A hemorrhagic transformation model of mechanical stroke therapy with acute hyperglycemia in mice

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Stroke is the fourth leading cause of death and the leading cause of long‐term disability worldwide (Benjamin et al., 2017; Mozaffarian et al., 2016). Acute pre‐ischemic hyperglycemia (HG), independently of pre‐existing diabetic status, is an important factor of poor outcome in acute ischemic stroke (AIS) (Kim, Jahan, Saver, & SWIFT Investigators, 2016). Blood glucose elevation during AIS is related in part to a reaction to stress and to a potential nonfasting state (Capes, Hunt, Malmberg, Pathak, & Gerstein, 2001). Both diabetic and nondiabetic patients that undergo ischemic stroke are adversely affected by HG, suggesting that acute increased blood glucose concentration at the onset of stroke is sufficient to worsen the related damage (Luitse, Biessels, Rutten, & Kappelle, 2012; Pulsinelli, Levy, Sigsbee, Scherer, & Plum, 1983). Accordingly, many studies show that HG also worsens the clinical outcome after both ischemic and hemorrhagic stroke even in patients without diabetes (Bruno et al., 2002; Capes et al., 2001; Dorsemans et al., 2017). A strong association was observed between blood glucose levels and symptomatic intracerebral hemorrhage and more generally poor clinical outcomes following thrombolytic therapy (recombinant tissue plasminogen activator [rtPA] for stroke) (Desilles et al., 2013; Lansberg, Albers, & Wijman, 2007). Studies have stratified the hemorrhagic risk according to the severity of HG which appears to be twofold increased for each 5.5 mM increase in blood glucose at admission (Bruno et al., 2002; Demchuk et al., 1999).
Most preclinical studies of hemorrhagic transformation (HT) in mice and rats have been performed with very high blood glucose levels (>400 mg/dL) (Fan et al., 2012; Hafez, Coucha, Bruno, Fagan, & Ergul, 2014). However, in clinical setting, stroke patients with blood glucose levels higher than 400 mg/dL during AIS represent only 0.5% of patients and are excluded from therapeutic strategies (Hacke et al., 2008). Mild elevation in blood glucose levels increases vascular damage and poor outcomes (Elgebaly et al., 2011). Hafez et al. have shown that combination of moderate HG and low dose of rtPA increased the vascular damage and reduced the favorable outcome in both sutured and embolic rat occlusion models (Hafez et al., 2015). The mechanisms of HT in acute HG conditions are not fully understood.
A strong correlation has been noticed between the duration of ischemia and reperfusion‐induced HT. In rat models of middle cerebral artery occlusion (MCAO), HT is increased with the duration of ischemia. The therapeutic window for AIS treatment in human is 4.5 hr for intravenous therapy by rtPA (Hacke et al., 2008). History of both diabetes and prior ischemic stroke are additional exclusion criteria for rtPA administration (Jauch et al., 2013). This therapeutic window has been extended to 8 hr for mechanical thrombectomy (MT) in order to treat most of these patients. The goal of mechanical therapy is to completely restore cerebral blood flow. In the MCAO model, a complete reperfusion occurs promptly after monofilament withdrawal, mimicking what occurs after MT. Mechanical therapy for AIS was not shown to increase HT or mortality compared with rtPA alone (Saver et al., 2015). However, an association between HG and worse outcome at 3 months in patients treated with mechanical therapy has been recently demonstrated (Kim et al., 2016). In this study, admission of patients displaying blood glucose levels up to 140 mg/dL was independently associated with a poor outcome at 3 months, while it was not associated with an increase in HT rates. Moreover in this study, Kim et al. suggested that the negative impact of HG on functional outcome may differ according to reperfusion status (no perfusion to minimal, partial, or complete perfusion).

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