Published online before print May 19, 2005, doi: 10.1161/01.STR.0000169924.60783.d4
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(Stroke. 2005;36:1410.)
© 2005 American Heart Association, Inc.
Original Contributions |
Markers of Endothelial and Hemostatic Activation and Progression of Cerebral White Matter Hyperintensities
Longitudinal Results of the Austrian Stroke Prevention Study
From Clinical Neuroscience (H.S.M.), St George’s Hospital Medical School, St George’s Hospital, London, UK; Haematology (B.H., K.P.), St Thomas’s Hospital, London, UK; and the Department of Neurology (C.E., R.S.) and Institute of Medical Molecular Biology and Biochemistry (H.S.), Medical University, Graz, Austria.
Correspondence to Hugh Markus, Clinical Neuroscience, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. E-mail h.markus{at}sghms.ac.uk
Background and Purpose— The pathogenesis of cerebral small vessel disease (SVD) is poorly understood, but endothelial activation and dysfunction may play a causal role. Cross-sectional studies have found increased circulating markers of endothelial activation, but this study design cannot exclude causality from secondary elevations. Confluent white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) appear to represent asymptomatic cerebral SVD. In a prospective study, we determined whether circulating markers of endothelial activation predicted progression of WMH.
Methods— In the community-based Austrian Stroke Prevention Study, MRI was performed at baseline in 296 subjects and repeated at 3 and 6 years. The following were measured on baseline plasma samples: intercellular adhesion molecule (ICAM), thrombomodulin, tissue factor plasma inhibitor, prothrombin fragments 1 and 2, and D-dimers.
Results— ICAM was associated with age- and gender-adjusted WMH lesion progression at both 3 and 6 years, respectively; (odds ratio [OR], 1.007; 95% confidence interval [CI], 1.002 to 1.012; P=0.004; and OR, 1.004; 95% CI, 1.000 to 1.009 per ng/mL; P=0.057). After multivariate analysis controlling for other cardiovascular risk factors and C-reactive protein, 3-year OR was 1.010 (95% CI, 1.004 to 1.017; P=0.001) and 6-year OR was 1.008 (1.002 to 1.014 per ng/mL; P=0.006). Baseline log lesion volume was a strong independent predictor of progression but associations remained after controlling for this (3-year OR, 1.011; 95% CI, 1.002 to 1.020; P=0.013; and 6-year OR, 1.009; 95% CI, 1.000 to 1.017; P=0.039 per ng/mL). There was no association between WMH progression and other markers.
Conclusions— ICAM levels are related to progression of WMH on MRI. The prospective study design increases the likelihood that this association is causal and supports a role of endothelial cell activation in disease pathogenesis. In contrast, we found no evidence for coagulation activation being important.
Key Words: cerebrovascular disorders • lacunar infarction • magnetic resonance imaging • risk factors • white matter
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