Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice
Originally published27 Aug 2018Stroke. 2018;49:2163–2172
Abstract
Background and Purpose—
Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological therapy available for patients with ischemic stroke. However, the percentage of patients who may receive this therapy is limited by the risk of hemorrhagic transformation (HT)—the main complication of ischemic stroke. Our aim is to establish whether iron overload affects HT risk, to identify mechanisms that could help to select patients and to prevent this devastating complication.Methods—
Mice fed with control or high-iron diet were subjected to thromboembolic stroke, with or without tPA therapy at different times after occlusion. Blood samples were collected for determination of malondialdehyde, matrix metalloproteinases, and fibronectin. Brain samples were collected 24 hours after occlusion to determine brain infarct and edema size, hemorrhage extension, IgG extravasation, and inflammatory and oxidative markers (neutrophil infiltration, 4-hydroxynonenal, and matrix metalloproteinase-9 staining).Results—
Despite an increased rate of recanalization, iron-overload mice showed less neuroprotection after tPA administration. Importantly, iron overload exacerbated the risk of HT after early tPA administration, accelerated ischemia-induced serum matrix metalloproteinase-9 increase, and enhanced basal serum lipid peroxidation. High iron increased brain lipid peroxidation at most times and neutrophil infiltration at the latest time studied.Conclusions—
Our data showing that iron overload increases the death of the compromised tissues, accelerates the time of tPA-induced reperfusion, and exacerbates the risk of HT may have relevant clinical implications for a safer thrombolysis. Patients with stroke with iron overload might be at high risk of HT after fibrinolysis, and, therefore, clinical studies must be performed to confirm our results.(Whom in stroke leadership have you contacted to get this followup research initiated? Or did you do nothing because it is not your responsibility?)
Introduction
Stroke is a leading cause not only of death but also of long-term disability and dementia in developed countries. Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological therapy available for patients with ischemic stroke.1,2 However, to limit hemorrhagic transformation (HT)—the main complication of intravenous thrombolysis, this drug is used only under restrictive conditions.3 The percentage of patients with stroke who receive intravenous tPA remains between 5% and 10%, and successful recanalization is achieved approximately in <40% of the treated patients—another factor that limits the benefits of the therapy. Endovascular thrombectomy with new-generation devices improves clinical outcome in patients with large anterior cerebral arterial occlusions who have contraindications or have failed intravenous tPA revascularization.4 Because of the mechanic retrieval of the clot by thrombectomy, effective recanalization is achieved in >80% of the patients, extending the beneficial effect of the thrombolysis. The meta-analysis of clinical trials has shown similar proportion of symptomatic intracranial hemorrhage in the thrombectomy and control groups, most of them treated with intravenous tPA,4 so intracerebral bleeding remains the main complication of revascularization therapies.During an ischemic episode, the blood-brain barrier (BBB) is damaged and undergoes structural alterations that contribute to brain injury. Several studies have focused on elucidating the mechanisms by which the vasculature is altered during stroke. Among others, oxidative stress, activation of proteases, and infiltration of circulating white cells seem to play an important role in short-term BBB damage and HT, in particular after tPA-induced recanalization.5
Because of its double redox nature, iron is an essential element that catalyzes processes such as mitochondrial respiration, oxygen transport in blood,6,7 and neurotransmitter synthesis in the brain. Paradoxically, this bivalence also makes iron potentially toxic because by undergoing Haber-Weiss reactions, it can generate reactive oxygen species, which damage cellular substrates. Iron toxicity is generally avoided by highly regulated homeostatic mechanisms that keep iron under its less reactive, ferric form (Fe3+), and chelated by specific binding proteins. These controlling mechanisms are especially important in brain, which maintains iron levels constant by the regulation of its uptake through the BBB. Even in disorders causing systemic iron accumulation, such as hemochromatosis, brain iron levels remain unaltered.8 However, it is widely accepted that iron homeostasis is impaired early after cerebral ischemia, being one of the first mediators of damage in the ischemic cascade.9 Importantly, iron overload in patients has been described to be associated to poor outcome after stroke.10–13 Experimental studies confirm this detrimental effect14,15 and suggest that iron overload could accelerate the damage of the compromised tissue during acute ischemia.16 BBB could be also more vulnerable in patients with iron overload—a fact supported by some clinical studies that found high levels of iron associated with a higher rate of HT after intravenous tPA therapy.10,17
The aim of this study is to establish experimental evidence of iron overload on the HT risk, to identify the mechanisms involved in this effect and to find some related prognostic markers that could help to avoid this feared complication.
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