This article reviews the evidence that homocysteine is a risk factor for coronary artery disease. This evidence ranges from that obtained from in-vitro experiments sometimes using non-physiological concentrations of homocysteine to epidemiological studies involving large numbers of subjects. Despite the variety of studies and methodologies employed, the hypothesis that homocysteine is a risk factor remains plausible. The relationship between certain nutrients and serum homocysteine and the therapeutic implications of this relationship are discussed.
MuddSHFinkelsteinJDIrreverreFLasterL: Homocystinuria: An enzymatic defectScience1964, 143:1443–1445.
2.
MuddSHLevyHLSkovbyF: Disorders of transsulphuration. In The Metabolic Basis of Inherited Disease, 6th edn, vol 1. Edited by ScriverCBeaudetALSlyWSValleD.New York: McGraw Hill, 1989:693–734.
3.
BrattstromLIsraelssonBLindgardeFHultbergB: Higher total plasma homocysteine in vitamin B12 deficiency than in heterozygosity for homocystinuria due to cystathionine B-synthase deficiencyMetabolism1988, 37:175–178.
4.
KangSSWongPWKNorusisM: Homocysteinemia due to folate deficiencyMetabolism1987, 36:458–462.
5.
SwiftMESchultzTD: Relationship of vitamin B6 and B12 to homocysteine levels: Risk for coronary heart diseaseNutr Rep Int1986, 34:1–14.
6.
HultbergBAnderssonGSternerG: Plasma homocysteine in renal failureClin Nephrol1993, 40:230–235.
7.
ClarkeRDalyLRobinsonKNaughtenECahalaneSFowlerB: Hyperhomocysteinemia: An independent risk factor for vascular diseaseN Engl J Med1991, 324:1149–1155. Theauthors assess the strength, independence and prevalence of hyperhomocysteinaemia as a risk factor for coronary artery disease.
8.
GallagherPMWardPTanKSNaughtenEKrausJPSellarGC: High frequency (71%) of cystathionine B-synthase mutation G307S in Irish homocystinuria patientsHuman Mutation1994, 4:24–28. Evidenceis presented of the high frequency (71%) of a single gene mutation in a homogeneous population in whom homocystinuria is relatively common (1 in 50 000).
9.
KangSSPassenELRuggieNWongPWKSoraH: Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery diseaseCirculation1993, 88:1463–1469.
10.
WuLLWuJHuntSJJamesBCVincentGMWilliamsRR: Plasma homocyst(e)ine as a risk factor for early familial coronary artery diseaseClin Chem1994, 40:552–561. Theauthors present further data linking homocysteine and premature coronary artery disease. In addition, they quantify the contribution of genetic influences on homocysteine to its role as a risk factor.
11.
DalyLRobinsonKTanKSGrahamIM: Hyperhomocysteinaemia: A metabolic risk factor for coronary heart disease determined by both genetic and environmental influences?Quart J Med1993, 86:685–689. Theauthors suggest that nutritional rather than genetic influences are of more relevance in hyperhomocysteinaemia.
12.
MalinowMR: Hyperhomocyst(e)inemia. A common and easily reversible risk factor for occlusive atherosclerosisCirculation1990, 81:2004–2006.
13.
UelandPMRefsumH: Plasma homocysteine, a risk factor for vascular disease: Plasma levels in health, disease and drug therapyJ Lab Clin Med1989, 114:473–501.
14.
RobinsonK (ed): Homocysteinaemia and Vascular Disease. Luxembourg: Commission of the European Communities; EUR 12834 EN; 1990.
15.
UelandPMRefsumHBrattstromL: Plasma homocysteine and cardiovascular disease In Atherosclerotic Cardiovascular Disease, Hemostasis and Endothelial Function. Edited by FrancisRB.New York: Marcell Dekker; 1992:183–235. Acomprehensive review of homocysteine metabolism, assay methods, case-control studies and nutritional factors that influence serum homocysteine methods.
16.
McCullyKSRagsdaleBD: Production of arteriosclerosis by homocysteinemiaAm J Pathol1970, 61:1–11.
17.
HarkerLARossRSchlicterSJScottCR: Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelets in its genesisJ Clin Invest1976, 58:731–741.
WallRTHarlanJMHarkerLAStrikerGE: Homocysteine-induced endothelial cell injury in vitro: A model for the study of vascular injuryThromb Res1980, 18:113–121.
20.
RogersGMKaneWH: Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activatorJ Clin Invest1986, 77:1909–1916.
21.
StarkebaumGHarlanM: Endothelial cell injury due to coppercatalysed hydrogen peroxide generation from homocysteineJ Clin Invest1986, 77:1370–1376. Theauthors suggest a mechanism whereby homocysteine could injure endothelial cells. This mechanism involves the copper-catalysed generation of hydrogen peroxide, which was found to be inhibited by catalase, the peroxide scavenger.
22.
DudmanNPBWilckenDEL: Increased plasma copper in patients with homocystinuria due to cystathionine beta synthase deficiencyClin Chem Acta1983, 77:1370–1376.
23.
StamlerJSOsborneJAJarakiORabbiniLEMullinsMSingelD: Adverse vascular effects of homocysteine are modulated by endotheliam-derived relaxing factor and related oxides of nitrogenJ Clin Invest1993, 91:303–318. Evidenceis presented of a biologically plausible mechanism by which homocysteine may damage the endothelium and induce thrombosis.
24.
GraeberJESlottJHUlaneRESchulmanJDStuartMJ: Effect of homocysteine and homocystine on platelet and vascular arachidonic acid metabolismPediatr Res1982, 16:490–493.
25.
WangJDudmanNPWilckenDE: Effects of homocysteine and related compounds on prostacyclin production by cultured human vascular endothelial cellsThromb Haemost1993, 70:1047–1052.
26.
NishinagaMOzawaTShimadaK: Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulphate expression in cultured porcine aortic endothelial cellsJ Clin Invest1993, 92:1381–1386. Theauthors provide evidence that homocysteine may express its prothrombotic potential by inhibiting heparan sulphate. This inhibitory effect was observed at concentrations of homocysteine similar to those found in vivo.
27.
PalaretiGCoccheriS: Lowered antithrombin III activity and other clotting changes in homocystinuria. Effects of a pyridoxine-folate regimenHaemostasis1989, 19 (suppl 1):24–28.
28.
BienvenuTChadefauxBAnkriALeblondVCoudeMSalehianB: Antithrombin III is not related to plasma homocysteine concentrationsHemostasis1991, 21:65–67.
29.
BrattstromLIsraelssonBTengbornLHultbergB: Homocysteine, factor VII and antithrombin III in subjects with different gene dosage for cystathionine B-synthaseJ Inher Metab1989, 12:475–482.
30.
MunnichASaudubrayJMDautzenbergMDParvyPOgierHGirotR: Diet-responsive proconvertin (factor VII) deficiency in homocystinuriaJ Paediatr1983, 102:730–734.
31.
RogersGMConnMT: Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cellsBlood1990, 75:895–901.
32.
LentzSRSadlerJE: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteineJ Clin Invest1991, 88:1906–1914. Theauthors suggest a mechanism by which homocysteine acts as a procoagulant by inhibiting cell surface expression of protein C. In addition, the authors show that homocysteine irreversibly inactivates thrombomodulin and protein C by the reduction of their sulphydryl groups.
33.
HajjarKA: Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptorJ Clin Invest1993, 91:2873–2879.
34.
HarpelPCChangVTBorthW: Homocysteine and other sulphydryl compounds enhance the binding of lipoprotein(a) to fibrinProc Natl Acad Sci USA1992, 89:10193–10197.
35.
LentzSRSadlerJE: Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulumBlood1993, 81:683–689.
BlannAD: Endothelial cell damage and homocysteineAtherosclerosis1992, 94:89–92.
38.
SteinbergDParthasarathySCarewTEKhooJCWitztumJL: Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicityN Engl J Med1989, 320:915–924.
39.
MuddSHSkovbyFLevyHLPettigrewKDWilckenBPyeritzRE: The natural history of homocystinuria due to cystathionine B-synthase deficencyAm J Hum Genet1985, 37:1–31. Amajor review of the natural history of homocystinuria based on data from an international questionnaire.
40.
WilckenDELWilckenB: The pathogenesis of coronary artery disease: A possible role for methionine metabolismJ Clin Invest1976, 57:1079–1082.
41.
WilckenDELReddySGGuptaVJ: Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuriaMetabolism1983, 32:363–370.
42.
BrattstromLHardeboJEHultbergBL: Moderate homocysteinemia – a possible risk factor for arteriosclerotic cerebrovascular diseaseStroke1984, 15:1012–1016.
43.
TaylorLMDe FrangRDHarrisEJPorterJM: The association of elevated plasma homocysteine with progression of symptomatic peripheral vascular diseaseJ Vase Surg1991, 13:128–136.
44.
StampferMJMalinowRWilletWCNewcomerLUpsonBUllmanD: A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physiciansJAMA1992, 268:877–881. Theauthors demonstrate in a prospective trial the independence of homocysteine as a risk factor for coronary artery disease. The relative risk is quantified and a threshold effect is demonstrated.
45.
ArnesenERefsumHBonaaKHUelandPFordeOHNordrehaugJE: The Tromsø study: Serum total homocysteine and myocardial infarction. A prospective study [abstract]. In Proceedings of the 3rd International Conference on Preventive Cardiology. Oslo, Norway; 1993:295. Datafrom this paper show a graded dose-response effect between the level of serum homocysteine and the incidence of myocardial infarction.
46.
Murphy-ChutorianDAldermanEL: The case that hyperhomocysteinemia is a risk factor for coronary artery diseaseAm J Cardiol1994, 73:705–707.
47.
AlfthanGPekkanenJJauhianenMPitkaniemiJKarvonenMTuomilehtoJ: Relations of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population-based studyAtherosclerosis1994, 106:9–19.
48.
GrahamIM: Homocysteinaemia and vascular disease In Epidemiology. Edited by VuylsteekKHallenM.IOS Press; 1994.
49.
PancharunitiNLewisCASauberlichHEPerkinsLLGoRCPAlvarezJO: Plasma homocyst(e)ine, folate, and vitamin B12 concentrations and risk for early-onset coronary artery diseaseAm J Clin Nutr1994, 59:940–948. Thiscase-control study demonstrates the independence of plasma homocysteine as a risk factor for coronary artery disease. Uniquely, this increased risk from hyperhomocysteinaemia could be attributed to the lower serum folate levels found among cases.
50.
SelhubJJacquesPFWilsonPWFRushDRosenbergIH: Vitamin status and intake as primary determinants of homocysteinemia in an elderly populationJAMA1993, 270:2693–2698.
51.
BrattstromLIsraelssonBNorrvingBBergqvistDThorneJHultbergB: Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial diseaseAtherosclerosis1990, 81:51–60.
52.
SwiftMESchultzTD: Relationship of vitamins B6 and B12 to homocysteine levels: Risk for coronary heart diseaseNutr Rep Int1986, 34:1–14.
