doi: 10.1161/01.STR.0000026987.36199.EC
(Stroke. 2002;33:2146.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
C-Reactive Protein in Ischemic Stroke
brahim yigün, MDDepartment of Neurology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
To the Editor:
I read with interest the article by Di Napoli et al,1 who reported the first-ever ischemic stroke to further analyze the relationship between C-reactive protein (CRP) values measured immediately and at different times after stroke, and the 1-year outcome. The important message of this article is that the relationship between CRP and prognosis after cerebral ischemia could be of greater utility for risk stratification and may predict future cardiovascular events or death.
Ischemic cerebrovascular disease accounts for a substantial proportion of all strokes. Although the proximate cause of most brain infarcts is thrombus formation, atherosclerosis is the chief underlying cause.2 CRP, one of the acute-phase reactants, is an indicator of underlying systemic inflammation and a novel plasma marker of atherothrombotic disease.3 Furthermore, elevated plasma levels of CRP are not disease specific but are sensitive markers produced in response to tissue injury, infectious agents, immunologic stimuli, and inflammation.4,5
Plasma CRP levels are known to be higher in smokers, obese individuals, individuals with abnormal fibrinolytic activity (plasmin-antiplasmin complex), and individuals with subclinical atherosclerosis.
We believed that the use of plasma CRP levels may aid in identifying a potentially large number of men and women who are at risk for cerebrovascular events, as described by Rost et al.5
Our clinical prospective data6 from a large community-based cohort of men and women of stroke and transient ischemic attack demonstrate a strong association between CRP and fibrinogen in both sexes. In our cases, 25.3% of patients have normal levels of CRP after stroke, and our data indicate that 21.6% of patients with ischemic stroke who have CRP levels 
1.5 mg/dL have died, as Di Napoli et al described. We have also detected that some of the ischemic stroke patients have history of the trauma.6
As a result, the detection of especially CRP and fibrinogen is very important in patients with ischemic stroke and transient ischemic attack in determination of possible risk factors, subsequent vascular events or death, and severe neurological deficit and disability, and stratify poststroke patients into relatively high-risk groups.
References
1. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001; 32: 917–924.
2. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
3. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999; 340: 448–454.
4. Grau AJ. Infection, inflammation, and cerebrovascular ischemia. Neurology. 1997; 49 (suppl 4): S47–S51.
5. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PWF. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke. 2001; 32: 2575–2579.
6. Bakirci Y. Fibrinogen and C-reactive protein levels determination in ischemic stroke patients. PhD thesis, Department of Neurology, Faculty of Medicine, Atatürk University, Erzurum, Turkey; 2001.
Response
Department of Neurology and Neurorehabilitation, Casa di Cura Villa Pini d’Abruzzo, Chieti, Italy
We thank Dr yigun for his interest in our report. Ischemic stroke is a multifactorial disease. It would not be reasonable to consider inflammation as the precipitating cause in all patients, nor to search for a common cause of inflammation in all patients with ischemic stroke. The consistency of data concerning CRP in primary prevention does not imply that screening for CRP among ischemic stroke patients will have clinical utility, thus, rather than generalizing results from primary prevention,1 carefully controlled studies in ischemic stroke patients that include information on stroke severity and other important prognostic factors are needed to determine whether CRP evaluation has utility in secondary prevention. Actually, recent available data suggest that ischemic stroke triggers an acute phase response resulting in a rise of circulating CRP level.2–4 Although infarct size and stroke severity are major determinants for short-term prognosis after ischemic stroke, CRP predicts prognosis, in particular mortality or new vascular events during the first 1-year, independent of infarct size and stroke severity.3,4 However, the degree of the inflammatory response to ischemic stroke is variable: about 25% of patients with first-ever ischemic stroke have normal levels of CRP after stroke, implying that ischemic stroke itself does not induce a full-blown acute phase response.3,4 CRP elevation can result from a variable intensity of the individual acute phase response to cerebral ischemia such that determining an individual’s underlying basal level is difficult. However, the patients in whom the inflammation system reacts most intensely showed a greater 1-year risk of death and a worse functional status with a relevant disability at 1 year.5 CRP levels can increase a thousand-fold, and there is evidence that in some patients constitutional hyperresponsiveness might lead to very high CRP levels even following mild stimuli. Of course, in the presence of overt inflammatory and infectious disease, the data should be interpreted cautiously. Furthermore, distribution of CRP is rightward skewed such that clinical application will likely require recasting measured levels into an ordinal system. A useful approach is to divide CRP values into quartiles. In the Villa Pini Stroke Data Bank, the risk estimate based on such an analysis is shown in the Figure. The relative risk of death or new nonfatal vascular events was 7.38 (95% CI, 4.19 to 13.00) in individuals with a fibrinogen level in the highest quartile compared with those with a level in the lowest quartile and 8.68 (95% CI, 5.17 to 14.55) for CRP. There is a clearly increased risk of death or suffering of a future vascular event only for patients above a threshold of CRP: there is no evidence of moderate elevation (middle quartile) conferring greater risk of a combined end point. The strong correlation between levels of fibrinogen and CRP (r=0.45; P<0.001) indicates a possible common mechanism, making both fibrinogen and CRP prognostic risk factors.3 However, the increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen, which indicates that a separate mechanism also contributes.3
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These findings suggest that patients with an enhanced acute-phase response after an ischemic stroke may differ from other patients and may have a higher risk because of an exaggerated response to some stimuli. This line of evidence may also help to explain why healthy subjects with borderline increased CRP are at higher risk for stroke or transient ischemic attack up to 12 years after the baseline sampling.1 Individual susceptibility in immune response is based at least in part on genetic background.6 Variations in baseline plasma CRP of individuals may reflect differences in CRP responses caused, for example, by genetic differences in the CRP gene yielding high and low responders, the former being at risk for cardiovascular disease.7 However, the search for a candidate gene per se is unlikely to be successful because of the multifactorial pathogenesis of ischemic stroke. An enhanced inflammatory response might depend also on the failure to turn off inflammation when it is not more useful to the organism. Thus it is possible that the search for the prognostic factors in ischemic stroke should be moved from the conventional prognostic factors to the individual predisposing causes. Careful clinical identification of very homogeneous subgroups of patients according to their history, risk factors, and inflammatory markers will be the first step of this search. From this standpoint, CRP measurements should be included according to the standardized protocols and reported on appropriate registries together with patient outcome. These registries will provide the presently lacking information and will gradually improve the prognostic information obtainable from CRP measurements according to age, sex population, clinical variables, and selected clinical endpoints. This is the objective of the ongoing C-reactive protein worldwide study in ischemic stroke (CRPWSIS): an international, multicenter, long-term, prospective, observational study to evaluate the prognostic impact of inflammation markers in ischemic stroke (available at mariodinapoli@katamail.com). Once these data are available, the profile of patients will be drawn; the causes, genetic or acquired, of the hyper-responsiveness can be sought; and new insights will be provided in ischemic stroke medicine.
References
1. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, D’Agostino RB, Franzblau C, Wilson PWF. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham Study. Stroke. 2001; 32: 2575–2579.
2. Di Napoli M, Di Gianfilippo G, Sollecito A, Bocola V. C-reactive protein and outcome after first-ever ischemic stroke. Stroke. 2000; 31: 238–239.[Medline] [Order article via Infotrieve]
3. Di Napoli M, Papa F, Bocola V. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke. 2001; 32: 133–138.
4. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001; 32: 917–924.
5. Di Napoli M, Papa F, Bocola V. Periodontal disease, C-reactive protein, and ischemic stroke. Arch Intern Med. 2001; 161: 1234–1235.
6. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001; 103: 2236–2241.
7. Margaglione M, Cappucci G, Colaizzo D, Vecchione G, Grandone E, Di Mimmo G. C-reactive protein in offspring is associated with the occurrence of myocardial infarction in first-degree relatives. Arterioscler Thromb Vasc Biol. 2000; 20: 198–203.
8. Di Napoli M, Papa F, for the Villa Pini Stroke Data Bank Investigators. Inflammation, hemostatic markers and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients. Stroke. 2002; 33: 1763–1771.
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