Advertisement
Mayo Clinic Proceedings Home

Homocysteine: The Rubik's Cube of Cardiovascular Risk Factors

      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.
      • Dawber TR
      • Kannel WB
      • Revotskie N
      • Stokes III, J
      • Kagan A
      • Gordon T
      Some factors associated with the development of coronary heart disease: six years' follow-up experience in the Framingham study.
      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.
      • Khot UN
      • Khot MB
      • Bajzer CT
      • et al.
      Prevalence of conventional risk factors in patients with coronary heart disease.
      Of these, homocysteine, a homologue of the naturally occurring amino acid cysteine, is a promising candidate. McCully
      • McCully KS
      Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.
      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.
      • Loscalzo J
      Homocysteine trials—clear outcomes for complex reasons [editorial].
      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,
      • Hofmann MA
      • Lalla E
      • Lu Y
      • et al.
      Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.
      • Zhou J
      • Møller J
      • Danielsen CC
      • et al.
      Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice.
      as well as to impair endothelium-dependent vasorelaxation in humans.
      • Chambers JC
      • McGregor A
      • Jean-Marie J
      • Kooner JS
      Acute hyperhomocysteinaemia and endothelial dysfunction [letter].
      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.
      • Lentz SR
      Does homocysteine promote atherosclerosis [editorial]?.
      • Loscalzo J
      The oxidant stress of hyperhomocyst(e)inemia [editorial].
      Homocysteine has been shown to activate platelets and promote expression of the CD40/CD40 ligand from activated platelets.
      • Mehra MR
      • Uber PA
      • Scott RL
      • Park MH
      • Milani RV
      Effect of immunosuppressive regimen on novel markers of atherothrombosis in heart transplantation: homocysteine, c-reactive protein, and mean platelet volume.
      • Mohan IV
      • Jagroop IA
      • Mikhailidis DP
      • Stansby GP
      Homocysteine activates platelets in vitro.
      • Prontera C
      • Martelli N
      • Evangelista V
      • et al.
      Homocysteine modulates the CD40/CD40L system.
      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.
      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.
      • Hofmann MA
      • Lalla E
      • Lu Y
      • et al.
      Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.
      • Lentz SR
      Does homocysteine promote atherosclerosis [editorial]?.
      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).
      • Mehra MR
      • Uber PA
      • Scott RL
      • Park MH
      • Milani RV
      Effect of immunosuppressive regimen on novel markers of atherothrombosis in heart transplantation: homocysteine, c-reactive protein, and mean platelet volume.
      During the past decade, several large prospective trials have established homocysteine as an independent risk factor for stroke, CHD, venous thromboembolism, and death.
      Homocysteine Studies Collaboration
      Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.
      • Wald DS
      • Law M
      • Morris JK
      Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.
      The current meta-analysis by Humphrey et al
      • Humphrey LL
      • Fu R
      • Rogers K
      • Freeman M
      • Helfand M
      Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis.
      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.
      Homocysteine Lowering Trialists' Collaboration
      Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.
      Other therapies, including methionine restriction and exercise training, have also shown modest effects in reducing levels of homocysteine.
      • Ali A
      • Mehra MR
      • Lavie CJ
      • et al.
      Modulatory impact of cardiac rehabilitation on hyperhomocysteinemia in patients with coronary artery disease and “normal” lipid levels.
      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.
      • Yap S
      • Boers GH
      • Wilcken B
      • et al.
      Vascular outcome in patients with homocystinuria due to cystathionine β-synthase deficiency treated chronically: a multicenter observational study.
      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.
      • Toole JF
      • Malinow MR
      • Chambless LE
      • et al.
      Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
      • Lonn E
      • Yusuf S
      • Arnold MJ
      • Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
      • et al.
      Homocysteine lowering with folic acid and B vitamins in vascular disease [published correction appears in N Engl J Med. 2006;355 (7):746].
      • Bonaa KH
      • Njølstad I
      • Ueland PM
      • NORVIT Trial Investigators
      • et al.
      Homocysteine lowering and cardiovascular events after acute myocardial infarction.
      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.
      • Toole JF
      • Malinow MR
      • Chambless LE
      • et al.
      Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
      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.
      • Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      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.
      • Spence JD
      • Bang H
      • Chambless LE
      • Stampfer MJ
      Vitamin Intervention For Stroke Prevention trial: an efficacy analysis.
      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.
      • Lonn E
      • Yusuf S
      • Arnold MJ
      • Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
      • et al.
      Homocysteine lowering with folic acid and B vitamins in vascular disease [published correction appears in N Engl J Med. 2006;355 (7):746].
      Homocysteine concentrations were measured in only 19% of participants after 5 years, and the reduction in homocysteine concentration was not statistically significant.
      • Lonn E
      • Yusuf S
      • Arnold MJ
      • Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
      • et al.
      Homocysteine lowering with folic acid and B vitamins in vascular disease [published correction appears in N Engl J Med. 2006;355 (7):746].
      • McCully KS
      Homocysteine, vitamins, and vascular disease prevention.

      Potential Adverse Effects From B Vitamins

      Folic acid may affect endothelial function and support cell growth through mechanisms that are independent of homocysteine.
      • Bonaa KH
      • Njølstad I
      • Ueland PM
      • NORVIT Trial Investigators
      • et al.
      Homocysteine lowering and cardiovascular events after acute myocardial infarction.
      This effect may explain the increased rate of in-stent restenosis in patients treated with B vitamins after percutaneous interventions.
      • Loscalzo J
      Homocysteine trials—clear outcomes for complex reasons [editorial].
      • Lange H
      • Suryapranata H
      • De Luca G
      • et al.
      Folate therapy and in-stent restenosis after coronary stenting.
      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.
      • Loscalzo J
      Homocysteine trials—clear outcomes for complex reasons [editorial].
      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.
      • Bonaa KH
      • Njølstad I
      • Ueland PM
      • NORVIT Trial Investigators
      • et al.
      Homocysteine lowering and cardiovascular events after acute myocardial infarction.

      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.
      • Sarnak MJ
      • Levey AS
      • Schoolwerth AC
      • et al.
      Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.
      The kidneys have an important role in homocysteine metabolism; as renal function declines, homocysteine concentrations increase.
      • Friedman AN
      • Bostom AG
      • Selhub J
      • Levey AS
      • Rosenberg IH
      The kidney and homocysteine metabolism.
      • Rodionov RN
      • Lentz SR
      The homocysteine paradox [editorial].
      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.
      • Potter K
      • Hankey GJ
      • Green DJ
      • Eikelboom JW
      • Arnolda LF
      Homocysteine or renal impairment: which is the real cardiovascular risk factor?.
      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.

      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.

      REFERENCES

        • Dawber TR
        • Kannel WB
        • Revotskie N
        • Stokes III, J
        • Kagan A
        • Gordon T
        Some factors associated with the development of coronary heart disease: six years' follow-up experience in the Framingham study.
        Am J Public Health Nations Health. 1959; 49: 1349-1356
        • Khot UN
        • Khot MB
        • Bajzer CT
        • et al.
        Prevalence of conventional risk factors in patients with coronary heart disease.
        JAMA. 2003; 290: 898-904https://doi.org/10.1001/jama.290.7.898
        • McCully KS
        Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis.
        Am J Pathol. 1969; 56: 111-128
        • Loscalzo J
        Homocysteine trials—clear outcomes for complex reasons [editorial].
        N Engl J Med. 2006 Apr 13; 354 (Epub 2006 Mar 12.): 1629-1632https://doi.org/10.1056/NEJMe068060
        • Hofmann MA
        • Lalla E
        • Lu Y
        • et al.
        Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model.
        J Clin Invest. 2001; 107: 675-683https://doi.org/10.1172/JCI10588
        • Zhou J
        • Møller J
        • Danielsen CC
        • et al.
        Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1470-1476https://doi.org/10.1161/hq0901.096582
        • Chambers JC
        • McGregor A
        • Jean-Marie J
        • Kooner JS
        Acute hyperhomocysteinaemia and endothelial dysfunction [letter].
        Lancet. 1998; 351: 36-37https://doi.org/10.1016/S0140-6736(05)78090-9
        • Lentz SR
        Does homocysteine promote atherosclerosis [editorial]?.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1385-1386
        • Loscalzo J
        The oxidant stress of hyperhomocyst(e)inemia [editorial].
        J Clin Invest. 1996; 98: 5-7https://doi.org/10.1172/JCI118776
        • Mehra MR
        • Uber PA
        • Scott RL
        • Park MH
        • Milani RV
        Effect of immunosuppressive regimen on novel markers of atherothrombosis in heart transplantation: homocysteine, c-reactive protein, and mean platelet volume.
        Transplant Proc. 2002; 34: 1866-1868https://doi.org/10.1016/S0041-1345(02)03075-0
        • 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
        • 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
        • Homocysteine Studies Collaboration
        Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.
        JAMA. 2002; 288: 2015-2022https://doi.org/10.1001/jama.288.16.2015
        • Wald DS
        • Law M
        • Morris JK
        Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.
        BMJ. 2002; 325: 1202https://doi.org/10.1136/bmj.325.7374.1202
        • Humphrey LL
        • Fu R
        • Rogers K
        • Freeman M
        • Helfand M
        Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis.
        Mayo Clinic Proc. 2008; 83: 1203-1212
        • Homocysteine Lowering Trialists' Collaboration
        Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.
        BMJ. 1998; 316: 894-898
        • Ali A
        • Mehra MR
        • Lavie CJ
        • et al.
        Modulatory impact of cardiac rehabilitation on hyperhomocysteinemia in patients with coronary artery disease and “normal” lipid levels.
        Am J Cardiol. 1998; 82 (A1548.): 1543-1545
        • Yap S
        • Boers GH
        • Wilcken B
        • et al.
        Vascular outcome in patients with homocystinuria due to cystathionine β-synthase deficiency treated chronically: a multicenter observational study.
        Arterioscler Thromb Vasc Biol. 2001; 21: 2080-2085https://doi.org/10.1161/hq1201.100225
        • Toole JF
        • Malinow MR
        • Chambless LE
        • et al.
        Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.
        JAMA. 2004; 291: 565-575https://doi.org/10.1001/jama.291.5.565
        • Lonn E
        • Yusuf S
        • Arnold MJ
        • Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators
        • et al.
        Homocysteine lowering with folic acid and B vitamins in vascular disease [published correction appears in N Engl J Med. 2006;355 (7):746].
        N Engl J Med. 2006 Apr 13; 354 (Epub 2006 Mar 12.): 1567-1577https://doi.org/10.1056/NEJMoa060900
        • Bonaa KH
        • Njølstad I
        • Ueland PM
        • NORVIT Trial Investigators
        • et al.
        Homocysteine lowering and cardiovascular events after acute myocardial infarction.
        N Engl J Med. 2006 Apr 13; 354 (Epub 2006 Mar 12.): 1578-1588https://doi.org/10.1056/NEJMoa055227
        • Scandinavian Simvastatin Survival Study Group
        Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet. 1994; 344: 1383-1389
        • 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
        • McCully KS
        Homocysteine, vitamins, and vascular disease prevention.
        Am J Clin Nutr. 2007; 86: 1563S-1568S
        • Lange H
        • Suryapranata H
        • De Luca G
        • et al.
        Folate therapy and in-stent restenosis after coronary stenting.
        N Engl J Med. 2004; 350: 2673-2681https://doi.org/10.1056/NEJMoa032845
        • Sarnak MJ
        • Levey AS
        • Schoolwerth AC
        • et al.
        Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.
        Circulation. 2003; 108: 2154-2169https://doi.org/10.1161/01.CIR.0000095676 .90936.80
        • Friedman AN
        • Bostom AG
        • Selhub J
        • Levey AS
        • Rosenberg IH
        The kidney and homocysteine metabolism.
        J Am Soc Nephrol. 2001; 12: 2181-2189
        • Rodionov RN
        • Lentz SR
        The homocysteine paradox [editorial].
        Arterioscler Thromb Vasc Biol. 2008; 28: 1031-1033https://doi.org/10.1161/ATVBAHA.108.164830
        • 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

      Linked Article