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Homocysteine: A new 
   coronary heart disease 
   risk factor
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   เสี่ยงในการเกิดโรคหัวใจ 

Homocysteine, Folic Acid 
  and Cardiovascular 
  Disease


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  Cardiac Markers : Homocysteine      
Related tests: CK / Myoglobin / Troponin / CK-MB

Homocysteine: A new coronary heart disease risk factor 

Fodor, J.G., LeGrand, C.
University of Ottawa Heart Institute Prevention & Rehabilitation Centre 

The issue of homocysteine is at present at the center of attention of those interested in preventive cardiology.

What is Homocysteine?
Homocysteine is a sulfur-containing amino acid formed during the processing of methionine. Of no known biological role, it can be re-methylated to methionine or sulfoconjugated with serine to form cysteine in a series of enzymatic reactions. The former steps use vitamin B12 and folic acid while the latter uses vitamin B6 as a co-factor.

Under normal conditions, methionine is derived from food protein. Thus, the higher the meat consumption, the higher the methionine supply. To smoothly run the methionine transformation, the body requires a sufficient supply of the above listed vitamins. If there is a dearth of these vitamins, and if there is a high intake of protein, e.g. excessive meat intake, the intermediary product, homocysteine, starts to accumulate. Accumulation of homocysteine in the blood has a direct toxic effect on the endothelium by impairing EDRF-NO production as well as stimulating smooth cell proliferation. All these effects have a strong atherogenic potential.

Serum homocysteine is measured from a blood sample taken after a twelve hour fast. A normal homocysteine level is between 5 and 15 micromoles per liter (ตmol/L). Abnormal levels are classified as moderate (16 to 30 ตmol/L), intermediate (31 to 100 ตmol/L) and severe (> 100 ตmol/L). Severely elevated levels of homocysteine can be caused by either genetic or dietary factors.

History of Homocysteine
In the mid 1960s a Harvard physician, Dr. McCully, treated an eight year old girl with the rare inherited metabolic condition (homocystinuria) that causes homocysteine levels to rise. The autopsy of this patient showed massive generalized atherosclerosis. Dr. McCully speculated the cause of atherosclerosis to be high homocysteine levels and wondered if the same was true for atherosclerosis in adults. Dr. McCully hypothesized that even slightly elevated homocysteine levels could cause atherosclerosis in older individuals, but his hypothesis failed to get acceptance.

Recent studies are now confirming Dr. McCully’s work of more than 20 years ago. Mild to moderate elevations (15-30 ตmol/L) of plasmatic homocysteinemia have been associated with cardiovascular diseases, including ischemic heart disease, cerebrovascular disorders and ischemic disorders of the lower limbs. The association is stronger between homocysteine and peripheral vascular disease and cerebrovascular disorders, than the association between homocysteine and ischemic heart disease (1). Multiple case-control studies have demonstrated that the homocysteine level is higher among patients with proven ischemic heart disease and premature CAD as compared to a clinically healthy population (1). In the Physicians Health Study (2) a threefold increase risk of MI was observed with plasma homocysteine levles above 15.8 nmol/mL as compared with those having lower plasma levels of this amino acid. A cross sectional analysis done on the Framingham study respondents found that those with homocysteine levels greater than 14.4 nmol/mL had a twofold increase in carotid stenosis. This study was included subjects 65 years of age or older. Similar findings were reported concerning aortoiliac occlusive disease. On the basis of recent retrospective, prospective and epidemiological studies from Europe, the United States and Canada, it is now widely accepted that mild hyperhomocysteinemia is an independent risk factor for cardiovascular disease even after taking into account the presence of other traditional risk factors. Evidence from these studies has shown the association between homocysteine and cardiovascular disease to be equally valid in both men and women.

Several lines of evidence suggest that homocysteine obviously plays a causal role in atherothrombotic disease. Repeated observations suggest that homocysteine may affect the coagulation system and the resistance of the endothelium to thrombosis (3), and as mentioned above, it may interfere with the vasodilator and anti-coagulation functions of nitric oxide (NO) (4). Several authors emphasize the ability of homocysteine to increase production of intracellular free radicals in endothelial cells. With increased production of free radicals and a decreased ability of endothelial cells to scavenge these radicals, molecules of NO become vulnerable to oxidative stress (5,6). 

The role homocysteine plays in atherogenesis is complicated by its binding to plasma protein carriers and the fact that several factors are involved in its metabolism. The majority of homocysteine (up to 80%) is in the bound form (7), and the other 20 % consists of i) free homocysteine, ii) homocystin, reduced form or iii) homocystein-cystein mixed disulfide.

From the population perspective, the mild hyperhomocysteinemia is of greater concern than the more symptomatic homocystinuria because of its increased prevalence and initially asymptomatic clinical course (8). It is estimated that approximately 20% of Canadians may have elevated homocysteine levels. Population-based studies to date have confirmed that nutritional intake and plasma levels of vitamins B12, B6 (and its metabolite pyridoxal 5-phosphate, PLP) and folic acid, are important determinants of plasma levels of homocysteine. Studies involving analysis of family members have also shown that genetic factors are involved in the determination of homocysteine levels (9). The recent characterization of a common mutation at the methylene tetrahydrofolate reductase gene (MTHRF, a key enzyme in the conversion of homocysteine to methionine) shed light on the mechanism of genetic predisposition.

A large, case control, multi-centre European trial, involving men and women younger than 60 years of age, found that the overall risk of coronary and other vascular disease risk was 2.2 times higher in those with plasma total homocysteine levels in the top fifth of the normal range as compared to those in the bottom four-fifths. This risk was independent of other risk factors, but was notably higher in smokers and individuals with high blood pressure (10).

A Norwegian study published in 1997, found that among 587 patients with coronary heart disease, the risk of death after four to five years was proportional to plasma total homocysteine levels. The risk rose from 3.8 percent in those with the lowest levels (below 9 ตmol/L) to 24.7% with the highest levels (greater than 15 ตmol/L) (11).

There have been several intervention studies illustrating that supplementation with vitamin B6, B12 and folic acid effectively reduce plasma homocysteine levels (12,13), however, the therapeutic influence of this reduction of homocysteine on cardiovascular mortality and morbidity did not yield unequivocal results. The topic is fueled by controversy and there is no definitive evidence one way or the other. A well designed randomized controlled trial to determine whether or not vitamin supplementation effectively decreases cardiovascular disease morbidity and mortality in individuals with elevated homocysteine is urgently needed.

Conclusion
To date, a massive database exists which confirms the importance of plasma homocysteine as a powerful predictor of future risk of coronary heart disease and other complications of atherosclerosis. Elevated homocysteine levels can be reduced through adequate intake of folic acid, vitamin B6 and vitamin B12. On the other hand we do not have any evidence from randomized clinical trials that supplementation of these vitamins would reduce the probability of atherosclerotic complications. It is unwise to make therapeutic recommendations based on substitute indicators.

However, avoidance of excessive meat intake and increased consumption of vegetables and fruits is a dietary measure which has many health benefits, including a potential to reduce elevated homocysteine levels.



J. George Fodor, M.D., Ph.D., F.R.C.P.(C):

References
Genest JJ Jr, McNamara JR, Salem DN, Wilson PW, Schaefer EJ, Malinow MR. Plasma homocysteine levels in men with premature coronary artery disease. JACC 1990;16(5):114-9.

Stamfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268(7):877-81.

Malinow MR, Axthelm MK, Meredith MJ, MacDonald NA, Upson BM. Synthesis and transsulfuration of homocysteine in blood. Journal of Laboratory & Clinical Medicine. 1994;123(3):421-9.

Stamler JS, Slivka A. Biological chemistry of thiols in the vasculature and in vascular-related disease. Nutrition Reviews 1996;54(1 Pt 1):1-30.

Upchurch GR Jr. et al. Homocysteine decreases bioavailable nitric oxide mechanism involving glutathione peroxidase. J Biol Chem 1997, 272(27): 17012-17017.



Homocysteine, Folic Acid and Cardiovascular Disease

AHA Recommendation
The American Heart Association has not yet called hyperhomocysteinemia (hi"per-ho"mo-sis-TE'in-E'me-ah) (high homocysteine level in the blood) a major risk factor for cardiovascular disease. We don't recommend widespread use of folic acid and B vitamin supplements to reduce the risk of heart disease and stroke. We advise a healthy, balanced diet that includes at least five servings of fruits and vegetables a day. For folic acid, the recommended daily value is 400 micrograms (mcg). Citrus fruits, tomatoes, vegetables and grain products are good sources. Since January 1998, wheat flour has been fortified with folic acid to add an estimated 100 micrograms per day to the average diet. Supplements should only be used when the diet doesn't provide enough.


What is homocysteine, and how is it related to cardiovascular risk?
Homocysteine (ho"mo-sis-TE'in) is an amino acid in the blood. Too much of it is related to a higher risk of coronary heart disease, stroke and peripheral (peh-RIF'er-al) vascular disease (fatty deposits in peripheral arteries).

Two reports have strengthened the evidence for this relationship:

A large multi-center European trial found that men and women under 60 had a 2.2 times overall higher risk of cardiovascular disease if total homocysteine levels in their blood were in the top fifth of the normal range. This risk was independent of other risk factors but was notably higher in smokers and people with high blood pressure. 
A Norwegian study of 587 patients with coronary heart disease found that their risk of death after four to five years was proportional to total homocysteine levels in the blood. The risk rose from 3.8 percent in those with the lowest levels (below 9 micromol per liter) to 24.7 percent with the highest levels (greater than 15 micromol per liter). 
Other evidence suggests that homocysteine may promote atherosclerosis (ath"er-o-skleh-RO'sis) (fatty deposits in blood vessels) by damaging the inner lining of arteries and promoting blood clots. However, a causal link hasn't been established.


How do folic acid and other B vitamins affect homocysteine levels?
Folic acid and other B vitamins help break down homocysteine in the body. Homocysteine levels in the blood are strongly influenced by diet and genetic factors. Dietary folic acid and vitamins B-6 and B-12 have the greatest effects. Several studies found that higher blood levels of B vitamins are related, at least in part, to lower concentrations of homocysteine. Other evidence shows that low blood levels of folic acid are linked with a higher risk of fatal coronary heart disease and stroke.

So far, no controlled treatment study has shown that folic acid supplements reduce the risk of atherosclerosis or that taking these vitamins affects the development or recurrence of cardiovascular disease. Researchers are trying to find out how much folic acid, B-6 and/or B-12 are needed to lower homocysteine levels. Screening for homocysteine levels in the blood isn't widely available and may cost from $85-200, which isn't covered by insurance. However, it may be useful in patients with a personal or family history of cardiovascular disease, but in whom the well-established risk factors (smoking, high blood cholesterol, high blood pressure, physical inactivity, obesity and diabetes) don't exist.

Although evidence for the benefit of lowering homocysteine levels is lacking, patients at high risk should be strongly advised to be sure to get enough folic acid and vitamins B-6 and B-12 in their diet. They should eat at least five servings of fruits and green, leafy vegetables daily.

This is just one possible risk factor. A physician taking any type of nutritional approach to reducing risk should consider a person's overall risk factor profile and total diet.



Detailed Research
AHA Science Advisory on Folic Acid, Homocysteine and Atherosclerosis (July 3, 1996)

AHA Science Advisory on New Evidence for Role of Homocysteine in Cardiovascular Disease (Sept. 1997)

AHA Science Advisory: Homocyst(e)ine, Diet, and Cardiovascular Diseases, #71-0157 Circulation. 1999;99:178-182



 

 
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