• ATEROSCLEROSI Athere pappa Sclerosis indurimento •
Morfologicamente o in termini dei processi biologici coinvolti nella genesi e progressione
The vascular wall
A, Graphic representation of the cross section of a small muscular artery (e.g., renal or coronary artery). B, Photomicrograph of histologic section containing a portion of an artery (A) and adjacent vein (V). Elastic membranes are stained black (internal elastic membrane of artery highlighted by arrow). Because it is exposed to higher pressures, the artery has a thicker wall that maintains an open, round lumen, even when blood is absent. Moreover, the elastin of the artery is more organized than in the corresponding vein. In contrast, the vein has a larger, but collapsed, lumen, and the elastin in its wall is diffusely distributed. (B, Courtesy of Mark Flomenbaum, M.D., Ph.D., Office of the Chief Medical Examiner, New York City.)
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Endothelial cells •
ECs comprise the single cell-thick, continuous lining of the entire cardiovascular system, collectively called the endothelium. Endothelial structural and functional integrity is fundamental to the maintenance of vessel wall homeostasis and normal circulatory function. ECs uniquely contain Weibel-Palade bodies, 0.1 μm-wide, 3 μm-long membrane-bound storage organelles that contain von Willebrand factor (vWF). ECs can be identified immunohistochemically with antibodies to PECAM-1 (CD31, a protein localized to interendothelial junctions), CD34, and vWF.
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Vascular endothelium is a versatile, multifunctional tissue having many synthetic and metabolic properties, and it is an active participant in blood-tissue interactions. As a semipermeable membrane, endothelium controls the transfer of small and large molecules across the vascular wall. In most regions the intercellular junctions are normally impermeable to large molecules such as plasma proteins; however, the relatively labile junctions between ECs may widen under the influence of hemodynamic factors (e.g., high blood pressure) and vasoactive agents (e.g., histamine in inflammation).
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Moreover, ECs play a role in the maintenance of a nonthrombogenic blood-tissue interface, the modulation of blood flow and vascular resistance, the metabolism of hormones, the regulation of immune and inflammatory reactions, and the growth regulation of other cell types, particularly SMCs. Frank loss (denudation) of EC stimulates thrombosis and SMC proliferation.
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The vascular endothelium has substantial phenotypic variability based on anatomic site and dynamic adaptation to local environmental cues. For example, EC populations that develop embryologically from different sites (large vessels vs. capillaries, arterial vs. venous) may have different characteristics.
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Structurally intact ECs can respond to various pathophysiologic stimuli by adjusting their usual (constitutive) functions and by expressing newly acquired (inducible) properties-a process termed endothelial activation.
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Inducers of endothelial activation include cytokines and bacterial products, which cause inflammation and septic shock; hemodynamic stresses and lipid products, critical to the pathogenesis of atherosclerosis (see later); advanced glycosylation end products (important in diabetes, as well as viruses, complement components, and hypoxia. Activated ECs, in turn, express adhesion molecules, and produce other cytokines and chemokines, growth factors, vasoactive molecules that result either in vasoconstriction or in vasodilation, major histocompatibility complex molecules, procoagulant and anticoagulant moieties, and a variety of other biologically active products.
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ECs influence the vasoreactivity of the underlying smooth muscle cells through the production of both relaxing factors (e.g., nitric oxide [NO]) and contracting factors (e.g., endothelin). Normal endothelial function is characterized by a balance of these factors and the ability of the vessel to respond appropriately to various pharmacologic stimuli (e.g., vasorelaxation in response to acetylcholine)
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Endothelial cell response to environmental stimuli: causes (activators) and consequences (induced genes).
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Endothelial Cell Properties and Functions Maintenance of Permeability Barrier Elaboration of Anticoagulant, Antithrombotic, Fibrinolytic Regulators Prostacyclin Thrombomodulin Heparin-like molecules Plasminogen activator Elaboration of Prothrombotic Molecules Von Willebrand factor Tissue factor Plasminogen activator inhibitor Extracellular Matrix Production (collagen, proteoglycans) Modulation of Blood Flow and Vascular Reactivity Vasconstrictors: endothelin, ACE Vasodilators: NO, prostacyclin Regulation of Inflammation and Immunity IL-1, IL-6, chemokines Adhesion molecules: VCAM-1, ICAM, E-selectin P-selectin Histocompatibility antigens Regulation of Cell Growth Growth stimulators: PDGF, CSF, FGF Growth inhibitors: heparin, TGF-β Oxidation of LDL
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Schematic diagram of the mechanism of intimal thickening, emphasizing smooth muscle cell migration to, and proliferation and extracellular matrix elaboration in, the intima. (Modified and redrawn from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, W.B. Saunders Co., 1989, p. 254.) Downloaded from: StudentConsult (on 8 May 2009 07:17 AM) © 2005 Elsevier
American Heart Association classification of human atherosclerotic lesions from the fatty dot (type I) to the complicated type VI lesion. The diagram also includes growth mechanisms and clinical correlations. (Modified from Stary HC, et al: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 92:1355, 1995.) Downloaded from: StudentConsult (on 8 May 2009 07:17 AM) © 2005 Elsevier
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Pathogenesis •
Understandably, the overwhelming importance of atherosclerosis has stimulated enormous efforts to discover its cause. Historically, two hypotheses for atherogenesis were dominant: • One emphasized cellular proliferation in the intima, whereas the other emphasized organization and repetitive growth of thrombi. The contemporary view of the pathogenesis of atherosclerosis incorporates elements of both older theories and accommodates the risk factors previously discussed. This concept, called the response to injury hypothesis, considers atherosclerosis to be a chronic inflammatory response of the arterial wall initiated by injury to the endothelium. Moreover, lesion progression is sustained by interaction between modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall. Central to this thesis are the following:
L’aterosclerosi • colpisce soprattutto le grosse arterie elastiche muscolari (aorta, carotidi, coronarie e cerebrali) • assente nei capillari nelle vene e nei vasi linfatici
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ATEROSCLEROSI • Ispessimento dell’intima dovuto ad accumulo di materiale amorfo costituito da lipidi di derivazione plasmatica; le strie lipidiche sono le prime evidenze della lesione. • I costituenti di una placca aterosclerotica sono: – Lipidi contenuti all’interno delle cellule schiumose o presenti come massa extracellulare – Collageno prodotto dalle cellule muscolari lisce – Calcio
ATEROSCLEROSI • EVOLUZIONE: – – – – – – –
Accumulo di lipidi Migrazione di macrofagi e linfociti T Migrazione di cellule muscolari lisce nell’intima Formazione della placca fibrolipidica Demolizione della placca Danno al cappuccio di rivestimento Formazione del trombo
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Chronic endothelial injury, usually subtle, with resultant endothelial dysfunction, yielding increased permeability, leukocyte adhesion, and thrombotic potential Accumulation of lipoproteins, mainly LDL, with its high cholesterol content, in the vessel wall Modification of lesional lipoproteins by oxidation Adhesion of blood monocytes (and other leukocytes) to the endothelium, followed by their migration into the intima and their transformation into macrophages and foam cells Adhesion of platelets Release of factors from activated platelets, macrophages, or vascular cells that cause migration of SMCs from media into the intima Proliferation of smooth muscle cells in the intima, and elaboration of extracellular matrix, leading to the accumulation of collagen and proteoglycans Enhanced accumulation of lipids both within cells (macrophages and SMCs) and extracellularly.
Accumulo eccessivo di lipoporoteine a bassa densità (LDL)
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Migrazione dei monociti e linfociti
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Placche lipidiche
Placca calcificata
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Ulcerazione dell’ dell’endotelio espone collagene con formazione di un trombo di fibrinafibrina-piastrine il trombo
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trombo
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ATEROSCLEROSI • MECCANISMO MOLECOLARE: – 1. ossidazione delle LDL e APOLIPOPROTEINE (lecitina convertita in iso-lecitina chemiotattica per i macrofagi)
– 2. perossidazione dei lipidi e la formazione di aldeidi (alchenali) – 3. aldeidi modificano l’apolipoproteina B100 – 4. l’apolipoproteina B100 modificata viene riconosciuta dai recettori scavanger dei macrofagi
Modificazione degli epitopi, rottura della tolleranza e formazione di anticorpi contro LDL modiicate
ATEROSCLEROSI • LA PROVA DEL MECCANISMO: – – – –
A. Gli antiossidanti prevengono la formazione di strie B. Le LDL estratte dagli animali e uomini sono ossidate C. Sono presenti Anticorpi verso gli epitopi di Ox-LDL D. Dati epidemiologici dimostrano una correlazione inversa tra patologia e consumo di antiossidanti come vitamina C e βcarotene – E. Anti-infiammatori riducono la fromazione delle placche
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Fattori di rischio
Non modificabili
Modificabili
Età Sesso Predisposizione ereditaria
Iperlipidemia Diabete Ipertensione Fumo Omocisteina
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IPERLIPIDEMIA e IPERTENSIONE: angiotensina-II, anione superossido, citochine infiammatorie IL-6 e MCP-1 (cellule muscolari) VCAM (endotelio)
INFEZIONI: attivazione generale (presenza di clamidia nelle placche, CRP correla con prognosi sfavorevole)
DIABETE: Reazione del glucosio con proteine: GLICAZIONE
OBESITA’: alterazione equilibrio VLDL/HDL e quindi del potenziale aterogenico attivazione del tessuto adiposo e sintesi di TNF-a e IL-6 HDL trasportano antiossidanti
Iperlipidemia familiare di tipo II Aumento della concentrazione plasmatica di LDL dovuta all’assenza o alla ridotta funzione dell’LDL receptor responsabili del catabolismo delle LDL. L’eccesso di LDL si lega agli SCAVENGER RECEPTOR presenti sui monociti che attivati in macrofagi diventeranno FOAM cells and…… Iperlipidemia familiare combinata Eccessiva secrezione della proteina di trasporto apoproteina B che porta ad eccessiva produzione di LDL e VLDL
IPERTENSIONE vasocostrizione
Angiotensina II
Crescita cellule muscolare Ca++ intracellulare Contrazione Sintesi proteica Ipertrofia Effetto proinfiammatorio
Radicali liberi/Superox NO2 Adesività dei leucociti Resistenza periferica
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