Arteriosclerosis

Question 1

Arteriosclerosis

Answer 1

“hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity.

Question 2

Arteriolosclerosis

Answer 2

affects small arteries and arterioles and may cause downstream ischemic injury. The two vari-ants, hyaline and hyperplastic arteriolosclerosis

Question 3

Mönckeberg medial sclerosis is

Answer 3

characterized by the pres-ence of calcif i c deposits in muscular arteries, usually centered on the internal elastic lamina
( not imp clinically)
Individuals > 50 years

Question 4

Fibromuscular intimal hyperplasia

Answer 4

non-atherosclerotic process that occurs in muscular arteries larger thanarterioles.
An SMC & ECM-rich lesion
Such a healing response can cause substantial stenosis of the vessel; indeed such inti-mal hyperplasia underlies stent restenosis and is the major long-term limitation of solid organ transplants

Question 5

Atherosclerosis

Answer 5

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

Question 6

Atheromatous plaques

Answer 6

are raised lesions composed of soft friable (grumous) lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps

Question 7

Factors

Answer 7

Genetic abnormalities Family history Increasing age Male gender

Modif i able Hyperlipidemia Hypertension Cigarette smoking Diabetes Inf l ammation
Hyperhomocysteinemia
Metabolic syndrome. Associated with central obesity
Clonal hematopoiesis.

Question 8

Atheroma pathogenesis

Answer 8

begin at sites of intact, but dysfunctional, endothelium. These dysfunctional ECs exhibit increased permeability, enhanced leukocyte adhe-sion, and altered gene expression, all of which may con-tribute to the development of atherosclerosis.

Question 9

Hemodynamic disturbances and atherosclerosis plaques

Answer 9

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 fl ow

Question 10

Do not memorise

Answer 10

homozygous famil-ial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction by 20 years of age.
g., diabetes mel-litus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis.
dominant lipids in atheromatous plaques are cho-lesterol and cholesterol esters.

Question 11

Why is LDL implicated in atherosclerosis

Answer 11

hyperlipidemia, particularly hypercholesterolemia, can directly impair EC function by increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.

Question 12

Pathogenesis continued

Answer 12

lipoproteins accumulate within the intima, where they are hypothesized to gen-erate two pathogenic derivatives, oxidized LDL and cho-lesterol crystals.

LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or ECs and ingested by macrophages through the scav-enger receptor, resulting in foam cell formation.

Question 13

What does oxidized LDL do

Answer 13

Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to ECs and SMCs
Also trigger inflammation
minute extracel-lular cholesterol crystals found in early atherosclerotic lesions serve as signals that can activate innate immune cells such as monocytes and macro-phages to produce IL-1 and other pro-inflammatory mediators.

Question 14

Inflammation in atherosclerosis

Answer 14

dysfunctional ECs express adhesion mol-ecules that promote leukocyte adhesion, in particular, monocytes and T cells which migrate into the intima under the inf l uence of locally produced chemokines.

Monocytes engulf lipoproteins, including oxidized LDL and small cholesterol crystals. Cholesterol crystals activate inflammasome and subsequent release of IL-1.Activated macrophages also pro-duce toxic oxygen species that drive LDL oxidation and elaborate growth factors that stimulate SMC proliferation.
T cells contribute to chronic inflammation

Question 15

Fatty streak

Answer 15

Intimal SMC proliferation and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into a mature atheroma, contributing to the progressive growth of atherosclerotic lesions
platelet-derived growth factor (released by locally adherent platelets, macrophages, ECs, and SMCs), fi broblast growth factor, and TGF-α. The recruited SMCs synthesize ECM (most notably collagen), which sta-bilizes atherosclerotic plaques.

Question 16

Morphology fatty stteaks

Answer 16

Fatty streaks begin as minute yellow, flat macules that join into elongated lesions, 1 cm or greater. composed of lipid-f i lled foamy macrophages but are only minimally raised and do not cause any significant f l ow disturbance. Fatty streaks can appear in the aortas of infants younger than 1 year of age and are present in all children > 10 years of age, regardless of genetic, clinical, or dietary risk factors. Not all fatty streaks are destined to progress to atherosclerotic plaques.coronary fatty streaks form during adolescence at the same anatomic sites that are prone to plaques

Answer 17

The key features of these lesions are intimal thickening and lipid accumulation
plaques are white to yellow raised lesions; they range from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses. Thrombus
Thrombus superimposed on ulcerated plaques imparts a red-brown color (Fig. 10.12).
Atherosclerotic plaques are patchy, usually involving only a portion of any given arterial wall; on cross-section, therefore, the lesions appear “eccentric” (Fig. 10.13A). The focal nature of ath-erosclerotic lesions may be related to the vagaries of vascular hemodynamics. Local f l ow disturbances, such as turbulence at branch points, make certain parts of a vessel wall especially susceptible to plaque formation.

Question 18

Structure of a plaque

Answer 18

plaques have a superf i cial f i brous cap composed of SMCs and relatively dense collagen. Where the cap meets the vessel wall (the “shoulder”) is a cellular area containing macrophages, T cells, and SMCs.

Deep to the f i brous cap is a necrotic core, containing lipid (pri-marily cholesterol and cholesterol esters), necrotic debris, lipid-laden macrophages and SMCs (foam cells), f i brin, variably organized thrombus, and other plasma proteins.

The extracellular cholesterol frequently takes the forms of crystalline aggregates that are washed out during routine tissue processing, leaving behind empty “cholesterol clefts.” The periphery of the lesions shows neovascularization (proliferating small blood vessels) (see Fig. 10.13C). The media deep to the plaque may be attenu-ated and exhibit f i brosis secondary to smooth muscle atrophy and loss. Typical atheromas contain relatively abundant lipid, but some so-called f i brous plaques are composed almost exclu-sively of SMCs and fibrous tissue.
The extracellular cholesterol frequently takes the forms of crystalline aggregates that are washed out during routine tissue processing, leaving behind empty “cholesterol clefts.” The periphery of the lesions shows neovascularization The media deep to the plaque may be attenu-ated and exhibit f i brosis secondary to smooth muscle atrophy and loss. Typical atheromas contain relatively abundant lipid, but some so-called fibrous plaques are composed almost exclusively of SMCs and fibrous tissue.