טרשת עורקים-מצגת מספר 2

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<p> 2' " " 9002-40 H.Cohen 1</p> <p>9002</p> <p>Pathogenesis of AtherosclerosisH.Cohen 04-2009 2</p> <p>: </p> <p>Harrison's Principles of Internal Medicine 16th Edition / Harrison's OnlineChapter 224. The Pathogenesis of Atherosclerosis</p> <p>Basic &amp; Clinical Endocrinology Francis S. Greenspan, David G. Gardner 7th edition 2004 chapter 19</p> <p>Immune and Inflammatory Mechanisms of Atherosclerosis. Annu. Rev. Immunol. 2009. 27:16597 </p> <p>H.Cohen 04-2009</p> <p>3</p> <p>Atherosclerosis-definition</p> <p>Atherosclerotic plaqueH.Cohen 04-2009 4</p> <p>AtherosclerosisDyslipidemia Diabetes HTN Smoking FHx</p> <p>Risk Factors</p> <p>clinical manifestationsCoronary Heart Disease</p> <p>BiologyInflammation Coagulation Endothelial function T cell Macrophages</p> <p>Cerebro Vascular Disease PVD</p> <p>H.Cohen 04-2009</p> <p>5</p> <p>Major Vascular Manifestations of AtherothrombosisIschemic stroke Carotid vertebral</p> <p>coronary Myocardial infarction Angina pectoris mesenteric ischemia</p> <p>renal artery stenosis splanchnic circulation</p> <p>Femoral iliac</p> <p>Peripheral arterial disease: Gangrene Necrosis</p> <p>H.Cohen 04-2009Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16</p> <p>6</p> <p>Atherothrombosis is the Leading Cause of Death WorldwideAtherothrombosis*Cancer Infectious Disease Pulmonary disease Violent death AIDS 05% 14% 12% 19% 24% 52%</p> <p>Mortality (%) 10 20 30 40 50 60</p> <p>Cardiovascular disease is a leading cause of global mortality, accounting for almost 17 million deaths annually or 30% of all global mortality . 2007Cardiovascular disease, ischemic heart disease and cerebrovascular disease</p> <p>World Health Organization. The World Health Report 2001. Geneva: WHO; 2001.</p> <p>H.Cohen 04-2009</p> <p>7</p> <p>??? Atherothrombosis and Cause of Death in Israel" -8991 4002</p> <p> -000,001 041 311 63 34 63 249002-40 H.Cohen</p> <p>641</p> <p> 911 </p> <p>8</p> <p>smooth muscle</p> <p>Slide 20. The arterial wall consists of three functionally separate layers: 1) the intima (composed of a single monolayer of endothelial cells, in contact with circulating blood), 2) the media (composed mainly of smooth muscle cells, embedded in extracellular matrix), and 3) the 9 adventitia (harbours nutrient vessels, nerves and dense fibroelastic H.Cohen 04-2009 tissue). Reproduced with permission from Ross R, Glomset JA. The pathogenesis of atherosclerosis (part 1). N Engl J Med 1976; 295:369-377. 1976 Massachusetts Medical Society. All rights reserved.</p> <p>Cross section of an artery</p> <p>sub-intimal space</p> <p>H.Cohen 04-2009</p> <p>10</p> <p>Atherosclerosis TimelineFoam Cells Fatty Streak Intermediate Atheroma Lesion Fibrous Complicated Plaque Lesion/Rupture</p> <p>Endothelial DysfunctionFrom first decade From third decade From fourth decadeSmooth muscle and collagen</p> <p>Growth mainly by inflammation and lipid accumulation H.Cohen 04-2009Adapted from Stary HC et al. Circulation. 1995;92:1355-1374.</p> <p>Thrombosis,11</p> <p>inflammation</p> <p>Atherogenesis in autopsy of young and healthy individuals</p> <p>H.Cohen 04-2009</p> <p>12</p> <p>H.Cohen 04-2009</p> <p>13</p> <p>Cross section of an coronary atherosclerotic artery</p> <p>Initiation of AtherosclerosisH.Cohen 04-2009 14</p> <p>Localization of atherosclerosis </p> <p>hemodynamic forces may influence cellular events provide an explanation for the localization of atherosclerotic lesions</p> <p>at sites of disturbance to laminar shear stress.</p> <p>H.Cohen 04-2009</p> <p>15</p> <p>Fatty streak initial lesion of atherosclerosis arise from increases in the content of lipoproteins inside the intima</p> <p>Fatty streaksInflammation</p> <p>Endothelial cells</p> <p>Foam cells</p> <p>Adventitia</p> <p>H.Cohen 04-2009</p> <p>17</p> <p>Endothelial cells Inflammation</p> <p>Foam cells</p> <p>Adventitia</p> <p> Fatty streaks</p> <p> - ) (LPextracellular matrix</p> <p>1</p> <p> -</p> <p> - )(ox LP ox 9002-40 H.Cohen 81</p> <p>2</p> <p>3</p> <p>Endothelial cells Inflammation</p> <p>Foam cells</p> <p>Adventitia</p> <p>Fatty streaks LEUKOCYTE RECRUITMENT</p> <p>ADHESION PENETRATION Chemoattractant- cytokines : monocyte chemoattractant protein 1</p> <p>3</p> <p>4</p> <p>H.Cohen 04-2009</p> <p>19</p> <p>Intercellular adhesion molecule-1 (ICAM-1) vascular cell adhesion molecule1(VCAM-1</p> <p>chemoattractant factorsmonocyte chemotactic protein : produced by vascular wall cells in response to modified lipoproteins</p> <p>ADHESION PENETRATION</p> <p>H.Cohen 04-2009</p> <p>20</p> <p>Endothelial cells Inflammation</p> <p>Foam cells</p> <p>Adventitia</p> <p>Accumulation of leukocytes characterizes the formation of early atherosclerotic lesions</p> <p>macrophage</p> <p> ACCUMULATION</p> <p>5</p> <p>NON REGULATED</p> <p> 21</p> <p>6</p> <p>7</p> <p>H.Cohen 04-2009</p> <p>) tumor necrosis factor (TNF- ) interleukin-1 (IL-1</p> <p>H.Cohen 04-2009</p> <p>22</p> <p>(1) </p> <p>H.Cohen 04-2009</p> <p>23</p> <p>The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56</p> <p>(2) .</p> <p>H.Cohen 04-2009</p> <p>24</p> <p>The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56</p> <p>(3) </p> <p>H.Cohen 04-2009</p> <p>25</p> <p>The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56</p> <p>(4) </p> <p>H.Cohen 04-2009</p> <p>26</p> <p>The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56</p> <p>(5) </p> <p>H.Cohen 04-2009</p> <p>27</p> <p>The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56</p> <p>(6) </p> <p>H.Cohen 04-2009</p> <p>28</p> <p>The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56</p> <p>Foam Cellsmononuclear phagocytes ingest lipids and become foam cells, represented by a cytoplasm filled with lipid droplets</p> <p>H.Cohen 04-2009</p> <p>29</p> <p>FATTY STREAK</p> <p>Not all fatty streaks progress to form complex atheromata Some lipid-laden macrophages leave the artery wall, exporting lipid in the process. Reverse cholesterol transport mediated by high-density lipoproteins (HDL),H.Cohen 04-2009</p> <p>provides an30</p> <p>independent pathway for lipid removal from atheroma</p> <p>Stable atherosclerotic plaque Fibrous plaque evolves from the fatty streak accumulation of connective tissue increased number of smooth muscle cells deeper extracellular lipid pool.</p> <p>Characteristics of the stable atherosclerotic plaqueEndothelial cellsInflammationLipid core</p> <p>Fibrous cap(VSMCs and matrix)</p> <p>Intimal VSMCs</p> <p>Cytokines induce local production of growth factors</p> <p>growth factors and cytokines produced locally -stimulate the proliferation of smooth-muscle cells in the intima +media and stimulates interstitial collagen production by smooth-muscle cells</p> <p>Adventitia</p> <p>Vascular Smooth Muscle Cells</p> <p>H.Cohen 04-2009</p> <p>Medial VSMCs</p> <p>32</p> <p>A stable atherosclerotic plaque is at low risk of ruptureH.Cohen 04-2009 33</p> <p>Features of stable plaquesI. II.</p> <p>thick fibrous cap of uniform density confers mechanical stability. high VSMC and collagen content in the lipid-rich core that occupies less than 40% fibrous cap. of the total volume of the plaque</p> <p>III. IV.</p> <p>low infiltration of inflammatory cells (macrophages and T-lymphocytes)</p> <p>H.Cohen 04-2009</p> <p>34</p> <p>The stable atherosclerotic plaquevascular remodellingNo reduction in the dimensions of the lumen</p> <p>Thick, VSMC-rich fibrous cap</p> <p>H.Cohen 04-2009</p> <p>35</p> <p>Vulnerable atherosclerotic plaquePlaques that are considered vulnerable are at high risk of rupture</p> <p>PLAQUE EVOLUTION during the evolution of the atherosclerotic plaque there is a complex balance between : entry and way out of lipoproteins and leukocytes cell proliferation and cell death extracellular matrix production and remodelingH.Cohen 04-2009 37</p> <p>The vulnerable atherosclerotic plaque Fibrous cap</p> <p>InflammationT cellderived cytokine IFN-inhibit collagen synthesis of vsmc proteolytic enzymesdegrade the extracellular matrix.</p> <p>Intimal VSMCs</p> <p>Lipid core</p> <p>Adventitia inflammatory mediators processes that weaken the plaque's fibrous cap + enhance its vulnerability to ruptureH.Cohen 04-2009 38</p> <p>Characteristics of vulnerable Plaques1.</p> <p>lipid core that exceeds 40% of the total volume of the plaque high infiltration of macrophage and cells. T-lymphocyte</p> <p>2.</p> <p>3.</p> <p>thin, friable fibrous cap with a reduced collagen and VSMC content. increased circumferential wall stress on the fibrous cap.</p> <p>4. </p> <p>H.Cohen 04-2009</p> <p>39</p> <p>Characteristics of Vulnerable and Stable PlaquesFibrous cap MediaLumenArea of detail</p> <p>Lipid core</p> <p>Vulnerable PlaqueLumen Lipid core</p> <p> T lymphocyte Macrophage foam cell (tissue factor+) Activated intimal SMC</p> <p>Stable Plaque</p> <p> Normal medial SMCH.Cohen 04-2009</p> <p>40</p> <p>Libby. Circulation. 1995;91:28442850.</p> <p>Unstable Plaque</p> <p>Thin Fibrous Cap Lipid Core</p> <p>H.Cohen 04-2009</p> <p>41</p> <p>The relation between atherosclerosis and acute cardiac events</p> <p>Vulnerable plaques are believed to account for only 1020% of all coronary lesions. Responsible for the majority of acute clinical events !H.Cohen 04-2009 42</p> <p>Plaque Rupture</p> <p>Disruption or erosion of an atherosclerotic plaque:Allows circulating blood to contact the lesion and its</p> <p>highly thrombogenic, lipid-rich core.Adhesion and aggregation of platelets at the site of</p> <p>rupture.Formation of a partially occlusive, platelet-rich</p> <p>thrombus.</p> <p>H.Cohen 04-2009</p> <p>44</p> <p>Plaque RupturePlatelets aggregate at the site of rupture /erosionlipid core Lipidcore</p> <p>AdventitiaH.Cohen 04-2009 45</p> <p>Weissberg, 1999</p> <p>Unstable Angina With Plaque Disruption</p> <p>thrombus</p> <p>fibrous cap is tornH.Cohen 04-2009 46</p> <p>Davies. Atlas of Coronary Artery Disease. Lippincott-Raven, Philadelphia, Pennsylvania: 1998:81</p> <p>Ruptured Plaquearterial thrombosis by allowing blood coagulant factors to contact thrombogenic collagen of the extracellular matrix and tissue factor produced by foam cells in the lipid core of lesions</p> <p>Thrombus forms and extends into the lumenThrombus</p> <p>lipid core Lipidcore</p> <p>AdventitiaH.Cohen 04-2009 47</p> <p>If the initial disruption of the plaque is superficial, the thrombus will easily displaced.</p> <p>Plaque healing and growth will ensue. The thrombotic episode will pass either silently or with transient symptoms.H.Cohen 04-2009 48</p> <p>Ruptured PlaqueThromb usInflammat ory Cells Few SMC s</p> <p>Activated Macrophag es</p> <p>H.Cohen 04-2009</p> <p>49</p> <p>Clinical correlation</p> <p>Occlusion that is partial or intermittent -symptoms of Unstable Angina.</p> <p>Myocardial Infarction is the result of either a more persistent partial occlusion or total occlusion.</p> <p>H.Cohen 04-2009</p> <p>50</p> <p>Whether the attack is diagnosed as an episode of Unstable Angina or Myocardial Infarction upon: will depend</p> <p>the duration and extent of occlusion caused by the</p> <p>thrombus:</p> <p>H.Cohen 04-2009</p> <p>51</p> <p>..... </p> <p>In some cases, the thrombus may lyse without occluding the vessel - fibrinolytic or antithrombotic mechanisms.</p> <p>Such instances may be clinically silent. The healing process in arteries, as in skin wounds, involves the laying down of new extracellular matrix and fibrosis</p> <p>H.Cohen 04-2009</p> <p>52</p> <p>healing process in arteries</p> <p>The subsequent fibrosis and healing causes a fibroproliferative response that can lead to a more fibrous lesion</p> <p>"vulnerable" atheroma with a thin fibrous cap prone to rupture turns into a more "stable" fibrous plaque with a reinforced cap.</p> <p>Angioplasty of unstable coronary lesions may "stabilize" the lesions by a similar mechanism, producing a wound followed by healing.H.Cohen 04-2009 53</p> <p>Harrisons 2008</p> <p> A.</p> <p>Arterial remodeling -</p> <p>compensatory enlargement accounts for coronary arteriography to underestimate atherosclerosis. B. Rupture</p> <p>of the plaque's</p> <p>fibrous cap+thrombosis.Blood coagulant factors contact with thrombogenic collagen of the extracellular matrix .</p> <p> C. arterialH.Cohen 04-2009</p> <p>occlusion. and healing54</p> <p>Plaque rupture, thrombosis, and healing</p> <p> D. fibrosis</p> <p>Not all atheromata exhibit the same propensity to rupture</p> <p>H.Cohen 04-2009</p> <p>55</p> <p>Balancing the Stability EquationIncreased lipids Lipid oxidation Increased lipids Lipid oxidation Immune response Immune response Genetic susceptibility Genetic susceptibility Lipid-lowering drugs Lipid-lowering drugs Antioxidants? Antioxidants? ?????? ??????</p> <p>Inflammation</p> <p>Repair</p> <p>Unstable plaqueH.Cohen 04-2009</p> <p>Stable plaque56</p> <p>Weissberg, 1999</p> <p>Progression of AtherosclerosisCoronary artery at lesion-prone location Type II lesion Type III (preatheroma)</p> <p>Adaptive thickening (smooth muscle) Intima Media</p> <p>Macrophage foam cells</p> <p>Small pools of extracellular lipid</p> <p>Type IV (atheroma)</p> <p>Type Va (fibroatheroma)</p> <p>Type VI (complicated lesion)</p> <p>Core of extracellular lipid</p> <p>Fibrous thickening</p> <p>Thrombus Fissure and hematoma</p> <p>H.Cohen 04-2009 57 Adapted from Stary, in Fuster et al, eds. Atherosclerosis and Coronary Artery Disease. 1996.</p> <p>)Intravascular ultrasound (IVUS</p> <p>IVUS -documents the thickness and composition of plaque in the arterial wall. IVUS is compared with angiography to show that tight H.Cohen 04-2009 58 stenosis is not necessarily the site of an active plaque</p> <p>The Tight Stenosis Is Not the Active LesionA B</p> <p>B A AAtheroma Lumen</p> <p>B</p> <p>Rupture Site</p> <p>Lipid CoreH.Cohen 04-2009 Images supplied by Steven E. Nissen, MD, Cleveland Clinic. 59</p> <p>Most Acute MIs Are Associated With Less Severe Stenoses80 70</p> <p>Severity of Coronary Artery Stenosis Before Acute MI (n=195)</p> <p>% Patients</p> <p>60 50 40 30 20 10 0</p> <p> MI=</p> <p>70</p> <p>60</p> <p>Prevention and Treatment</p> <p>Correlation of Heart Disease with Cholesterol Levels</p> <p> LDL-C9002-40 H.Cohen 26</p> <p>H.Cohen 04-2009</p> <p>63</p> <p>Treatment of HyperlipidemiaHigh LDL-C High LDL-C Therapeutic Lifestyle Change Therapeutic Lifestyle Change Drug Therapy Drug Therapy</p> <p>H.Cohen 04-2009</p> <p>64</p> <p>Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.</p> <p>H.Cohen 04-2009</p> <p>65</p> <p>diet and exerciseH.Cohen 04-2009 66</p> <p>H.Cohen 04-2009</p> <p>67</p> <p>30 % Fat Low trans Low saturated</p> <p>50% Carb</p> <p>10-15% protein</p> <p>300 mg CholesterolH.Cohen 04-2009 68</p> <p>drugs in the treatment of hypercholesterolemia</p> <p>H.Cohen 04-2009</p> <p>69</p> <p>HMG CoA Inhibitors</p> <p>MEVASTATIN C23H36O6</p> <p>H.Cohen 04-2009</p> <p>70</p> <p>Statins: Mechanism of ActionCholesterol synthesis</p> <p>LDL receptor synthesisIntracellular Cholesterol</p> <p>VLDLR VLDLR</p> <p>LDL receptor mediated VLDL hepatic uptake of LDL and VLDL remnants Serum LDL-C Serum VLDL remnantsSerum IDL</p> <p>LDL</p> <p>Hepatocyte</p> <p>Systemic Circulation</p> <p>H.Cohen 04-2009</p> <p>71</p> <p>Pleiotropic Effects of Statin TherapyNon lipid-lowering effects of statin therapy</p> <p>Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels.</p> <p>it is possible that statins exert cholesterol-independent or 'pleiotropic' effectsH.Cohen 04-2009 72</p> <p>Pleiotropic Effects of Statins</p> <p>H.Cohen 04-2009</p> <p>73</p> <p> serum inflammatory markers plaque stabilization + thrombogenicity</p> <p>H.Cohen 04-2009</p> <p>74</p> <p>Potential Time Course of Statin EffectsLDL-C loweredVulnerable Inflammation plaques reduced stabilized Ischemic episodes reduced (12)</p> <p>Endothelial function restored</p> <p>Cardiac events reduced</p> <p>Days</p> <p>MonthsH.Cohen 04-2009</p> <p>Years75</p> <p> Reduction in LDL cholesterol levels, reduces the i...</p>