B12, homocysteine, & heart disease

[Korn]

Our creatine levels influence our homocysteine levels. Creatine supplementation has caused increased homocysteine levels, so we don't want too high creatine levels. Too low creatine levels aren't good either, because dietary creatine intake also reduces the levels of homocysteine in the blood stream. Maybe high dietary intake of creatine (from meat and fish) to some degree can explain cases of hyperhomocysteina among non-vegans.

People who don't eat 'skeletal muscle sources' (meat and fish) rely on their body’s capacity to synthesize creatine from the amino acids arginine, glycine and methionine.
L-arginine is found in peanuts, walnuts, brazilnuts, coconuts, oat, wheat, legumes such as soybean and chickpea - and even chocolate. Glycine is found eg. in beans and some nuts/seeds (peanuts, sesame, safflower, cotton) - look here for more info: http://top200foodsources.com/Nutrients/Glycine/516/g.
Methionine can be found in fruits, vegetables, whole grains and fermented foods. Since excessive methionine intake, together with inadequate intake of B9/B6/B12 can increase the conversion of methionine to homocysteine, we don't want too much of it of course, and since methionine is found in animal products, and animal products also sometimes contain high B12 levels, the negative effect of the Hcy-increasing amino acids in these products may, at least to some extent, regulate by the higher B12 levels. This both suggests that people on a diet high in animal products also may need more B12 than vegans, but also that vegans need to make sure they eat proper food, including protein rich food containing arginine, glycine and methionine, since these amino acids contribute to better homocysteine levels by helping the body to synthesize creatine.

Some related studies:
The effect of L-arginine and creatine on vascular function and homocysteine metabolism

The unexpected increase in homocysteine levels following creatine supplementation could have adverse effects and merits further study, since creatine is a commonly used dietary supplement.

Effects of creatine supplementation on homocysteine levels and lipid peroxidation in rats.

Hyperhomocysteinaemia is an independent risk factor for CVD. Recent data show a relationship between homocysteine (Hcy) and free radical formation. Since creatine synthesis is responsible for most of the methyl group transfers that result in Hcy formation, creatine supplementation might inhibit Hcy production and reduce free radical formation. The present study investigated the effects of creatine supplementation on Hcy levels and lipid peroxidation biomarkers.
[...]
We conclude that creatine supplementation reduces plasma Hcy levels and lipid peroxidation biomarkers, suggesting a protective role against oxidative damage.

Oral Creatine Supplements Lower Plasma Homocysteine Concentrations in Humans


http://pilladvised.com/2010/07/creat...e-supplement/:

Another study, from Boston University School of Medicine, found that 3 weeks of creatine supplementation raised blood levels of homocysteine by 10-20%. Homocysteine is an amino acid that is toxic to blood vessels. The authors of this study believed that the increase in homocysteine with creatine was due to impairment of kidney function.

Here's some info from a commercial site: http://www.creatinemonohydrate.net/homocysteinemia.html


More later.

[Korn]

Choline is often grouped with the B-vitamins, and can be found in eg. cauliflower, spinach, wheat germ, quinoa, amaranth, soy lecithin, navy/kidney beans, tofu, almonds and peanuts (peanut butter) grapefruit, rice and more. As with everything else, we don't want too much or too little of it.

Vegans who eat too much junk food will eat less real food, and may therefore have reduced choline levels. This will affect their homocysteine levels in a negative direction, as discussed in eg. this study:

Choline, homocysteine, and pregnancy (2005)

[Korn]

Physiologic changes in homocysteine metabolism in pregnancy: A longitudinal study in Spain (March 2011):

CONCLUSION: Although tHcy seems to be physiologically low in this Spanish population and unrelated to folate and B12 nutritional status, C677T MTHFR genotype, and some pregnancy complications, we support the statement that appropriate folate concentration may be important throughout pregnancy to prevent abnormalities associated with altered status (e.g., neural tube defects). According to our study, supplementation with folic acid seems to achieve this purpose because diet alone may be insufficient. In addition, a poor vitamin B12 status, as measured by plasma levels, may indicate that supplementation of both vitamins is needed.

[Korn]

Homocysteine levels ["HH"] and the metabolic syndrome ["MS") in a Mediterranean population: A case-control study

Our results do not indicate a link between MS or its individual components with HH, and diabetes was the only relevant contribution. Cardiovascular disease risk due to MS and HH seems to share no common mechanisms.

[Korn]

Intake of folate, vitamin B6 and vitamin B12 and the risk of CHD: the Japan Public Health Center-Based Prospective Study Cohort (Feb 2008)

RESULTS: After 468,472 person-years of follow-up, 251 coronary heart disease incidents were documented. Coronary heart disease and definite myocardial infarction were inversely associated with dietary intake of folate, VB(6) and VB(12) after adjustment for age and sex, but the associations were attenuated after further adjustment for smoking, dietary and other cardiovascular risk factors. However, among non-multivitamin supplement users, multivariable hazard ratios (95% confidence intervals) in the highest vs. lowest quintiles of VB(6) intake were 0.60 (0.37-0.97) for total coronary heart disease and 0.52 (0.29-0.91) for definite myocardial infarction, and the inverse associations with VB(12) were marginally significant. The combination of below-median intake of three vitamins or of only B(6) conferred a twice excess risk of total coronary heart disease.
CONCLUSIONS: Dietary intake of VB(6) was associated with a reduced risk of coronary heart disease among middle-aged non-multivitamin supplement users. Dietary folate and VB(12) were also suggested to be protective factors for coronary heart disease.

PMID: 18460491

[Korn]

This study from January this year, suggests that hyperhomocysteinemia decreases bone blood flow, and contains an interesting element. The homocysteine levels were altered by adding Hcy (0.67 g/L) in the test objects' drinking water for 8 weeks - in other words, not by giving them B12. And yes - for some silly reason this was not performed on humans....

Body weight, Hcy, vitamin B12, and folate were measured. And this is the part that could be more significant that it may seem at first: "The results indicated that Hcy levels were significantly higher in the Hcy-treated group than in control rats, whereas vitamin B12 levels were lower in the Hcy-treated group compared with control rats."

Doesn't this somehow suggest that increased homocysteine lowers the B12 levels? If this is correct, this would affect how many of these researchers would interpret findings about B12 and homocysteine in the future. It could suggest that the link that some people still seem to insist as the most valid 'fact' about this, namely that studies finding that people with high Hcy levels often have low B12 levels also could be a result of something in their bodies/lifestyle/diet that would increase the Hcy levels, which again would lower the B12 levels.

This, of course, wouldn't alter the fact that B12 levels also may increase Hcy levels.


PMID: 21339911

[Korn]

Here's another new study, again questioning the theory that "normal B12 levels = normal homocysteine levels" or "low B12 levels = elevated Hcy levels:
Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages (Jan 2011)

RESULTS: Eight patients had vitamin B(12) concentrations below normal. Out of these eight patients, two had elevated MMA and/or Hcy concentrations. Ten other patients with normal vitamin B(12) concentrations had elevated concentrations of MMA and/or Hcy.
CONCLUSIONS: A vitamin B(12) concentration within the reference range does not automatically imply a sufficient vitamin B(12) status. We recommend measuring serum MMA, or alternatively plasma Hcy, yearly in all PKU patients to diagnose functional vitamin B(12) deficiency.

PMID: 21030277

[Korn]

Effect of Folic Acid and B-Vitamins on Risk of Cardiovascular Events and Total Mortality among Women at High Risk for Cardiovascular Disease: A Randomized Trial (May 2009)

CONCLUSION
Over the longest follow-up recorded thus far, a combination of folic acid/vitamin B6/vitamin B12 did not reduce a combined endpoint of total cardiovascular events among high-risk women despite significant homocysteine lowering.

(PMCID: PMC2684623)


So - this study suggests that even heavy supplementation didn't help these people much in terms of "a combined endpoint of total cardiovascular events"- but the supplementation did lower the homocysteine levels significantly. The result may of course not be transferable to people with very low B12 levels.

[Korn]

The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease? (2010)

Although evidence suggests that the homocysteine hypothesis is still relevant as a predictor of cardiovascular risk, we cannot conclude that measuring the homocysteine level is useful in guiding treatment. Furthermore, studies of primary and secondary prevention show no evidence that taking folic acid or other B vitamins lowers the risk of cardiovascular events.

Key points

Factors that can cause the plasma homocysteine concentration to be high include deficiencies of vitamin B6, vitamin B12, and folic acid; renal insufficiency; and genetic variants in enzymes responsible for homocysteine metabolism.

Higher plasma homocysteine levels are associated with a higher risk of cardiovascular, cerebrovascular, and peripheral arterial disease.

Supplementation of B vitamins and folic acid can lower plasma homocysteine levels.

Randomized controlled trials of supplementation to prevent cardiovascular events and other adverse outcomes have had mostly negative results. However, most patients in these trials had normal baseline plasma homocysteine levels.

Needed are randomized trials to see if supplementation improves outcomes in patients with high homocysteine levels.

doi: 10.3949/ccjm.77a.10036
Cleveland Clinic Journal of Medicine December 2010 vol. 77 12 911-918

[vegetarian_cat]

Hi there Korn, just a question. A few days ago I was reading a post of yours with a study showing that people taking B12 supplements actually had increased risks of heart deasease. I can't find it anymore. Do you remember where it could have been posted? thank you

[Korn]

Hi,
maybe you are thinking of some of these findings:
Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods.

Among the results, the researchers found that participants assigned to the B-vitamin group had a greater decrease in radionuclide GFR (and subsequently poorer kidney function) compared with the placebo group.

Also, participants randomized to receive B vitamins had a significantly greater number of cardiovascular and cerebrovascular events, with the 36-month risk of a composite outcome, including heart attack, stroke, revascularization, and all-cause mortality that was double in the B-vitamin group, compared to the placebo group.


Higher vitamin B12 levels were associated with greater mortality, but it is unclear whether vitamin B12 is a marker or a surrogate marker or even a substance that directly causes death. Further investigation is needed to clarify.

[Korn]

Homocysteine has been discussed for many decades. The first known case involving disease associated with high homocysteine levels is from 1933. For those who are interested, here's the article which gave the discussion about the link between B vitamins, homocysteine and heart disease a major boost back in 1969:
Vascular Pathology of Homocysteinemia: Implications for the Pathogenesis of Arteriosclerosis

Here's an article from Time, 1997, which comments how the focus on homocysteine has increased:
Beyond Cholesterol

A few years later (2003), this article, also based around the same, Norwegian group of researchers, shows that when looking at the link between homocysteine/heart disease factors like smoking, exercise, BMI, coffee consumption, certain types of medication, diet, some members of the vitamin B family etc had to be taken into consideration. The article stated that further studies will show if the treatments that reduce homocysteine will improve the situation for patients with heart disease. (Some of these studies have been quoted earlier in this thread.)


The Kilmer McCully Heart Protection Diet, (McCully launched the homocysteine/heart disease theory) is discussed here:

"Another area McCully would modify is the FDA recommendation to consume two or three servings of meat, poultry, fish, dry beans, eggs or nuts a day. Putting beans and nuts in this group is problematic, he says, because it suggests that plant and animal proteins are interchangeable: "The truth is that plant protein, lacking in the essential amino acids, is quite different from animal protein, which contains plentiful essential amino acids. Therefore, depending only on plants for protein is not a good idea because the protein is inferior." McCully is now around 80, and I don't know when this interview was made, but it seems that it must have been quite a while ago. Or - it may may be quite a while ago since "the father" of the homocysteine theory was updating his info about proteins from plants...

From the same article/interview:
"He suggests a daily intake of two or three servings of protein from fish, meats, poultry, eggs or cheese. Yes we have said eggs, which along with whole milk and fresh butter represent a major departure from the failed low cholesterol / low fat diet of the past. Fallon and Enig's "The Oiling of America" should be required reading for every primary care physician in this country. A return to the farm diet of rural American youth with lard, butter and whole milk is now very much back in vogue."

In this interview, McCully states that "As we understand it now, perhaps the single most important factor is a dietary imbalance between too much methionine from dietary protein and too little of the three B vitamins which are needed to break down or get rid of excess levels of homocysteine; namely vitamin B-6, vitamin B-12 and folic acid." This could possibly suggest (as mentioned in another post) that people on a diet very high in protein/methionine have an increased heart disease/homocysteine risk compared with others.

McCully says in the same interview: "The clearest evidence in humans is that homocysteine is involved in the increased risk of neural tube defects in children that are born to mothers who are deficient in folic acid. These folate-deficient mothers tend to have a higher level of homocysteine in their blood, and the amniotic fluid itself has a higher level of homocysteine than in those in mothers who have a normal folate intake."

He also says "In these synthetic studies I have discovered a compound that is formed between homocysteine thiolactone and vitamin A acid (retinoic acid), a substance called thioretinamide. This substance is anticarcinogenic and antineoplastic in animal models. Furthermore, thioretinamide forms an additional complex with vitamin B-12, a substance known as thioretinaco. This compound is also anticarcinogenic and antineoplastic in animal models. We believe, as I published in my 1994 monograph, that the activation of this thioretinaco occurs through ozone oxidation of the sulfur atoms of homocysteine. This oxidation reaction may cause it to be a highly effective anti-cancer compound." Since high B12 levels are associated both associated with increased mortality in elders and certain cancer types in general, and since increased intake of animal products in general is associated with increased risk of the most common cancer types and other severe health problems, it seems that it would be better to achieve good levels of the thioretinaco substance by combining vitamin A acid with B12 from non-animal sources.

[Korn]

Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification. PMID: 12738890
Many other studies have found links between homocysteine and heart disease, but getting enough B6 (and B9/B12) is a good idea anyway!

Here are some B6 sources:

Ready-to-eat cereal, 100% fortified, ¾ c 2.00 mg 100 % of RDA
Potato, Baked, flesh and skin, 1 medium 0.70 mg 35 % of RDA
Banana, raw, 1 medium 0.68 mg 34 % of RDA
Garbanzo beans, canned, ½ c 0.57 mg 30 % of RDA

Ready-to-eat cereal, 25% fortified, ¾ c 0.50 mg 25 % of RDA
Oatmeal, instant, fortified, 1 packet 0.42 mg 20 % of RDA


Sunflower seeds, kernels, dry roasted, 1 oz 0.23 mg 10 % of RDA
Spinach, frozen, cooked, ½ c 0.14 mg 8 % of RDA
Tomato juice, canned, 6 oz 0.20 mcg 10 % of RDA
Avocado, raw, sliced, ½ cup 0.20 mg 10 % of RDA

Wheat bran, crude or unprocessed, ¼ c 0.18 mg 10 % of RDA
Peanut butter, smooth, 2 Tbs. 0.15 mg 8 % of RDA
Walnuts, English/Persian, 1 oz 0.15mg 8 % of RDA

[Korn]

The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. PMID: 12638029

RESULTS: There was no significant difference in vitamin B-6 intake between the two groups, although the vegetarian group had a significantly lower vitamin B-12 intake than the nonvegetarian group. Vegetarian subjects had significantly lower mean plasma PLP and vitamin B-12 concentrations than did nonvegetarian subjects (p < 0.05); however, a significantly higher mean plasma folate concentration was found in the vegetarian group. Vegetarian subjects had a significantly higher mean plasma homocysteine concentration than nonvegetarian subjects (13.2 +/- 7.9 vs. 9.8 +/- 2.2 micromol/L). Negative correlations were seen between plasma homocysteine and vitamin B-12 concentrations in the vegetarian (p = 0.004), nonvegetarian (p = 0.026), and pooled (p < 0.001) groups. From best subsets regression analyses, the plasma homocysteine concentration could be significantly predicted by total protein intake (p = 0.027) and plasma vitamin B-12 concentration (p = 0.005) in the pooled group. When the intake of protein is not considered, vitamin B-12 concentration is still a strong predictor of plasma homocysteine concentration (p = 0.012).

CONCLUSIONS: Vitamin B-12 intake and mean plasma vitamin B-12 concentration were lower for vegetarian subjects than for nonvegetarian subjects, leading to an increase in plasma homocysteine concentration. Vitamin B-6 and folate had little effect on plasma homocysteine concentration when individuals had adequate vitamin B-6 and folate status.

[Korn]

Homocysteine, Folic Acid and the Heart: an Association Unravels

by Alice Park, Feb. 22, 2012

We may have the final word on homocysteine: higher blood levels of the amino acid don’t raise people’s risk of heart disease after all.Several decades ago, studies of children born with an unusual genetic defect, which led them to make excessive amounts of homocysteine, found that they also suffered from higher rates of heart disease. That led researchers to wonder whether the amino acid, which is critical to many proteins, was an independent risk factor for heart problems.Because people with high levels of homocysteine also tend to have low levels of B vitamins, doctors speculated that giving them supplements of the B vitamin folic acid, which helps break down homocysteine, would protect them from heart attacks. But research failed to bear out the theory: in a seven-year study of 12,064 heart-attack survivors, published in 2010, participants who took daily supplements of folic acid and vitamin B12 had 28% lower levels of homocysteine in the blood, but no reduction in heart events or stroke, compared with people taking placebo.Other studies investigating the connection between homocysteine and heart disease were inconclusive; some showed that higher levels of the amino acid were linked to an increased risk of problems, while others failed to show a strong connection.

MORE: Folic Acid, B12 Don’t Lower Heart Disease Risks

In the latest study, led by Robert Clarke, of the University of Oxford Clinical Trials Service Unit, researchers took advantage of genetic studies to clarify the relationship. Clarke and his team studied 116,000 patients, some of whom had heart problems and all of whom had genetic analysis done for mutations in a gene involved in homocysteine production.The genetic aberration led to a 20% increase in the participants’ blood homocysteine levels, compared with those without the genetic change, but they were not at any increased risk of having heart disease. “These results settle the homocysteine question fairly reliably,” says Clarke, whose study was published in PLoS Medicine. “These people have a lifelong increase of 20% in their homocysteine levels, but we convincingly showed there is no association between this genetic variant and cardiovascular disease risk. We think this closes the door on that chapter.”Due to the lack of strong evidence favoring a connection, the American Heart Association (AHA) does not consider homocysteine a risk factor for heart disease, nor does it discuss folate as way to protect the heart. “There is no evidence to recommend [folic] acid supplementation for heart disease,” says Dr. Donna Arnett, president-elect of the AHA and chair of the department of epidemiology at University of Alabama Birmingham. “This study closes the door on that.”Subgroups of patients, however, may still benefit from folate for heart. (And, of course, pregnant moms should take it to lower the risk of neural tube defects.) Arnett says that the elderly tend to lose folate as they age, and supplementing their deficiencies may lower their risk of heart disease as well, but there are no studies confirming this theory yet.

MORE: Low Vitamin B12 Linked to Smaller Brains and Cognitive Decline
In the meantime, the results serve as a reminder that supplements aren’t always effective at preventing disease, and as appealing as they might seem, their effect isn’t often supported by solid scientific evidence.

Read more: http://healthland.time.com/2012/02/2...#ixzz1nC0HbNwZ

[Consistency]

"Elevated homocysteine levels are easily reduced with the intake of certain nutrients involved in methylation. Such nutrients include folic acid with its cofactors, vitamins B6 and B12, plus what is proving to be the most efficient and cost-effective methyl donor of all, Trimethylglycine (TMG).
**TMG (also known as anhydrous betaine) is a naturally occurring phytonutrient found in a variety of plants and animals, with highest concentrations in beets, leafy green vegetables, and legumes. Since it can be difficult to eat enough of these foods to provide the body with sufficient methyl groups, supplementation may be necessary. Studies have demonstrated that TMG, folic acid, and B12 can reduce elevated levels of homocysteine to normal. The best methyl donor is TMG, because it has 3 methyl groups.

I eat a lot of beets, broccoli, and spinach, all known to contain homocystine lowering betaine (TMG). But I don't eat the green leaves of the broccoli, just the broccoli itself – what about you guys? Do you use the leaves?

We humans have the enzymes for the biosynthesis of Trimethylglycine (TMG) from Choline. Choline is found in fruits, vegetables, etc..

[Korn]

Treatment With B Vitamins and Incidence of Cancer in Patients With Previous Stroke or Transient Ischemic Attack: Results of a Randomized Placebo-Controlled Trial. [PMID: 22474057] [April 2012]

An excerpt:

Daily administration of folic acid, vitamin B(6), and vitamin B(12) to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack.

That's yet another reason to get B9 from food and not from supplements, isn't it?

[Korn]

This article somehow questions the valiue of looking at homocysteine levels as the only marker for B12 status - at least among patients of vascular disease:
Lowering homocysteine and modifying nutritional status with folic acid and vitamin B(12) in Indian patients of vascular disease.

Hyperhomocysteinemia is more commonly associated with vascular disease in Indians than in the western populations. It is caused by genetic polymorphisms or dietary deficiencies of the B vitamins. We attempted to identify the association of hyperhomocysteinemia with vitamin B(12) and folate in Indian patients of vascular disease. Homocysteine, vitamin B(12) and folate levels were estimated in 100 controls and 100 patients of vascular disease. Homocysteine estimation was repeated in 73 patients on different vitamin supplements for 6 months. Homocysteine exhibited a significant negative correlation with B(12) only in cerebrovascular disease and peripheral vascular diseasepatients, and with folate in coronary artery disease and cerebrovascular disease patients as well as controls. Single daily dose of folate was as effective as a combination of folate and cobalamin in reducing plasma homocysteine concentrations. Low levels of B(12) contribute to the higher incidence of cerebrovascular disease and peripheral vascular disease, and low folate levels account for higher prevalence of hyperhomocysteinemia in coronary artery disease and cerebrovascular disease. Moreover, irrespective of the cause of hyperhomocysteinemia, folate is known to ameliorate it. Hence, large-scale corrective measures like food fortification or dietary supplementation with folate might benefit the Indian population and reduce the incidence and morbidity of vascular disease.

"Single daily dose of folate was as effective as a combination of folate and cobalamin in reducing plasma homocysteine concentrations", could, if seen isolated from the other information in tha text, suggest that taking B12 in order to improve homocysteine levels and ther by reduce the risk of heart disease doesn't make sense... but here's the important part: "Low levels of B(12) contribute to the higher incidence of cerebrovascular disease and peripheral vascular disease [...]".

In other words: even if B12 according to this particular study doesn't help in order to reduce homocysteine levels, B12 is still important to reduce cerebrovascular disease and peripheral vascular disease.

[Korn]

New research finds that vegetarians are 32 percent less likely to die or need hospital treatment as a result of heart disease.

An excerpt:

New research from University of Oxford may provide some clues. A study of 44,500 people in England and Scotland revealed that vegetarians were 32 percent less likely to die or to need hospital treatment as a result of heart disease.

The scientists looked at data from 15,100 vegetarians and 29,400 people who ate meat and fish. During the course of the 11-year study, 169 participants died from heart disease and 1,066 required hospital treatment —and those individuals were more likely to have been meat and fish eaters than vegetarians.

Differences in cholesterol levels, blood pressure and body weight are thought to be behind the numbers.

“Most of the difference in risk is probably caused by effects on cholesterol and blood pressure,” said Dr. Francesca Crowe, lead author of the study at the Cancer Epidemiology Unit, University of Oxford. “Vegetarians probably have a lower intake of saturated fat, so it makes senses there is a lower risk of heart disease."

The Oxford team calculated the risk reduction at 32 percent after accounting for other factors such as age, smoking, alcohol intake, physical activity, educational level and socioeconomic background. Crowe said, "The main message is that diet is an important determinant of heart health.”

[Korn]

Link: Cardiovascular disease mortality and cancer incidence in vegetarians: a meta-analysis and systematic review. [PMID 22677895]

Conclusions: Our results suggest that vegetarians have a significantly lower ischemic heart disease mortality (29%) and overall cancerincidence (18%) than nonvegetarians.

[Geoff_N]

Sadly the National Health Service in the UK do not allow our GPs to order Homocysteine tests even where the doc agrees that it would be useful to have such data, especially in cases like mine with a proven CHD. She was able to order B12 and related tests and as they are in the normal range she supposes that my homocysteine level is too.