Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke.
BACKGROUND
Matrix metalloproteinase-9 (MMP9) is expressed in acute ischemic stroke and up-regulated by tissue plasminogen activator (tPA) in animal models. The authors investigated plasma MMP9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP1), in tPA-treated and -untreated stroke patients.


METHODS
Nonstroke control subjects and consecutive ischemic stroke patients presenting within 8 hours of onset were enrolled. Blood was sampled within 8 hours and at 24 hours, 2 to 5 days and 4 to 6 weeks. MMP9 and TIMP1 were analyzed by ELISA and gel zymography.


RESULTS
Fifty-two cases (26 tPA treated, 26 tPA untreated) and 27 nonstroke control subjects were enrolled. Hyperacute MMP9 was elevated in tPA-treated vs tPA-untreated patients (medians 43 vs 28 ng/mL; p = 0.01). tPA therapy independently predicted hyperacute MMP9 after adjustment for stroke severity, volume, and hemorrhagic transformation (p = 0.01). There was a trend toward lower hyperacute TIMP1 levels in tPA-treated vs tPA-untreated patients (p = 0.06). Hyperacute MMP9 was correlated to poor 3-month modified Rankin Scale outcome (r = 0.58, p = 0.0005).


CONCLUSIONS
Tissue plasminogen activator independently predicted plasma matrix metalloproteinase-9 (MMP9) in the first 8 hours after human ischemic stroke. As MMP9 may be an important mediator of hemorrhagic transformation, alternative thrombolytic agents or therapeutic MMP9 inhibition may increase the safety profile of acute stroke thrombolysis.
Ning
M
M
Stroke Service, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Furie
K L
KL
Koroshetz
W J
WJ
Lee
H
H
Barron
M
M
Lederer
M
M
Wang
X
X
Zhu
M
M
Sorensen
A G
AG
Lo
E H
EH
Kelly
P J
PJ
D000368:Aged; D015415:Biomarkers; D001921:Brain / Q000473:pathology; D001925:Brain Damage, Chronic / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016022:Case-Control Studies; D003289:Convalescence; D017352:Echo-Planar Imaging; D004790:Enzyme Induction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D005500:Follow-Up Studies; D006474:Hemorrhagic Disorders / Q000139:chemically induced* / Q000201:enzymology; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D012720:Severity of Illness Index; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D015415:Biomarkers; D005343:Fibrinolytic Agents; D019715:Tissue Inhibitor of Metalloproteinase-1; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9