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Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of  Medicine; Neurologist, Stroke Subspecialist
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Introduction to Stroke Pathophysiology And Atherosclerosis Prepared By Arlyn M. Valencia, M.D. Associate Professor Of Neurology University Of Nevada School Of Medicine; Neurologist, Stroke Subspecialist

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Supplementary material for the stroke lecture

Supplementary material for the stroke lecture

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  • 1. Arlyn M. Valencia, M.D. OUTLINE OF POWERPOINT PRESENTATION •Stroke in Perspective I.Epidemiology II.Types of Stroke III.Risk Factors •Pathogenesis and Pathophysiology I.Atherosclerosis and Thrombogenesis II.Cerebral Embolism Formation III.Effects of Stroke on Brain Function IV.Cellular Injury During Ischemia V.The Ischemic Penumbra •Evaluation and Management I.Emergent Evaluation and Intervention II.Clinical Presentations of Acute Stroke III.Localization IV.Work-up and Neuroimaging Techniques V.Emergent Supportive Care and Treatment VI.Stroke Prevention IV. Case Studies/ Questions and Answers
  • 2. ATHEROSCLEROSIS AND THROMBOSIS Atherosclerosis: decades-long process; progression favored by hypercholesterolemia, HTN, cigarette smoking •Fatty streak: yellowish discoloration on intimal surface of blood vessel; microscopically, lipid –filled macrophages called “foam cells” (may be present even in childhood) •Focal plaques: eccentric thickening at bifurcations; addition of massive extracellular lipids that displaced normal cells and matrix (late childhood or early adolescence) •Complicated fibrous plaques: central acellular area of lipid covered by a cap of smooth muscle cells and collagen (third decade of life); with endothelial injury, caps thicken quickly as a result of thrombosis- dependent fibrotic organization
  • 3. ATHEROGENESIS: “RESPONSE TO INJURY” HYPOTHESIS Atherosclerosis begins as a response to chronic minimal injury to the endothelium and interactions among monocytes, lipoproteins, platelets, lymphocytes, and smooth muscle cells abet and continue the pathogenic process 3 TYPES OF VASCULAR INJURY 1. Type I injury: functional alterations of endothelial cells; primarily caused by turbulence of blood flow Other factors: HTN, hypercholesterolemia, circulating vasoactive amines, immunocomplexes, viral infections, and a chemical irritant in tobacco smoke •Type II injury: denuding of endothelium and superficial intimal injury accompanied by platelet deposition with or without thrombus formation •Type III injury: deep intimal and medial damage with marked platelet aggregation and mural thrombosis (usually seen following plaque rupture)
  • 4. ROLE OF MONOCYTES AND T-LYMPHOCYTES Monocytes bind to endothelium after vascular cell adhesion molecule (VCAM) is expressed, insinuate themselves between endothelial cells . Once in the intima, they are transformed into macrophages and ingest modified lipids (primarily oxidized lipids). T lymphocytes help to mobilize macrophages. OXIDATION OF LDL-CHOLESTEROL “Scavenger receptor” on macrophages readily takes up oxidized LDL Oxidation induced by free radicals produced by macrophages, endothelial cells, or smooth muscle cells Oxidized LDL-cholesterol contribute to atherogenesis in 3 other ways: 1) its cytotoxic properties promote endothelial injury; 2) acts as chemoattractant for monocytes; and 3) inhibits egress of macrophages from plaques SMOOTH MUSCLE CELL MIGRATION AND PROLIFERATION Makes up substantial bulk of plaque Factors involved: 1) growth factors (PDGF), 2) eicosanoids, 3) certain cytokines (eg, tumor necrosis factor, interleukin-1 and interferon), and 4) nitric oxide
  • 5. ROLE OF PLATELETS Contribute to formation of capsule of “fatty lesions”, of subendothelial “fibrointimal lesions” and stimulate migration and proliferation of smooth muscle cells Platelet activation: incited by exposed collagen; activated platelets acquire enhanced capacity to catalyze interactions between activated coagulation factors Platelet adhesion: promoted by damage to intimal surface, toxic products released by macrophages; platelets adhere to subendothelial receptors (mainly, GP-Ib-IX) Platelet aggregation: interplatelet bridging (receptor GP IIb-IIIa) THROMBOSIS Activation of coagulation cascade culminates in generation of thrombin which converts soluble fibrinogen to fibrin forming a blood clot. Fibrin molecules aggregate together, trapping platelets, erythrocytes, and leukocytes Thrombosis on atherosclerotic plaque may precipitate acute episodes of transient ischemia and ischemic stroke (as well as MI and unstable angina)
  • 6. Duration, severity and location of focal cerebral ischemia determine the severity of brain dysfunction and thus the severity of stroke. REQUIREMENT OF CONSTANT ENERGY SUPPLY The transient change in voltage induced by the action potential is determined by the concentration of ions on either side of cell membrane. Maintaining these ionic gradients is an energy-consuming process that requires constant supply of glucose and oxygen to the neuron. INADEQUATE ENERGY SUPPLY Cellular energy stores depleted due to lack of glucose and oxygen “Leaky” membrane leads to K+ and ATP loss 5-10 minutes required for irreversible brain damage One or more branching mechanisms may independently lead to cell death: May involve 1) deterioration of ion gradients or 2) effects of anaerobic metabolism
  • 7. DETERIORATION OF ION GRADIENTS LEADING TO EXCITOTOXICITY •Anoxic depolarization (equilibrium of intracellular and intracellular ions) causes potassium exit & sodium, chloride and calcium entry •Massive release of glutamate & aspartate •Glutamate further activates sodium & calcium ion channels in the neuron membrane ---- cytotoxic edema •Activation of calcium channels result in furher influx of calcium •Entry of calcium through N-methyl-D-aspartate (NMDA) channel activation: further depletion of energy, activation of proteases, lipases, and nucleases •These enzymes & their metabolic products (oxygen free radicals) cause cell death •Neuroprotective agents: drugs that would block above steps; still investigational
  • 8. THE ISCHEMIC PENUMBRA •Core ischemic zone: blood flow below 10% to 25 %, severe ischemia can result in necrosis of neurons and glial cells •Penumbral zone: mild to moderately ischemic tissue between normally perfused area and the area in which infarction is evolving; ailing but salvageable tissue; supplied by collaterals; extent varies directly with the number and patency of collateral arteries; if reperfusion not established in the early hours, cells may die
  • 9. CEREBRAL INFARCTION/ EFFECTS OF EDEMA •Edema may cause further damage by compressing neurons, nerve tracts, and cerebral arteries •May increase intracranial pressure (ICP) or shift structures within cranial vault •Two major types of edema: 1) Cytotoxic: onset within minutes to hours; swelling of all cellular elements of the brain (neurons, glia, endothelial cells); increased intracellular calcium activates phospholipases and the release of arachidonic acid, leading to release of free radicals and infarction, 2) Vasogenic: increase in extracellular fluid volume due to increased permeability of brain capillary endothelial cells (onset within hours to days) ANAEROBIC GLYCOLYTIC PATHWAYS •Compensate for loss of oxygen & provide source of energy Produce damaging byproducts including lactic acid and hydrogen ions (latter facilitate ferrous-iron-mediated free radical mechanisms; irreversibly affect neuronal integrity)

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