doi: 10.1161/01.STR.0000016298.42331.9D
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(Stroke. 2002;33:1453.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Helicobacter pylori, CagA-Positive Strains, and Ischemic Stroke
Department of Internal Medicine, Catholic University of Sacred Heart, Rome, Italy
To the Editor:
In their interesting study, Heuschmann et al1 showed the chronic Helicobacter pylori infection to be associated with a higher risk of stroke caused by small-artery occlusion, a subtype of ischemic stroke also sharing pathomechanisms with atherosclerotic disease. A similar trend was demonstrated for stroke caused by large-artery atherosclerosis, although this trend was not statistically significant. We would like to make some comments on it. Several studies have shown that the clinical outcome of H pylori infection is strictly related to the genetic polymorphism of both the bacterium2 and the host.3 In fact, recent findings have demonstrated H pylori infection to be only weakly associated with ischemic heart disease in multivariate analysis. On the other hand, the more cytotoxic H pylori strains, bearing the cytotoxin-associated gene A (CagA), were highly prevalent in patients with ischemic heart disease.4 On the basis of these observations, it could be interesting to investigate the prevalence of CagA-positive strains of the bacterium in patients with ischemic stroke. Various pathogenetic mechanisms have been postulated to explain the association between infection by the cytotoxic H pylori strains and the atherosclerotic process. Because atherosclerosis is a chronic inflammatory disease, the stronger persistent low-grade immunoinflammatory burden evoked by the infection by CagA-positive strains could play a role in this association. Moreover, a cross-mimicry between CagA protein and antigens of the endothelial wall of cerebral arteries has been demonstrated5 and has been postulated to promote the atherosclerotic process by inducing endothelial damage. More recently, authors hypothesized that CagA-positive strains of H pylori, predisposing to gastric atrophy, may induce vitamin malabsorption and therefore hyperhomocystinemia, a well-documented risk factor for ischemic heart disease. However, not all patients infected by H pylori and its CagA-positive strains are affected by atherosclerosis-related diseases. The most convincing explanation for this observation could be found in the complex interaction between bacterium and host. In conclusion, the presence of particular factors, such as infection by CagA-positive strains, in subjects with a genetic susceptibility to develop ischemic stroke may explain the different clinical outcome of the infection in different patients.
References
1.
Heuschmann PU, Neureiter D, Gesslein M, Craiovan B, Maass M, Faller G, Beck G, Neundoerfer B, Kolominsky-Rabas PL. Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: results from a population-based case-control study. Stroke. 2001; 32: 2253–2258.
2.
Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N, Rappuoli R. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci U S A. 1993; 90: 5791–5795.
3. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000; 404: 398–402.[CrossRef][Medline] [Order article via Infotrieve]
4.
Pasceri V, Cammarota G, Patti G, Cuoco L, Gasbarrini A, Grillo RL, Fedeli G, Gasbarrini G, Maseri A. Association of virulent Helicobacter pylori strains with ischaemic heart disease. Circulation. 1998; 97: 1675–1679.
5. Franceschi F, Sepulveda AR, Gasbarrini A, Gasbarrini G, Graham DY, Genta RM. Cross-reactivity between anti-VacA and anti-CagA antibodies and antigens of either normal or atherosclerotic blood vessels. Gut. 2000; 47 (suppl 1): A88.Abstract.
Response
Unit for Stroke Research and Public Health Medicine, Department of Neurology, University of Erlangen, Germany
We appreciate the comments of Dr Gabrielli and colleagues and their interest in our article on chronic Helicobacter pylori and Chlamydia pneumoniae infection in acute ischemic stroke.1 We agree that chronic H pylori infection in general seems only to have a weakly positive association with coronary artery disease, but this association could be caused by confounding and/or biases.2 Gabrielli and colleagues hypothesized that infection with more virulent H pylori strains, eg, strains bearing cytotoxin-associated gene A (CagA), might increase the relative risk of coronary artery disease, based on the findings of a retrospective case-control study on 88 subjects.3 However, a recently published prospective study failed in reproducing these results.4
Although there have been dozens of studies seroepidemiologically linking coronary artery disease and H pylori infection, until now 3 studies have investigated the potential association between ischemic stroke and chronic H pylori infection.1,5,6 All of these studies found similar results, as follows: Grau et al.6 reported elevated antibodies to H pylori in ischemic stroke by atherothrombotic mechanism (adjusted odds ratio [OR] 3.5, 95% CI 1.1 to 11.4),6 Markus and Mendall5 demonstrated a positive association between chronic H pylori infection and stroke caused by large-vessel and lacunar subtype (adjusted OR 2.2, 95% CI 1.1 to 4.2, and adjusted OR 2.5, 95% CI 1.2 to 5.3, respectively),5 and in our analysis a higher risk of stroke caused by small-artery occlusion was found for H pylori–seropositive participants (adjusted OR 3.3, 95% CI 1.2 to 9.6).1 One possible explanation for the different findings on the causative role of chronic H pylori infection between ischemic stroke and coronary artery disease might be the fact that risk factors for stroke differs from risk factors for coronary artery disease. Although many studies assume that risk factors for coronary artery disease are very similar—or even identical—to those for ischemic stroke, in contrast to coronary artery disease, ischemic stroke is a heterogeneous mixture of different etiologic subtypes caused by atherosclerotic as well as nonatherosclerotic mechanisms.7 A recently published report could demonstrate that different etiologic subtypes are associated not only with different risk factors but also with differences in age at onset, recurrence rates, and outcome.8
Thus, we agree that it would be of great interest to investigate a potential association between CagA-positive strains of H pylori and the risk of ischemic stroke. Future seroepidemiological studies about the role of H pylori infection in stroke will have to regard carefully the impact of chronic infection within the different etiologic subtypes. Ischemic stroke etiology should be classified according to a standardized classification scheme, such as the TOAST classification,7 to allow valid comparisons between the results of different investigations. Power calculations have to consider the number of patients in each etiologic subtype that are necessary to detect a potential association between chronic infection and different subtypes of ischemic stroke.
References
1.
Heuschmann PU, Neureiter D, Gesslein M, Craiovan B, Maass M, Faller G, Beck G, Neundoerfer B, Kolominsky-Rabas PL. Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: results from a population-based case-control study. Stroke. 2001; 32: 2253–2258.
2. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: is there a link? Lancet. 1997; 350: 430–436.[CrossRef][Medline] [Order article via Infotrieve]
3.
Pasceri V, Cammarota G, Patti G, Cuoco L, Gasbarrini A, Grillo RL, Fedeli G, Gasbarrini G, Maseri A. Association of virulent Helicobacter pylori strains with ischemic heart disease. Circulation. 1998; 97: 1675–1679.
4.
Whincup P, Danesh J, Walker M, Lennon L, Thomson A, Appleby P, Hawkey C, Atherton J. Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation. 2000; 101: 1647–1652.
5.
Markus HS, Mendall MA. Helicobacter pylori infection: a risk factor for ischaemic cerebrovascular disease and carotid atheroma. J Neurol Neurosurg Psychiatry. 1998; 64: 104–107.
6. Grau AJ, Buggle F, Lichy C, Brandt T, Becher H, Rudi J. Helicobacter pylori infection as an independent risk factor for cerebral ischemia of atherothrombotic origin. J Neurol Sci. 2001; 186: 1–5.[CrossRef][Medline] [Order article via Infotrieve]
7.
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial: TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24: 35–41.
8.
Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke. 2001; 32: 2735–2740.
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