Leukocyte activation: relation to cardiovascular mortality after cerebrovascular ischemia.

Activated leukocytes are believed to be involved in the pathogenesis and progression of atherosclerotic vascular disease and its consequences. In a 4-year observational follow-up study, we investigated whether markers for systemic leukocyte activation (leukocyte-derived inflammatory mediators) were related to cardiovascular mortality after cerebrovascular ischemia. Using enzyme-linked immunosorbent assays, we measured the plasma levels of soluble tumor necrosis factor receptor protein-1 (sTNFR-1), neutrophil gelatinase-associated lipocalin (NGAL) and neutrophil protease-4 (NP4) in 144 patients (90 stroke, 54 transient ischemic attack) 1-3 days after cerebral ischemia. During the 4 years of follow-up, 42 (29%) of the 144 patients died; 38 of cardiovascular causes and 4 of other causes. Patients with evidence of higher leukocyte activation (n = 47) had a higher 4-year cardiovascular mortality rate than those without evidence of leukocyte activation (n = 97; p < 0.005). Logistic regression analysis with age, sex and other significant predictors as covariates showed higher plasma levels of sTNFR1 and NGAL both to be significant independent predictors of cardiovascular mortality, the respective odds ratio, 95% confidence intervals, and p values being 2.0, 1.2-3.4, p < 0.01, and 3.6, 1.2-10.5, p = 0.02, respectively. We concluded that in patients with acute cerebral ischemia, plasma markers of leukocyte activation were significant predictors of long-term cardiovascular mortality. This may indicate an important role of activated leukocytes in the progression of these diseases.

Calf pain in middle-aged individuals as a predictor of ischemic cerebrovascular disease.

In middle-aged individuals, calf pain while walking may be an early marker of generalized ischemic vascular disease. We investigated whether the symptom of calf pain while walking was a predictor of ischemic cerebrovascular disease (CVD). In a nested case control study, part of the Malmö Prevention Program Project, we evaluated 105 patients with ischemic CVD for the symptom of calf pain reported at screening more than a decade before their illness. Their baseline characteristics were compared with those of an age- and sex-matched control group drawn from the population cohort. Calf pain while walking was reported by 16.2% of the patient group but by only 7.6% of the control group; p < 0.0001. Multiple logistic regression analysis with adjustment for all other significant risk factors showed a history of calf pain while walking to be an independent predictor of ischemic CVD (odds ratio, 1.9; 95% confidence interval, 1.3-3.7; p < 0.002). Thus, in middle-aged individuals, the symptom of calf pain while walking would seem to be a significant independent predictor of ischemic CVD. Our data serve to target a high-risk group for improved preventive efforts.

Three-year survival and recurrence after stroke in Malmö, Sweden: an analysis of stroke registry data.

BACKGROUND AND PURPOSE: Data from the Malmö Stroke Registry were analyzed to determine whether any change in survival or nonfatal stroke recurrence rates had occurred during the 4-year period from 1989 through 1992 and whether prognosis was related to area of residence. METHODS: The series comprised 2290 patients, 1051 men and 1239 women, followed up for 3 years after their first stroke during the period 1989 through 1992. RESULTS: Of the series as a whole, 959(43.4%) died and 137(6%) suffered a second nonfatal stroke. Multivariate analysis showed age, type of stroke, severity of stroke, and the presence of diabetes mellitus or cardiac disease each to be an independent predictor of mortality, and the presence of diabetes, atrial fibrillation, and history of transient ischemic attacks each to be associated with increased risk of recurrence. Treatment for hypertension was associated with a protective effect. As compared to those with first stroke in 1989, those with first stroke in 1992 were characterized by a lower recurrence rate, which was reduced by 70% in the male subgroup (P=0.003) and by 80% in the female subgroup (P=0.006), the corresponding reduction in all-cause mortality being 30% (P=0.007) and 10% (P=0.5, NS). Recurrence-free survival rates differed markedly between the 17 residential areas studied. CONCLUSIONS: The present study showed that survival rates after stroke have improved and recurrence rates have declined in this urban population. Further studies are needed to ascertain to what extent intraurban variation in the proportion of recurrence-free 3-year survivors is to be explained by differences in the severity of initial stroke and other prognostic markers, or in initial treatment and secondary preventive measures.

Leukocyte activation in atherosclerosis: correlation with risk factors.

Leukocytes have been implicated in the development of atherosclerotic vascular diseases, and numerous abnormalities of leukocytes in conjunction with atherosclerosis have been reported. The aim of this study of middle-aged asymptomatic subjects with early atherosclerosis was to determine whether a relationship exists between the levels of plasma markers of leukocyte activation, i.e. cytokines and proteases and risk factors for atherosclerosis or the degree of atherosclerotic disease. Using ELISAs we measured the plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), neutrophil protease 4 (NP4) as markers for neutrophil activation, tumor necrosis factor alpha (TNF) and soluble TNF receptor-1 (sTNFR-1) as markers of monocyte/macrophage activation in 156 subjects with asymptomatic carotid artery plaque detected at ultrasound examination. Plasma TNF and sTNFR-1 levels were found to correlate with systolic blood pressure (r = 0.32, P < 0.04 and r = 0.22, P < 0.05, respectively). plasma NGAL level to correlate with diastolic blood pressure (r = 0.22; P < 0.005), the plasma levels of sTNFR-1 and NGAL to correlate with age (r = 0.28, P < 0.001 and r = 0.20, P < 0.05, respectively). As compared with non-smokers (n = 112), smokers (n = 43) had higher plasma levels of TNF (2.9 vs. 1.4 microg/l; P < 0.02) and of NP4 (27.5 vs. 23.4 microg/l; P < 0.05). The plasma NGAL level was higher in hypertensive women (n = 7) than in normotensive women (n = 85) (109 vs. 87 microg/l; P < 0.05). We thus demonstrated that, in subjects with asymptomatic early atherosclerosis, the plasma levels of markers of systemic leukocyte activation were correlated with age and blood pressure, and were higher in smokers and hypertensives. These results support the hypothesized relationship between the level of systemic leukocyte activation and risk factors for atherosclerotic vascular disease.

Leukocyte activation detected by increased plasma levels of inflammatory mediators in patients with ischemic cerebrovascular diseases.

BACKGROUND AND PURPOSE: Leukocytes have been implicated in the development of ischemic atherosclerotic vascular diseases. In a prospective study we investigated whether the plasma concentrations of inflammatory mediators, ie, proteases and cytokines, as markers for systemic leukocyte activation, are increased in patients with acute ischemic cerebrovascular diseases. METHODS: Using enzyme-linked immunosorbent assays, we measured the plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), neutrophil proteinase 4 (NP4), tumor necrosis factor-alpha (TNF), and soluble TNF receptor protein-1 p55 (sTNFR-1) in 120 patients with acute ischemic cerebrovascular insult (72 with stroke and 48 with transient ischemic attack [TIA]) and in 35 age- and sex-matched healthy subjects. RESULTS: Compared with the control group, plasma NGAL levels were higher in the stroke group (P < .0001) and the TIA group (P < .01); plasma NP4 levels were higher in the stroke group (P < .0001) and the TIA group (P < .01); and plasma sTNFR-1 levels were higher in the stroke group (P < .04). There was significant correlation between the plasma levels of fibrinogen and those of both sTNFR-1 (r = .32; P = .005) and NGAL (r = .40; P = .0001) and between the erythrocyte sedimentation rate and the plasma levels of both sTNFR-1 (r = .35; P = .001) and NGAL (r = .34; P = .002). CONCLUSIONS: Our study demonstrated that markers for systemic leukocyte activation, ie, plasma levels of cytokines and proteases, were higher in patients with acute ischemic cerebrovascular disease than in healthy control subjects. Activated leukocytes and leukocytic mediators may have an important role in acute cerebrovascular ischemia and its consequences.