Atherosclerosis and Restenosis Mechanisms

Question 1

Age adjusted death rate from CVD have decreased by over 60% since 1960 due to what 2 things?

Answer 1

-50% from ID and treatment of risk factors -50% from new treatments and therapies

Question 2

Primary PCI and STEMI

Answer 2

-compared to conservative management, PCI leads to improved LV function and survival in STEMI pts -benefits seen if performed within 90 minutes after initial medical contact

Question 3

Use of STEMI in STABLE angina pectoris

Answer 3

-no significant differences between the groups receiving PCI vs medial rx

Question 4

T/F: Atherosclerosis progression begins early in life

Answer 4

-true: progresses in first 3 decades and remains stable until later in life when symptoms arise

Question 5

6 stages of atherosclerosis progression

Answer 5

1. monocyte adhesion/migration 2. foam cells gain more intracellular lipid in neointima 3. extracellular lipid pools 4. atheroma: core of extracell. lipid 5. fibroatheroma: lipid core and fibrotic layer 6. surface defect,thombus– complicated lesion

Question 6

Fatty stream formation: type II

Answer 6

-observed in coronary arteries of adolescents (but not all become plaques) -lipid-laden foam cells with mainly INTRAcellular lipids -response to injury/inflammation -furthers foam cell recruitment and formation via cytokine release

Question 7

Fatty streak formation is in response to injury/inflammation: list 4 main things that fall under this category

Answer 7

1. endothelial dysfunction 2. monocyte adhesion/emigration 3. SMC migration to intima 4. ECM and lipid accumulation

Question 8

Atheroma and fibroatheroma (type IV and V lesions): location and components

Answer 8

-location: plaques develop mainly in elastic arteries (aorta, iliac, carotid) and large-medium size arterioles (coronaries) -components: cells (SMCs, macrophages, leukocytes), ECM (collagen, elastic fibers, PGs), lipid (free and intracellular)

Question 9

What is in the core vs cap of a fibroatheroma

Answer 9

-cap: SMCs, ECM -core: macrophages, lipids, debris from apoptosis

Question 10

Describe process of plaque expansions

Answer 10

1. leukocyte infiltration 2. cell death and degeneration 3. synthesis of ECM 4. organization of thrombus

Question 11

Type IV (complicated) plaques are at risk for…

Answer 11

-rupture, ulceration, erosion

Question 12

Vulnerable plaque characteristics

Answer 12

-Characterized by thin fibrous cap and large hypocellular lipid-rich core. Large percentage of lymphocytes and activated macrophages. Abundant cytokine production and MMPs (low pH, hot). Shoulder regions are particularly vulnerable

Question 13

Plaque rupture may lead to _______. It may be accompanied by ____.

Answer 13

May leads to acute ischemic syndromes (ACS). It may be accompanied by hemorrhage into the plaque, superimposed thrombosis (exposure of ECM) and/or anuerysmal dilation (aortic aneurysm)

Question 14

Fibrotic plaques rarely rupture, but can cause _________.

Answer 14

-stable angina syndromes

Question 15

2 components contributing to restenosis after PCI and which one stenting can stop

Answer 15

-2 parts: constrictive remodeling due to EEL contraction and SMC migration out of media to narrow the lumen -stenting stops the geometric remodeling, but does not stop the SMC migration

Question 16

Initiation and SMC activation involved in restenosis

Answer 16

-initiation: endothelial cell denudation, exposure to ECM, platelet activation and release of cytokines and growth factors -SMCs activated and reenter cell cycle to limitedly proliferation and modulate phenotype from contractile to synthetic and secrete abundant ECM, migrate to intima forming a neointima within 7 days of injury

Question 17

ECM accumulation accounts for _______% of the restenotic lesion

Answer 17

-90%

Question 18

What allows the SMCs to migrate in to neointima?

Answer 18

-loss of IEL with PCI

Question 19

4 restenotic growth factors and their roles and who makes them

Answer 19

1. PDGF: induces SMC migration (NOT required for SMC proliferation); released from platelets, endothelial cells, macrophages, SMCs in response to vessel wall injury 2. FGF: released by SMCs in stretch/crush injury; induces initial wave of SMC proliferation 3. Ang II: SMC proliferation**; and SMC migration via PDGF R binding; ACEI attenuates neotinima formation in rats, but not humans 4. TGF-B: made by SMCs, endo, platelets following PTCA; Primary driver of extracellular matrix secretion from SMCs

Question 20

_______ was seen to inhibit SMC proliferation. What did this lead to?

Answer 20

-Rapamycin -drug-eluting stents: sirolimus and taxol

Question 21

Sirolimus (rapamycin)

Answer 21

-macrolide Abx that inhibits cytokine and GF mediated cell proliferation -arrests SMCs at end of G1 -less than 10% restenosis as 6 months

Question 22

Paclitaxel (taxol)

Answer 22

-antineoplastic agent -polymerized tubulin to make nonfunctional MTs and inhibit G2/M phase and cell migration -restenosis less than 10%

Question 23

End result of all drug-eluting stents is __________________.

Answer 23

-inhibition of cell cycle

Question 24

Issues DES and PCI still face

Answer 24

-DES also inhibit endothelial cell proliferation and migration; this doesnt allow for proper healing around the stent making it prone to late thrombosis!! and neoatherosclerosis -future development may be bioabsorbable stent

Question 25

Atherosclerosis vs restenosis: initiation, pathogenesis, histology, clinical course

Answer 25

-athero is multi cellular vs restenosis