Matrix Metalloproteinase Expression Is Related to Hemorrhagic Transformation After Cardioembolic Stroke

Abstract

Background and Purpose-In animal models of cerebral ischemia, matrix metalloproteinase (MMP) expression was significantly increased and related to blood-brain barrier disruption, edema formation, and hemorrhagic transformation (HT). MMP inhibitors reduce HT after embolic ischemia in tissue-type plasminogen activator-treated animals. We aimed to determine the relationship between MMPs and HT after human ischemic stroke. Methods-Serial MMP-2 and MMP-9 determinations were performed by means of ELISA in 39 cardioembolic strokes in the middle cerebral artery territory. Hemorrhagic events were classified according to clinical and CT criteria (hemorrhagic infarction [HI] and parenchymal hematoma [PH]). HT was evaluated on CT at 48 hours (early HT) and again between day 5 and 7 (late HT). Results-HT was present in 41% of the patients (43.75% early HI, 25% early PH and 31.25% late HI). MMP-2 values were within normal range and were unrelated to HT. Increased expression of MMP-9 (normal range Ͻ97 ng/mL) was found among patients with and without HT (159.3Ϯ82 versus 143.9Ϯ112.6 ng/mL; Pϭ0.64). According to HT subtypes, the highest baseline MMP-9 levels corresponded to patients with late HI (240.4Ϯ111.2 versus 102.5Ϯ76.7 ng/mL for all other patients, Pϭ0.002). Baseline MMP-9 was the only variable associated with late HI in the multiple logistic regression model (OR 9; CI 1.46, 55.24; Pϭ0.010). Peak of MMP-9 at the 24-hour time point (250.6 ng/mL) was found before appearance of PH. Conclusions-MMPs are involved in some subtypes of HT after human cardioembolic stroke. Baseline MMP-9 level predicts late HI and a 24-hour peak precedes early PH. Key Words: cerebral ischemia Ⅲ embolism, cerebral Ⅲ hematoma, parenchymal Ⅲ hemorrhagic stroke Ⅲ matrix metalloproteinase H emorrhagic transformation (HT) is a feared event that may follow ischemic stroke. Thrombolytic therapy has been shown to be beneficial for acute stroke, although this therapy increases risk of HT. 1 Therefore, identification of the underlying mechanisms of this complication is critical to improvement of the safety profile of thrombolytic agents for stroke treatment.Matrix metalloproteinases (MMPs) belong to a family of zinc-binding proteolytic enzymes that normally remodel the extracellular matrix. 2 MMP-2 and MMP-9 specifically attack type IV collagen, laminin, and fibronectin, the major components of the basal lamina around cerebral blood vessels. 3 In animal models of cerebral ischemia, MMP expression was increased significantly and related to blood-brain barrier disruption, edema formation, and HT. 4,5 However, whether HT in humans also is related to MMP action remains unknown.We hypothesize that after MMPs degrade ECM components of the basal lamina, blood elements may extravasate, which leads to HT. In the present exploratory study, we aimed to correlate the expression of MMPs after human cardioembolic stroke with the appearance of different subtypes of HT. Subjects and Methods Study PopulationFrom June 1999 through March 2000, we studied prospectively consecut...

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“…Moreover, to our knowledge, only a few preclinical studies have been conducted to assess the effects of the pharmacological modulation of hematoma growth 6. On the other hand, MMPs have been implicated in brain injury after ICH in animal models and in humans12, 13, 26; in particular, blood MMP‐9 concentration has been associated with hemorrhagic transformation 27. Rapid MMP upregulation after ICH has been proposed to cause neurovascular matrix degradation, proteolyzing the basal lamina around blood vessels and disrupting endothelial tight junctions, leading to edema, hemorrhage, and cell death 13.…”

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“…Those with severe strokes had significantly higher levels of MMP-9 at baseline, and the elevated levels persisted for 48 h (Montaner et al, 2001a). When hemorrhagic transformation or parenchymal hemorrhages were present, the highest levels of MMP-9 were found in those patients with late hemorrhagic transformation (Montaner et al, 2001b). Studies in nonhuman primates have shown that the levels of MMP-9 were associated with hemorrhagic transformation, while MMP-2 correlated with neuronal injury (Heo et al, 1999).…”

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“…Once released upon neutrophil activation, MMP-9 breaks down the extracellular matrix, leading to vascular dilation/ weakening. 24,[26][27][28][29][30][31][32][33][34][35][36][37] Using substrate zymography, Hashimoto et al 30 determined that the expression of total MMP-9, pro-MMP-9, and active MMP-9 was significantly increased in AVMs in comparison to control brain tissue. The levels of MMP inhibitors, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-3, were also increased in AVMs, although to a lesser extent than MMP-9.…”