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Methylation & HomocysteineTheir Vital Roles in Heart Health

A subject that is gaining much attention in many circles of medicine these days is methylation, as it pertains to our body’s functions and in particular the management of homocysteine.With respect to statistics of heart disease in Canada, according to the Heart and Stroke Foundation, every 7 minutes in Canada someone will die of heart disease or stroke. They are both in the top three causes of death for Canadians. Although numbers have improved with respect to heart disease over the years, these are still very sobering statistics.Thus, in looking at a preventative approach and management strategy for heart health, the investigation of the process of methylation and specifically homocysteine is an interesting exploration. Methylation (see Figure 1) is defined as the addition of a methyl group (1 carbon atom bound to 3 hydrogen atoms) to a substrate (molecule upon which enzymes act). This process is used to transport nutrients throughout the body as well as to turn genes on and off. Defaults in methylation have shown to set the stage for assaults from environmental toxins, infectious agents and inflammatory processes, resulting in a wide range of conditions including cardiovascular disease.

The Importance of the Methylation Pathway

New cell synthesis and repair- defects in methylation can cripple the body’s ability to produce adequate amounts of DNA and RNA. This means that new cell production is impaired and more cells will die than will be created over time. This impairs all aspects of the body as the capacity to heal on any level is reduced.

Methylation and Heart Disease

Coenzyme Q10 (CoQ10) has been identified as a beneficial molecule for heart health as it feeds the mitochondria within each of our cells. Cardiac tissue is packed with mitochondria, more so than other tissue types in the body. Clinically CoQ10 has been used in the treatment of angina, prevention of heart attack, and protection from reperfusion injury after bypass surgery. The synthesis of CoQ10 in the body relies on components of the methylation cycle, particularly S-adenosyl methionine (SAMe). Poor methylation results in a rise in homocysteine levels and a drop in SAMe levels, thus depleting levels of CoQ10 for proper mitochondrial function within our cells (see Figure 1).

So What is Homocysteine?

Homocysteine (see middle of Figure 1) is a sulfur containing amino acid and a normal intermediate of methionine metabolism in the methylation cycle. When excess homocysteine is produced and not converted to cysteine (downstream) or back into methionine (upstream), it is excreted out of the cells and into the blood. It is the role of the liver and kidneys to deal with these excess levels, if and when they do occur. Issues with genetic conditions, diseases of the liver or kidneys, nutrient deficiencies or the use of certain pharmaceuticals can cause elevations in homocysteine to be mismanaged and this can lead to adverse health concerns.The role of elevated homocysteine levels in clinical practice has been hotly debated; the central theme being whether or not it is beneficial to measure and treat elevated levels of homocysteine. Some may consider homocysteine simply a marker but not a causative agent, while others ignore it as a coincidental metabolite, scientific evidence suggests otherwise.1,2From a historical perspective, as early as the 1960s, researchers described several inborn errors of metabolism in children which led to extremely high levels of homocysteine in the blood, resulting in mental retardation and death, often the result of a cardiac event. Post mortem examination of these patients revealed an emerging pattern of atherosclerosis due to formation of fibrous plaques and a loss of vascular elasticity. It was concluded by the researchers that these high levels of homocysteine were a directly responsible for these vascular lesions and set the stage for the cardiac events and death.Homocysteine can be measured with a conventional blood test, albeit important to follow the proper directions for collection so as to ensure consistent homocysteine measurements. Average fasting total homocysteine for “healthy “subjects is considered to be in the range of 6 to 12 umol/L. That being said, many proponents of preventative medicine like to see patients in the lower ranges as close to 6umol/L as possible. Figure 2. displays a graph showing the relationship of odds ratios for coronary artery disease (CAD) increasing with increasing levels of homocysteine in the blood. You can see an almost linear fashion of increased risk between the levels of 6 and 20 umol/L of homocysteine in the blood.


Figure 2. CAD Risk and Homocysteine Level(adapted from Guilliams, T et al., 2004)


Figure 1. Methylation Cycle

Risk Factor Assessment

In a prospective cohort study following 2127 men and 2639 women over four years, increasing levels of plasma homocysteine were directly correlated with increasing mortality (3). The authors concluded at the end of the study, based on their findings, an increase of 5umol/L of homocysteine would increase the all cause mortality by 49%, cardiovascular mortality by 50%, cancer mortality by 26%, and non cancer, non cardiovascular mortality by 104%.

Possible Mechanisms Associated With High Levels of Homocysteine

• Oxidative damage – much of the endothelial dysfunction associated with high homocysteine is thought to be from oxidative stress.4,5• Nitric oxide – studies have shown that homocysteine suppresses the vasodilator nitric oxide contributing to decreased vascular endothelial compliance and changes in platelet coagulation (6-10)• Vascular smooth muscle proliferation – studies have shown homocysteine’s ability to trigger proliferation of vascular smooth muscle cells thereby decreasing the lumen size of the vessel (11-15)• Endothelial cell cytotoxicity – high levels of homocysteine have been shown to be a contributor towards this issue, causing the formation of vascular lesions within the cardiovascular system and beyond (13)

Homocysteine lowering ideas

• Folic acid – while lower doses of folic acid have been shown to be effective in reducing homocysteine in the general population, those with cardiovascular concerns require much higher levels to be therapeutic, 2-15 mg/day have been used.16-18 It should be noted that at these higher folate levels, vitamin B12 be given in conjunction, to prevent any masked B12 deficiencies.

• Vitamin B12 – vitamin B12 deficiency can be common with vegetarians and the elderly, and is often detected with a finding of elevated homocysteine.19

• Vitamin B6 – usually given in conjunction with the above 2 vitamins, B6 shows much less benefit as a monotherapy.

• TMG – trimethyl glycine – using TMG to remethlyate homocysteine, this nutrient has shown promise as well in lowering elevated homocysteine levels.

• Combination product (MaxMethyl from AOR) – has been shown to significantly reduce homocysteine levels after just 6 weeks of supplementation.

Summary

Proper methlyation is an important process that occurs within our bodies. Homocysteine is a valuable marker to follow with respect to management of heart health both from a preventative aspect but also to monitor it when dealing with cardiovascular disease or in a post surgical protocol. It is important to realize the significant benefit of vitamins like folic acid, B12 an B6 and products like MaxMethyl from AOR as effective strategies for reducing the body’s level of homocysteine if it is shown to be elevated. It is also valuable to utilize these nutrients to promote the proper function of the methylation cycle as a key to long term wellness.

References

1. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000;72(2):324-332

2. Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr. 2000;72(2):315-323.

3. Vollset SE, Refsum H, et al. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001;74(1):130-136.

4. Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D. Impaired homocysteine metabolism and atherothrombotic disease. Lab Invest. 2001;81(5):645-672.

5. Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation. 1999;100(11):1161-1168.

6. Leoncini G, Pascale R, Signorello MG. Effects of homocysteine on l-arginine transport and nitric oxide formation in human platelets. Eur J Clin Invest. 2003;33(8):713-719.

7. Bilsborough W, et al. Endothelial nitric oxide synthase gene polymorphism, homocysteine, cholesterol and vascular endothelial function. Atherosclerosis. 2003;169(1):131-138.

8. Stuhlinger MC, et al. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation. 2003;108(8):933-938.

9. Wanby P, Brattstrom L, Brudin L, Hultberg B, Teerlink T. Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading. Scand J Clin Lab Invest. 2003;63(5):347-353.

10. Jonasson TF, Hedner T, Hultberg B, Ohlin H. Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease. Eur J Clin Invest. 2003;33(7):543-549.

11. Taha S, Azzi A, Ozer NK. Homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells by a hydrogen-peroxide-independent mechanism. Antioxid Redox Signal. 1999 Fall;1(3):365-369.

12. Woo DK, Dudrick SJ, Sumpio BE. Homocysteine stimulates MAP kinase in bovine aortic smooth muscle cells. Surgery. 2000;128(1):59-66.

13. Chen C, Halkos ME, Surowiec SM, Conklin BS, Lin PH, Lumsden AB. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models. J Surg Res. 2000;88(1):26-33.

14. Buemi M, et al. Effects of homocysteine on proliferation, necrosis, and apoptosis of vascular smooth muscle cells in culture and influence of folic acid. Thromb Res. 2001;104(3):207-213.

15. Carmody BJ, Arora S, Avena R, Cosby K, Sidawy AN. Folic acid inhibits homocysteine-induced proliferation of human arterial smooth muscle cells. J Vasc Surg. 1999;30(6):1121-1128.

16. Stanford JL, et al. Oral folate reduces plasma homocyst(e)ine levels in hemodialysis patients with cardiovascular disease. Cardiovasc Surg. 2000;8(7):567-571.

17. Manns B, et al. Oral vitamin B12 and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia. Kidney Int. 2001;59(3):1103-1109.

18. Beaulieu AJ, et al. Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients. Arterioscler Thromb Vasc Biol. 1999;19(12):2918-2921.

19. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67(5):979-986.

Additional References:

uilliams, T et al. Homocysteine – a Risk Factor for Vascular Diseases: Guidelines for the Clinical Practice. JANA Vol 7, No. 1. 2004http://www.heartandstroke.on.ca/site/c.pvI3IeNWJwE/b.3581729/k.359A/Statistics.htmhttp://www.drkendalstewart.com/wp-content/uploads/2011/09/Methylation-Overview-for-Professionals-10.11.pdfhttp://www.nature.com/cdd/journal/v11/n1s/images/4401451f1.jpg

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