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

Way out of my league, so you'll have to contact a genius somewhere to decipher this.
http://journal.frontiersin.org/article/10.3389/fneur.2015.00121/full?

Benedetta Piccardi¹*, Vanessa Palumbo², Mascia Nesi², Patrizia Nencini², Anna Maria Gori³, Betti Giusti³, Giovanni Pracucci¹, Paolina Tonelli¹, Eleonora Innocenti¹, Alice Sereni³, Elena Sticchi³, Danilo Toni⁴, Paolo Bovi⁵, Mario Guidotti⁶, Maria Rosaria Tola⁷, Domenico Consoli⁸, Giuseppe Micieli⁹, Rossana Tassi¹⁰, Giovanni Orlandi¹¹, Francesco Perini¹², Norina Marcello¹³, Antonia Nucera¹⁴, Francesca Massaro¹⁵, Maria Luisa DeLodovici¹⁶, Giorgio Bono¹⁶, Maria Sessa¹⁷, Rosanna Abbate³ and Domenico Inzitari^1,18, On behalf of the MAGIC Study Group

• ¹Neuroscience Section, Department of Neurofarba, University of Florence, Florence, Italy
• ²Stroke Unit, Department of Neurology, Careggi University Hospital, Florence, Italy
• ³Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence, Florence, Italy
• ⁴Emergency Department Stroke Unit, Department of Neurological Sciences, Sapienza University of Rome, Rome, Italy
• ⁵SSO Stroke Unit, U.O. Neurologia d.O., DAI di Neuroscienze, Azienda Ospedaliera Integrata, Verona, Italy
• ⁶Neurology Unit, Valduce General Hospital, Como, Italy
• ⁷U.O. Neurologia, DAI Neuroscienze-Riabilitazione, Azienda Ospedaliera-Universitaria S. Anna, Ferrara, Italy
• ⁸U.O. Neurologia, G. Jazzolino Hospital, Vibo Valentia, Italy
• ⁹Istituto Neurologico Nazionale C. Mondino, Pavia, Italy
• ¹⁰U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese, Siena, Italy
• ¹¹Department of Neurosciences, Neurological Clinic, University of Pisa, Pisa, Italy
• ¹²UOC di Neurologia e “Stroke Unit”, Ospedale San Bortolo, Vicenza, Italy
• ¹³Neurology Unit, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
• ¹⁴Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, ON, Canada
• ¹⁵Neurology Unit, Misericordia e Dolce Hospital, Prato, Italy
• ¹⁶Stroke Unit, Department of Neurology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
• ¹⁷Department of Neurology, Istituti Ospitalieri, Cremona, Italy
• ¹⁸Institute of Neuroscience, Italian National Research Council, Florence, Italy

Background: Experimentally, 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.

Methods: Blood 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 outcomes

Results: Adjusting 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).

Discussion: Our 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.

Introduction

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in extracellular matrix (ECM) degradation (1). The turnover of ECM is regulated by the balance between MMPs and a group of endogenous proteins called tissue inhibitor of metalloproteinases (TIMPs) (2). Active MMPs and some MMP proenzymes form 1:1 complexes with TIMPs and the unbalance between these two families of molecules appears implicated in a variety of diseases (3). A list of MMPs and TIMPs with their putative role in acute ischemic stroke is shown in Table S1 in Supplementary Material.

After cerebral ischemia, the general neuronal response to excitotoxic injury determines the release of pro-inflammatory cytokines that stimulate the local production of MMPs and TIMPs (4). In experimental models of brain ischemia, MMPs and MMP/TIMP unbalance play a detrimental role related to blood–brain barrier (BBB) disruption leading to hemorrhagic transformation and edema of an ischemic brain lesion (5). Circulating levels of MMP9 have been proved associated with poor outcomes in stroke patients treated with tissue plasminogen activator (rtPA) (6, 7). Furthermore, recent studies suggest that rtPA adverse effects may be mediated through MMPs upregulation and activation (2). No clinical study has hitherto considered selectively the effect of the balance between MMPs and their physiological inhibitor related to stroke outcomes after thrombolysis. Theoretical effects of rtPA on MMP/TIMP unbalance have been shown in Figure 1.

FIGURE 1

Figure 1. Impact of tissue plasminogen activator on MMP/TIMP unbalance at the neurovascular unit level. After acute ischemic stroke, rtPA may cross blood–brain barrier (BBB), enter the brain parenchyma, and thereby damage neurovascular unit components by promoting metalloproteinase (MMPs) production and activation. Indeed, unbalance between MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases, TIMPs) may exacerbate BBB disruption leading to hemorrhagic transformation and edema of an ischemic brain lesion.

The aim of this study was to evaluate the effect of MMPs/TIMPs ratio on outcomes of ischemic stroke in the same cohort of the biological markers associated with acute ischemic stroke (MAGIC) study. Because MMP inhibition is considered a possible therapeutic target for stroke patients (8), a clearer understanding of MMP/TIMP interplay, compared with the effect of MMPs only, would have important implications for acute stroke therapies.

More at link.