Arteriosclerosis is the hardening and narrowing of arteries due to plaque buildup. The three main types are arteriolosclerosis (small arteries), Monckeberg medial sclerosis (calcification of muscular arteries), and atherosclerosis (most common). Atherosclerosis features atheromas that protrude into the vessel lumen. Risk factors like age, gender, genetics, hyperlipidemia, hypertension, smoking, and diabetes accelerate atherosclerosis. Inflammation and infection also contribute to plaque formation and rupture, which can cause acute issues like heart attack or stroke.

1. PATHOLOGY:
Arteriosclerosis
nianderthalNOTES

2. ARTERIOSCLEROSIS
DEF:
-hardening of the arteries
-generic term reflecting arterial wall thickening and
loss of elasticity
THREE GENERAL PATTERNS:
1. Arteriolosclerosis
2. Monckeberg medial sclerosis
3. Atherosclerosis

3. 1. Arteriolosclerosis
-affects small arteries and arterioles
-anatomic variants:
a. hyaline
b. hyperplastic

4. 2. Monckeberg medial sclerosis
-has calcific deposits in muscular arteries that
may undergo metaplasia to bone
-lesions do not encroach vessel lumen thus NOT
CLINICALLY SIGNIFICANT

5. 3. Atherosclerosis
-most frequent and clinically important pattern
-characterized by intimal lesions called
ATHEROMAS that protrude into the vessel
lumen
-consists of a raised lesion:
a. Grumuous Core – made of lipid, (cholesterol
or cholesterol ester) yellow, soft
b. Fibrous Cap – white

6. 3. Atherosclerosis
EPIDEMIOLOGY
-Risk factors have a multiplicative effect
-Constitutional Risk Factors in IHD
a. Age – clinically manifests middle age or later
b. Gender – premenopausal women are relatively
protected due to favorable influence of estrogen
-but clinical trials have failed to demonstrate
any utility of hormonal therapy for vascular diseases
prevention
a. Genetics – MOST SIGNIFICANT INDEPENDENT RISK
FACTOR

7. 3. Atherosclerosis
EPIDEMIOLOGY
-Modifiable Risk Factors in IHD
a. Hyperlipidemia – esp. hypercholesterolemia,
increased LDL, decreased HDL, increased
lipoprotein a
*STATINS – a class of drugs that lower circulating
cholesterol levels by inhibiting HMG-Coa
reductase, the rate-limiting enzyme in
hepatic cholesterol biosynthesis

8. 3. Atherosclerosis
EPIDEMIOLOGY
-Modifiable Risk Factors in IHD
b. Hypertension – both systolic and diastolic
components are important
- MOST IMPORTANT CAUSE OF LEFT
VENTRICULAR HYPERTROPHY
c. Cigarette smoking – prolonged smoking of
one pack of cigarettes or more daily doubles
the death rate from IHD

9. 3. Atherosclerosis
EPIDEMIOLOGY
-Modifiable Risk Factors in IHD
d. Diabetes mellitus – induces
hypercholesterolemia

10. 3. Atherosclerosis
EPIDEMIOLOGY
-Additional Risk Factors
a. Inflammation – present during all stages of
atherogenesis and is intimately linked with
atherosclerotic plaque formation and rupture
*C-reactive Protein (CRP) has emerged as one of
the simplest and most sensitive inflammatory
markers; decreased by STATINS

11. 3. Atherosclerosis
EPIDEMIOLOGY
-Additional Risk Factors
b. Hyperhomocysteinemia – seen in CAD, PAD,
stroke and venous thrombosis
-elevated homocysteine levels can be caused
by low folate and Vitamin B12 intake
c. Metabolic syndrome

12. 3. Atherosclerosis
EPIDEMIOLOGY
-Additional Risk Factors
d. Lipoprotein (a) – an altered form of LDL,
associated with CAD and CVD
e. Factors affecting Hemostasis
f. Other Factors – lack of exercise; competitive
stressful lifestyle (type A personality); obesity

13. 3. Atherosclerosis
PATHOGENESIS
Hypotheses:
a. Intimal Cellular Proliferation
b. Repetitive Formation and Organization of Thrombi
c. Response-To-Injury
-views atherosclerosis as a chronic inflammatory and
healing response of the arterial wall to injury
-lesion progression occurs through the interaction of
modified lipoproteins, monocyte-derived
macrophages, and T-lymphocytes with the normal
cellular constituents of the arterial wall

14. 3. Atherosclerosis
PATHOGENESIS
c. Response-To-Injury
-PATHOGENIC EVENTS INVOLVED:
i. Endothelial Injury
-increased vascular permeability
-leukocyte adhesion
-thrombosis
ii. Accumulation of Lipoproteins in vessel wall
-usually LDL and its oxidized forms
iii. Monocyte adhesion to the endothelium, followed
by migration into the intima and transformation into
macrophages and foam cells

15. 3. Atherosclerosis
PATHOGENESIS
c. Response-To-Injury
-PATHOGENIC EVENTS INVOLVED:
iv. Platelet adhesion
v. Factor release from activated platelets, macrophages
and vascular wall cells, inducing smooth muscle cell
recruitment
vi. Smooth muscle cell proliferation and ECM
production
vii. Lipid accumulation
-extracellular and within cells (macropahes and
smooth muscle cells)

16. 3. Atherosclerosis
PATHOGENESIS
MAJOR MECHANISMS
+Endothelial Cell Injury
-results in intimal thickening
-early human lesions begin at sites of morphologically
intact endothelium, THUS, endothelial dysfunction
underlies human atherosclerosis
-can be caused by:
-hypertension -hyperlipidemia
-toxins from cigarette smoke -infectious agents
-inflammatory cytokines -homocysteine

17. 3. Atherosclerosis
PATHOGENESIS
MAJOR MECHANISMS
+Endothelial Cell Injury
2 MOST IMPORTANT CAUSES OF
ENDOTHELIAL DYSFUNCTION
-hemodynamic disturbances
-hypercholesterolemia

18. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Hemodynamic Disturbances
-plaques tend to occur at areas of disturbed flow
patterns:
a. Ostia of exiting vessels
b. Branch points
c. Along the Posterior wall of the abdominal aorta

19. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Hemodynamic Disturbances
-nonturbulent laminar flow in normal
vasculature leads to the induction of
endothelial genes whose products protect
against atherosclerosis e.g. SUPEROXIDE
DISMUTASE

20. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Lipids
-Lipoprotein abnormalities present in many MI survivors:
-Increased LDL
-Decreased HDL
- Increased Lipoprotein (a)
-DOMINANT LIPIDS IN ATHEROMATOUS PLAQUES ARE:
-Cholesterol
-Cholesterol Esters

21. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Lipids
-Lowering serum cholesterol by diet or drugs
slows the rate of progression of
atherosclerosis, causes regression of some
plaques, and reduces the risk of
cardiovascular events

22. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Lipids
-Mechanisms by which HYPERLIPIDEMIA
contributes to ATHEROGENESIS:
-impair endothelial cell function by increasing
local oxygen free radical production
-accumulate lipoproteins within the intima,
which are then oxidized by oxygen free radicals

23. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Lipids
-Oxidized LDL is ingested by macrophages
through a SCAVENGER RECEPTOR, distinct from
LDL receptor
-MACROPHAGES become FOAM CELLS after
accumulation of Oxidized LDL within the
phagocyte

24. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Inflammation
-dysfunctional arterial endothelial cells express adhesion
molecules that encourage leukocyte adhesion
-VCAM1 – binds monocytes and T cells
-Monocyte recruitment and differentiation is theoretically
protective because they remove harmful lipid
particles, but the presence of OXIDIZED LDL
AUGMENTS Macrophage activation and cytokine
production

25. 3. Atherosclerosis
PATHOGENESIS
+Endothelial Cell Injury
*Infection
-Microorganisms detected in atherosclerotic
plaques:
-Herpesvirus
-Cytomegalovirus
-Chlamydiae pneumoniae

26. 3. Atherosclerosis
PATHOGENESIS
+Smooth Muscle Proliferation
-intimal smooth muscle cell proliferation and ECM
deposition convert a fatty streak into a mature
atheroma
*FATTY STREAK = EARLIEST LESION
-Growth Factors involved:
-PDGF
-FGF
-TGF-a

27. 3. Atherosclerosis
PATHOGENESIS
+Smooth Muscle Proliferation
-Smooth muscle cells synthesize ECM that
stabilizes atherosclerotic plaques
- Active Inflammatory cells in atheromas can
cause intimal smooth muscle cell apoptosis,
and increase ECM catabolism leading to
unstable plaques

28. 3. Atherosclerosis
MORPHOLOGY
*FATTY STREAKS
-EARLIEST LESIONS IN ATHEROSCLEROSIS
-begin as minute, flat yellow spots and then colaesce
-not significantly raised and 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

29. 3. Atherosclerosis
MORPHOLOGY
*ATHEROSCLEROTIC PLAQUE
-KEY PROCESSES: 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

30. 3. Atherosclerosis
MORPHOLOGY
*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

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

32. 3. Atherosclerosis
MORPHOLOGY
*ATHEROSCLEROTIC PLAQUE
-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

33. 3. Atherosclerosis
MORPHOLOGY
*ATHEROSCLEROTIC PLAQUE
-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

34. 3. Atherosclerosis
MORPHOLOGY
*ATHEROSCLEROTIC PLAQUE
-Plaques are susceptible to the following
CLINICAL CHANGES:
1. Rupture, ulceration, erosion
2. Hemorrhage into a plaque
3. Atheroembolism
4. Aneurysm formation

35. 3. Atherosclerosis
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

36. 3. Atherosclerosis
CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
*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

37. 3. Atherosclerosis
CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
*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

38. 3. Atherosclerosis
CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
*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

39. 3. Atherosclerosis
CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
*ACUTE PLAQUE CHANGE
INTRINSIC and EXTRINSIC FACTORS THAT
INFLUENCE RISK OF PLAQUE RUPTURE:
INTRINSIC EXTRINSIC
Plaque Structure Blood Pressure
Plaque Composition Platelet Reactivity
Adrenergic stimulation

40. 3. Atherosclerosis
CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
*ACUTE PLAQUE CHANGE
VULNERABLE Plaques:
-contain 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

41. 3. Atherosclerosis
CONSEQUENCES OF ATHEROSCLEROTIC DISEASE
*ACUTE PLAQUE CHANGE
-Peak time of onset of acute myocardial
infarction is between 6 AM and 12 NOON

42. 3. Atherosclerosis
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
cells