MD Conference Express ISC 2012 - (Page 9)
matrix responses to focal ischemia and their relationship to pro-MMP-2, urokinase (u-PA), and neuron injury; and plasminogen activator expression by microvessels. Table 1. Focal "No-Flow" Phenomenon.
Element PMN leukocytes Fibrinogen Platelets Event Activation Fibrin formation Activation Effect Adherence/obstruction Deposition/obstruction Thrombosis/obstruction
that trials have not necessarily supported changes in clinical care. "Understanding why at the level of mechanisms of tissue injury is essential to correct our course." The Need to Know Endothelial cells facilitate cellular inflammation and rapidly generate and respond to proinflammatory stimuli following ischemia onset. But how individual cells within the unit communicate with each other during postischemic inflammatory responses is not clear: a unifying synthesis of inflammatory responses has not yet been developed [del Zoppo GJ. J Intern Med 2010]. In microvessel-neuron relationships, there are regionspecific arrangements of the microvasculature. This is in agreement with differences in regional cerebral blood flow, whereby flow is lowest in the corpus striatum and highest in the cortical grey matter. The relative arrangements and densities of the neurons (and neuron subtypes) to the ‘supply’ microvessels in these regions are not known [del Zoppo GJ. J Intern Med 2010]. The coordinated and potentially unitary nature of microvessel-neuron relationships in the acute setting of focal ischemia is suggested by known matrix responses to focal ischemia. As a framework for understanding the responses to acute intervention during ischemic strokes, further basic information is required that adequately relates microvessel reactivity and changes in neuron integrity in mammalian systems [del Zoppo GJ. J Intern Med 2010]. The Way Ahead Dr. del Zoppo observed that the proper acute delivery of plasminogen activators is very effective. Microvessel responses are as rapid as those of neurons and include endothelial cell activation, altered matrix architecture, and decreased adhesion receptor expression. He noted that the acute appearance of proteases with matrixdegrading capability and the events in microvessels are heterogeneously distributed. The responses of the endothelium, the permeability barrier and tight junction proteins, astrocytes, and their matrix adhesion are all connected in time and space. Dr. del Zoppo cited the need to identify the cellular sources of proteases that are acutely related to microvessel responses and regions of neuronal injury. These observations suggest that great care in the translation from experimental studies to Phase 1/2 clinical safety assessments and the design and conduct of Phase 3 trials is needed [del Zoppo GJ. Ann NY Acad Sci 2010].
Highlights from the International Stroke Conference 2012
The generation of matrix proteases during ischemia is rapid, as are changes in endothelial cell adhesion and adhesion of astrocyte end-feet. These changes involve loss of the matrix adhesion receptors αβ-dystroglycan and integrin α6β4 on astrocytes and β1-integrins on endothelial cells. They occur following middle cerebral artery occlusion in a large animal model of focal ischemia and can be reproduced in cell culture. The microvessel basal lamina is degraded in the ischemic core, and astrocytes detach. An important recent finding is that the endothelial cell permeability barrier opens at the same time that adhesion receptor expression changes. The loss of β1-integrins from endothelium leads to disruption of tight junction proteins that form the endothelial cell barrier and increased permeability. The Global Search for Solutions Early acute intervention studies focused on the feasibility and safety of plasminogen activator infusions, intracerebral hemorrhage risk control, and potential improvements with specific agents, including urokinase and tissue plasminogen activator. In the laboratory, the del Zoppo group has used focal ischemia as a “wedge” to elucidate interactions of microvessels with the neurons they serve. Findings are based on precise clinical observations of acute events in the microvasculature in a high-quality, nonhuman primate focal ischemia model, with direct application to patients in clinical trials. Early investigations centered on whether decreased patency of capillaries could be prevented or reversed; whether adherence of leukocytes—as well as fibrin formation, platelet activation, and peripheral inflammation—could be blocked; and whether the “no-reflow phenomenon” could be prevented. If no-reflow could be prevented, and fibrin formation, platelet activation, and adherence of leukocytes that occlude microvessel adhesion receptors could all be blocked, patency would be increased and preserved. “We all want to stop or reverse ischemic cerebral tissue injury, but the transition of knowledge from the lab to the clinical environment is an inexact art,” Dr. del Zoppo said, adding
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Table of Contents for the Digital Edition of MD Conference Express ISC 2012
MD Conference Express ISC 2012
From Neurovascular Laboratory to Clinic: A Journey Through Time
No Compelling Evidence to Use Warfarin or Aspirin in Heart Failure Patients
AXIS 2 Clinical Outcomes No Different Than Placebo
SAMMPRIS: 30-Day Outcomes After Angioplasty and Stenting
Aggressive Medical Therapy Benefits Those Who Fail Antithrombotic Therapy
Initial Clinical Results with TREVO® Mechanical Thrombectomy Device are Promising
Linking sICH Definitions to Outcomes
Solitaire™ Flow Restoration Device Achieves Successful Recanalization Free of Symptomatic Hemorrhage Transformation
FIA II Seeks Genetic Underpinnings of Familial Intracranial Aneurysm
SPS3 Study Does Not Support the Use of Combination Therapy for Stroke Prevention
Novel Agent NA-1 Proves that Ischemic Neuroprotection is Possible in Older Patients
Acute Endovascular Treatment
Neuroimaging
Stroke Guidelines: Current Recommendations in Principle and Practice
The Rising Trend of Ischemic Stroke in the Young
Advanced Neuroimaging Adds Time, Reduces Endovascular Treatment in Clinical Practice
MD Conference Express ISC 2012
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