Homocysteine as a risk factor for cardiovascular disease – fact or myth?

Cardiovascular diseases remain the leading cause of death worldwide and present a serious public health issue. The development of cardiovascular diseases has been connected to many risk factors, including those we can’t act on, such as age, sex or genetic predisposition, while other risk factors can be removed with lifestyle changes. That category consists of smoking, obesity, lack of physical activity, alcohol consumption, unregulated arterial hypertension and similar problems. Lately, alongside the usual risk factors, the role of homocysteine as a potential risk factor in cardiovascular disease development has been considered. Increased concentrations of homocysteine in plasma have been connected to endothelial damage, heightened oxidative stress and a procoagulant effect. Although homocysteine levels can be regulated with diet, vitamin B complex status and certain genetic polymorphisms, its real role in pathogenesis has not yet been explained.

What is homocysteine and how is it metabolized?

Homocysteine is an amino-acid formed as a byproduct during normal synthesis of methionine and cysteine. It’s present in the plasma in the form of unbound thiols; it’s mostly bound to plasma proteins but it can also bind to itself forming homocysteine dimers or bind to other thiols. It’s generated during the demethylation of methionine from food. The first step in demethylation is the reaction of methionine with ATP, forming S-adenosyl-L-methionine (SAM), a methyl group donor. SAM donates its methyl group to acceptor molecules (DNA, RNA, amino acids, proteins, phospholipids, etc.), thereby forming the demethylated molecule S-adenosyl homocysteine (SAH). SAH then undergoes S-adenosyl homocysteine hydrolase mediated deadenosylation which results in the formation of homocysteine. Homocysteine can be metabolised in two ways, either by remethylating back to methionine or transsulfurating into cysteine. Remethylation is mediated by methionine synthase whose cofactor is vitamin B12, by using 5-N-methyl tetrahydrofolate as a methyl group donor. Another important enzyme in this reaction is methylenetetrahydrofolate reductase (MTHFR) which catalyses the reaction that forms 5-N-methyl tetrahydrofolate. Transsulfuration is catalysed by the enzyme cystathionin-β-synthase, which uses vitamin B6 as a cofactor, where homocysteine condenses with serine to form cystathionine which further cleaves into cysteine with the help of cystathionine-γ-lyase.

The development of hyperhomocysteinemia

Hyperhomocysteinemia is a condition characterised by increased blood levels of homocysteine. It can be a result of genetic defects of enzymes necessary for the metabolism of homocysteine. The affected enzymes include methylenetetrahydrofolate reductase, methionine synthase and cystathionine-β-synthase. The most common mutations found all around the world and exhibiting a high occurrence in different populations are mononucleotide MTHFR polymorphisms, connected to mild and moderate hyperhomocysteinemia. The most common genetic cause of severe hyperhomocysteinemia is thought to be a homozygotic lack of cystathionine-β-synthase resulting in an increase of homocysteine up to 40 times. Other than from genetic defects, hyperhomocysteinemia can also form from a nutritional lack of folates, vitamin B6 and vitamin B12, which are cofactors of enzymes that are part of homocysteine metabolism. Likewise, some diseases like kidney and thyroid gland dysfunction, cancer, psoriasis and diabetes, as well as various medication, alcohol, tobacco, coffee, old age and menopause can also correlate to a moderate increase in homocysteine concentrations.

Homocysteine and cardiovascular diseases

Numerous studies have shown that increased levels of homocysteine correlate to cardiovascular diseases, as well as other pathologies such as Alzheimer’s disease, strokes and Parkinson’s disease. Hyperhomocysteinemia lowers the bioavailability of nitrous monoxide (NO), causing endothelial dysfunction as a result. NO acts as a vasodilator, thereby enabling unobstructed blood flow through the blood vessels. Otherwise, vasoconstriction, meaning a narrowing of the blood vessels, occurs, which can lead to hypertension and inflammation of the arterial wall, resulting in atherosclerosis and an increased production of thrombocytes and the formation of blood clots. The most probable mechanism of the decrease in NO bioavailability is mediated by asymmetric dimethylarginine (ADMA). ADMA, an endogenous inhibitor of endothelial nitrous monoxide synthase, competes with its natural substrate L-arginine, which limits the synthesis of NO. Homocysteine encourages ADMA synthesis and blocks its degradation.

Fact or myth?

Although numerous research has confirmed the connection between hyperhomocysteinemia and an increased cardiovascular risk, it is still not completely clear whether homocysteine is a
direct cause or a biomarker of increased risk. The therapeutical approach to hyperhomocysteinemia includes correction of nutritional status, primarily supplementation with folic acid, vitamin B12 and vitamin B6, which encourages the processes of remethylation and transsulfuration. In certain cases, especially with genetic disorders such as homocystinuria, therapy can also include high doses of vitamin B6, betaine as a methyl group donor and specific dietary measures with a limited intake of methionine. However, although these approaches lower plasmatic homocysteine concentrations, their role in lowering the incidence of cardiovascular event remains the target of further research.

Translated by: Anđela Jakiša