In the 20th century, the United States witnessed a steady and dramatic increase in the prevalence of coronary heart disease (CHD), with CHD ranking as the leading cause of death every year after 1910. After World War II, the National Heart Institute (now known as the National Heart, Lung, and Blood Institute) embarked on an ambitious longitudinal study of healthy men and women to identify potential causes of this growing epidemic and funded the Framingham Heart Study in 1948. A decade later, the study's director, Dr Thomas Dawber, published a series of landmark articles from the Framingham cohort identifying what he coined risk factors for the development of heart disease; these included hypertension, high cholesterol, and smoking.
1
Today, the Framingham risk assessment tool, which incorporates these “conventional” risk factors, is routinely used to calculate the 10-year risk of developing a myocardial infarction and remains an integral component of the Adult Treatment Panel III guidelines for the evaluation and treatment of high cholesterol.Although the importance of conventional risk factors is now well established, several studies have suggested that from 10% to 50% of patients with CHD lack any of the conventional risk factors, stressing the need to discover less common factors that may have a supporting role.
2
Of these, homocysteine, a homologue of the naturally occurring amino acid cysteine, is a promising candidate. McCully3
first suggested a pathogenic role for homocysteine on the basis of findings of severe atherosclerosis at autopsy of children with homocystinuria. This hypothesis was later expanded to include general populations with mild hyperhomocysteinemia, typically caused by dietary deficiencies of vitamin cofactors (folic acid, vitamin B12, vitamin B6) required for metabolism of homocysteine.Homocysteine is a sulfur-containing amino acid generated during metabolism of the essential amino acid methionine. It is in turn metabolized by 1 of 2 pathways: through transsulfuration by the vitamin B6-dependent cystathionine β-synthase in hepatic cells or via remethylation to methionine in nonhepatic cells.
4
Elevated levels of homocysteine may promote atherothrombosis by multiple mechanisms. Elevated levels of homocysteine have been shown to accelerate the development of atherosclerotic lesions in animal models,5
, 6
as well as to impair endothelium-dependent vasorelaxation in humans.7
Hyperhomocysteinemia promotes inflammation by increasing expression of vascular cell adhesion molecule 1 (VCAM1) and tumor necrosis factor-α and increases oxidative modification of low-density lipoproteins, thereby promoting uptake of low-density lipoprotein cholesterol by macrophages.
8
, 9
Homocysteine has been shown to activate platelets and promote expression of the CD40/CD40 ligand from activated platelets.10
, 11
, - Mohan IV
- Jagroop IA
- Mikhailidis DP
- Stansby GP
Homocysteine activates platelets in vitro.
Clin Appl Thromb Hemost. 2008 Jan; 14 (Epub 2007 Dec 26.): 8-18https://doi.org/10.1177/1076029607308390
12
The CD40/CD40 ligand engagement on the surface of endothelial cells, smooth muscle cells, or macrophages triggers an additional inflammatory response, characterized by the release of inflammatory cytokines (interleukins 1B, 6, 8, 12) and chemokines (chemokine [C-C motif] ligand 2 [CCL2]) as well as expression of adhesion molecules (E selectin, VCAM1, P selectin).- Prontera C
- Martelli N
- Evangelista V
- et al.
Homocysteine modulates the CD40/CD40L system.
J Am Coll Cardiol. 2007 Jun 5; 49 (Epub 2007 May 18.): 2182-2190https://doi.org/10.1016/j.jacc.2007.02.044
12
Hyperhomocysteinemia also increases concentrations of procoagulant tissue factor and reduces anti-thrombin III activity. This, in addition to the findings of enhanced activation of metalloproteinases after increases in homocysteine, suggests a predisposition to plaque rupture and thrombosis.- Prontera C
- Martelli N
- Evangelista V
- et al.
Homocysteine modulates the CD40/CD40L system.
J Am Coll Cardiol. 2007 Jun 5; 49 (Epub 2007 May 18.): 2182-2190https://doi.org/10.1016/j.jacc.2007.02.044
5
, 8
Elevated homocysteine levels are typically caused by either genetic defects in the enzymes involved in homocysteine metabolism or by nutritional deficiencies in vitamin cofactors (folate, vitamin B12, and vitamin B6). Other factors affecting homocysteine metabolism include chronic kidney disease, hypothyroidism, psoriasis, certain cancers, and several drugs (most commonly methotrexate, phenytoin, theophylline, niacin, and immunosuppressive agents).
10
During the past decade, several large prospective trials have established homocysteine as an independent risk factor for stroke, CHD, venous thromboembolism, and death.
13
, 14
The current meta-analysis by Humphrey et al15
reconfirms these findings and shows that homocysteine remains a significant predictor of new cardiovascular (CV) events in persons without known CHD, independently of other Framingham risk factors. In that analysis, the risk of any CHD event was increased approximately 20% for each 5 μmol/L increase in homocysteine levels.Reduction of homocysteine levels has been most readily accomplished by supplementation of the diet with the B vitamins (folate, vitamins B6 and B12); reductions of up to 39% have been reported.
16
Other therapies, including methionine restriction and exercise training, have also shown modest effects in reducing levels of homocysteine.17
In patients with hereditary homocystinuria resulting in severe homocysteinemia (plasma concentrations >100 μmol/L), treatment with high-dose B vitamins in combination with dietary methionine restriction resulted in a marked reduction in adverse vascular events.
18
These improvements in vascular outcomes occurred despite moderate residual hyperhomocysteinemia. In contrast, results from trials aimed at lowering homocysteine levels in patients with mild hyperhomocysteinemia (10-30 μmol/L) have been disappointing.19
, 20
, 21
These contradictory results could be due to trial design, potential adverse effects from B vitamins, and homocysteine as a risk marker and not a risk factor.Trial Design
The Vitamin Intervention for Stroke Prevention (VISP) trial was a 2-year secondary prevention trial of patients with stroke who were randomized to high- vs low-dose B vitamins. Reduction in total plasma homocysteine concentration was 2 μmoL greater in the high-dose group, and there was no effect on any CV end point.
19
A 2-year period may be insufficient for a significant change in CV outcomes because many of the early statin trials showed no benefit at such an early time frame.22
Moreover, a recent subgroup analysis of this trial that eliminated participants with confounding factors in study design (ie, those with renal impairment, those with malabsorption of vitamin B12, or those taking nonstudy vitamin B12 supplements), reported a significant 21% reduction in adverse vascular events from high-dose B vitamins.23
- Spence JD
- Bang H
- Chambless LE
- Stampfer MJ
Vitamin Intervention For Stroke Prevention trial: an efficacy analysis.
Stroke. 2005 Nov; 36 (Epub 2005 Oct 20.): 2404-2409https://doi.org/10.1161/01.STR.0000185929.38534.f3
In the Heart Outcomes Prevention Evaluation (HOPE) 2 trial of patients with diabetes or vascular disease, B-vitamin therapy significantly reduced stroke (by 25%) but not myocardial infarction or death.
20
Homocysteine concentrations were measured in only 19% of participants after 5 years, and the reduction in homocysteine concentration was not statistically significant.20
, 24
Potential Adverse Effects From B Vitamins
Folic acid may affect endothelial function and support cell growth through mechanisms that are independent of homocysteine.
21
This effect may explain the increased rate of in-stent restenosis in patients treated with B vitamins after percutaneous interventions.4
, 25
Moreover, folic acid and vitamin B12 may alter the methylation potential of vascular cells, resulting in a change in the cell phenotype that promotes the development of plaque.4
Vitamin B6 is involved in numerous enzymatic reactions and biological functions, including cell growth, immunocompetence, and cholesterol metabolism; high levels of B6 may inhibit angiogenesis.21
Homocysteine as a Risk Marker and not a Risk Factor
Homocysteine is elevated in kidney disease, and renal dysfunction is a recognized risk factor for CV disease.
26
The kidneys have an important role in homocysteine metabolism; as renal function declines, homocysteine concentrations increase.27
, 28
In a recent post hoc analysis of the Vitamins to Prevent Stroke (VITATOPS) trial, adjustment for renal function eliminated the relationship between total homocysteine and carotid intima medial thickness as well as flow-mediated dilatation of the brachial artery.29
These findings suggest that renal dysfunction may account for the epidemiologic association between mild hyperhomocysteinemia and increased CV risk and that lowering homocysteine levels with B vitamins would not eliminate the relationship between renal function and CV risk.- Potter K
- Hankey GJ
- Green DJ
- Eikelboom JW
- Arnolda LF
Homocysteine or renal impairment: which is the real cardiovascular risk factor?.
Arterioscler Thromb Vasc Biol. 2008 Jun; 28 (Epub 2008 Mar 20.): 1158-1164https://doi.org/10.1161/ATVBAHA.108.162743
Summary
What can we conclude from these data? Clearly, elevated homocysteine levels are associated with an increased risk of CV events, but B vitamins may not provide a preventive benefit in patients with mild homocysteinemia. Future studies must take into account renal function when evaluating the pathogenicity of homocysteine, as well as therapies for reducing homocysteine levels other than B vitamins (eg, novel future therapies, as well as various combinations of exercise training, methionine restriction, and use of betaine-homocysteine methyltransferase and N-acetylcysteine). Homocysteine, however, remains an important field of study as an unconventional risk factor, one facet of a complex metabolic puzzle—a veritable Rubik's cube—that promotes atherosclerosis.
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- Homocysteine Level and Coronary Heart Disease Incidence: A Systematic Review and Meta-analysisMayo Clinic ProceedingsVol. 83Issue 11
