Ischemic Cerebrovascular Disease: Risk Factors and Outcome Predictors with special reference to the role of leukocytes and inflammatory mediators

University dissertation from Department of Medicine, Lund University

Abstract: Ischemic cerebrovascular disease (CVD) is usually a consequence of atherosclerosis and is the commonest cause of stroke. The identification of risk factors and outcome predictors and the initiation of preventive measures constitute the cornerstone of efforts to reduce the risk of stroke and improve outcome. The trend for long-term outcome after stroke and the predictors of this outcome were evaluated in the light of data accumulated during the first four years after the founding of the Malmö Stroke Registry in 1989. Early predictors of ischemic CVD were studied in middle-aged, apparently healthy individuals, from the Malmö Prevention Project cohort. Since leukocytes are believed to play important parts regarding the risk and outcome of ischemic CVD, their possible involvement was the focus of special interest in this study. Although stroke incidence remained unchanged during the first four years of the Malmö stroke registry (1989-92), there was a trend toward a decline in the long-term recurrence and mortality rates following stroke. The long-term outcome predictors were evaluated. The age-standardized recurrence-free survival rate differs significantly between different residential areas in the city. In middle-aged, apparently healthy individuals, apart from traditional risk factors, a history of calf pain while walking (OR 1.9; p=0.002), a high serum uric acid level (OR 1.2; p<0.05) were found to be significant predictors of future ischemic CVD. In subjects with asymptomatic atherosclerosis (n=156), plasma levels of leukocyte activation markers neutrophil protease 4 (NP4), neutrophil gelatinase associated lipocalin (NGAL), tumor necrosis factor a (TNFa) and soluble TNF receptor-1 (sTNFR-1) were related to atherosclerosis risk factors (age, blood pressure, history of hypertension, and smoking). Patients with acute ischemic CVD (n=120) manifested higher plasma levels of NP4, NGAL and sTNFR-1 than did controls. During 4-year follow-up of patients with ischemic CVD (n=144) plasma levels of leukocyte activation markers at the time of acute cerebral ischemia, NGAL (OR 3.6; p<0.05) and sTNFR-1 (OR 2.0; p<0.01), were independent predictors of cardiovascular mortality. In conclusion, despite the observed trend of improving long-term outcome following stroke, the burden of this disease is still high. The observed variation of the long-term stroke free survival rate between different residential areas of the same city might be due to intra-urban differences in risk factor exposure or might indicate the importance of sociodemographic factors vis-à-vis long-term prognosis after stroke. Apart from traditional factors predicting ischemic CVD, the routine use of a simple questionnaire on calf pain while walking, and determination of the serum uric acid level might help in identifying those at high risk of ischemic CVD. Leukocyte activation seems to be an important factor both in atherosclerosis and ischemic CVD, and regarding outcome after ischemic CVD. The plasma levels of leukocyte activation markers might be useful in risk assessment, and possible targets for therapeutic medical intervention.

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