C-Reactive Protein and Outcome After First-Ever Ischemic Stroke
To the Editor:
We have carefully read the study of Keith Muir and colleagues published in Stroke1 regarding the putative role of C-reactive protein (CRP) as outcome predictor after ischemic stroke and would like to add further observations to their data. Despite the theoretical importance of CRP in ischemic stroke, very little direct evidence exists to implicate CRP in stroke. In their study, Muir and colleagues had not only investigated the CRP role but also discussed the causative role of inflammation in acute ischemic stroke. They found an intriguing association between CRP levels within 72 hours of stroke and an increased risk of death with an excess of cardiovascular mortality. The authors suggest three possible explanations to support the CRP role as predictor of outcome. They state that (1) CRP concentration may reflect the degree of stroke severity correlating with the degree of inflammation directly consequent to cerebral infarction, (2) CRP concentration may indicate underlying unstable atherosclerotic lesions, and (3) CRP may be raised as a consequence of secondary complications of stroke at the time of sampling. Although the mechanism responsible for this increased risk was unclear, the authors’ recommendation to stratify patients with ischemic stroke into relatively high-risk and low-risk groups according to inflammation level sounds appropriate, considering that the relevance of inflammation in cerebrovascular disease is not completely established.2
Their data are in agreement with the preliminary results of our study on CRP in ischemic stroke.3 4 We found increased CRP levels in our stroke patients, with a notable difference in mean level of CRP between patients and healthy control subjects. Higher CRP levels were correlated with a significant neurological deficit and a relevant disability.3 4 To shed some light on these issues, we would like to present our recent results in a larger series of stroke patients (n=72; 30 men and 42 women; mean±SD age 73±9 years) included in the Villa Pini Stroke Data Bank, Chieti, Italy. In this series we investigated whether CRP levels remain elevated after stroke event and whether persistent elevation is associated with new vascular events or death. We measured plasma levels (within 24 hours) of CRP, fibrinogen, total serum C3c (C3) and C4 (C4) complement fractions, ferritin, and total cholesterol after stroke and at discharge (mean±SD 12±5 days). Patients were followed for 6 months. To avoid confounding factors, we excluded patients with history of recent clinical infection; concurrent major renal, hepatic, and cancerous diseases; and obvious signs and clinical evidence of acquired infection within 2 weeks after stroke. At discharge, CRP was elevated (>10 mg/L) in 57 patients (79%); of these, 26% had elevated levels within the first 24 hours after stroke. Only 1 patient (7%) with discharge levels of CRP ≤10 mg/L died, but 35% of those with elevated CRP (n=20; P=0.04, log-rank test) died or had a new vascular event. New vascular events or death occurred in 12.5% of patients in the lower tertile of CRP (≤14 mg/L), in 25% of those in the intermediate tertile (15–28 mg/L), and 50% of those in the upper tertile (≥29 mg/L; P=0.01, log-rank test; P=0.005 χ2 for trend). In conclusion, our data suggest that CRP was increased in patients with cerebral ischemia, may remain elevated after stroke, and is associated with the prognosis of such patients.
We believe that the role of CRP after ischemic stroke is far more complicated than perhaps we realize. CRP may be primarily an indicator of other vascular risk factors that are themselves related to prognosis. In our patients, CRP levels were positively correlated with serum ferritin levels (r=0.6; P<0.001; Pearson correlation coefficient), which suggests that the elevation of CRP may be an epiphenomenon. Iron overload may elevate the risk of atherosclerotic disease by promoting the oxidation of LDL cholesterol and has been identified as risk factor and outcome predictor in recent studies on vascular diseases.5 6 CRP displays both anti-inflammatory and proinflammatory effects, including the ability of ligand-bound CRP to activate the complement system.7 Interestingly, patients with activated complement system, detected by total C3 and C4 serum levels, had a significantly higher occurrence of new vascular events or death (40% versus 7%; P=0.02, log-rank test). Probably, CRP may reflect something fundamental about the patient’s inflammation system. Some patients might be predisposed to intense activation of inflammation in response to a variety of stimuli such as stroke. We speculate that stroke patients in whom the inflammation system reacts most intensely may be at greater risk for subsequent events. In this way a stroke may show the abnormal reactivity of the inflammation system. CRP levels would identify those patients whose inflammation system responds most actively to stimuli. These might be the patients at highest risk for subsequent new vascular events or death, in whom more aggressive therapy and clinical surveillance might be appropriate.
If confirmed in larger studies, our findings may have relevant practical implications because low serum levels of CRP at the time of hospital discharge identify a group of patients at low risk. Conversely, elevated CRP levels at discharge identify patients at high risk who therefore may benefit from a more careful clinical follow-up and appropriate antithrombotic (and probably anti-inflammatory) treatment. Precise knowledge of the possible triggers of the inflammation and the determinants of its individual response may open novel therapeutic avenues.
- Copyright © 2000 by American Heart Association
Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR. C-reactive protein and outcome after ischemic stroke. Stroke.. 1999;30:981–985.
Dirnage U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–397.
Di Napoli M, Di Gianfilippo G, Paciucci A, Villani S, Bocola V. C-reactive protein (CRP) as outcome predictor after first-ever ischemic stroke. Neurology. 1999;52:A151–A152.
Di Napoli M, Di Gianfilippo G, Bocola V. C-reactive protein after first-ever ischemic stroke. Circulation
Salonen JK, Nyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992;86:803–811.
Dàvalos A, Fernandez-Real JM, Ricart W, Soler S, Molins A, Planas E, Genís D. Iron-related damage in acute ischemic stroke. Stroke. 1994;25:1543–1546.
Lagrand WK, Visser CA, Hermens WT, Niessen HWM, Verheugt FWA, Wolbink G-J, Hack CE. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999;100:96–102.