Hyperhomocysteinemia associated with an increased risk for peripheral arterial disease: truth or myth?

EDITORIAL

Hyperhomocysteinemia associated with an increased risk for peripheral arterial disease: truth or myth?

Nelson Wolosker

Associate professor, School of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil.

Atherothrombosis causes the largest number of deaths in the North Hemisphere, and it is responsible for 54% of all deaths.¹ In Brazil, it is also the most important cause of deaths,² and the peripheral arterial disease (PAD) is one the main clinical manifestatons.³

PAD is a systemic disease that evolves throughout the years and remains asymptomatic most of the time (asymptomatic phase). When it is symptomatic, PAD can lead to walking limitations (intermittent claudication)^4,5 or to situations in which the supply of oxygen and nutrients is not enough to maintain the basal metabolism of the tissues of the lower limbs (critical ischemia).⁶

The search for the mechanisms that cause PAD has stimulated researchers to investigate specific risk factors. Several factors have already been defined and deeply studied in clinical and experimental studies. For instance, today there is no doubt about the role of diabetes mellitus (DM), smoking, hypercholesterolemia, and congenital factors in the development of PAD. While trying to achieve better results in the treatment of PAD, the knowledge about predictive factors enables us to get a better idea of the prognosis for each case.^6-8

Forty years ago, McCully found that children with higher serum levels of homocysteine caused by congenital factors had early atherosclerosis and he suggested that this amino acid led to arterial and venous atherothrombosis.⁹

Homocysteine is an amino acid produced by the catabolism of methionine or cysteine, which are present in all individuals, being high under certain conditions. Experimental studies confirmed that the vascular lesion is associated with the exposure to high levels of this catabolite, and these high levels of homocysteine are caused by oxidative stress, endothelial lesion, endothelial dysfunction, inflammation, thrombosis, and cell proliferation.¹⁰

Many studies have confirmed the association between hyperhomocysteinemia and the increase in the risk for atherosclerosis,¹⁰ thrombosis,¹¹, stroke,¹², and PAD.¹³ In a meta-analysis, Boushey et al.¹¹ found that levels of homocysteine increased from 3 to 4 &micromol/L, could lead to an increase in the risk of cardiovascular disease of up to 30%. In this investigation, the authors analyzed 27 studies, correlating the serum levels of homocysteine and atherosclerotic disease, and carried out meta-analysis in five of them, demonstrating an association between high levels of homocysteine and PAD. The study was updated in 2009 by Khandanpour et al.,¹⁴ who analyzed 14 relevant studies, demonstrating that homocysteine was significantly higher in patients with PAD in comparison with the control group.

Robinson et al.¹⁵ conducted a multicenter study in patients with PAD, cerebrovascular disease, and heart disease, and they found that the plasma concentration of homocysteine higher than the 80th percentile were associated with increase in the risk of PAD, regardless of the presence of DM, smoking, hypertension, and chronic pulmonary histoplasmosis.

Bergmark et al. found that the increase in the levels of homocysteine is associated with the increase in the extent of PAD, since homocysteine levels were lower in patients with only one level of the disease regarding those with several levels of the disease.¹⁶ Frier et al. found that the increase in the homocysteine level is related to the occurrence of symptoms in younger individuals.¹⁷

Most meta-analysis and also case-control multicenter studies were conducted in countries of the North Hemisphere. Therefore, it is very important to know if these findings can be replicated in Brazil. In this issue of J Vasc Bras, Venâncio et al.,¹⁸ of the group from Botucatu, present a very interesting case-control clinical trial, comparing a group of patients with PAD confirmed by means of Doppler ultrasound and a group of individuals who did not have this disease selected at a Brazilian public health care center. The authors confirmed the international findings and provided objective data on the plasma concentrations of fasting homocysteine. They found that patients with PAD had mean levels of 16.7 &micromol/L, while normal patients had mean levels of homocysteine 12.9 µmol/L. From now on, we can use these data to provide the Brazilian patients with information about the best choices for their treatment.

Plasma levels of homocysteine are influenced by congenital factors that cannot be changed, but also by plasma levels of folic acid and vitamin B12.¹⁹ Several studies have demonstrated that in some cases the levels of homocysteine may be reduced by means of supplementation of these substances, decreasing the cardiovascular risk.²⁰

More than 20,000 patients have already been included in clinical trials for the study of the relation between dietary supplementations (folic acid and vitamin B12) and heart or brain disease. However, only 290 patients with PAD were consistently investigated. This lack of knowledge creates a scientific opportunity that must be stimulated in our research centers, which will be able to broaden the knowledge about this interesting and important topic.¹⁴

References

• 1. Belch JJ, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL. Prevention of atherothrombotic disease network. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med. 2003;163:884-92.
• 2. de Souza MF, Alencar AP, Malta DC, Moura L, Mansur AP. Serial temporal analysis of ischemic heart disease and stroke death risk in five regions of Brazil from 1981 to 2001. Arq Bras Cardiol. 2006;87:735-40.
• 3. Wolosker N, Nakano L, Rosoky RA, Puech-Leão P. Evaluation of walking capacity over time in 500 patients with intermittent claudication who underwent clinical treatment. Arch Intern Med. 2003;163:2296-300.
• 4. Ayzin Rosoky RM, Wolosker N, Muraco-Netto B, Puech-Leão P. Ground reaction force pattern in limbs with intermittent claudication. Eur J Vasc Endovasc Surg. 2000;20:254-9.
• 5. Ferrari FB, Wolosker N, Rosoky RA, DIppolito G, Wolosker AM, Puech-Leão P. Natural history of stenosis in the iliac arteries in patients with intermittent claudication undergoing clinical treatment. Rev Hosp Clin Fac Med Sao Paulo. 2004;59:341-8.
• 6. Wolosker N, Muraco Neto B, Munia MA, Rosoky RA, Ramos RS, Puech-Leão P. External aggression to the limb as a predictive factor in the evolution of patients undergoing arterial revascularization. Clinics. 2005;60:451-4.
• 7. Wolosker N, Rosoky RA, Nakano L, Basyches M, Puech-Leão P. Predictive value of the ankle-brachial index in the evaluation of intermittent claudication. Rev Hosp Clin Fac Med Sao Paulo. 2000;55:61-4.
• 8. Nasser M, Wolosker N, Uint L, et al. Relationship between soluble thrombomodulin in patients with intermittent claudication and critical ischemia. Thromb Res. 2006;117:271-7.
• 9. McCully KS. Vascular pathology of homocystinemia. Am J Pathol. 1969;56:111-28.
• 10. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-50.
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• 12. The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. JAMA. 2002;288:2015-22.
• 13. Eikelboom JW, Lonn E, Genest J, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease. Ann Intern Med. 1999;131:363-75.
• 14. Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2009;38:316-22.
• 15. Robinson K, Arheart K, Refsum H, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group. Circulation. 1998;97:437-43.
• 16. Bergmark C, Mansoor MA, Swedenborg J, de Faire U, AM Svardal, Ueland PM. Hyperhomocysteinemia in patients operated for lower extremity ischaemia below the age of 50: effect of smoking and extent of disease. Eur J Vasc Surg. 1993;7;391-6.
• 17. Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers GM. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb. 1993;13:1327-33.
• 18. Venâncio LS, Burini RC, Yoshida WB. Concentração de homocisteína em pacientes portadores de doença arterial periférica atendidos em um serviço público de saúde. J Vasc Bras. 2009;8:313-321.
• 19. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007;369:1876-82.
• 20. Homocysteine Lowering Trialists Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine. Am J Clin Nutr. 2005;82:806-12.

Publication Dates

• Publication in this collection
  26 Mar 2010
• Date of issue
  Dec 2009