Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Abstract

A cute ischemic stroke (AIS) remains a leading cause of disability, cognitive impairment, and mortality worldwide, despite the development of revascularization therapies. Besides recanalization status, other prognostic factors in AIS patients are associated with clinical outcome. Among them, hyperglycemia has been found to be associated with hemorrhagic transformation (HT) and worsened neurological outcomes. 1,2 Given that 40% to 50% of AIS patients present with hyperglycemia, 3 understanding and reducing hyperglycemia-induced neurovascular injury constitute an important clinical stake. Experimental studies have investigated extensively the relationship between hyperglycemia and poor outcome after AIS. [4][5][6] Notably, these studies have shown that preexisting hyperglycemia, whether acute or prolonged, was an important determinant of brain injury in AIS. In contrast, hyperglycemia induced after the period of ischemia had no effect on experimental stroke outcome.5 Hyperglycemia was further shown to increase cerebral ischemia-reperfusion-induced blood-brain Background and Purpose-Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. Methods-Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. Results-Hyperglycemic rats had an increased infarct volume with an increased blood-brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. Conclusions-We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion-induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood-brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a po...

Downstream Microvascular Thrombosis in Cortical Venules Is an Early Response to Proximal Cerebral Arterial Occlusion

“…In agreement with an earlier study by del Zoppo and Mabuchi, we showed recently that neutrophils represented the vast majority of leukocytes being recruited to the ischemic hemisphere microvasculature during AIS . A previous study using intravital microscopy to investigate leukocyte–endothelium interactions also reported that neutrophil recruitment to the ischemic brain was predominant in the venous compartment .…”

“…In fact, we showed in this study that BBB disruption originates from sites of neutrophil recruitment. As reported previously, hemorrhagic transformation in the form of petechiae is promoted by hyperglycemia, which primes neutrophils for activation and interactions with endothelial cells . In the same study, hemorrhagic transformation originated from areas showing persistent hypoperfusion in magnetic resonance imaging despite recanalization.…”

“…At present, the dominant paradigm is that they would mostly develop during the reperfusion phase and contribute to reperfusion injury . We observed in a recent study that leukocyte accumulation, mainly neutrophils, in microvessels of the ischemic hemisphere occurred as early as 30 minutes after proximal artery occlusion . The latter phenomenon was also reported in earlier studies including models of permanent focal cerebral ischemia, indicating that the thromboinflammatory response to cerebral ischemia was not necessarily the consequence of reperfusion .…”

“…As reported previously, hemorrhagic transformation in the form of petechiae is promoted by hyperglycemia, which primes neutrophils for activation and interactions with endothelial cells. 4 In the same study, hemorrhagic transformation originated from areas showing persistent hypoperfusion in magnetic resonance imaging despite recanalization. Taken together, these observations suggest that hemorrhagic transformation might be a consequence of persisting occlusion rather than reperfusion.…”

“…8 In agreement with an earlier study by del Zoppo and Mabuchi, 1 we showed recently that neutrophils represented the vast majority of leukocytes being recruited to the ischemic hemisphere microvasculature during AIS. 4,7 A previous study using intravital microscopy to investigate leukocyte-endothelium interactions also reported that neutrophil recruitment to the ischemic brain was predominant in the venous compartment. 6 The thrombosis pattern we described in this study, with a phenomenon of venous thrombosis developing in a context of stasis and neutrophil margination, strongly recalls that observed in animal models of deep vein thrombosis.…”