Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis.
OBJECTIVE
The molecular pathways involved in the progression of intracranial large artery atherosclerosis (ILA) are largely unknown. Our objective was to prospectively study the relationship between circulating levels of inflammatory markers and fibrinolysis inhibitors, and the risk of progression of symptomatic ILA.


METHODS
Seventy-five consecutive patients with first-ever symptomatic intracranial atherostenosis were studied. Blood levels of C-reactive protein (CRP), E-selectin, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinases 1, 2, 3, 8, 9, 10, and 13, plasminogen activator inhibitor-1 (PAI-1), and lipoprotein(a) were measured 3 months after the qualifying stroke or transient ischemic attack. Thereafter, patients underwent long-term transcranial Doppler follow-up to detect progression of ILA.


RESULTS
During a median follow-up time of 23 months, 25 (33%) patients showed ILA progression. Multivariable adjusted Cox regression models and Kaplan-Meier curves showed that high baseline level of CRP, E-selectin, intercellular adhesion molecule-1, matrix metalloproteinase 9, PAI-1, and lipoprotein(a) predicted ILA progression independently of vascular risk factors. Of them, only CRP (CRP>5.5 mg/L; HR, 5.4 [2.3 to 12.7]; P=0.0001) and PAI-1 (PAI-1>23.1 ng/mL; HR, 2.4 [1.0 to 5.8]; P=0.05) predicted ILA progression also independently of the other studied molecules.


CONCLUSIONS
Progression of symptomatic ILA is associated with a proinflammatory state, as reflected by high levels of inflammatory markers, and with defective fibrinolysis, as indicated by raised concentrations of endogenous fibrinolysis inhibitors.
Arenillas
Juan F
JF
Neurovascular Unit, Vall d'Hebron Universitary Hospital, Barcelona, Spain. juanfarenillas@terra.es
Alvarez-Sabín
José
J
Molina
Carlos A
CA
Chacón
Pilar
P
Fernández-Cadenas
Israel
I
Ribó
Marc
M
Delgado
Pilar
P
Rubiera
Marta
M
Penalba
Anna
A
Rovira
Alex
A
Montaner
Joan
J
D000368:Aged; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis / Q000378:metabolism; D002536:Cerebral Arteries / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D018932:Chemokine CCL2 / Q000032:analysis / Q000097:blood; D018450:Disease Progression; D019040:E-Selectin / Q000032:analysis / Q000097:blood; D005260:Female; D005342:Fibrinolysis; D005500:Follow-Up Studies; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis / Q000097:blood*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000097:blood; D002537:Intracranial Arteriosclerosis / Q000097:blood / Q000503:physiopathology*; D008074:Lipoproteins / Q000032:analysis / Q000097:blood; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000097:blood; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D017585:Ultrasonography, Doppler, Transcranial; D020293:Vasculitis, Central Nervous System / Q000097:blood / Q000150:complications / Q000503:physiopathology*
D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019040:E-Selectin; D018836:Inflammation Mediators; D008074:Lipoproteins; D017395:Plasminogen Activator Inhibitor 1; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein; D020782:Matrix Metalloproteinases