g., B-vitamin deficiencies, renal dysfunction) rather than being a primary driver. The focus on Asian populations in recent studies warrants further exploration of genetic and environmental modifiers. Routine testing remains uncommon due to cost, limited availability, and lack of evidence for intervention efficacy.

Recommendations:

• Clinical Practice: Homocysteine testing may be considered in high-risk patients (e.g., those with unexplained vascular disease, MTHFR mutations, or B-vitamin deficiencies), but it is not standard. Dietary improvements (e.g., folate-rich foods like spinach, B6-rich foods like bananas) are reasonable but not proven to reduce CVD risk.
• Research: Future studies should focus on direct homocysteine measurements in diverse populations, explore stroke-specific mechanisms, and investigate interactions with other biomarkers (e.g., CRP, oxidative stress markers).
• Public Health: Public interest on X suggests a demand for education on homocysteine’s role. Clinicians should clarify its secondary importance compared to smoking cessation, blood pressure control, or lipid management.

Note – Consult with your own primary care doctor or cardiologist to determine what is best for your individual situation. A big problem with “nutrition science” is that it makes a recommendation for a statistical population and does not take in to account individual health issues. Thus, recommending everyone eat vegan or plant-based might make some sense in a broad way but will cause harm to individuals prone to B-12 deficiency. Guidance must be directed to individuals and individual health needs.