1. Atherosclerosis By Dr S. Homathy 1

2. What is arteriosclerosis? Arteriosclerosis (from the Greek arteria, meaning artery) is a general term for hardening of the arteries. Arteriosclerosis can occur in several forms, including atherosclerosis. What is arteriolosclerosis? What is atherosclerosis? In Greek, athere means gruel, and skleros means hard. 2

3. Atherosclerosis Atherosclerosis is a chronic inflammatory disease of the arterial blood vessels (arteries), – in which the walls of the blood vessels become thickened and hardened by "plaques.“ 3

4. It is characterized by – intimal lesion called atheroma / atheromatous / fibrofatty plaques, – that protrude into and obstruct the lumina, weaken the underlying media and undergo serious complications. 4

5. The plaques consist of a raised lesion with a soft, yellow, grumous core of lipid, mainly cholesterol and other lipids, inflammatory cells, and calcium deposits covered by a firm, white fibrous cap. 5

6. Clinical significance Atherosclerosis is a chronic disease that remains asymptomatic for decades. Primarily affect elastic arteries- – Aorta, carotid, iliac arteries Large and medium - sized muscular arteries – Coronary, popliteal arteries 6

7. Major consequences of AS – Obstructing the blood vessel- MI, Cerebral infarction – Weaken the wall - Aortic aneurysm – Peripheral vascular disease – Acute thrombosis 7

8. Mechanism of causing the clinical consequences  Occlusion of lumen – in small arteries – Cause ischaemia  AS plaque may undergo disruption and precipitate thrombi – Further occlusion of the lumen  Plaque encroching the media and weaken the vessel wall – in large arteries – Aneurysm and rupture.  Extensive atheromas –friable – Emboli into the distal circulation 8

9. Epidemiology Common in developed nations Prevalence and severity of AS are related to several risk factors – Constitutional ( less controlable) – Acquired ( amenable to manipulation) 9

10. Risk factors Divided into  Major risk factors – Nonmodifiable – Potentially controllable  Nonquantitated risk factors 10

11. Nonmodifiable major risk factors  Increasing age  Male gender  Family history (polygenic factors)  Genetic abnormalities (derangement of lipoprotein metabolism- familial hypercholesterolemia) 11

12. Accumulation of AS plaque is a progressive process. Clinically manifest when reach a critical threshold Begins to precipitate organ injury in middle age or later incidence of MI increases to 5 fold between 40- 60 years 12

13. Premenopausal women are relatively protected against AS compared to aged match males – MI and other complications of AS are uncommon in premenopausal women unless otherwise have the other risk factors DM, hyperlipidaemia, severe HT. After menopause AS related diseases increases in females 13

14. Potential controllable risk factors  Hyperlipidemia  Especially hypercholesterolemia- even in the absence of other risk factors, it is sufficient to stimulate AS development Major risk factor – High LDL-c and low HDL-c High dietary intake of Cholesterol and saturated fats  Hypertension Major risk factor at all ages Increase the risk of IHD by 60%  DM Induces hypercholesterolemia Incident of MI 2 fold Increase risk of stroke 100 fold increase risk of AS induced gangrene in lower extremities  Cigarette smoking 14

15.  Other risk factors ( responsible for 20% of all cardiovascular events ) Obesity Physical inactivity Stress Postmenopausal estrogen deficiency High CHO diet Lipoprotein (a) – Lipoprotein (a) – independent risk factor regardless of level of total cholesterol Harden unsaturated fat intake Chlamydia pneumonia 15

16. Inflammation It is present during all stages of AS Linked with AS plaque formation and rupture It does play a significant role in IHD Number of systemic markers of inflammation correlate with IHD risk – IL-6, – CRP – cheapest and most sensitive 16

17. CRP Synthesized primarily by the liver. When locally synthesized within AS intima – Regulate local endothelial adhesion and thrombotic states It is strongly and independently predicts the risk of – MI – Sroke – Peripheral arterial disease – Sudden cardiac death Cessation of smoking, weight loss and exercise reduce CRP Statins reduce the CRP level independentbof their effects on LDL cholesterol. 17

18. Homocystinuria Elevated levels (> 100μmol/ L) associated with premature vascular disease. Multiple risk factors have a multiplicative effect – 2 risk factors- 4 fold rise – 3 risk factors – 7 fold rise Strong correlation between total serum homocysteine levels and – coronary artery disease – Peripheral vascular disease – Stroke – Venous thrombosis 18

19. Lipoprotein (a) Increased level associated with a higher risk of coronary and cerebrovascular disease 19

20. Pathogenesis There are several hypothesis for development of AS Inhibition theory Thrombotic theory Injury to the endothelium theory 20

21. According to injury hypothesis considers Atherosclerosis to be a chronic inflammatory response of the arterial wall initiated by injury to the endothelium. 21

22. Major processes in plaque formation Disease of the intima –Intimal thickening – Intra-and extra-cellular lipid accumulation –Chronic Inflammation Basic Lesion: is termed atheroma, fibro-fatty plaque, or atheromatousplaque 22

23. Progression of lesion occurs through interactions of – Modified lipoprotein – MP,T lymphocytes – Normal cellular constituent of the arterial wall 23

24. Sequence of events 1 chronic endothelial injury – Increased permeability – Leukocyte adhesion – Thrombotic potential 2 insudation of lipoproteins [LDL] – Mainly LDL 3 modification of lipoproteins by oxidation 4 adhesion of blood monocytes – Migration into the intima and transform into MP and foam cells 5 adhesion of platelets 24

25. 6 migration of smooth muscle cells from the media into the intima 7 proliferation of smooth muscle cells in the intima – Synthesis EC matrix 8 Enhanced accumulation of intra and extra cellular lipids 25

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27. Role of vascular endothelial cells in atherogenesis Normal intact endothelium inhibits thrombosis and regulates transfer of macromolecule into the vessel wall Agents which – damage endothelium or – impair its function Could be important for pathogenesis of AS 27

28. Chronic or repetitive endothelial injury is the cornerstone of the response to injury hypothesis Endothelial injury to any kind results in intimal thickening. But, early lesion begins at sites of morphologically intact endothelium – Endothelial dysfunction underlies human AS. Leads to Increased endothelial permeability Enhanced leucocytes adhesion Altered gene expression 28

29. Causes of endothelial dysfunction Circulating derivatives of – Cigarette smoke – Homocystein – Viruses – Other infectious agents Haemodynamic stress – HT Hypercholesterolemia Inflammation 29

30. Cellular Components of Atherosclerotic Lesion Development 30

31. Endothelial Cells (dietary fats) Nicotine (smoking) EC damage 1  EDRF  Endothelin 3 Altered surface  anticoagulants,  plasminogen activators,  PAI - 1 2  chemoattractants to: - platelets & Mø, - growth factors for SMC Viral infection Homocysteine Hypoxia Shear stress Cytokines EC Oxidized lipids/ Free radicals Leukocyte adhesion Altered permeability Procoagulant activity Vasoactive substances Growth factors/ chemoattractants ACTIVATION RESPONSE 31

32. In haemodynamic alteration plaque tend to occur at – Ostea of vessels – Branch points – Along the posterior wall of the abdominal aorta 32

33. Inflammation Cells and mediators are involved in the initiation, progression and the complication of AS. Dysfunctional endothelial cells express adhesion molecules Then the cells migrate into the intima under the influence of locally produced molecule. 33

34. Role of smooth muscle cells An important event in the evaluation of an AS plaque is intimal deposition of – Collagen – Elastin – GAG Stabilize AS plaques. These are secreted by smooth muscle cells They also accumulate lipids- become foam cells. SM cells of AS plaque differ from normal SM cells – Features more typical of secretory activity than muscular contraction 34

35. Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma. Contribute to the progressive growth of AS lesion. 35

36. Stimulus for the changes of SM cells Hyperlipidemia (LDL-c) ECDGF MPDGF PDGF 36

37. -Predominant cell type -In Atherosclerosis  deviate from N behaviour:  proliferation &  migration due to  bFGF & PDGF production by Mø & dysfunctional EC but also SMC become responsive (see  next O / H) **** Smooth Muscle Cells NormalDeveloping lesion PDGF (exon 6) PDGF Migration Intimal growth PDGF t-PA Ang II SMC migration β3 integrin Intimal replication bFGF SMC replication AT 1 α adrenergic Receptor inhibitor (e.g.: prazosin ) TGF β PDGF antibody Heparin 37

38. Normal Addition bFGF  no response (no receptor) NormalDeveloping lesion SMC Released bFGF SMC replication SMC death bFGF FGF-r FGF-toxin No enhanced replication No injury +bFGF PCNA antisense c-myb antisense Heparin Membrane disruption Mechanical injury EC bFGF 38

39. Role of MP Monocytes and Mp play a key role – Dysfunctional endothelial cells- (endothelial adhesion molecule) causes dhesions of cells Migrate into the intima Engulf lipoproteins (largely oxidized LDL)and become foam cells. Oxidized LDL drives lesion progression 39

40. Secrete several factors –recruit leukocytes into the plaque. Produce toxic oxygen species – – Causes oxidation of the LDL in the lesion by reactive oxygen species. – Produce GF stimulate SMC proliferation T lymphocytes also present in atheroma – Interact with MP – Generate a chronic immune inflammatory state. 40

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42. As a result of the chronic inflammatory state, – activated leukocytes and EC secretes GF- promote SMC proliferation and ECM synthesis. 42

43. Role of lipids Major lipids in atheromas are plasma derived cholesterol and CE. Significant correlation between the severity of AS and the level of the total plasma cholesterol / LDL-c. 43

44. Chronic hyperlipidemia directly impair EC function ( increased production of oxygen free radicals. Lipoproteins accumulate within the intima LDL converted into oxidized LDL-c by locally generated free oxygen radical Then – ingested by MP, – increased monocyte accumulation in the lesion – Stimulate release of GFs – Cytotoxic to ECs, SMCs – Induce EC dysfunction 44

45. Oxidized LDL Modified protein & lipid = immunogenicity  Concentration  Residence time in arterial wall  Opportunity to be oxidized, taken up by macrophage, glycated and be trapped MEDIA INTIMA Endothelium LUMEN LDL, VLDL IEL Oxidized LDL Free radicals Initial Lipoprotein Oxidation ? Free radicals 45

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47. Oxidized LDL can: 1-  leucocyte influx 2-  chemotactic factors 3-  thrombosis 4-  toxicity 5-  response acetylcholine 6-  macrophage foam cells 7-  cytokine factors 47

48. -Present at very low to very high levels -Concentration is strongly influenced by hereditary -Not influenced by Rx Lp (a) (LDL with a tail) B 100 apo (a) S-S B 100 apo (a) S-S (lp a + )(lp a - ) S SSSS Kringle 4 5 3 2 1 Plasminogen 4 4 4 4 444 4 4 5 apo (a) 48

49. Causes of dyslipidaemia Primary hypercholesterolaemia Secondary – DM – Hypothyroidism – Nephrotic syndrome – alcoholism 49

50. AHA Classification of atherosclerosis 50

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52. Morphology 52

53. Normal artery 53

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55. Fatty streak Composed of lipid filled form cells Not significantly raised Do not cause any disturbance in blood flow. Appears as multiple minute yellow, flat spots Then they coalesce into elongated streeaks. Can be seen in aorta of < one year Coronary fatty streak forms in adolescence 55

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57. Atherosclerotic plaque(fibrous/ fibrofatty plaques) Grossly appears as white to yellow Imping on the lumen of the artery Usually patchy Involving only a portion of any vessel – Eccentric on cross section Thrombosis superimposed over the ulcerated plaques- ( red brown) 57

58. Abdominal aorta is typically more involved than the thoracic aorta. Lower abdominal aorta > coronary arteries> popliteal artery > internal carotid arteries and circle of willis. Vessels of the upper extremities are usually spared Renal and mesenteric arteries- only in their ostia 58

59. The coronary at the left is narrowed by 60 to 70%. The coronary at the right is even worse with evidence for previous thrombosis with – organization of the thrombus and recanalization – such that there are three small lumens remaining, – one of which contains additional recent thrombus. 59

60. Major components of plaque Cells - SMC, macrophages and other WBC ECM - Collagen, elastin, and PGs Lipid - Cholesterol (Intra/extracellular) Often calcification 60

61. Superficial fibrous cap is composed SMC and relatively dense collagen Beneath and to the side of the cap(shoulder) is a more cellular area – Containing MP, T lymphocytes and SMC. Deep to the fibrous cap is a necrotic core contain lipid, – cell debris, foam cells, fibrin, plasma proteins – Empty cholesterol clefts At the periphery of the lesions – neovascularization 61

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63. 63 Foam Cells/Cholesterol Crystals

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65. 65 Fibrous cap Cholesterol clefts Elastin membrane destroyed Neovas. Calcification Inflam. cells

66. Plaque continue to change and progressively enlarge Often undergo calcification – Advanced coronary calcification associated with increased risk for coronary events 66

67. Other pathological changes Rupture, ulceration or erosion – Thrombogenic substances induces thrombus formation Partly or completely occlude the lumen and leads to ischaemia. Sometimes organized and incorporated into the growing plaque Haemorrhage into plaque – Expand the plaque / induce plaque rupture Atheroembolism Aneurysm formation. 67

68. Fibrous Plaques Complicated Lesions 68

69. Hemorrhage into Plaque 69

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71. Ulceration/Hemorrhage/Cholesterol Crystals 71

72. Complicated Lesion/Calcification 72

73. Thrombosis/Complicated Lesion 73

74. Complicated lesion/Ulceration/Thrombosis 74

75. AS:Pathology, athogenesis, Complications, Natural History 75

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77. Consequences of plaque formation Generalized –Narrowing/Occlusion –Rupture –Emboli Leading to specific problems: – Myocardial and cerebral infarcts – Aortic aneurysms – Peripheral vascular disease 77

78. Altered Vessel Function Vessel change –Plaque narrows lumen –Wall weakened –Thrombosis –Breaking loose of plaque –Loss of elasticity Consequence –Ischemia, turbulence –Aneurysms, vessel rupture –Narrowing, ischemia, embolization –Athero-embolization –Increase systolic blood pressure 78