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Volume 43, Issue 10 (Oct 2005)


Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Kilmer S. McCully
  • Pathology and Laboratory Medicine Service, Veterans Affairs Medical Center, West Roxbury, MA, and Harvard Medical School, Boston, MA, United States of America
Published Online: 2005-09-30 | DOI: https://doi.org/10.1515/CCLM.2005.172


Early concepts of the origin of arteriosclerosis were introduced in the 19th century by Rokitansky and Virchow, who described mural thrombosis, inflammatory damage to arterial intima, increased intimal permeability to plasma, mucoid degeneration of arterial wall, deposition of plasma lipids in plaques, and fibrosis and calcification of plaques. Experimental production of arteriosclerosis by feeding animal foods to rabbits was attributed to protein intoxication by Ignatowsky in 1908 and to dietary cholesterol by Anitschkow in 1913. Newburgh confirmed the protein hypothesis in 1915–1925 but failed to identify which amino acid produced plaques because methionine (1922) and homocysteine (1932) had not yet been discovered. Cases of homocystinuria from inherited deficiency of cystathionine synthase were found to be associated with thrombosis and vascular disease in 1964. The index case of methionine synthase deficiency (cobalamin C disease) was found by McCully in 1969 to be associated with arteriosclerosis, leading to the homocysteine theory of arteriosclerosis. The theory explains experimental arteriosclerosis by deficiency of vitamin B6 in monkeys, choline deficiency in rats, thyroid deficiency in rats, and methionine deficiency in monkeys. The thrombogenic and atherogenic effects of homocysteine were demonstrated in rabbits, baboons and other species, reproducing the pathological findings found in homocystinuria. Clinical and epidemiological studies in the past two decades have demonstrated that elevated plasma homocysteine is a potent independent risk factor for arteriosclerosis in the general population, supporting the validity of the theory.

Keywords: arteriosclerosis; atherogenesis; homocysteine; homocystinuria; methionine


  • 1.

    Vesalius A. De Humani Corporis Fabrica Libri Septem. Basel, 1543.

  • 2.

    Long ER. Development of our knowledge of arteriosclerosis. In: Blumenthal HT, editor. Cowdry's Arteriosclerosis. 2nd ed. Springfield: Charles C. Thomas, 1967:5–20.

  • 3.

    Lobstein JF. Lehrbuch der Pathologischen Anatomie, 2. Bd. Stuttgart: Fr. Brodhagische Buchhandlung, 1835.

  • 4.

    Rokitansky C. Lehrbuch der Pathologischen Anatomie, Volume 2. Specielle Pathologische Anatomie. Wien: W Braumueller, 1856:305–15.

  • 5.

    Virchow R. Gesammelte Abhandlung zur Wissenschaftlichen Medicin. Frankfurt: Meidinger, 1856:499–513.

  • 6.

    Aschoff L. Lectures in pathology. New York: Hoeber, 1924:131–53.

  • 7.

    Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340:115–26.

  • 8.

    Ignatowsky MA. Influence de la nourriture animale sur l'organisme des lapins. Arch Med Exp Anat Pathol 1908; 20:1–20.

  • 9.

    Ignatowsky A. Über die Wirkung des tierischen Eiweisses auf die Aorta und die parenchymatosen Organe der Kaninchen. Virchow Arch Pathol Anat Physiol Klin Med 1909; 198:248–70.

  • 10.

    Anitschkow N, Chalatow S. Über experimentelle Cholesterinsteatose und deren Bedeutung fur die Entstehung einiger pathologischer Prozesse. Centralbl Allg Pathol Pathol Anat 1913; 24:1–9.

  • 11.

    Newburgh LH, Clarkson S. The production of atherosclerosis in rabbits by feeding diets rich in meat. Arch Int Med 1923; 31:653–76. [Crossref]

  • 12.

    Newburgh LH, Marsh PL, Clarkson S, Curtis AC. The dietetic factors in the etiology of chronic nephritis. J Am Med Assoc 1925; 85:1703–5. [Crossref]

  • 13.

    Mueller JH. A new sulphur containing amino acid isolated from casein. Proc Soc Exp Biol Med 1922; 19:161–3. [Crossref]

  • 14.

    Barger G, Coyne FP. The amino acid methionine; constitution and synthesis. Biochem J 1928; 22:1417–25. [Crossref]

  • 15.

    Butz LW, DuVigneaud V. The formation of a homologue of cystine by the decomposition of methionine with sulfuric acid. J Biol Chem 1932; 99:135–42.

  • 16.

    DuVigneaud V. A trail of research in sulfur chemistry and metabolism. Ithaca, NY: Cornell University Press, 1952:25–56.

  • 17.

    Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child 1962; 37:505–15. [Crossref]

  • 18.

    Gerritsen T, Vaughn JG, Waisman HA. The identification of homocystine in the urine. Biochem Biophys Res Commun 1962; 9:493–6. [Crossref]

  • 19.

    Spaeth GL, Barber GW. Homocystinuria in a mentally retarded child and her normal cousin. Trans Am Acad Opththalmol Otolaryngol 1965; 69:912–30.

  • 20.

    Gibson JB, Carson NA, Neill DW. Pathological findings in homocystinuria. J Clin Pathol 1964; 17:427–37. [Crossref]

  • 21.

    Mudd SH, Finkelstein JD, Irrevere F, Laster L. Homocystinuria: an enzymatic defect. Science 1964; 143:1443–5.

  • 22.

    Case Records of the Massachusetts General Hospital, Case 19471. Marked cerebral symptoms following a limp of three months' duration. N Engl J Med 1933;209:1063–6.

  • 23.

    McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56:111–28.

  • 24.

    Kanwar YS, Manaligod JR, Wong WK. Morphologic studies in a patient with homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency. Pediatr Res 1976; 10:598–609. [Crossref]

  • 25.

    Rinehart JF, Greenberg LD. Arteriosclerotic lesions in pyridoxine-deficient monkeys. Am J Pathol 1949; 25:481–91.

  • 26.

    Hartroft WS, Ridout JH, Sellers EA, Best CH. Atheromatous changes in aorta, carotid and coronary arteries of choline deficient rats. Proc Soc Exp Biol Med 1952; 81:384–93. [Crossref]

  • 27.

    Meeker DR, Kesten HD. Effect of high protein diets on experimental atherosclerosis of rabbits. Arch Pathol 1941; 31:147–62.

  • 28.

    Howard AN, Gresham GA, Jones D, Jennings IW. The prevention of rabbit atherosclerosis by soya bean meal. J Atheroscl Res 1965; 5:330–7. [Crossref]

  • 29.

    Mann GV, Andrus SB, McNally A, Stare FJ. Experimental atherosclerosis in cebus monkeys. J Exp Med 1953; 98:195–218. [Crossref]

  • 30.

    Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 1992; 55:131–8.

  • 31.

    Fillios LC, Andrus SB, Mann GV, Stare FJ. Experimental production of gross atherosclerosis in the rat. J Exp Med 1956; 104:539–52. [Crossref]

  • 32.

    Thomas WA, Hartroft WS. Myocardial infarction in rats fed diets containing high fat, cholesterol, thiouracil and sodium cholate. Circulation 1959; 19:65–72. [Crossref]

  • 33.

    White A. The production of a deficiency involving cysteine and methionine by the administration of cholic acid. J Biol Chem 1936; 112:503–9.

  • 34.

    Daniel KT. The whole soy story. Washington, DC: New Trends Publishing, 2005:311–30.

  • 35.

    McCully KS. Abnormal homocysteine thiolactone metabolism in malignant cells. Cancer Res 1976; 36:3198–202.

  • 36.

    McCully KS. Chemical pathology of homocysteine. II Carcinogenesis and homocysteine thiolactone metabolism. Ann Clin Lab Sci 1994; 24:27–59.

  • 37.

    Kazimir M, Wilson FR. Prevention of homocysteine thiolactone induced atherogenesis in rats. Res Commun Mol Pathol Pharmacol 2002; 111:179–98.

  • 38.

    McCully KS. Homocysteinemia and arteriosclerosis. Am Heart J 1972; 83:571–3. [Crossref]

  • 39.

    McCully KS, Wilson RB. Homocysteine theory of arteriosclerosis. Atherosclerosis 1975; 22:215–27. [Crossref]

  • 40.

    McCully KS. Homocysteine theory of arteriosclerosis: Development and current status. In: Gotto AM Jr, Paoletti R, editors. Atherosclerosis reviews, vol 11. New York: Raven Press, 1983:157–246.

  • 41.

    Schroeder HA. Losses of vitamins and trace minerals resulting from processing and preservation of foods. Am J Clin Nutr 1971; 24:562–73.

  • 42.

    Gruberg ER, Raymond SA. Beyond cholesterol. Vitamin B6, arteriosclerosis and your heart. New York: St. Martin's Press, 1981:128–49.

  • 43.

    McCully KS, Ragsdale BD. Production of arteriosclerosis by homocysteinemia. Am J Pathol 1970; 61:1–11.

  • 44.

    Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis. Role of endothelial cell injury and platelet response to its genesis. J Clin Invest 1976; 58:731–41. [Crossref]

  • 45.

    Smolin LA, Crenshaw TD, Kurtycz, Benevenga NJ. Homocyst(e)ine accumulation in pigs fed diets deficient in vitamin B6: relationship to atherosclerosis. J Nutr 1983; 113:2122–33.

  • 46.

    Kuzuya F, Yoshimine N. Homocysteine theory of arteriosclerosis. J Jpn Atheroscl Soc 1978; 6:135–9. [Crossref]

  • 47.

    McCully KS. Atherogenesis and the chemical pathology of homocysteine. Eur J Lab Med 1996; 4:121–8.

  • 48.

    Wilcken DE, Wilcken, B. The pathogenesis of coronary heart disease. A possible role for methionine metabolism. J Clin Invest 1976; 57:1079–82. [Crossref]

  • 49.

    Wilcken DEL, Gupta VJ. Cysteine-homocysteine mixed disulfide: differing concentrations in normal men and women. Clin Sci 1979; 57:211–5. [Crossref]

  • 50.

    Wilcken DE, Gupta VJ, Reddy SG. Accumulation of sulfur containing amino acids including cysteine-homocysteine in patients on maintenance hemodialysis. Clin Sci 1980; 58:427–30. [Crossref]

  • 51.

    Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998; 49:31–62. [Crossref]

  • 52.

    Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324:1149–55.

  • 53.

    Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. J Am Med Assoc 1995; 274:1049–57.

  • 54.

    Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 1993; 270:2693–8.

  • 55.

    Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332:286–91.

  • 56.

    Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. J Am Med Assoc 1992; 268:877–81.

  • 57.

    Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. J Am Med Assoc 1995; 274:1526–33.

  • 58.

    Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. J Am Med Assoc 1997; 277:1775–81.

  • 59.

    Rimm EB, Willett WC, Hu FB, Sampson L, Colditz GA, Manson JE, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. J Am Med Assoc 1998; 279:359–64.

  • 60.

    McCully KS. Homocysteine, folate, vitamin B6, and cardiovascular disease. J Am Med Assoc 1998; 279:392–3.

  • 61.

    Ingenbleek Y, Barclay D, Dirren H. Nutritional significance of alterations in serum amino acid patters in goitrous patients. Am J Clin Nutr 1986; 43:310–9.

  • 62.

    Stolzenberg-Solomon RZ, Miller ER, Maguire MG, Selhub J, Appel LJ. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am J Clin Nutr 1999; 69:467–75.

  • 63.

    Ingenbleek Y, Young VR. The essentiality of sulfur is closely related to nitrogen metabolism: a clue to hyperomocysteinemia. Nutr Res Rev 2004; 17:135–51. [Crossref]

  • 64.

    Araki A, Sato Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 422:43–52.

  • 65.

    Shipchandler MT, Moore EG. Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott Imx Analyzer. Clin Chem 1995; 417:991–4.

  • 66.

    McCully KS. Homocysteine and vascular disease. Nat Med 1996; 2:386–9. [Crossref]

  • 67.

    Olszewski AJ, Szostak WB, Bialkowska M, Rudnicki S, McCully KS. Reduction of plasma lipid and homocysteine levels by pyridoxine, folate, cobalamin, choline, riboflavin, and troxerutin in atherosclerosis. Atherosclerosis 1989; 75:1–6. [Crossref]

  • 68.

    McCully KS. Atherosclerosis, serum cholesterol and the homocysteine theory: a study of 194 consecutive autopsies. Am J Med Sci 1990; 299:217–21.

  • 69.

    Olszewski AJ, McCully KS. Homocysteine content of lipoproteins in hypercholesterolemia. Atherosclerosis 1991; 88:61–8. [Crossref]

  • 70.

    Naruszewicz M, Mirkiewicz E, Olszewski AJ, McCully KS. Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages. Nutr Metab Cardiovasc Dis 1994; 4:70–7.

  • 71.

    Lacinski M, Skorupski W, Cieslinski A, Sokolowska J, Trzeciak WH, Jakubowski H. Determinants of homocysteine-thiolactonase activity of the paraoxonase-1 (PON1) protein in humans. Cell Mol Biol 2004; 50:885–93.

  • 72.

    Ellis JM, McCully KS. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharmacol 1995; 89:208–20.

  • 73.

    Conner SL, Ojeda LS, Sexton G, Weidner G, Conner WE. Diets lower in folic acid and carotenoids are associated with the coronary disease epidemic in Central and Eastern Europe. J Am Diet Assoc 2004; 104:1793–9. [Crossref]

  • 74.

    Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340:1449–54.

  • 75.

    Yang Q, Friedman JM, Botto LD. Folic acid fortification may have lowered stroke deaths. In: American Heart Association 44th Annual Conference on Cardiovascular Disease Epidemiology and Prevention, Mar 5, 2004 (www.americanheart.org/presenter.jhtml?identifier=3019554).

  • 76.

    Spence JD, Blake C, Landry A, Fenster A. Measurement of carotid plaque and effect of vitamin therapy for total homocysteine. Clin Chem Lab Med 2003; 41:1498–1504.

  • 77.

    Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) on clinical outcome after percutaneous coronary intervention: The Swiss Heart study: a randomized controlled trial. J Am Med Assoc 2002; 288:973–9.

  • 78.

    Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 2000; 72:315–23.

  • 79.

    Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br Med J 2002; 325:1202–9.

  • 80.

    Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C-T polymorphism and risk of coronary heart disease. J Am Med Assoc 2002; 288:2023–31.

About the article

Corresponding author: Kilmer S. McCully, MD, Chief, Pathology and Laboratory Medicine Service, VA Boston Healthcare System, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA Phone: +1-857-203-5990, Fax: +1-857-203-5623,

Published Online: 2005-09-30

Published in Print: 2005-10-01

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2005.172. Export Citation

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