Safety profile of tissue plasminogen activator treatment among stroke patients carrying a common polymorphism (C-1562T) in the promoter region of the matrix metalloproteinase-9 gene.
OBJECTIVE
Matrix metalloproteinase-9 (MMP-9) expression, related to blood-brain barrier disruption, has been implicated in the appearance of hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment in stroke patients. Because an in vitro functional polymorphism of the promoter region of MMP-9 gene (C-1562T) has been described, we hypothesize that patients carrying this mutation might have higher MMP-9 levels and greater susceptibility to developing HT when receiving tPA.


METHODS
We studied strokes involving the middle cerebral artery territory of 61 patients who received tPA <3 hours after stroke onset. Blood samples were obtained before tPA administration. Plasmatic MMP-9 determinations were performed (enzyme-linked immunosorbent assay, ng/mL), and C-1562T genotype was determined by polymerase chain reaction. Healthy age-matched control subjects were used to study allele distribution (n=59). Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI,1 to 2] and large parenchymal hemorrhages [PH,1 to 2]).


RESULTS
Allele distribution was similar in patients and control subjects (CC/CT/TT: 72.3/27.7/0% versus 79.7/20.3/0%, respectively; P=0.37). Among patients, mutation carriers (CT/TT alleles) had similar rates of HT and PH than noncarriers (HT: 23.1% versus 38.2%, P=0.49; PH: 15.4% versus 17.6%, P=1.0). Although the highest MMP-9 level corresponded to patients who later developed a PH (PH, 191.4 ng/mL; non-PH, 68.05 ng/mL; P=0.022), no relation between MMP-9 mutation presence and plasmatic levels was found (CC, 127.12 ng/mL; CT/TT, 46.31 ng/mL; P=0.11).


CONCLUSIONS
Although MMP-9 level predicts PH appearance after tPA treatment, no relationship exists with the C-1562T polymorphism, probably because this mutation is not functional in response to cerebral ischemia in vivo.
Montaner
Joan
J
Neurovascular Research Laboratory, Stroke Unit, Vall d'Hebron Hospital, Barcelona, Spain. 31862jmv@comb.es
Fernández-Cadenas
Israel
I
Molina
Carlos A
CA
Monasterio
Jasone
J
Arenillas
Juan F
JF
Ribó
Marc
M
Quintana
Manolo
M
Chacón
Pilar
P
Andreu
Antoni L
AL
Alvarez-Sabín
José
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000235:genetics; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012016:Reference Values; D012307:Risk Factors; D012449:Safety; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed
D015415:Biomarkers; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9