Atherosclerosis is characterized by plaques that form within arteries and can rupture, causing blockages. It is caused by risk factors like hyperlipidemia, hypertension, smoking, and diabetes that lead to endothelial injury and inflammation. Over time, lesions containing macrophages, smooth muscle cells, and lipids develop and can restrict blood flow or rupture. This disrupts blood vessels and causes complications like heart attack and stroke. The document discusses the pathogenesis of atherosclerosis 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