PATHOLOGY CHAPTER -ATHEROSCLEROSIS DISCUSSED IN DETAIL

1. ATHEROSCLEROSIS
DR KAMALESH LENKA

2. • Atherosclerosis is characterized by intimal lesions called atheromas
(or atheromatous or atherosclerotic plaques) that impinge on the
vascular lumen and can rupture to cause sudden occlusion

3. Epidemiology of Atherosclerosis
• Atherosclerosis is virtually ubiquitous among most developed nations
• The mortality rate for IHD in the United States is among the highest in
the world, approximately five times higher than that in Japan.
• However, IHD is increasing in Japan,
• Furthermore, Japanese emigrantswho come to the United States and
adopt American lifestyles and dietary customs acquire the same
atherosclerosis risk as U.S.-born individuals

6. RISK FACTORS
• Constitutional Risk Factors
• Genetics.-Family history is the most important independent risk factor
for atherosclerosis
• Certain mendelian disorders are strongly associated with
atherosclerosis (e.g., familial hypercholesterolemia)

7. • Age.-
• Atherosclerosis usually remains clinically silent until lesions reach a
critical threshold in middle age or later.
• Thus, the incidence of myocardial infarction increases 5-fold between
40 and 60 years of age.

8. • Gender-
• All other factors being equal, premenopausal women are relatively
protected against atherosclerosis
• Thus, myocardial infarction and other complications of atherosclerosis
are uncommon in premenopausal women in the absence of other
predisposing factors such as diabetes, hyperlipidemia,hypertension
• After menopause, however, the incidence of atherosclerosis-related
disease increases and can even exceed that in men.

9. Modifiable Major Risk Factors
• Hyperlipidemia-
• and, more specifically, hypercholesterolemia— is a major risk factor
for development of atherosclerosis and is sufficient to induce
lesions in the absence of other risk factors
• The main cholesterol component associated with increased risk is
low-density lipoprotein (LDL) cholesterol (“bad cholesterol”);
• By contrast, high-density lipoprotein (HDL) cholesterol (“good
cholesterol”) mobilizes cholesterol from developing and existing
vascular plaques and transports it to the liver for biliary excretion.

10. • High dietary intake of cholesterol and saturated fats (e.g., present in
egg yolks, animal fats, and butter) raises plasma cholesterol levels
• Omega-3 fatty acids (abundant in fish oils) are beneficial
• whereas (trans)-unsaturated fats produced by artificial hydrogenation
of polyunsaturated oils (used in baked goods and margarine)
adversely affect cholesterol profiles.
• Exercise and moderate consumption of ethanol raiseHDL levels
• whereas obesity and smoking lower them.
• Statins are a widely used class of drugs that lower circulating
cholesterol

11. • Hypertension-risk factor for development of atherosclerosis.
• On its own, hypertension can increase the risk for IHD by
approximately 60%

12. • Cigarette smoking-
• is a well-established risk factor in men and probably accounts for the
increasing incidence and severity of atherosclerosis in women
• Prolonged (years) smoking of one or more packs of cigarettes per day
doubles the rate of IHD-related mortality
• while smoking cessation reduces the risk.

13. • Diabetes mellitus-
• is associated with raised circulating cholesterol levels and markedly
increases the risk for atherosclerosis.
• disorder is associated with an increased risk for stroke and a 100-fold
increase in atherosclerosis-induced gangrene of the lower
extremities.

14. • Additional Risk Factors-
• There is some evidence that a systemic pro-inflammatory state is
associated with the development of atherosclerosis and hence
measures of systemic inflammation have been used in risk
stratification.
• systemic markers of inflammation, determination of C-reactive
protein (CRP) has emerged as one of the simplest and most sensitive
• CRP is an acute-phase reactant synthesized primarily by the liver

15. • Hyperhomocysteinemia.-Serum homocysteine levels correlate with
coronary atherosclerosis, peripheral vascular disease, stroke, and venous
thrombosis
• Metabolic syndrome-Associated with central obesity this clinical entity is
characterized by
• insulin resistance,
• hypertension,
• dyslipidemia (elevated triglycerides and depressed HDL),
• hypercoagulability,
• and a pro-inflammatory state, which may be triggered by cytokines
released from adipocytes.

16. • Lipoprotein(a) levels.-Lipoprotein(a) is an LDL-like particle that
contains apolipoprotein B-100 linked to apolipoprotein(a).
• Lipoprotein(a) levels are correlate with risk of coronary and
cerebrovascular disease, independent of total cholesterol or LDL
levels
• Elevated levels of procoagulants are potent predictors of risk for
major cardiovascular events including myocardial infarction and
stroke

17. • Clonal hematopoiesis-defined by the presence of a major clone of
cells in the bone marrow that have acquired somatic driver mutations
in one or more wellcharacterized oncogenes or tumor suppressor
genes
• clonal hematopoiesis is strongly associated with an increased risk of
death from cardiovascular disease,

18. • Other factors associated with difficult-to-quantify risks include lack of
exercise and living a competitive, stressful lifestyle (“type A
personality”).

19. Pathogenesis
• The currently held view of pathogenesis is embodied in the
response-to-injury hypothesis. This model views atherosclerosis as a
chronic inflammatory response of the arterial wall to endothelial
injury

20. • EC injury—and resultant endothelial dysfunction—
• leading to increased permeability, leukocyte adhesion, and thrombosis
• Accumulation of lipoproteins (mainly oxidized LDL and cholesterol
crystals) in the vessel wall
• Platelet adhesion
• Monocyte adhesion to the endothelium, migration into the intima, and
differentiation into macrophages and foam cells
• Lipid accumulation within macrophages, which respond by releasing
inflammatory cytokines
• SMC recruitment due to factors released from activated platelets,
macrophages, and vascular wall cells
• SMC proliferation and ECM production

22. Endothelial Injury
• EC injury is the cornerstone of the response to injury hypothesis
• EC loss due to any kind of injury—induced experimentally by
mechanical denudation, hemodynamic forces, immune complex
deposition, irradiation, or chemicals—results in intimal thickening; in
the presence of high-lipid diets, typical atheromas ensue
• Early human atherosclerotic lesions begin at sites of intact but
dysfunctional, endothelium.

23. • Suspected triggers of early atheromatous lesions include
• hypertension,
• hyperlipidemia,
• toxins from cigarette smoke,
• homocysteinemia.
• Inflammatory cytokines

24. • Hemodynamic Disturbances-
• plaques tend to occur at ostia of exiting vessels, at branch points, and
along the posterior wall of the abdominal aorta, where there is
turbulent blood flow.
• nonturbulent laminar flow leads to the induction of endothelial genes
whose products protect against atherosclerosis.

25. • Lipids-
• Dyslipoproteinemias can result from mutations in genes that encode
apoproteins or lipoprotein receptors, or from disorders that derange
lipid metabolism,
• Common lipoprotein abnormalities-
• (1) increased LDL cholesterol levels,
• (2) decreased HDL cholesterol levels
• 3) increased levels of lipoprotein

26. • The mechanisms by which dyslipidemia contributes to atherogenesis
include the following
• Chronic hyperlipidemia, particularly hypercholesterolemia, can
directly impair EC function by increasing local oxygen free radical
production
• oxygen free radicals accelerate NO decay, damping its vasodilator
activity

27. • With chronic hyperlipidemia, lipoproteins accumulate within the
intima
• to generate two pathogenic derivatives, oxidized LDL and cholesterol
crystals.
• LDL is oxidized through the action of oxygen free radicals generated
locally by macrophages or ECs and ingested by macrophages through
the scavenger receptor,

28. • resulting in foam cell formation

29. • Inflammation-
• Inflammation contributes to the initiation, progression, and
complications of atherosclerotic lesions
• Monocytes differentiate into macrophages-and avidly engulf
lipoproteins, including oxidized LDL and small cholesterol crystals.
• Activated macrophages also produce toxic oxygen species that drive
LDL oxidation and elaborate growth factors that stimulate SMC
proliferation

30. • T lymphocytes recruited to the intima interact with the macrophages
and also contribute to chronic inflammation.
• activated T cells in the growing intimal lesions elaborate inflammatory
cytokines
• chronic inflammatory state, activated leukocytes and vascular wall
cells release growth factors that promote SMC proliferation and
matrix synthesis.

31. SMC Proliferation and Matrix Synthesis
• Intimal SMC proliferation and ECM deposition lead to conversion of the
earliest lesion, a fatty streak, into a mature atheroma, thus contributing to
the progressive growth of atherosclerotic lesions
• Several growth factors are implicated in SMC proliferation and matrix
synthesis, including
• platelet-derived growth factor (released by locally adherent platelets,
macrophages, ECs, and SMCs),
• fibroblast growth factor
• TGF-α.
• The recruited SMCs synthesize ECM which stabilizes atherosclerotic
plaques.

32. MORPHOLOGY
• Fatty Streaks.--EARLIEST LESIONS IN ATHEROSCLEROSIS
• -begin as minute, flat yellow spots and then colaesce-not significantly
raised
• do not cause flow disturbance-virtually in all children older than 10
years-coronary fat streaks begin to form in adolescence,
• at the same anatomic sites that later tend to develop plaques
• They are composed of lipid-filled foamy macrophages

34. • ATHEROSCLEROTIC PLAQUE-
• KEY FEATURES: Intimal Thickening & Lipid Accumulation-
• Gross: -Color: White or Yellow (Ulcerated Plaques: Red- brown)
• -Size: 0.3-1.5 cm in diameter (can coalesce)-
• In humans, the ABDOMINAL AORTA affected MORE than THORACIC
AORTA

36. • ATHEROSCLEROTIC PLAQUE-Commonly involved Vessels (Descending
Order):
• 1. Lower Abdominal Aorta
• 2. Coronary Arteries
• 3. Popliteal Arteries
• 4. Internal Carotid Arteries
• 5. Circle of Willis

37. • ATHEROSCLEROTIC PLAQUE-Principal Components (CEL):
• 1. Cells -smooth muscle cells, macrophages, T cells
• 2. ECM -collagen, elastic fibers, proteoglycans
• 3. Lipids -intracellular and extracellular

38. • -Configuration: 1. Fibrous cap – superficial; made of smooth muscle
cells, collagen
• 2. Shoulder – beneath and to the side of the cap; more cellular with
macrophages, T cells, smooth muscle cells
• 3. Necrotic core – deep into cap, made of lipid primarily cholesterol
and cholesterol esters, debris from dead cells, foam cells, fibrin,
thrombus, other plasma proteins

40. • The periphery of the lesions show neovascularization-Plaques enlarge
due to:
• 1. Cell death and degenration
• 2. Synthesis and degradation of ECM
• 3. Organization of thrombus-Atheromas often undergo
CALCIFICATION

41. • -Plaques are susceptible to the following CLINICAL CHANGES:
• 1. Rupture, ulceration, erosion
• 2. Hemorrhage into a plaque
• 3. Atheroembolism
• 4. Aneurysm formation

42. CONSEQUENCES OF ATHEROSCLEROTIC
DISEASE
• Large Elastic and Large and Medium Muscular arteries are the MAJOR
TARGETS of ATHEROSCLEROSIS
• smaller vessels can become occluded, compromising distal tissue
perfusion
• Ruptured plaque can embolize atherosclerotic debris and cause distal
vessel obstruction, or can lead to acute thrombosis
• Destruction of the underlying vessel wall can lead to aneurysm
formation, which can rupture and/or be a thrombi

44. ATHEROSCLEROTIC STENOSIS
• plaques can gradually occlude vessel lumens, compromising blood
flow causing ischemic injury
• -outward remodeling preserves lumen diameter-effects of vascular
occlusion depend on arterial supply and metabolic demand of
affected tissue

45. ACUTE PLAQUE CHANGE-
• plaque erosion or rupture is typically promptly followed by partial or
complete vascular thrombosis resulting in acute tissue infarction-
THREE CATEGORIES OF PLAQUE CHANGES
• :1. Rupture/Fissuring – exposing thrombogenic constituents
• 2. Erosion/Ulceration – exposing subendothelial basement membrane
to blood
• 3. Hemorrhage into the atheroma

46. ACUTE PLAQUE CHANGE
• the precipitating lesion in patients who develop MI or other coronary
syndromes is NOT NECESSARILY a severely stenotic and
hemodynamically significant lesion BEFORE ITS ACUTE CHANGE

47. ACUTE PLAQUE CHANGE
• NTRINSIC and EXTRINSIC FACTORS THAT INFLUENCE RISK OF PLAQUE
RUPTURE:
INTRINSIC FACTOR EXTRINSIC FACTOR
Plaque Structure Blood Pressure
Plaque Composition Platelet Reactivity
Adrenergic stimulation

48. VULNERABLE Plaques:
• ontain large areas of foam cells and extracellular lipids-with thin
fibrous caps
• *collagen represents the major structural component of the fibrous
cap and accounts for its mechanical strength and stability
• -contain few smooth muscle cells
• -have clusters of inflammatory cells
• *STATINS stabilize plaques by reducing plaque inflammation

50. ACUTE PLAQUE CHANGE-
• Peak time of onset of acute myocardial infarction is between 6 AM
and 12 NOON

51. CONSEQUENCES OF ATHEROSCLEROTIC
DISEASE
• THROMBOSIS
• *VASOCONSTRICTION
• compromises lumen size and by increasing local mechanical forces
can potentiate plaque disruption-stimulated by
• :1. Adrenergic agonists
• 2. Local platelet contents
• 3. impaired secretion of cell relaxing factors
• 4. mediators released from perivascular inflammtory cell