(Stroke. 2001;32:275.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
Hyperhomocysteinemia and Oxidative Stress in Ischemic Stroke
Institute of Gerontology and Geriatrics, Perugia University Hospital, Perugia, Italy
To the Editor:
We read with interest the data recently published by El Kossi and Zakhary.1 In this study, the authors found significantly higher levels of plasma homocyst(e)ine, lipid peroxides, and oxidation products of nitric oxide, as well as significantly lower plasma vitamin C levels, in 30 patients with thrombotic cerebrovascular stroke within 2 hours from the onset of symptoms compared with healthy control subjects.1 Furthermore, the authors observed a strong positive correlation between homocyst(e)ine and lipid peroxides and an inverse relationship both between plasma vitamin C and homocyst(e)ine levels and between plasma vitamin C and lipid peroxide levels. As the authors noted, oxidative stress may play an important role in the pathogenesis of ischemic brain injury,2 and homocyst(e)ine might act as pro-oxidant in stroke.3 With their work, they concluded that indeed the association between hyperhomocyst(e)inemia and indexes of oxidative stress might reflect an ischemia-related free radical hyperproduction, and lowering plasma homocysteine levels might help in prevention of oxidative damage to the brain in stroke patients.1
We studied 42 patients (24 men and 18 women, aged 85.6±2.3 years) 5.1±1.4 days after the onset of ischemic stroke of thromboembolic origin. Patients with transient ischemic attack, highly disabling stroke as assessed by Rankin Scale score, alterations of lipid metabolism, severe organ failure (eg, kidney, liver), and smoking habit, as well as patients taking antioxidant supplements or unable to swallow/eat, were excluded. Patients were compared with 42 healthy controls (16 men and 26 women, aged 85.2±2.1 years). Blood was drawn in all subjects after informed consent, and plasma levels of homocyst(e)ine and vitamin C, as well as serum levels of vitamin B12 and folic acid were measured by HPLC (with fluorescence detection for homocyst(e)ine and with electrochemical detection for vitamin C) and by RIA (vitamin B12 and folic acid).
Plasma homocysteine levels were significantly higher in
stroke patients than in controls (P<0.002; Table 1
), with values >15 µmol/L in 13 stroke patients
(31%). Mean vitamin B12, folic acid, and
vitamin C plasma levels were lower in stroke patients than controls,
but these differences were not statistically significant
(Table 1); however, it is noteworthy that mean vitamin C
levels were below the normal range (30 to 50 µmol/L) in stroke
patients (Table 1). No significant correlations were found between
homocyst(e)ine and levels of vitamin B12,
vitamin C, and folic acid, respectively, nor between age or gender and
any of the studied parameters. Thus, our results do not
support a substantial role of a poor vitamin status in the pathogenesis
of hyperhomocyst(e)inemia in an oldest-old population with stroke.
Despite this, the absence of a statistically significant difference of
plasma vitamin C concentrations and of serum vitamin
B12 concentrations between stroke patients and
controls can be explained in part by the age-dependent, relatively low
levels of these vitamins also in
controls.4 Thirty percent of
our stroke patients were shown to be hyperhomocyst(e)inemic, which
confirmed previous research, but plasma homocyst(e)ine levels were not
related to vitamin B12 or folic acid serum
levels. A study of 19 stroke
patients5 showed increased
plasma homocyst(e)ine levels both before and after methionine load
compared with those found in controls, but stroke patients showed
higher mean levels of serum vitamin B12 and
folic acid than controls.
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Our data might be explained by the biological complexity of our sample of subjects (ie, oldest-old subjects), which has not yet been described in great detail. It is conceivable that low blood levels of vitamin C, vitamin B12, and folic acid considered pathological in younger individuals may be considered "normal" in very old subjects, in relation to a lower homeostatic level of specific metabolic pathways. This could be true for both old healthy subjects and old stroke patients. Nevertheless, the lack of a correlation between plasma vitamin C levels and homocyst(e)ine levels observed in our study is supported by recent trials showing that high doses of vitamin C are ineffective on plasma homocyst(e)ine levels in patients with coronary artery disease6 and that supplementation with B-group vitamins reduces mildly elevated homocyst(e)ine levels whether or not this supplementation contains an antioxidant mixture incorporating vitamin C.7
Although the differences between our results and those of El Kossi and Zakhary could result from the differences of age between samples of subjects studied (our patients are roughly 30 years older) and to the time of the evaluation (our patients were studied roughly 3 days later), there is a great need for further studies in this field, in such a way that the reciprocal relationships between ischemic stroke, age, pro-oxidant effects of hyperhomocyst(e)inemia, and antioxidant vitamins are sorted out. The elucidation of these aspects of the pathogenesis of stroke could have important nutritional as well therapeutic implications.8
References
1.
El Kossi
MMH, Zakhary MM. Oxidative stress in the context of acute
cerebrovascular stroke. Stroke. 2000;31:1889–1892.
2. Polidori MC, Frei B, Cherubini A, Nelles G, Rordorf G, Keaney JF Jr, Schwamm L, Mecocci P, Koroshetz W, Beal MF. Increased plasma levels of lipid hydroperoxides in patients with ischemic stroke. Free Radic Biol Med. 1998;25:561–567.[Medline] [Order article via Infotrieve]
3. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest. 1996;98:5–7.[Medline] [Order article via Infotrieve]
4. Polidori MC, Mecocci P, Cherubini A, Senin U. Plasma homocyst(e)ine and vitamin status in the oldest-old with stroke. Cerebrovasc Dis. Abstract. 1999;9(S1):16.
5.
Brattstrom LE,
Hardebo JE, Hultberg BL. Moderate homocysteinemia: a possible risk
factor for arteriosclerotic cerebrovascular
disease. Stroke. 1984;15:1012–1016.
6. Bostom AG, Yanek L, Hume AL, Eaton CB, McQuade W, Nadeau M, Perrone G, Jacques PF, Sehlub J. High dose ascorbate supplementation fails to affect plasma homocyst(e)ine levels in patients with coronary artery disease. Atherosclerosis. 1994;111:267–270.[Medline] [Order article via Infotrieve]
7. Woodside JV, Yarnell JW, McMaster D, Young IS, Harmon DL, McCrum EE, Patterson CC, Gey KF, Whitehead AS, Evans A. Effect of B-group vitamins and antioxidant vitamins on hyperhomocyst(e)inemia: a double blind, randomized, factorial-design, controlled trial. Am J Clin Nutr. 1998;67:858–866.[Abstract]
8. Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T, Di Iorio A, Senin U, Mecocci P. Antioxidant profile and early outcome in stroke patients. Stroke.2000;31:2295–2300.
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