Unbalanced Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinases Ratios Predict Hemorrhagic Transformation of Lesion in Ischemic Stroke Patients Treated with Thrombolysis: Results from the MAGIC Study

Abstract

BackgroundExperimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients.MethodsBlood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomesResultsAdjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17–2.38], p = 0.005; 1.74 [1.21–2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17–2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007).DiscussionOur data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.

Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

“…Indeed, the correlation of MMP-9/TIMP-1 ratio with cerebral edema was even stronger than that of MMP-9 alone following ischemic stroke in rats (Li et al, 2013 ). Similar findings were observed in a clinical study with the relative increase in MMP-9/TIMP-1 ratio independently associated with symptomatic ICH in ischemic stroke patients (Piccardi et al, 2015 ). In keeping with the role of MMP-9 and TIMP-1 in the pathogenesis of stroke, mild hypothermia provided protection from ischemia/reperfusion injury via decreasing the expression of MMP-9 (Burk et al, 2008 ; Zhao et al, 2013 ) and TIMP-1 (Zhao et al, 2013 ).…”

Temporal analysis of blood–brain barrier disruption and cerebrospinal fluid matrix metalloproteinases in rhesus monkeys subjected to transient ischemic stroke

“…To note, the substrates of MMPs are all located in the base membrane, such as the gelatins, fibronectin, laminin, and collagen. 35 The multiplexing method enabled us to measure all these MMPs and their inhibitors using only 50 mL samples. The MMP-2 and MMP-9 results from the multiplexing method were validated using traditional ELISA method (Supplementary Figure 4).…”

Hemorrhagic transformation of ischemic stroke

“…TIMP-1 could be a potential target of neuroprotective therapy [144]. Also, the increase of the MMP9/TIMP1 ratio is significantly associated with symptomatic HT [145].…”