Published online before print June 10, 2004, doi: 10.1161/01.STR.0000135296.93614.94
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(Stroke. 2004;35:1785.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
Homocysteine, Vitamin B6, and Endothelial Dysfunction in Circulatory Disorders
Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan
To the Editor:
We read with interest the recent article by Kelly and colleagues1 dealing with the relationship among serum vitamin B6 measured as pyridoxal 5'-phosphate (PLP), serum total homocysteine (tHcy), and C-reactive protein (CRP) in patients after ischemic stroke. The results of their study with univariate and multivariable analyses demonstrated that among stroke patients, CRP was a predictor of PLP. In addition, they indicated that among control subjects, both CRP and tHcy were independent predictors of PLP, although there was no association between CRP and tHcy. The authors proposed that vitamin B6 but not tHcy might be a marker of inflammatory status and vascular diseases.
There is evidence that homocysteines might disturb the bioavailability of nitric oxide (NO), which would, at least in part, contribute to the pathophysiology of circulatory disorders. Stühlinger et al2 examined the relationship among homocysteine, NO, and endothelial function in patients with peripheral arterial disease, and demonstrated that experimentally-induced hyperhomocysteinemia increased plasma asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, an effect that was temporally related to a decline in endothelial vasodilator function. This is an important mechanism for the endothelial dysfunction that occurs in hyperhomocysteinemia.3 In a study presented earlier, we demonstrated that estrogen-induced improvement of membrane fluidity (a reciprocal value of microviscosity) of erythrocytes was counteracted by ADMA, suggesting that ADMA might actively participate in the regulation of rheologic behavior of cell membranes and microcirculation in postmenopausal women.4 In this context, we speculate that the decreased bioavailability of NO due to ADMA might partially explain the increased risk for endothelial dysfunction in subjects with hyperhomocysteinemia. Because accumulation of ADMA and increased oxidative stress might be involved in vascular diseases,5 we would like to know whether vitamin B6 and CRP might be linked to plasma NO metabolite and ADMA levels in the present study of Kelly and colleagues. It would be important to assess more precisely the relationships among vitamin B6, CRP, and tHcy, and their contribution to the mechanisms underlying endothelial dysfunction and vascular complications in circulatory disorders.
References
- Kelly PJ, Kistler JP, Shih VE, Mandell R, Atassi N, Barron M, Lee H, Silveira S, Furie KL. Inflammation, homocysteine, and vitamin B6 status after ischemic stroke. Stroke. 2004; 35: 12–15.
[Abstract/Free Full Text] - Stühlinger MC, Oka RK, Graf EE, Schmolzer I, Upson BM, Kapoor O, Szuba A, Malinow R, Wascher TC, Pachinger O, Cooke JP. Endothelial dysfunction induced by hyperhomocyst(e)inemia. Role of aymmetric dimethylarginine. Circulation. 2003; 108: 933–938.
[Abstract/Free Full Text] - Tsuda K, Nishio I. Asymmetric dimethylarginine and circulatory disorders in postmenopausal women. Circulation. 2004; 109: e35.[Medline] [Order article via Infotrieve]
- Tsuda K, Kinoshita Y, Kimura K, Nishio I, Masuyama Y. Electron paramagnetic resonance investigation on modulatory effect of 17beta-estradiol on membrane fluidity of erythrocytes in postmenopausal women. Arterioscler Thromb Vas Biol. 2001; 21: 1306–1312.
[Abstract/Free Full Text] - Sydow K, Schwedhelm E, Arakawa N, Bode-Boger SM, Tsikas D, Hornig B, Frohlich JC, Boger RH. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res. 2003; 57: 244–252.
[Abstract/Free Full Text]
Response
Department of Neurology, Stroke Service, Massachusetts General Hospital, Boston, Massachusetts
We thank Drs Tsuda and Nishio for their interest in our paper. We agree that both experimental and clinical evidence suggests that accumulation of asymmetric dimethylarginine (ADMA) may be an important mediator of homocysteine-related systemic and cerebral endothelial dysfunction, likely via inhibition of endothelial nitric oxide synthase (eNOS).1–4 These data add to previous studies suggesting that homocysteine may cause endothelial injury and dysfunction by other mechanisms, including free radical-induced membrane lipid peroxidation, reduced nitric oxide production, and impaired expression and activity of the antioxidant enzyme glutathione peroxidase.1
In population health terms, these mechanisms are likely to be most relevant in individuals with plasma total homocyst(e)ine (tHcy) in the mild-to-moderate range (15 to 100 µmol/L). Internationally, the reported prevalence of elevated tHcy varies according to the nutritional status of the specific population. In the United States, data from the Framingham cohort and other sources indicate that the prevalence of elevated tHcy has fallen by approximately 50% since the introduction of folic acid grain fortification in 1998, with greatest benefit observed among individuals with higher prefortification tHcy levels.5
In our postfortification sample, we found identical tHcy distributions among individuals with stroke and matched controls, perhaps reflecting a disproportionate benefit of fortification among patients with vascular disease and higher prefortification tHcy. In our study, low B6 status was associated with stroke independent of established risk factors, a relationship that was partly mediated via inflammation as measured by C-reactive protein.6,7 We did not measure ADMA in this sample, but we are investigating the relationships between inflammation, nutritional status, and oxidant stress following acute ischemic stroke in ongoing studies.
References
- Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke. 2004; 35: 345–347.
[Free Full Text] - Faraci FM, Brian JE, Heistad DD. Responses of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase. Am J Physiol. 1995; 269; H1522–H1527.[Medline] [Order article via Infotrieve]
- Boger RH, Bode-Boger SM, Sydow K, Heistad DD, Lentz SR. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2000; 20: 1557–1564.
[Abstract/Free Full Text] - Stühlinger MC, Oka RK, Graf EE, Schmolzer I, Upson BM, Kapoor O, Szuba A, Malinow R, Wascher TC, Pachinger O, Cooke JP. Endothelial dysfunction induced by hyperhomocyst(e)inemia. Role of aymmetric dimethylarginine. Circulation. 2003; 108: 933–938.
[Abstract/Free Full Text] - 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: 1449–1454.
[Abstract/Free Full Text] - Kelly PJ, Shih VE, Kistler JP, Barron M, Lee H, Mandell R, Furie KL. Low vitamin B6, but not homocyst(e)ine, is associated with increased risk of stroke/TIA in the era of folic acid grain fortification. Stroke. 2003; 34: e51–e54.[Medline] [Order article via Infotrieve]
- Kelly P, Kistler J, Shih V, Mandell R, Atassi N, Barron M, Silveira S, Furie KL. Inflammation, homocysteine, and vitamin B6 status following ischemic stroke. Stroke. 2004; 35: 12–15.
[Abstract/Free Full Text]
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