Diese Präsentation wurde erfolgreich gemeldet.
Die SlideShare-Präsentation wird heruntergeladen. ×

The vascular biology of atherosclerosis

Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Anzeige
Wird geladen in …3
×

Hier ansehen

1 von 89 Anzeige
Anzeige

Weitere Verwandte Inhalte

Diashows für Sie (20)

Andere mochten auch (20)

Anzeige

Ähnlich wie The vascular biology of atherosclerosis (20)

Anzeige

Aktuellste (20)

The vascular biology of atherosclerosis

  1. 1. PATHOPHYSIOLOGY OF ATHEROSCLEROSIS 23/05/2016
  2. 2. • Atherosclerosis- An epidemic of 21st century • As populations increasingly survive early mortality caused by communicable diseases and malnutrition(as in 18-19th centuries) • Economic development and urbanization promoted habits of poor diet (e.g., a surfeit of saturated fats) and diminished physical activity, which can favor atherogenesis.
  3. 3. • Atherosclerosis is characterized by intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques) that protrude into vessel lumens. • Besides mechanically obstructing blood flow, atherosclerotic plaques can rupture, leading to catastrophic vessel thrombosis; plaques also weaken the underlying media and thereby lead to aneurysm formation.
  4. 4. An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a white fibrous cap.
  5. 5. • CABG surgery is the standard of care for patients with three-vessel disease or left main disease with reduced ejection fraction, as supported by many studies showing a reduction in morbidity and mortality relative to percutaneous coronary intervention. • Of the graft options — vein graft versus internal mammary arteries (IMAs) — the latter have the better long-term patency; however, only 5–10% of patients receive bilateral IMAs, because of the increased perioperative morbidity, mortality, duration of operation, and risk of sternal wound problems that are reported for this type of graft. • Of note, 10–25% of saphenous vein grafts (SVGs) occlude from thrombosis within 1 year after CABG surgery, and an additional 1–2% occlude each year from 1 year to 5 years after CABG surgery. Moreover, 4–5% occlude each year from 6 years to 10 years postoperatively, owing to accelerated development of atherosclerosis.
  6. 6. • Currently, percutaneous coronary intervention with stents (either bare-metal stents (BMS) or drug-eluting stents (DES)) is the most commonly performed procedure for the treatment of patients with symptomatic CAD. • Delayed arterial healing with poor strut coverage is recognized as the primary substrate for stent thrombosis attributed to the first-generation DES. • However, we have reported that neoatherosclerosis within the ‘in-stent’ segment is another complication of first-generation and second-generation DES, resulting in late stent failure from restenosis or stent thrombosis induced by plaque rupture.
  7. 7. • The temporal presentation of atherosclerosis in the form of clinical events differs between native CAD, which develops over decades, and vein graft atherosclerosis and in-stent neoatherosclerosis, which occur within months to a few years. • Todays’ discussion is focused on the structural characteristics of human atherosclerotic plaques for these three entities, with emphasis on disease progression where divergent or shared characteristics of lesion morphology exist.
  8. 8. • Atherosclerosis also displays heterogeneity in time; this disease has both chronic and acute manifestations. Few human diseases have a longer “incubation” period than atherosclerosis, which begins to affect the arteries of many Americans in the second and third decades of life. • Indeed, many young Americans have abnormal thickening of the coronary arterial intima; yet typically, symptoms of atherosclerosis emerge only after several decades of delay.
  9. 9. Strong JP, Malcolm GJ, McMahan CA, et al: Prevalence and extent of atherosclerosis in adolescents and young adults. JAMA 281:727, 1999
  10. 10. slightly slower progression of lesions affects the right coronary artery Strong JP, Malcolm GJ, McMahan CA, et al: Prevalence and extent of atherosclerosis in adolescents and young adults. JAMA 281:727, 1999
  11. 11. ATHEROSCLEROSIS • Heterogenous in time? • Heterogenous in location? • Why stenosis in some and ectasia in others?
  12. 12. Native coronary artery disease
  13. 13. HISTORY • 1970- Russell Ross- SMC proliferation in response to injury to arterial wall. • 1990- libby and co- complex interaction between risk factors and inflammation • 1990- Fuster and co- plaque progression a staged event(endothelium- intima-media) • Deep plaque fissures and ulcerations were identified as cause of luminal thrombosis and clinical presentation of ACS.
  14. 14. Basic events are……………..
  15. 15. FAILED TO INCLUDE ALL CAUSES OF THROMBOSIS- PLAQUE RUPTURE, SURFACE EROSION(25-30%) AND ERUPTIVE CALCIFIED NODULES(<5%). NO MENTION OF PRECURSOR LESIONS TO PLAQUE RUPTURE- VULNERABLE PLAQUES (aka THIN CAP FIBROATHEROMA) NO CONCEPT OF PLAQUE HEALING
  16. 16. Simplified scheme for classifying atherosclerotic lesions in human coronary arteries. Solid arrows indicate the main pathway of plaque progression, and dashed arrows indicate infrequent pathways. Abbreviations: MMP, matrix metalloproteinase; SMC, smooth muscle cell.
  17. 17. ATHEROSCLEROSIS INITIATION • On initiation of an atherogenic diet, typically rich in cholesterol and saturated fat, small lipoprotein particles accumulate in the intima Hyperlipidemia, hypertension,homocysteine, smoking,infection,toxins, hemodynamic factors
  18. 18. • These lipoprotein particles appear to decorate the proteoglycan of the arterial intima and tend to coalesce into aggregates. • The binding of lipoproteins to proteoglycan in the intima leads to their capture and retention, accounting for their prolonged residence time. • Lipoprotein particles bound to proteoglycan have increased susceptibility to oxidative or other chemical modifications, considered by many to contribute to the pathogenesis of early atherosclerosis • Contributors to oxidative stress in the nascent atheroma could include reduced (NADH/NADPH) oxidases expressed by vascular cells, lipoxygenases expressed by infiltrating leukocytes, or the enzyme myeloperoxidase.
  19. 19. Oxidized LDL - a potent inflammatory agent When an elevated serum levels of LDL cholesterol overwhelm the antioxidant properties of the healthy endothelium, it results in abnormal endothelial metabolism of LDL. • Stimulates the expression of adhesion molecules on endothelial cell. • OxLDL has chemoattractant activity on monocytes and promotes their differentiation into macrophages and also inhibits their mobility. • Triggers the release of proinflammatory cytokines in macrophages Altogether these findings point to a role of oxLDL as a very early trigger of vascular inflammation.
  20. 20. LEUKOCYTE RECRUITMENT AND RETENTION • Another hallmark of atherogenesis, leukocyte recruitment and accumulation also occurs early in lesion generation. • The normal EC generally resists adhesive interactions with leukocytes. • Even in inflamed tissues, most recruitment and trafficking of leukocytes occurs in postcapillary venules and not in arteries. • Very soon after initiation of hypercholesterolemia, however, leukocytes adhere to the endothelium and move between EC junctions, or even penetrate through ECs (transcytosis) to enter the intima, where they begin to accumulate lipids and become foam cells.
  21. 21. • In addition to the monocyte, T lymphocytes also tend to accumulate in early human and animal atherosclerotic lesions. • The expression of certain leukocyte adhesion molecules on the surface of the EC regulates the adherence of monocytes and T cells to the endothelium. • These include: – Vascular Cell Adhesion molecule(VCAM-1) (Interacts with only those classes of leukocytes that accumulate in nascent atheroma-monocytes and T cells) – P-Selectin – Intercellular adhesion molecule-1(ICAM-1) – E-Selectin
  22. 22. So far…..
  23. 23. LEUCOCYTE PENETRATION • Once adherent to the endothelium, leukocytes must receive a signal to penetrate the endothelial monolayer and enter the arterial wall. • The current concept of directed migration of leukocytes involves the action of protein molecules known as chemoattractant cytokines or chemokines. • Among the many chemokines implicated in atherogenesis, few are of particular interest in recruiting the mononuclear cells characteristic of the early atheroma. – Monocyte chemoattractant protein 1(MCP-1) – Fractalkine – Chemoattractants induced by Interferon-gamma
  24. 24. Leucocyte retention • The accumulation of monocytes in plaques depends not only on their recruitment, but also on their retention. • Recent work has implicated netrin-1 interacting with its receptor UNC5b (both induced by hypoxia) as a protein that retards macrophages from exiting plaques
  25. 25. So far…..
  26. 26. INTRACELLULAR LIPID ACCUMULATION: FOAM CELL FORMATION • The monocyte, once recruited to the arterial intima, can imbibe lipid and become a foam cell or lipid-laden macrophage. • Although most cells can express the classic cell surface receptor for LDL, that receptor does not mediate foam cell accumulation. • This is evident clinically, because tendinous xanthomas filled with foamy macrophages still develop in patients lacking functional LDL receptors (familial hypercholesterolemia homozygotes). • The LDL receptor does not mediate foam cell formation, because of its exquisite regulation by cholesterol. As soon as a cell collects enough cholesterol for its metabolic needs from LDL capture, an elegant transcriptional control mechanism quenches expression of the receptor.
  27. 27. WHAT MEDIATES EXCESSIVE LIPID UPTAKE OF MACROPHAGES? • SCAVENGER RECEPTORS- These surface molecules, belonging to several families, bind modified rather than native lipoproteins and participate in their internalization. • CD36 • MACROSIALIN
  28. 28. M-CSF GM-CSF INTERLEUKIN-3 FOAM CELL FORMATION REPLICATION SCAVENGER RECEPTORS, CD36, MACROSIALIN, Once macrophages have taken up residence in the intima and become foam cells, they can replicate. Monocyte recruitment from blood initially populates the nascent lesion with mononuclear phagocytes, but local proliferation predominates in the established lesion. The factors that trigger macrophage cell division in the atherosclerotic plaque include hematopoietic growth factors such as macrophage colony-stimulating factor (M-CSF), granulocyte- macrophage colony-stimulating factor (GM-CSF), and interleukin-3. Up to this point in the development of the nascent atheroma, the lesion consists primarily of lipid- engorged macrophages. Complex features such as fibrosis, thrombosis, and calcification do not characterize the fatty streak, the precursor lesion of the complex atheroma. Several lines of evidence suggest that such fatty streaks can regress, at least to some extent.
  29. 29. EVOLUTION OF ATHEROMA
  30. 30. SMOOTH MUSCLE CELL MIGRATION AND PROLIFERATION • Whereas the early events in atheroma initiation involve primarily altered endothelial function and recruitment and accumulation of leukocytes, the subsequent evolution of atheroma into more complex plaques also involves SMCs. • SMCs in the normal arterial tunica media differ considerably from those in the intima of an evolving atheroma. • Some SMCs probably arrive in the arterial intima early in life; others accumulate in advancing atheroma after recruitment from the underlying media into the intima or arise from blood-borne precursors.
  31. 31. • The accumulation of SMCs during atherosclerosis and growth of the intima does not occur in a continuous and linear fashion. • Bursts of SMC replication may occur during the life history of a given atheromatous lesion. • Episodes of plaque disruption with thrombosis may expose SMCs to potent mitogens, including the coagulation factor thrombin itself. This results in bursts of smooth muscle activity.
  32. 32. SMOOTH MUSCLE CELL DEATH DURING ATHEROGENESIS • In addition to SMC replication, death of these cells also may participate in complication of the atherosclerotic plaque Some SMCs in advanced human atheroma exhibit fragmentation of their nuclear DNA that is characteristic of programmed cell death or apoptosis. Apoptosis may occur in response to inflammatory cytokines present in the evolving atheroma. In addition to soluble cytokines that may trigger programmed cell death, T cells in atheroma may participate in eliminating some SMCs. Thus SMC accumulation in the growing atherosclerotic plaque probably results from a tug-of-war between cell replication and cell death
  33. 33. ARTERIAL EXTRACELLULAR MATRIX • Extracellular matrix, rather than cells themselves, makes up much of the volume of an advanced atherosclerotic plaque. • Accordingly, extracellular constituents of plaque also require consideration. • The major extracellular matrix macromolecules that accumulate in atheroma include interstitial collagens (types I and III) and proteoglycans such as versican, biglycan, aggrecan, and decorin. • Elastin fibers also may accumulate in atherosclerotic plaques. • Arterial SMCs produce these matrix molecules in disease, just as they do during development and maintenance of the normal artery. • Stimuli for excessive collagen production by SMCs include platelet-derived growth factor (PDGF) and TGF-β.
  34. 34. ARTERIAL EXTRACELLULAR MATRIX • Much as with the accumulation of SMCs, extracellular matrix secretion also depends on a balance, as noted earlier. • In this case, the counterpoise to biosynthesis of the extracellular matrix molecules is breakdown catalyzed in part by catabolic enzymes, notably the matrix metalloproteinases (MMPs). • Dissolution of extracellular matrix macromolecules undoubtedly contributes to the migration of SMCs as they penetrate into the intima from the media through a dense extracellular matrix, traversing the elastin-rich internal elastic lamina.
  35. 35. • Extracellular matrix breakdown also likely plays a role in arterial remodeling that accompanies lesion growth. • During the early life of an atheromatous lesion, plaques grow outwardly, in an abluminal direction, rather than inwardly, in a way that would lead to luminal stenosis. • This outward growth of the intima leads to an increase in the caliber of the entire artery. This so-called positive remodeling or compensatory enlargement must involve turnover of extracellular matrix molecules to accommodate the circumferential growth of the artery. • Luminal stenosis tends to occur only after the plaque burden exceeds some 40% of the cross-sectional area of the artery.
  36. 36. ANGIOGENESIS IN PLAQUES • Atherosclerotic plaques develop their own microcirculation as they grow, because of endothelial migration and replication. • Histologic examination with appropriate markers for ECs reveals a rich neovascularization in evolving plaques. • These microvessels probably form in response to angiogenic peptides overexpressed in atheroma. • These angiogenesis factors include vascular endothelial growth factor (VEGF) forms of fibroblast growth factors, placental growth factor (PlGF), and oncostatin M.
  37. 37. ANGIOGENESIS IN PLAQUES • These microvessels within plaques probably have considerable functional significance. • provide a relatively large surface area for the trafficking of leukocytes,. Indeed, in the advanced human atherosclerotic plaque, microvascular endothelium displays mononuclear cell–selective adhesion molecules such as VCAM-1 much more prominently than does the macrovascular endothelium overlying the plaque. • may allow growth of the plaque, overcoming diffusion limitations on oxygen and nutrient supply. • Finally, the plaque microvessels may be friable and prone to rupture like the neovessels in the diabetic retina. • Hemorrhage and thrombosis in situ could promote a local round of SMC proliferation and matrix accumulation in the area immediately adjacent to the microvascular disruption
  38. 38. Intraplaque hemorrhage surrounding neovessels in an atheroma. A, B, A typical human atherosclerotic plaque, stained for von Willebrand factor (VWF) (A) and for iron by Prussian blue (B). The von Willebrand factor stains the endothelial cells that line the microvascular channels and lakes. Note the extravasated von Willebrand factor, which colocalizes with iron deposition, indicating hemosiderin deposition consistent with an intraplaque hemorrhage.
  39. 39. PLAQUE MINERALIZATION • Plaques often develop areas of calcification as they evolve. • Some subpopulations of SMCs may foster calcification by enhanced secretion of cytokines such as bone morphogenetic proteins, homologues of TGF-β. • Receptor activator of NF-κB ligand (RANKL), a member of the tumor necrosis factor family, appears to promote SMC mineral formation through a bone morphogenetic protein 4 (BNP4)– dependent pathway. • The transcription factor Runx-2, activated by inflammatory mediators and oxidative stress among other stimuli, can promote SMC mineral formation by activating AKT (i.e., protein kinase B) • Microparticles elaborated by macrophages may provide niduses for plaque calcification, yielding another link between inflammatory cells and cardiovascular calcification
  40. 40. COMPLICATIONS OF ATHEROSCLEROSIS SO FAR….INITIATION AND EVOLUTION OF ATHEROSCLEROTIC PLAQUE
  41. 41. ARTERIAL STENOSIS • The initiation and evolution of the atherosclerotic plaque generally last many years, during which the affected person often has no symptoms. • After the plaque burden exceeds the capacity of the artery to remodel outward, encroachment on the arterial lumen begins. • During the chronic asymptomatic or stable phase of lesion evolution, growth probably occurs discontinuously, with periods of relative quiescence punctuated by episodes of rapid progression
  42. 42. • Human angiographic studies support this discontinuous growth of coronary artery stenoses. • Eventually, the stenoses may progress to a degree that impedes blood flow through the artery. Lesions that produce stenoses of greater than 70% can cause flow limitations under conditions of increased demand. • This type of athero-occlusive disease commonly produces chronic stable angina pectoris or intermittent claudication on increased demand. • Thus the symptomatic phase of atherosclerosis usually begins many decades after lesion initiation.
  43. 43. • In many cases of myocardial infarction, however, no history of previous stable angina heralds the acute event. • Several kinds of imaging data suggest that many myocardial infarctions result not from high-grade stenoses but from lesions that do not limit flow. • Acute coronary syndromes often result from thrombi that form as a consequence of disruption of plaques that do not produce a critical stenosis. • These findings do not imply that small atheromas cause most myocardial infarctions. • Indeed, culprit lesions of acute myocardial infarction may be sizable; but they may not produce a critical luminal narrowing because of compensatory enlargement. • Of course, critical stenoses do cause myocardial infarctions, and high-grade stenoses are more likely to cause acute myocardial infarction than are nonocclusive lesions; yet because the noncritical stenoses by far outnumber the tight focal lesions in a given coronary tree, the lesser stenoses cause more infarctions, even though high-grade stenoses have a greater individual probability of causing infarction.
  44. 44. THROMBOSIS AND ATHEROMA COMPLICATION • 2 MAJOR MODES OF PLAQUE DISRUPTION PROVOKE MOST CORONARY THROMBI : –PLAQUE RUPTURE (rupture of plaque’s fibrous cap) 75% –SUPERFICIAL PLAQUE EROSION 25%
  45. 45. PLAQUE RUPTURE AND THROMBOSIS • IMBALANCE BETWEEN MECHANICAL STRENGTH OF THE FIBROUS CAP AND THE FORCES THAT IMPINGE ON IT. • Interstitial forms of collagen provide most of the biomechanical resistance to disruption of the fibrous cap. Hence the metabolism of collagen probably participates in regulating the propensity of a plaque to rupture. • Factors that decrease collagen synthesis by SMCs can impair their ability to repair and to maintain the plaque’s fibrous cap. SO IF THE FACTORS THAT DEGRADE COLLAGEN OUTWEIGH THE FACTORS RESPONSIBLE FOR ITS PRODUCTION ------IT WILL RESULT IN A THIN CAP FIBROATHEROMA (previously called VULNERABLE PLAQUE)
  46. 46. • A RELATIVE LACK OF SMCs secondary to INFLAMMATORY MEDIATORS IS ALSO RESPONSIBLE. • PROMINENT ACCUMULATION OF MACROPHAGES WITH A LARGE LIPID POOL is also responsible
  47. 47. PROMINENT ACCUMULATION OF MACROPHAGES WITH A LARGE LIPID POOL • From a strictly biomechanical viewpoint, a large lipid pool can serve to concentrate biomechanical forces on the shoulder regions of plaques, where they frequently fracture. • From a metabolic standpoint, the activated macrophage characteristic of the plaque’s core region produces the cytokines and the matrix-degrading enzymes thought to regulate aspects of matrix catabolism and SMC apoptosis in turn. • Apoptotic macrophages and SMCs can generate particulate tissue factor, a potential instigator of microvascular thrombosis after spontaneous or iatrogenic plaque disruption. • The success of lipid-lowering therapy in reducing the incidence of acute myocardial infarction or unstable angina in patients at risk may result from a reduced accumulation of lipid and a decrease in inflammation and plaque thrombogenicity. • Animal studies and accumulated data from monitoring peripheral markers of inflammation in humans support this concept
  48. 48. THROMBOSIS DUE TO SUPERFICIAL EROSION OF PLAQUES • In humans, superficial erosion appears more likely to cause fatal acute myocardial infarction in women and in persons with hypertriglyceridemia and diabetes mellitus, but the underlying molecular mechanisms remain obscure. • VARIOUS POSSIBLE MECHANISMS OF ENDOTHELIAL DAMAGE: Apoptosis of ECs could contribute to desquamation of ECs in areas of superficial erosion. Likewise, MMPs, such as certain gelatinases specialized in degrading the nonfibrillar collagen found in the basement membrane (e.g., collagen type IV), also may sever the tetherings of the EC to the subjacent basal lamina and promote their desquamation. Vasospasm of atherosclerotic coronary arteries in rabbits can promote endothelial damage, thrombosis, and myocardial infarction
  49. 49. DO ALL PLAQUE DISRUPTIONS CAUSE ACS/ARTERIAL OCCLUSION • Most plaque disruptions do not give rise to clinically apparent coronary events. • Careful pathoanatomic examination of hearts obtained from patients who have succumbed to noncardiac death has shown a surprisingly high incidence of focal plaque disruptions with limited mural thrombi. • Moreover, hearts fixed immediately after explantation from persons with severe but chronic stable coronary atherosclerosis who had undergone transplantation for ischemic cardiomyopathy show similar evidence for ongoing but asymptomatic plaque disruption.
  50. 50. DO ALL PLAQUE DISRUPTIONS CAUSE ACS/ARTERIAL OCCLUSION • Experimentally, in atherosclerotic nonhuman primates, mural platelet thrombi can complicate plaque erosions without causing arterial occlusion. • Therefore repetitive cycles of plaque disruption, thrombosis in situ, and healing probably contribute to lesion evolution and plaque growth. • The “burned-out” fibrous and calcific atheroma may represent a Healed plaque with rupture and thrombosis. • Such episodes of thrombosis and healing constitute one type of crisis in the history of a plaque that may cause a burst of SMC proliferation, migration, and matrix synthesis Plaque disruptions with healing underlie many thrombi that cause sudden death, indicating that nonocclusive thrombosis may precede the fatal event more frequently than has been previously recognized
  51. 51. Thrombosis depends not only on the “solid state” of the plaque that may rupture or erode to trigger thrombosis but also on the “fluid phase” of blood that determines the consequences of a given plaque disruption. The amount of tissue factor in the lipid core of a plaque (the solid state) can control the degree of clot formation that will ensue after disruption. The level of fibrinogen in the fluid phase of blood can influence whether a plaque disruption will cause an occlusive thrombus that can precipitate an acute ST- segment elevation myocardial infarction or yield merely a small mural thrombus. Likewise, elevated levels of inhibitors of fibrinolysis, such as plasminogen activator inhibitor 1 (PAI-1), will impede the ability of endogenous thrombolytic enzymes to limit thrombus growth or persistence. Inflammation regulates both the fluid-phase and solid- state factors delineated earlier, including tissue factor, fibrinogen, and PAI-1. This notion helps explain the links between inflammation and thrombotic complications of atherosclerosis that have emerged from laboratory and clinical investigations.
  52. 52. Why atherosclerosis manifests as stenosis/aneurysms(directionally opposite manners)?? • Atherosclerosis mostly causes stenosis in the coronaries while ectasia of the abdominal aorta? WHY? • Histologic examination shows considerable distinction between occlusive atherosclerotic disease and aneurysmal disease. In typical coronary artery atherosclerosis, expansion of the intimal lesion produces stenotic lesions. The tunica media underlying the expanded intima often is thinned, but its general structure remains relatively well preserved. • By contrast, transmural destruction of the arterial architecture occurs in aneurysmal disease. • In particular, the usually well-defined laminar structure of the normal tunica media disappears with obliteration of the elastic laminae. The medial SMCs, usually well preserved in typical stenotic lesions, are notable for their paucity in the media of advanced aortic aneurysms.
  53. 53. Note the concentric laminae of elastic tissue that form sandwiches with successive layers of SMCs. Each level of the elastic arterial tree has a characteristic number of elastic laminae
  54. 54. • PATHOPHYSIOLOGY IS STILL OBSCURE. • Widespread destruction of the elastic laminae suggests a role for degradation of elastin, collagen, and other constituents of the arterial extracellular matrix. • Many studies have documented overexpression of matrix-degrading proteinases, including MMPs, in human aortic aneurysm specimens. Clinical trials are testing the hypothesis that MMP inhibitors can reduce the expansion of aneurysms. • In atherosclerotic mice, angiotensin II potentiates aneurysm formation. Alterations in TGF-β signaling can predispose to aneurysm formation. Mutations in TGF-β receptors can cause arterial ectasia. • Thus heightened elastolysis may explain the breakdown of the usually ordered structure of the tunica media in this disease. • Although extracellular matrix degradation and SMC death also occur in sites where atherosclerosis causes stenosis, they appear to predominate in regions of aneurysm formation and to affect the tunica media much more extensively, for reasons that remain obscure.
  55. 55. INFRARENAL AORTA IS HIGHLY PRONE TO THE DEVELOPMENT OF ATHEROSCLEROSIS? WHY? • Data from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study show that the dorsal surface of the infrarenal abdominal aorta has a particular predilection for the development of fatty streaks and raised lesions in Americans younger than 35 years of age who succumbed for noncardiac reasons . • Because of the absence of vasa vasorum, the relative lack of blood supply to the tunica media in this portion of the abdominal aorta might explain the regional susceptibility of this portion of the arterial tree to aneurysm formation. • In addition, the lumbar lordosis of the biped human may alter the hydrodynamics of blood flow in the distal aorta, yielding flow disturbances that may promote lesion formation.
  56. 56. Comparison of atherosclerotic processes In native vessel, vein grafts and in-stent neoatherosclerosis • Restenosis Vs Instent stenosis • In-stent atherosclerosis or ‘neoatherosclerosis’ is histologically identified by the lipid-laden foamy macrophages with or without complications of a necrotic core and/or calcification within the nascent intima. • In all cases, necrotic cores of neoatherosclerosis do not communicate with the underlying native plaque. • Clusters of macrophage-derived foam cells within the peristrut regions, or near the luminal surface, are the most- frequent and earliest lesion of neoatherosclerosis.
  57. 57. Comparison of atherosclerotic processes In native vessel, vein grafts and in-stent neoatherosclerosis • In contrast to the decades that it takes for atherosclerosis to develop in native coronary disease, vein-graft atherosclerosis and in-stent neoatherosclerosis develop over a period of months to a few years. • This temporal difference might reflect the morphological diversity relative to the natural history of progression among these entities. • Adaptive intimal thickening in native arteries within the first year after stent implantation parallels the neointimal hyperplasia observed in vein grafts
  58. 58. • SMC proliferation without macrophage foam cell infiltration is frequently observed in BMS implants, especially in those aged <5 years. • The most recognized feature of atherosclerosis common to vein grafts and stents is macrophage infiltration, which best resembles ‘fatty streaks’. • Rather than individual foam cells interspersed throughout the intima, macrophages in vein grafts and stents have a tendency to accumulate as surface clusters or in peristrut regions, which is different from native disease.
  59. 59. • Another important distinction is that intimal xanthomas or ‘fatty streaks’ in native arteries might regress and are considered nonprogressive lesions, whereas foamy macrophage clusters in stents or SVGs seem to progress to form necrotic cores through cell death. • In native coronary disease, pathological intimal thickening with lipid pools are common and considered a passageway to lesion progression; however, pathological intimal thickening is rarely present in vein grafts or DES, but can be seen in BMS.
  60. 60. • In native disease, lipid pools and necrotic cores are localized to the deep intimal layers. The necrotic cores in neoatherosclerosis are more frequently superficial and, consequently, rarely present as early fibroatheromas; they instead occur as late fibroatheromas or, in some cases, TCFAs. • Typical SVG atherosclerosis is often concentric and diffuse, with a less well-defined fibrous cap than in native coronary disease; the cap seems fragile and vulnerable to rupture
  61. 61. • Coronary thrombi in neoatherosclerosis are primarily associated with plaque rupture; • in-stent erosions are rarely observed in BMS and DES, although erosions in this setting might not always be directly tied to the entity of neoatherosclerosis. • Plaque erosion in vein grafts is a rare event and has been mostly observed at distal anastomotic sites. • chronic total occlusion lesions consisting of organized thrombi within the stent can originate from plaque rupture associated with neoatherosclerosis in addition to thrombi that develop as a consequence of incomplete healing of the stent.
  62. 62. CONCLUSIONS • Natural causes of luminal thrombosis in native coronary disease predominantly occur from plaque rupture, but also occur as a result of erosion. • Precursor lesion of plaque rupture, identified as ‘vulnerable plaque’ or ‘TCFA’, seems an appropriate target for interventional treatment irrespective of the extent of luminal narrowing.
  63. 63. CONCLUSIONS • Accelerated atherosclerosis in SVGs or occurring within stents (known as ‘neoatherosclerosis’) is typically identified by macrophage foam cell infiltration, intraplaque haemorrhage, and a thin fibrous cap. • Apoptosis of lipid-rich macrophages is thought to give rise directly to necrosis in accelerated disease, rather than transitioning through pathological intimal thickening, as occurs in native disease.
  64. 64. CONCLUSIONS • Within the past 5 years, neoatherosclerosis has been identified as a contributing factor to late thrombosis attributed to percutaneous coronary intervention with stents. The incidence of neoatherosclerosis is more frequent and rapid in DES than in BMS.
  65. 65. THANKYOU
  66. 66. Criteria for American Heart Association lesion classification system and correspondence with classification of gross arterial specimens
  67. 67. Coronary plaque features responsible for acute thrombosis, which comprise three different morphologies: rupture, erosion, and calcified nodules. Ruptured plaques are thin fibrous cap atheromas with luminal thrombi (Th). These lesions usually have an extensive necrotic core (NC) containing large numbers of cholesterol crystals and a thin fibrous cap (<65 µm) infiltrated by foamy macrophages and T lymphocytes. The fibrous cap is thinnest at the site of rupture and consists of a few collagen bundles and rare smooth muscle cells. The luminal thrombus is in communication with the lipid-rich necrotic core. Erosions occur over lesions rich in smooth muscle cells and proteoglycans. Luminal thrombi overlie areas lacking surface endothelium. The deep intima of the eroded plaque often shows extracellular lipid pools, but necrotic cores are uncommon; when present, the necrotic core does not communicate with the luminal thrombus. Inflammatory infiltrate is usually absent, but if present, is sparse and consists of macrophages and lymphocytes. Calcified nodules are plaques with luminal thrombi showing calcific nodules protruding into the lumen through a disrupted thin fibrous cap. There is absence of an endothelium at the site of the thrombus, and inflammatory cells (macrophages, T lymphocytes) are absent.
  68. 68. A) Intimal thickening is normal in all age groups and is characterized by smooth muscle cell accumulation within the intima. (B) Intimal xanthoma or so-called fatty streak corresponds to the accumulation of predominantly macrophages within the intima; these lesions have been shown to regress in later adult life. (C) Pathologic intimal thickening marks the first of the progressive lesions and denotes the accumulation of extracellular lipid in the absence of apparent necrosis.
  69. 69. (D) Fibrous cap atheroma indicates the presence of an encapsulated necrotic core. (E) The core may eventually become thinned (thin-cap fibroatheroma). (F) This lesion may rupture, allowing contact of the contents of the necrotic core, causing a luminal thrombosis. EL: extracellular lipid; NC: necrotic core; FC: fibrous cap; Th: thrombus.
  70. 70. The thrombus of a plaque erosion occurs in the absence of rupture and may overlie a substrate of pathologic intimal thickening (top left) or fibrous cap atheroma (top right). Eruptive calcified nodules represent a rare form of coronary thrombus. Acute rupture may progress to healing (healed plaque rupture) with resolution of the luminal occlusion. Ca 2+ : calcification; NC: necrotic core; FC: fibrous cap; Th: thrombus.
  71. 71. The lesions of atherosclerosis do not occur in a random fashion. •Hemodynamic factors •activated vascular endothelium Sites of predeliction: • regions of branching •marked curvature
  72. 72. activated vascular endothelium : Two contradictory hypotheses : •high shear stress (400 dyn/cm2) via endothelial injury and denudation, •low shear stress as an atherogenic force : the most accepted. CONCEPTS: •Vascular endothelium as a transducer of haemodynamic forces •Potential shear stress receptors and associated proteins : •potassium channel and a stretch-activated channel •Integrins •caveolae •G proteins Current Opinion in Lipidology 2000, 11:167±177
  73. 73. Endothelial gene regulation by complex shear forces : PDGF-A expressionPulsatile shear stress : Turbulent shear stress : PDGF-B transforming growth factor-b thrombomodulin basic fibroblast growth factor Oscillatory shear stress : Hemeoxygenase 1 Disturbed shear stress : VCAM-1 PDGFA connexin-43 Current Opinion in Lipidology 2000, 11:167±177 Fluid shear stresses generated by blood flow influence the phenotype of the endothelial cells by modulation of gene expression and regulation of expression of surface receptors.
  74. 74. AHA Lesion classification 1990s • The classification involved six distinct categories: Type I, Intimal thickening; Type II, Fatty streak; Type III, Transitional or intermediate lesion; Type IV, Advanced atheroma with well-defined region of the intima; Type V, Fibroatheroma or atheroma with overlaid new fibrous connective tissue; and Type VI, Complicated plaques with surface defects, haematoma or haemorrhage, thrombosis, or a combination of these characteristics. FAILED TO INCLUDE ALL CAUSES OF THROMBOSIS- PLAQUE RUPTURE, SURFACE EROSION(25-30%) AND ERUPTIVE CALCIFIED NODULES(<5%). NO MENTION OF PRECURSOR LESIONS TO PLAQUE RUPTURE- VULNERABLE PLAQUES (aka THIN CAP FIBROATHEROMA) NO CONCEPT OF PLAQUE HEALING

Hinweis der Redaktion

  • Prevalence maps of fatty streaks and raised lesions in the abdominal aorta: Pseudocolored representations of morphometric analysis of composite data, from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, on more than 2800 aortas from Americans younger than 35 years of age who succumbed for noncardiac reasons. A, Note the early involvement of the dorsal surface of the infrarenal abdominal aorta by fatty streaks, followed by raised lesions. B, A similar but slightly slower progression of lesions affects the right coronary artery. The bar scales at bottom in both A and B show the coding for the pseudocoloring
  • Restenosis results from
    1)constriction of vessel from the adventitial side (negative remodelling)- adventitial inflammation, scar formation and wound contraction
    2) Smooth muscle cell proliferation
  • this classification failed to capture two important clinical aetiologies of coronary thrombus that are distinct from plaque rupture — surface erosion, which accounts for 25–30% of thrombosis cases, and the less frequent, but still important, eruptive calcified nodules, which occur in <5% of patients. Moreover, in the mid‑1980s, Davies had identified active lesions characterized by plaque fissures as yet another form of communication between the lumen and underlying necrotic core26, which was not included in the AHA classification25. We have since clarified this concept27, which is best described as a mechanism of ‘intraintimal’ rather than true ‘intraluminal’ thrombosis.
    A second important concept not captured in the AHA consensus classification28 was the recognition of precursor lesions that potentially give rise to clinical events. Identification of important structural plaque characteristics conceivably leading to coronary thrombosis would not only provide important mechanistic insights into understanding lesion progression, but also support efforts leading to improvements and refinements in diagnostic imaging. The notion of vulnerable plaque, as a precursor to rupture, also fails to fit precisely into an orderly numerical classification as set forth by the AHA25,28. These constraints, therefore, prompted us to develop a modified scheme16, in which AHA lesion types I–IV were replaced by descriptive terms of: adaptive intimal thickening, intimal xanthoma (fatty streak), pathological intimal thickening, and fibroatheroma. Fibroatheromas were more recently subcategorized into ‘early’ stage and ‘late’ stage plaques, on the basis of lytic and nonlytic characteristics of the necrotic core29. In our scheme16, AHA categories V and VI were discarded because they failed to account for the three aetiologies (rupture, erosion, and calcified nodule) that give rise to coronary thrombosis. The precursor lesions to plaque rupture, originally known as ‘vulnerable plaques’, were classified as ‘thin-cap fibroatheroma’ (TCFA). Additional terms were also introduced to implicate the sudden enlargement of plaques from silent episodic thrombosis (healed plaque rupture (HPR)), and plaque fissures16.
    The concept of plaque healing is also not accounted for in the AHA numerical classification, as HPRs or healed erosions can eventually give rise to increased plaque burden, luminal narrowing, and possible negative remodelling, or even silent or symptomatic chronic total occlusion (CTO)16. Similarly, we added terms that inferred lesion stability, such as ‘fibrous’ or ‘fibrocalcific’, and ‘nodular calcification in the absence of thrombosis’, which are more commonly observed in patients presenting with stable CAD, or long-standing diabetes mellitus and chronic renal failure.

×