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Asia Pacific J Clin Nutr (1996) 5(3): 157-160

Homocysteine and cardiovascular diseases

Klaus Pietrzik MD and A Brönstrup MSc

Institute of Nutritional Science, Department of Pathophysiology of Nutrition, University of Bonn, Germany

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Elevated homocysteine blood concentrations have been identified as an independent risk factor for the development of atherosclerotic lesions. The metabolism of the amino acid homocysteine in the human body involves the vitamins folic acid, B-12 and B-6 as essential cofactors and coenzymes, respectively. There is an inverse relationship between the status of the relevant B-vitamins and the homocysteine blood concentration. Supplementation of these vitamins results in a significant reduction of the homocysteine level. However, nutritive amounts seems to be sufficient to obtain this reduction, even in the case of elevated homocysteine levels.

Key words: homocysteine, cardiovascular disease

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Homocysteine and cardiovascular diseases

Atherosclerotic diseases like coronary heart disease (CHD) and stroke are still the leading causes of death in the Western World. A variety of risk factors have been associated with the development of atherosclerotic diseases. Among them are hypertension, , hyperlipidaemia and smoking , which together account for about 50% of the cases of CHD. However, there must be additional reasons for CHD, since half of the cases cannot be explained by the presence of the established risk factors.

For several years, the amino acid homocysteine has been considered as a potential risk factor for the development of atherosclerotic diseases. The discovery of homocystinuria in 1962 drew first attention to the association between elevated homocysteine blood levels and the occurrence of vascular diseases. In this inherited metabolic disorder , homocysteine accumulates in the blood. This leads to partial oxidation of homocysteine to homocysteine, which is then excreted via the urine. If untreated, affected individuals develop large atherosclerotic lesions as well as thromboembolic events early in life and often die before the age of 30 from stroke or myocardial infarction.

Metabolism of homocysteine Homocysteine is exclusively derived from the essential amino acid methionine and not taken from the diet. Homocysteine can be remethylated to methionine or catabolised to cysteine. Three vitamins of the B-group are involved in the metabolism of homocysteine: folic acid as 5-methyl-tetrahydrofolic acid (5-methyl-THF) is the donor of the methyl group required for the remethylation reaction; Vitamin B-12 functions as coenzyme in this reaction; T 1000 he formation of cysteine requires 2 enzymes for which vitamin B-6 in the form of 5-pyridoxal-phosphate (PLP) serves as coenzyme (Fig. 1).

Figure 1. Metabolism of homocysteine

Relevance of homocysteine for the development of atherosclerosis

Homocysteine as a risk factor for vascular diseases

From observations of extended and early-onset vascular lesions in homocystinuric patients, the question arose whether homocysteine levels, as seen in the general population, would be associated with the development of atherosclerosis. Subsequently, several studies examined the association between (moderately) elevated homocysteine levels and the risk for atherosclerosis. In case-control studies, a high percentage of patients with CHD showed elevated homocysteine levels. Clarke et al¹ found high homocysteine levels in 42% of patients with cerebrovascular diseases, 28% of patients with peripheral vascular diseases and 30% of cases with coronary vascular diseases. However, none of the healthy control persons showed an elevation of homocysteine blood concentration. Others found that the mean homocysteine level of patients with coronary, peripheral and cerebrovascular diseases was significantly higher than that of comparable controls^2-9.

Despite differences in study design, there is a striking agreement between the numerous studies on this topic. So far, there are 38 studies investigating the association of elevated homocysteine levels and risk for atherosclerotic diseases. Of these 38 studies, 34 found such an association¹⁰. It was also shown that elevated homocysteine levels are an independent risk factor for the development of atherosclerotic diseases^1,7,9,11,12. In other words, even in the absence of other, established risk factors like hypertension, smoking or hypercholesterolaemia, an increase in homocysteine concentration alone can be responsible for the development of atherosclerosis.

There seems to be a graded increment in the risk of atherosclerosis with increasing homocysteine levels. It is now accepted that a threshold, indicating a significantly elevated risk for persons with homocysteine concentrations above that value, does not exist. Calculations show that the risk for coronary disease is elevated by 60% for men and 80% for women with every 5 µmol/l increase in homocysteine levels¹⁰.

Upon comparison of data on the relevance of various risk factors it becomes evident that homocysteine plays an important role as risk factor for atherosclerotic diseases^1,10. It is thought to be at least equally important as elevated cholesterol levels¹⁰.

Vitamin supplementation as a means to influence homocysteine levels

The metabolism and degradation of homocysteine in the body requires the presence of the vitamins folic acid, vitamin B-12 and vitamin B-6. A low status of these vitamins is rapidly reflected by an increase in the homocysteine blood level. Therefore, homocysteine can be referred to as a functional parameter of the vitamin nutritional status of the respective B-vitamins. Seventy-seven of 78 patients with vitamin B-12 -deficiency and 18 of 19 patients with confirmed deficiency of folic acid had elevated homocysteine levels compared to a healthy control group¹³. There exists an inverse relationship between homocysteine and the relevant B-vitamins (Fig. 2): whereas a low homocysteine level is associated with high blood concentrations of folic acid and vitamin B-12, respectively, the homocyst 1000 eine blood concentration increases with decreasing vitamin levels¹⁴.

Figure 2. Relationship between homocysteine level and concentrations of cobalamin and folate in serum (modified from [14]).

Effectiveness of vitamins to lower homocysteine levels By supplementing the vitamins involved in the metabolism of homocysteine, the blood level of this atherogenic amino acid can be lowered. A combination of folic acid, vitamin B-12 and B-6 given daily in an amount 2.5-4 times the RDA was able to lower the homocysteine level significantly by 17-50%15,16. The extent depends on the homocysteine concentration at the onset of supplementation: the higher the level, the greater the observed treatment effect. In our own studies, we were able to show that the homocysteine level could be influenced with low (nutritive) doses of the relevant vitamins even in the case of so-called "normal" homocysteine concentrations and adequate vitamin status prior to supplementation. In one of our studies, 72 female students were supplemented with a multivitamin tablet containing 400µg folic acid, 2mg vitamin B-6 and 6µg vitamin B-12 daily. Within four weeks, the mean homocysteine level decreased significantly by as much as 21% (Fig. 3). Ongoing supplementation did not lead to a further reduction. Folic acid, vitamin B-12 and vitamin B-6 differ in their potential to influence the homocysteine level. Vitamin B-6 alone does not seem to have a lowering effect10,15. Supplementing men with elevated homocysteine blood concentrations with vitamin B-12 resulted in a decrease by 15%16. However, in the respective study as much as 400 µg vitamin B-12 was given, which is about 133 times the daily requirement for healthy adults. Folic acid seems to play the key role in lowering homocysteine. In men, the reduction obtained by supplementing folic acid alone did not differ significantly from the effect obtained by giving a combination of folic acid, vitamin B-12 and vitamin B-6 (Fig. 4)16. Supplementation of folic acid to young women was as effective in reducing the homocysteine level as a combination of folic acid and vitamin B-615.

Figure 3. Influence of vitamin supplementation on homocysteine levels in young women (n = 72)

Figure 4. Response of homocysteine blood levels to different vitamin supplements in men with elevated homocysteine levels. A significant reduction of homocysteine was seen after supplementation with vitamin B-12 (0.4mg; p<0.01), folic acid (0.65mg; p<0.001) and the combination (10mg Vitamin B-6, 0.4mg Vitamin B-12, 0.65mg Folsäure; p<0.001) (modified from [16])

In their meta-analysis, Boushey et al10 estimated that an increase in folic acid intake could prevent up to 50 000 deaths per year due to CHD in the USA. Calculations for Germany show that the death rate from CHD could be reduced by up to 15 000 depending on the intervention strategy used for increasing the uptake of folic acid (Table 1). The key role of folic acid in lowering homocysteine is also supported by other authors10,12,16 and can be explained biochemically: In the metabolism of homocysteine, vitamins B-6 and B-12 serve as co-enzymes and thus are not used up during the reaction in which they are involved. Folic acid, however, functions as donor of the methyl group in the remethylation reaction and is used up quantitatively so that it has to be regenerated to 5-methyl-THF. During the remethylation reaction, the methyl group of 5-methyl-THF is transferred to vitamin B-12 and after that to homocysteine to form methionine. Therefore, folic acid acts as limiting factor for this reaction and the absence of the methyl donor cannot be compensated by vitamin B-12. Vitamin B-12 does not seem to play a key role because it is usually present in sufficient amounts due to large stores of this B-vitamin in the body. The minor role of vitamin B-6 is thought to result from the possibility of the body to increase the remethylation rate in the case of a lack of the respective coenzyme (PLP) and thus limited degradation of homocysteine to cysteine via the transsulfuration pathway. This increase in the remethylation rate seems sufficient to prevent an accumulation of homocysteine in the body17.

Table 1. Potential reduction of deaths from coronary heart disease (CHD) for persons aged 45 years and older based on different intervention strategies. 1000 Intervention strategy Annual number of potentially preventable deaths   USA Germany Food fortification (flour and cereal products) up to 50 000* 15 000** Folic acid supplements (assuming high effectiveness) up to 28 000* 10 000** Nutrition education (assuming high effectiveness) up to 26 500* 8 000** * Data for USA from JAMA 1995; 274: 1049 - 1057. ** Data calculated for Germany (Pietrzik 1995).

So far it is known that nutritive amounts of folic acid are able to lower homocysteine levels in young women. This age group usually has homocysteine levels below 10µmol/l. "Normal" levels have not been defined yet. The homocysteine blood concentration increases with age and reaches levels of 10-15µmol/l in healthy adults of middle age. Elderly persons show homocysteine concentrations of about 10-25µmol/l. We assume that nutritive amounts are still sufficient to effectively lower these levels and are currently investigating this topic. However, it might be possible that elderly people require a combination of all vitamins involved in the metabolism of homocysteine since they often have a suboptimal vitamin status. Data from the Framingham study show that 30% of the patients had an elevated homocysteine level. In 67% of these patients a suboptimal vitamin status of one or more of the three B-vitamins was found and thought to be the cause for the elevation of homocysteine¹⁸. It is also known that about 30% of elderly people have an atrophic gastritis which may lower the absorption of vitamin B-12 and lead to a suboptimal status of this vitamin over time.

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Homocysteine and cardiovascular diseases

Klaus Pietrzik and A Brönstrup

Asia Pacific Journal of Clinical Nutrition (1996) Volume 5, Number 3: 157-160

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References

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Copyright © 1996 [Asia Pacific Journal of Clinical Nutrition]. All rights reserved.
Revised: January 19, 1999 .
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