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Life history of atherosclerosis)

Life history of atherosclerosis). Structure of normal muscular artery. Evolution of atherosclerosis. VGH. 1. Modification of LDL ( ox-LDL) in the intima proteoglycan 2. Accumulation of LDL from oxidative stress 3. Elaboration of cytokines (interleukin-1, IL-1 )

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Life history of atherosclerosis)

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  1. Life history of atherosclerosis)

  2. Structure of normal muscular artery

  3. Evolution of atherosclerosis VGH 1. Modification of LDL (ox-LDL) in the intima proteoglycan 2. Accumulation of LDL from oxidative stress 3. Elaboration of cytokines (interleukin-1, IL-1) 4. Recruitment of monocytes entering arterial wall (CAMs + monocyte chemoattractant protein-1, MCP-1) 5. Macrophage transformation + scanvenger receptor (M-CSF)  uptake ox-LDL  Foam cell 6. Migration of smooth muscle cells (SMC) 7. Extracellular matrix accumulation (MMPs)  fibrosis  Fatty streak 8. Programmed death (apoptosis) of SMC calcification Fibrous cap

  4. Leukocyte and platelete adhere to subendocardium

  5. Dysfunctional endothelial cells in Atherosclerosis VGH • Decrease in endothelium-derived relaxing factor (EDRF)  promotes : • platelet aggregation, vasoconstriction, • leukocyte adhesion & increases shear • Decreasein the ratio of tissue plasminogen activator to plasminogen-activator inhibitor type 1 (t-PA / PAI-1)  promotes thrombosis • Increase in adhesion molecules •  promotes monocyte/macrophage retention

  6. Extracellular matrix (ECM) VGH Smooth muscle cells (SMCs) & endothelial cells (Ecs) produce ECM Matrix metalloproteinases (MMPs) help SMCs migrate from media to intima  hyperplasia Tissue inhibitors of metalloproteinases (TIMPs) delay SMC accumulation in the intima

  7. Ischemia VGH • Supply ( low-flow) ischemia •  increased vascular tone •  platelet aggregation •  thrombus formation • Demand ( high-flow) ischemia •  chronic stable coronary obstruction •  Exercise, tachycardia or emotion •  flow is not meet O2 demand

  8. The focality of lesion formation VGH Laminar shear stress augments expression of protective gene : superoxide dismutase (SOD) catabolize superoxide anion Nitric oxide synthase (NOS) produce vasodilator nitric oxide • Turbulent flow • Proximal portion of arteries after branch points • Bifurcations at flow dividers

  9. Effects of coronary stenoses • Severity of stenosis  increase flow resistance • Entrance and exit effects • Flow velocity (kinetic energy) increases • Pressure (static energy) decreases • (laminar flow  eddy currents) • Lengthof stenosis • Long lesion creats eddies impact on the wall • Dynamic changes in stenosis severity • Eccentricity of atherosclerotic plaque • Vascular tone may alter luminal caliber and • stenosis resistance • stenosis > 30~45%  alteration of resting flow • stenosis > 85%  alteration of maximal flow VGH

  10. Multifactorial pathogenesis of atherosclerosis

  11. Complications of Atherosclerosis Arterial stenosis VGH • Culprit lesion of Acute myocardial infarction • Antecedent coronary angiogram: • 15% of patients with stenosis > 60% • Most patients with stenosis < 50% • Coronary angiogram in post-thrombolytic cases: • 50% of patients with stenosis < 50%

  12. Plaque Rupture VGH • 2/3 cases  fracture of the fibrous cap • 1/4 cases  superficial erosion of the intima • Vulnerable plaque is : • relatively lack of SMCs • foam cells and large lipid pool • macrophages in advanced athermas • overexpress matrix metalloproteins (MMPs) • & cytokines

  13. Special cases of atherosclerosis VGH • Percutaneous transluminal coronary angioplasty • (PTCA) : • Animal  proliferation of SMCs • Human  constriction of adventitia • PTCA +Stenting “in-stent” srenosis •  highly hydrated extracellular matrix •  stellate SMCs • Graftatherosclerosis • Host T-cell  interferon-  SMCs growth • factor

  14. Gross pathological changes in AMI VGH • Transmural infarcts •  less sverely stenotic •  more common with thrombus •  single vessel • Subendocardial(non-transmural) infarcts •  severely narrowed vessel • Autopsy in cases with ST segment elevation •  A 90% incidence of total occlusion of culprit vessel

  15. Progression of myocardial necrosis

  16. Microscopic features of AMI VGH • One-day  coagulatiion necrosis • (nuclear shrinkage and loss, • mitochondrial damage) •  wavy fibers at border •  single vessel • 3rd-4th day neutrophilic infiltration • 7~10th day removal of necrotic myocytes by • macrophage • 3rd week granulation tissue with a rich • vascular network • 6th week well-healed by dense collagenous scar

  17. Post MI ventricular remodling VGH • Residual (noninfarcted) viable myocardium • LV dilatation • cause factors  loading condition •  infarct artery patency • mechanism maintain stroke volume • complication  nonuniform repolarization causes • life-threatening ventricular • arrhythmias • Infarct expansion •  slippage between muscle bundles across • the infarct wall •  disruption of normal myocytes •  tissue loss within necrotic zone

  18. VGH • Blood pressure • = peripheral resistance Xcardiac output • Cardiac output = stroke volume X heart rate • Laplace law • pressure X radius • wall tension = • wall thickness

  19. Causes of unstable angina VGH • Plaque rupture with superimposed thrombus • 2. Dynamic obstruction •  spasm of epicardial arteries •  constriction of the small muscular arteries • 3. Progressive mechanical obstruction • 4. Inflammation and infection  Chlamydia Pneumoniae • 5. Secondarily precipitatedby increased O2 demand • or decreased supply  anemia or • thryrotoxicosis

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