1. ATHEROSCLEROSIS

2. 22. [Path] Pathology of atherosclerosis:
Objectives
This lecture provides an understanding of atherosclerosis in terms of definition, epidemiology, risk factors, pathogenesis, and clinical significance of atherosclerosis 
Learning outcomes
At the end of the lecture, student will be able to
Explain the terms atherosclerosis, arteriosclerosis and Monckeberg medial calcific sclerosis
Discuss the epidemiology, risk factors, pathogenesis, and clinical consequences of atherosclerosis
Describe the gross and microscopic morphology of the atherosclerosis

3. COMPONENTS Intima, Media, Adventitia, M>A or A>M ENDOTHELIUM
INTERNAL ELASTIC LAMINA
ECM: Elastin ,collagen, mucopolysaccharides
Smooth Muscle
Connective Tissue
Fat

5. Aorta (elastic artery), artery, vein, capillary: Know all the differentiating histologic features

6. ARTERIO-SCLEROSIS GENERIC term for ANYTHING which HARDENS arteries
Three general patterns
Atherosclerosis (99%)
Mönckeberg medial calcific sclerosis (1%)
Arteriolosclerosis
- involving small arteries and arterioles, related to hypertension and/or diabetes
Atherosclerosis and arteriosclerosis are often used so interchangeably, it is hardly worth differentiating them anymore, other than to know they are different!

7. Arteriosclerosis
Arteriosclerosis literally means “hardening of the arteries” it is a generic term reflecting arterial wall thickening and loss of elasticity Atherosclerosis (Greek )words for “gruel” and “hardening,” is the most frequent and clinically important pattern

8. Arteriosclerosis Mönckeberg medial sclerosis is characterized by
calcific deposits in muscular arteries in persons typically older than age 50
deposits may undergo metaplastic change into bone
lesions do not encroach on the vessel lumen and are usually not clinically significant  

9. ATHEROSCLEROSIS (classical)
Etiology/Risk Factors
Pathogenesis
Morphology
Clinical Expression

10. ATHEROSCLEROSIS *Natural History *Epidemiology *Risk Factors
*Pathogenesis
*Other Factors
*Effects
*Prevention

11. ATHEROSCLEROSIS Atherosclerosis
is characterized by intimal lesions called atheromas that protrude into vessel lumens
(Atheroma = Atheromatous plaques = Atherosclerotic plaques)

12. ATHEROSCLEROSIS
An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a firm, white fibrous cap

14. ATHEROMATOUS PLAQUE

15. Effects of ATHEROSCLEROSIS
Mechanically obstructing blood flow
Rupture, leading to thrombosis
Weaken the underlying media leading to aneurysm formation

17. EPIDEMIOLOGY & RISK FACTORS

18. Epidemiology most developed nations
much less prevalent in Central and South America, Africa, and Asia
mortality rate for IHD in the United States is among the highest in the world

19. Epidemiology
prevalence and severity of atherosclerosis and IHD among individuals and groups are related to several risk factors
Major Risks factors
- Non modifiable
-Potentially Controllable
Lesser or Nonquantitated Risks factors

20. Risk Factors for Atherosclerosis
Major
Minor
NON-modifiable Modifiable
Increasing age
Obesity
Male gender
Physical inactivity
Family history
Stress ("type A" personality)
Genetic abnormalities
Postmenopausal estrogen deficiency
High carbohydrate intake
Modifiable
Hyperlipidemia
Alcohol
Hypertension
Lipoprotein Lp(a)
Cigarette smoking
Hardened (trans)unsaturated fat intake
Diabetes
Chlamydia pneumoniae

21. Major Risks factors Hyperlipidemia Hypertension Cigarette Smoking
Diabetes Mellitus

22. Additional risk factors
Inflammation (C-reactive protein)
Hyperhomocystinemia
Metabolic syndrome
Lipoprotein (a)
Other factors

23. HYPERLIPIDEMIA
Hypercholesterolemia-is a major risk factor for atherosclerosis even in the absence of other risk factors, hyercholesterolemia is sufficient to stimulate lesion development

24. HYPERLIPIDEMIA
The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol ("bad cholesterol") LDL cholesterol has an essential physiologic role delivering cholesterol to peripheral tissues

25. HYPERLIPIDEMIA
high-density lipoprotein (HDL, "good cholesterol") mobilizes cholesterol from developing and existing atheromas and transports it to the liver for excretion in the bile higher levels of HDL correlate with reduced risk

26. CHOLESTEROL CLEFTS
Needle shaped washed out spaces in arteries, are cholesterol clefts, and can be nothing else, and like all other fat, yellow grossly, white microscopically.

27. HYPERTENSION
major risk factor for atherosclerosis both systolic and diastolic levels are important

28. HYPERTENSION HYPERTENSION causes ATHEROSCLEROSIS. Why?
ATHEROSCLEROSIS causes HYPERTENSION. Why?

29. CIGARETTES
a well-established risk factor

30. DIABETES Diabetes mellitus induces hypercholesterolemia
100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities

31. NON-modifiable
Age is a dominant influence accumulation of atherosclerotic plaque is typically a progressive process incidence of myocardial infarction in men increases fivefold between ages 40 and 60 Death rates from IHD rise with each decade even into advanced age

32. NON-modifiable
Gender premenopausal women are relatively protected against atherosclerosis After menopause incidence of atherosclerosis-related diseases increases and with greater age eventually exceeds that of men

33. NON-modifiable Genetics
familial predisposition to atherosclerosis and IHD is multifactorial
well-defined genetic derangements in lipoprotein metabolism,
such as familial hypercholesterolemia that result in excessively high blood lipid levels
familial clustering of other risk factors, such as hypertension or diabetes

34. NON major factors
Homocysteinuria/homocysteinemia, related to low B6 and folate intake Coagulation defects Lipoprotein Lp(a), independent of cholesterol. Lp(a) is an altered form of LDL Inadequate exercise, Type “A” personality, obesity (independent of diabetes) Protective effect of moderate alcohol?

35. PATHOGENESIS Atherosclerosis is
a chronic inflammatory response of the arterial wall initiated by injury to the endothelium

36. PATHOGENESIS Lesion progression occurs through interactions of
modified lipoproteins
monocyte-derived macrophages
T lymphocytes
normal cellular constituents of the arterial wall

37. PATHOGENESIS Chronic endothelial injury
Accumulation of lipoproteins in arterial WALL
OXIDATION of lipoproteins
Monocytes migrate endothelium
Platelet adhesion and activation
Migration of SMOOTH MUSCLE from media to intima to activate macrophages (foam cells)
Proliferation of SMOOTH MUSCLE and ECM
Accumulation of lipids in cells and ECM

38. PATHOGENESIS
Endothelial Injury Causes hemodynamic forces, immune complex deposition, irradiation, or chemicals Early lesions begin at sites of morphologically intact endothelium

39. PATHOGENESIS
Non-denuding endothelial dysfunction underlies atherosclerosis
in the setting of intact but dysfunctional ECs there is
increased endothelial permeability
enhanced leukocyte adhesion
altered gene expression

40. PATHOGENESIS Causes of endothelial dysfunction
Hemodynamic disturbances
Hypercholesterolemia
Toxins from cigarette smoke,
Homocysteine
infectious agents
Inflammatory cytokines (e.g., tumor necrosis factor, TNF)

41. PATHOGENESIS
Hypercholesterolemia can directly impair EC function by increasing local production of reactive oxygen species With chronic hyperlipidemia, lipoproteins accumulate within the intima

42. PATHOGENESIS
These lipids are oxidized through the action of oxygen free radicals locally generated by macrophages or Ecs Oxidized LDL is ingested by macrophages through a scavenger receptor resulting in foam-cell formation

43. PATHOGENESIS Oxidized LDL
stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions
cytotoxic to ECs and SMCs and can induce EC dysfunction

44. PATHOGENESIS Causes of Dyslipoproteinemias
mutations that encode defective apoproteins
alter the lipoprotein receptors on cells
other underlying disorder that affects the circulating levels of lipids (e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus)

45. PATHOGENESIS
Common lipoprotein abnormalities in the general population include
increased LDL cholesterol levels
(2) decreased HDL cholesterol levels
(3) increased levels of the abnormal Lp(a)
Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis

46. PATHOGENESIS
Inflammation Inflammatory cells and mediators are involved in the initiation, progression, and the complications of atherosclerotic lesions

47. PATHOGENESIS Inflammation
Dysfunctional arterial ECs express adhesion molecules that encourage leukocyte adhesion
Monocytes and T cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines

48. PATHOGENESIS
Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL progressive accumulation of oxidized LDL drives lesion progression

49. PATHOGENESIS Activated macrophages
cytokine production (e.g., TNF) that further increases leukocyte adhesion and chemokine production that in turn propel mononuclear inflammatory cell recruitment
produce reactive oxygen species, aggravating LDL oxidation

50. PATHOGENESIS
T lymphocytes recruited to the intima interact with macrophages and can generate a chronic immune inflammatory state Activated T cells in the growing intimal lesions elaborate inflammatory cytokines, (e.g., interferon-γ), which in turn can stimulate macrophages as well as ECs and SMCsAs

51. PATHOGENESIS
A consequence of the chronic inflammatory state activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and ECM synthesis

52. PATHOGENESIS Infection
may drive the local inflammatory process that underlies atherosclerosis (hypothesis has yet to be conclusively proven)
Herpesvirus, cytomegalovirus, and Chlamydia pneumoniae have all been detected in atherosclerotic plaques but not in normal arteries
increased antibody titers to C. pneumoniae in patients with more severe atherosclerosis

53. PATHOGENESIS Smooth Muscle Proliferation
Intimal smooth muscle cell proliferation and ECM deposition
convert a fatty streak (the earliest lesion) into a mature atheroma
contribute to the progressive growth of atherosclerotic lesions
( intimal smooth muscle cells may be recruited from circulating precursors and they have a proliferative and synthetic phenotype distinct from the underlying medial smooth muscle cells)

54. PATHOGENESIS Growth factors (PDGF, FGF, TGF-α)
Smooth Muscle Proliferation & ECM synthesis
Growth factors (PDGF, FGF, TGF-α)
The recruited smooth muscle cells synthesize ECM (notably collagen) that stabilizes atherosclerotic plaques
Activated inflammatory cells in atheromas can cause intimal smooth muscle cell apoptosis, and also increase ECM catabolism resulting in unstable plaques

55. The intimal plaque may progressively
encroach on the vessel lumen
compress and cause degeneration of the underlying media
disruption of the fibrous cap can lead to thrombosis and acute vascular occlusion

56. A very well constructed graphic understanding of the pathogenesis of atherosclerosis. Please be expected to not only KNOW these five items, but their correct ORDER too.

57. Main FOUR STARS of PATHOGENESIS
1) Endothelial Injury
2) Inflammation
3) Lipids
4) Smooth Muscle Cells, SMCs

59. MORPHOLOGIC CONCEPTS Intimal Thickening Lipid Accumulation Streak
Atheroma
Smooth Muscle Hyperplasia and Migration
Fibrosis
Calcification
Aneurysm
Thrombosis

60. Morphology Most extensively involved vessels are lower abdominal aorta
coronary arteries
popliteal arteries
internal carotid arteries
vessels of the circle of Willis

61. Morphology Fatty Streaks composed of histologically
lipid-filled foam cells but are not significantly raised
Gross
Multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer

63. Morphology Atherosclerotic Plaque Grossly appear white to yellow
superimposed thrombus over ulcerated plaques is red-brown
Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses
patchy, usually involving only a portion of any given arterial wall

64. Morphology Atherosclerotic plaques have three principal components:
cells, including smooth muscle cells, macrophages, and T cells
ECM, including collagen, elastic fibers, and proteoglycans
intracellular and extracellular lipid
(These components occur in varying proportions and configurations in different lesions)

65. Morphology
A superficial fibrous cap composed of smooth muscle cells and relatively dense collagen
Beneath and to the side of the cap (the “shoulder”) is a more cellular area containing macrophages, T cells, and smooth muscle cells
Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters)

67. clinically important changes
Rupture, ulceration, or erosion & thrombosis
calcification
Hemorrhage into a plaque
Atheroembolism
Aneurysm formation

68. MILD ADVANCED

69. fibrous cap (F)
central necrotic (largely lipid) core (C)
lumen (L
Histologic features of atheromatous plaque in the coronary artery

70. *NATURAL HISTORY

72. 1) FATTY STREAK (non-palpable)
2) ATHEROMA
(plaque) (palpable)
3) THROMBUS (non-functional, symptomatic)
Atherosclerosis is a LIFELONG, even childhood, process. This chart is worth knowing.

73. Commonly affecting sites

74. CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
Myocardial infarction (heart attack)
cerebral infarction (stroke)
aortic aneurysms
peripheral vascular disease (gangrene of the legs)

75. Atherosclerosis affecting coronary artery

76. Atherosclerosis affecting cerebral artery

77. Myocardial infarction

78. Stroke
4/28/2017 7:35 AM

79. Aneurysm

80. CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
Atherosclerotic Stenosis
chronic occlusion - significantly limits flow
[mesenteric occlusion and bowel ischemia, chronic IHD, ischemic encephalopathy, and intermittent claudication (diminished extremity perfusion)]
acute plaque rupture -dangerous complication

81. CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
Acute Plaque Change
Rupture/fissuring, exposing highly thrombogenic plaque constituents
Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood
Hemorrhage into the atheroma expanding its volume
Plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis