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A high concentration of homocysteine is believed to increase the risk for an individual to get cardiovascular disease, although reducing this level may not help to stop such a disease from occurring. Research has shown that the high levels of homocysteine could contribute to atherosclerosis in three ways:
Has a harmful effect that directly affects and damages the inner cell lining of the arteries
Clotting factor activity being hampered by the high homocysteine concentration
Low-density lipoproteins (LDL) being oxidized more easily (Mediniche 2009)
Homocysteine is a product resulting from the metabolism of the amino acid methionine and is known to damage blood vessels. The figure below shows a part of the methionine pathway and how homocysteine can be metabolized. It also shows how homocysteine metabolism is affected by vitamin B12 and folate.
Figure 2: Methionine Metabolic Pathway (Journal of the American College in Nutrition 2010)
This increases the potential for cholesterol buildup in the bloodstream. The deficiencies of vitamins such as folic acid (B9), pyridoxine (B12) and cyancobalamin (B6) have been shown to lead to the increase of homocysteine levels. Although a high homocysteine level is often linked with cardiovascular diseases, the presence of hereditary mutations in an individual is another factor that may contribute to the excess. This hereditary condition is known as homocystinuria.
In this condition, an enzyme deficiency causes the homocysteine levels in the blood to increase and accumulate in the blood and is excreted in the urine. However, research has shown that people with vitamin B deficiency (hence leading to a high homocysteine level) have a lower level of homocysteine than people with hereditary mutations (Genetics Home Reference 2010).
After clinical studies of homocysteine in the blood, the 'normal' level of homocysteine has been considered to be around 6 Âµmol/l. Women have been known to be less prone to cardiovascular disease than men. This could be explained due to findings that show women have significantly less homocysteine in their blood than men. Vitamin B supplements have also been thought as a solution to high homocysteine levels, and this will be discussed later on. However, the issue now is whether lowering the amount of homocysteine in the blood actually decreases the cardiovascular risk. Taking into assumption that a decrease in the risk of getting cardiovascular disease can indeed be done by just increasing Vitamin B, the consumption of food products such as orange juice, breakfast cereals, fruits and vegetables, all foods rich in Vitamin B, has been widely recommended by researchers. These sources of food are rich in folic acid, which is vitamin B9. Researchers have also looked into a gene that helps to regulate homocysteine, known as methlenetetrahydrofolate reductase (MTHFR) (The Institute of Nutritional Medicine & Cardiovascular Research 2010).
Relation of Cardiovascular Disease with Escalated Homocysteine Levels
As mentioned before, high homocysteine levels can increase the risk of cardiovascular disease. In fact, high homocysteine levels may increase the occurrence of atherosclerosis and thrombosis in an individual.
One of the ways is harming and damaging the inner cell lining of the arteries, causing endothelial cell injury and allowing LDL molecules to adhere to the inner cell lining more easily. Endothelial cell injury compromises the vascular health by inhibiting hemostatic processes such as fibrinolysis, causing the body to be unable to break up the clot. One of the important systems used by endothelial cells for regulation involves nitric-oxide synthase (eNOS), which uses I-arginine to form nitric oxide (NO) and citrulline. These endothelium-derived NO serves various functions such as the maintaining of vessel tone and inhibiting platelets. Endothelial cell injury will cause a reduction in the availability of these cells and cause adverse effects of atherosclerosis and thrombosis.
High homocysteine concentration promotes clots by platelet activation and protein C activation, hampering their normal activity. Increased level of homocysteine concentration can cause a change of anticoagulant properties of the endothelial cells into a procoagulant phenotype that can cause impaired function of the vascular endothelium, or enhancing lipid oxidation. It affects the normal coagulation and fibrinolysis that increase the risk for a venous thrombosis. High homocysteine concentration also promotes the oxidation of LDL, which is known to contribute to atherosclerosis.
High homocysteine level can also cause decrease the expression of thrombomodulin and increase activity of tissue factor. This thrombosis cause by homocysteine may be the trigger for blockage of the vessels if the patient is already suffering from a certain degree of atherosclerosis. This thrombogenic effect due to high homocysteine level is one of the reasons why it is associated with increased risk of CVD.
Homocysteine is shown to have adverse effects on smooth muscle cells by inducing the expression of cyclin A gene and producing increasing amounts of cyclin-dependant kinase, which is a regulatory protein in mitosis. These actions will lead to the increased in smooth muscle cell proliferation that will promote atherosclerosis and thrombosis. Studies have been done using genetic techniques such as gene expression arrays to view the potentially pathogenic changes in the gene expression upon exposure of endothelial cells to high homocysteine concentrations (The American Journal of Clinical Nutrition 2000).
Effect of Smoking on Homocysteine Levels
According to studies done, it has been shown that smoking does increase one's homocysteine concentration. Smoking has already been labelled as a risk factor of cardiovascular disease. When looking at whether or not smoking can increase the homocysteine concentration, the effect of smoking and its chemicals on the vitamin B12 and folate, which are involved in the methionine pathway, must be observed.
Firstly, smoking is known to cause changes in the diet of an individual, and this may lead to a decrease in the consumption of essential vitamins. In the case of homocysteine concentration, vitamins B12 and folate are important in the conversion of homocysteine to other forms. Also, smoking may decrease vitamin B12 and folic acid's avidity for hepatic uptake, and thus may increase excretion of such substances through the urine. Therefore, deficiency and lack of intake of dietary vitamins will result in a rise in homocysteine concentration (Flatt 2006).
Smoking increases the cyanide levels in the blood, and a high affinity exists between cyanide ions and vitamin B12, which is needed to convert homocysteine to methionine in the pathway. Therefore, with a decrease in the amount of B12 available in the blood, there will be less methionine being formed, and there will be an accumulation of homocysteine, leading to high homocysteine levels (Cambridge Journals 2003).
In relation to folic acid, research has shown that folic acid coenzymes may be affected by the many chemicals found in cigarettes, or by the different pro-carcinogenic pathways initiated by smoking, which might lead to ineffective molecules of folic acid that are unable to carry out any activity (Wierzbicki 2007).
With regards to the information above, different studies on how smoking affects the B12 and folate concentration in the blood have led to different results, and thus may prove to be inconclusive.
Relation of Folate/B12 Supplements with Homocysteine Levels
As mentioned above, B6 and B12 vitamins and folate are involved in homocysteine metabolism, as they help to recycle homocysteine into methionine. When there are B6 and B12 vitamins or folate deficiency, an increase in homocysteine level could be expected because the recycling process is inefficient and thus causing insufficient function of methionine synthase. Methionine synthase is an enzyme that is responsible for the production of methionine from homocysteine in which homocysteine is used as a substrate (Harvard School of Public Health 2010 and Office of Dietary Supplements 2010).
Studies have shown that a high level of folic acid and B vitamins such as vitamins B6 and B12 in the body results in a lower homocysteine level. Folic acid and B vitamins are usually found in fruits and green leafy vegetables thus, the level of homocysteine in the body depends on the person's diet and genetic factors (Office of Dietary Supplements 2010).
However, so far, there are no studies that show folic acid supplements reducing the risk of atherosclerosis. This is because it would take very long for the results to be known and it is also expensive. Scientists are researching and trying to find out exactly how much folic acid or B vitamins are required to reduce homocysteine levels, but no results so far. Ultimately, folate and B vitamins supplement can only reduce risk of cardiovascular disease in people with low folate intake. Such as those people living in less developed countries whereby they do not get the nutrients they need (American Heart Association 2010).