Brain, Vol. 126, No. 2, 424-432,
February 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg040
Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis
1 Department of Clinical Neurosciences, St George’s Hospital Medical School, 2 Department of Haematology, Guy’s and St Thomas’s Trust, St Thomas’s Hospital, 3 Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, 4 Department of Neurology, St James’s Hospital, Leeds, 5 Department of Neurology, Stoke Mandeville Hospital, Buckinghamshire and 6 Thames Valley Nuffield Hospital, Slough, UK
Correspondence to: Professor H. Markus, Department of Clinical Neurosciences, St George’s Hospital Medical School, London SW17 ORE, UK E-mail: h.markus{at}sghms.ac.uk
Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood–brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic leukoaraiosis, defined as a clinical lacunar stroke and leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P 
0.006). The ischaemic leukoaraiosis group had a different endothelial marker profile, with lower levels of TFPI (P = 0.01) and a higher TF/TFPI ratio (P = 0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of lacunes (P = 0.008) and the leukoaraiosis score (P = 0.03), but TF levels and the TF/TFPI ratio were associated only with the extent of leukoaraiosis (P 0.02). These results suggest that there is evidence of chronic endothelial dysfunction in cerebral SVD, and endothelial prothrombotic changes may be important in mediating the ischaemic leukoaraiosis phenotype. Therapies which help to stabilize the endothelium may have a role in this group of patients.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R Topakian, T R Barrick, F A Howe, and H S Markus Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis J. Neurol. Neurosurg. Psychiatry, February 1, 2010; 81(2): 192 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Brandts, S. G. C. van Elderen, J. J. M. Westenberg, J. van der Grond, M. A. van Buchem, M. V. Huisman, L. J. M. Kroft, J. T. Tamsma, and A. de Roos Association of Aortic Arch Pulse Wave Velocity with Left Ventricular Mass and Lacunar Brain Infarcts in Hypertensive Patients: Assessment with MR Imaging Radiology, December 1, 2009; 253(3): 681 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Jickling, A. Salam, A. Mohammad, M. S. Hussain, J. Scozzafava, A. M. Nasser, T. Jeerakathil, A. Shuaib, and R. Camicioli Circulating Endothelial Progenitor Cells and Age-Related White Matter Changes Stroke, October 1, 2009; 40(10): 3191 - 3196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gomis, T. Sobrino, A. Ois, M. Millan, A. Rodriguez-Campello, N. P. de la Ossa, R. Rodriguez-Gonzalez, J. Jimenez-Conde, E. Cuadrado-Godia, J. Roquer, et al. Plasma {beta}-Amyloid 1-40 Is Associated With the Diffuse Small Vessel Disease Subtype Stroke, October 1, 2009; 40(10): 3197 - 3201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Tietjen Migraine as a Systemic Vasculopathy Cephalalgia, September 1, 2009; 29(9): 989 - 996. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Thompson and A. M. Hakim Living Beyond Our Physiological Means: Small Vessel Disease of the Brain Is an Expression of a Systemic Failure in Arteriolar Function: A Unifying Hypothesis Stroke, May 1, 2009; 40(5): e322 - e330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. T. Baune, G. Ponath, M. Rothermundt, A. Roesler, and K. Berger Association Between Cytokines and Cerebral MRI Changes in the Aging Brain J Geriatr Psychiatry Neurol, March 1, 2009; 22(1): 23 - 34. [Abstract] [PDF]
|
|
|
|
|
|
Y.-S. Kim, E. Nur, E. J. van Beers, J. Truijen, S. C.A.T. Davis, B. J. Biemond, and J. J. van Lieshout Dynamic Cerebral Autoregulation in Homozygous Sickle Cell Disease Stroke, March 1, 2009; 40(3): 808 - 814. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Versari, E. Daghini, A. Virdis, L. Ghiadoni, and S. Taddei The ageing endothelium, cardiovascular risk and disease in man Exp Physiol, March 1, 2009; 94(3): 317 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.J. Huynh, B. Murphy, J.A. Pettersen, H. Tu, D.J. Sahlas, L. Zhang, S.P. Symons, S. Black, T.-Y. Lee, and R.I. Aviv CT Perfusion Quantification of Small-Vessel Ischemic Severity AJNR Am. J. Neuroradiol., November 1, 2008; 29(10): 1831 - 1836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Khan, C. Crossley, L. Kalra, A. Rudd, C. D.A. Wolfe, P. Collinson, and H. S. Markus Homocysteine and Its Relationship to Stroke Subtypes in a UK Black Population: The South London Ethnicity and Stroke Study Stroke, November 1, 2008; 39(11): 2943 - 2949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nitkunan, T. R. Barrick, R. A. Charlton, C. A. Clark, and H. S. Markus Multimodal MRI in Cerebral Small Vessel Disease: Its Relationship With Cognition and Sensitivity to Change Over Time Stroke, July 1, 2008; 39(7): 1999 - 2005. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fornage, Y. A. Chiang, E. S. O'Meara, B. M. Psaty, A. P. Reiner, D. S. Siscovick, R. P. Tracy, and W.T. Longstreth Jr Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study Stroke, July 1, 2008; 39(7): 1952 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Wardlaw, A. Farrall, P. A. Armitage, T. Carpenter, F. Chappell, F. Doubal, D. Chowdhury, V. Cvoro, and M. S. Dennis Changes in Background Blood-Brain Barrier Integrity Between Lacunar and Cortical Ischemic Stroke Subtypes Stroke, April 1, 2008; 39(4): 1327 - 1332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O'Sullivan Leukoaraiosis Practical Neurology, January 1, 2008; 8(1): 26 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tanaka, H. Imai, K. Konno, T. Miyagishima, C. Kubota, S. Puentes, T. Aoki, H. Hata, K. Takata, Y. Yoshimoto, et al. Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig: Neurological Assessment and Histological, Immunohistochemical, and Physiological Evaluation of Dynamic Corticospinal Tract Deformation Stroke, January 1, 2008; 39(1): 205 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Markus Genes, endothelial function and cerebral small vessel disease in man Exp Physiol, January 1, 2008; 93(1): 121 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Khatri, C. B. Wright, T. L. Nickolas, M. Yoshita, M. C. Paik, G. Kranwinkel, R. L. Sacco, and C. DeCarli Chronic Kidney Disease Is Associated With White Matter Hyperintensity Volume: The Northern Manhattan Study (NOMAS) Stroke, December 1, 2007; 38(12): 3121 - 3126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Markus, U. Khan, J. Birns, A. Evans, L. Kalra, A. G. Rudd, C. D.A. Wolfe, and P. Jerrard-Dunne Differences in Stroke Subtypes Between Black and White Patients With Stroke: The South London Ethnicity and Stroke Study Circulation, November 6, 2007; 116(19): 2157 - 2164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Gretchen and M. Tietjen Migraine and Ischaemic Heart Disease and Stroke: Potential Mechanisms and Treatment Implications Cephalalgia, August 1, 2007; 27(8): 981 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Khan, L. Porteous, A. Hassan, and H. S Markus Risk factor profile of cerebral small vessel disease and its subtypes J. Neurol. Neurosurg. Psychiatry, July 1, 2007; 78(7): 702 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Khan, A. Hassan, P. Vallance, and H. S. Markus Asymmetric Dimethylarginine in Cerebral Small Vessel Disease Stroke, February 1, 2007; 38(2): 411 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Schmidt, H. Schmidt, M. Pichler, C. Enzinger, K. Petrovic, K. Niederkorn, S. Horner, S. Ropele, N. Watzinger, M. Schumacher, et al. C-Reactive Protein, Carotid Atherosclerosis, and Cerebral Small-Vessel Disease: Results of the Austrian Stroke Prevention Study Stroke, December 1, 2006; 37(12): 2910 - 2916. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. J. Carod-Artal Statins and Cerebral Vasomotor Reactivity: Implications for a New Therapy? Stroke, October 1, 2006; 37(10): 2446 - 2448. [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Chen, P. Y. Wang, W. H. Sheu, Y. T. Chen, Y. P. Ho, H. H. Hu, and H. Y. Hsu Changes of brachial flow-mediated vasodilation in different ischemic stroke subtypes. Neurology, September 26, 2006; 67(6): 1056 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. V. Immink, G. A. van Montfrans, J. Stam, J. M. Karemaker, M. Diamant, and J. J. van Lieshout Dynamic Cerebral Autoregulation in Acute Lacunar and Middle Cerebral Artery Territory Ischemic Stroke Stroke, December 1, 2005; 36(12): 2595 - 2600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Kalra, C. Rambaran, P. Chowienczyk, D. Goss, I. Hambleton, J. Ritter, A. Shah, R. Wilks, and T. Forrester Ethnic Differences in Arterial Responses and Inflammatory Markers in Afro-Caribbean and Caucasian Subjects Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2362 - 2367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H.G. Henskens, A. A. Kroon, M. P.J. van Boxtel, P. A.M. Hofman, and P. W. de Leeuw Associations of the Angiotensin II Type 1 Receptor A1166C and the Endothelial NO Synthase G894T Gene Polymorphisms With Silent Subcortical White Matter Lesions in Essential Hypertension Stroke, September 1, 2005; 36(9): 1869 - 1873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Napoli and F. Papa C-Reactive Protein and Cerebral Small-Vessel Disease: An Opportunity to Reassess Small-Vessel Disease Physiopathology? Circulation, August 9, 2005; 112(6): 781 - 785. [Full Text] [PDF]
|
|
|
|
|
|
E. J. van Dijk, N. D. Prins, S. E. Vermeer, H. A. Vrooman, A. Hofman, P. J. Koudstaal, and M. M.B. Breteler C-Reactive Protein and Cerebral Small-Vessel Disease: The Rotterdam Scan Study Circulation, August 9, 2005; 112(6): 900 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Gormley, S. Bevan, A. Hassan, and H. S. Markus Polymorphisms in Genes of the Endothelin System and Cerebral Small-Vessel Disease Stroke, August 1, 2005; 36(8): 1656 - 1660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Markus, B. Hunt, K. Palmer, C. Enzinger, H. Schmidt, and R. Schmidt Markers of Endothelial and Hemostatic Activation and Progression of Cerebral White Matter Hyperintensities: Longitudinal Results of the Austrian Stroke Prevention Study Stroke, July 1, 2005; 36(7): 1410 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Birns, H. Markus, and L. Kalra Blood Pressure Reduction for Vascular Risk: Is There a Price To Be Paid? Stroke, June 1, 2005; 36(6): 1308 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J M Wardlaw What causes lacunar stroke? J. Neurol. Neurosurg. Psychiatry, May 1, 2005; 76(5): 617 - 619. [Full Text] [PDF]
|
|
|
|
|
|
T. Hoshi, K. Kitagawa, H. Yamagami, S. Furukado, H. Hougaku, and M. Hori Relations of Serum High-Sensitivity C-Reactive Protein and Interleukin-6 Levels With Silent Brain Infarction Stroke, April 1, 2005; 36(4): 768 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Olivot, J. Labreuche, M. Aiach, P. Amarenco, and for the GENIC Investigators Soluble Thrombomodulin and Brain Infarction: Case-Control and Prospective Study Stroke, August 1, 2004; 35(8): 1946 - 1951. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. I. Sokol, E. L. Portnay, J. P. Curtis, M. A. Nelson, P. R. Hebert, J. F. Setaro, and J. M. Foody Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke Neurology, July 27, 2004; 63(2): 208 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hassan, B. J. Hunt, M. O'Sullivan, R. Bell, R. D'Souza, S. Jeffery, J. M. Bamford, and H. S. Markus Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction Brain, January 1, 2004; 127(1): 212 - 219. [Abstract] [Full Text] [PDF]
|
|