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Vascular Pathology > 2-Aterosclerosis > Flashcards

2-Aterosclerosis Flashcards

1
Q

1- Define Atherosclerosis

1

A

1- Literally means hardening of the arteries

2- Formation of intimal fibrous plaques with lipid core called atheromas

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2
Q

2- Affects of atherosclerosis
location
(1)

A

1- Elasctic arteries (aorta)

2- Muscular arteries (coronary)

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3
Q

3- Consequences of atherosclerosis

1

A

1- Myocardial infarction
2- Cerebral infarction
3- Aortic aneurysm
4- Lower limb gangrene

Athers contributes to more mortality and more serious morbidity than any other disorders in the western world.

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4
Q

4- Describe the atheomatous plaque

2

A

1- Located in the intima
2- lipid core (LDL)
3- Covered with fibrous cap
4- diameter 0.3 to 1.5 cm

5- Components:

1) Cells ( macrophages, smooth muscle cells, T lymphocytes
2) Connective tissue
3) Lipid deposits

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5
Q

5- What are foam cells?

3

A

1- A peculiar differentioation stage of macrophages

2- Macrophage binds with oxideized LDL (OxLDL), thus trapping the macrophage in the intima

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6
Q

6- Pathology and pathogenesis

Explain the type of lesions associateed with athers

(4)

A

1- The fatty streak
2- The fibrous atheromatous plaque
3- Complicated lesion

the ;atter 2 are responsible for the clinically significant manifestations of the disease

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7
Q

7- Sequences in progression of atherosclerosis

5

A 
1- Initial lesion
2- Fatty streak
3- Intermediate lesion
4-Atheroma
5- FIbroatheroma
6- Complicated lesion
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8
Q

8- Define fatty streaks

6

A

1- thin, flat yellow intimal discolorations that progressively enlarge by becoming thicker and slightly elevated as they grown in length
2- Consists of macrophages and smooth muscle cells distended with lipids ( foam cells)

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9
Q

9- Describe the formation of fatty streaks

7

A

1- Excess LDL-choestrol accumulation between the endothelium and connective tissues.
2- It is oxidized and phagocytosed.
3- The macrophages produce paracrines that attract smooth muscle cells.

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10
Q

10- Define atheromatous plaque

9

A

1- The basic lesion of clinical atherosclerosis
2- Accumulation of intracellular and extracellular lipids, proliferation of vascular smooth muscle cells, and formation of scar tissue
3- The lesion is an elevated thickening of the intima with a core of extracellular lipid.
4- The lumen increases in size, they cover the lumen ofd the artery

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11
Q

11- Histological appearance of an atheromatous plaque

10

A

1- Fibrous cap
(smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization)

2- Necrotic centre
(cell debris, cholestrol crystals, foam cells, calcium)

3- Media

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12
Q

12- Define Complicated lesions

11

A

1- Advanced complicated lesions are characterized by

  • Hemorrhage
  • Ulceration
  • Scar tissue deposits

2- Thrombosis is the most important complication of atheros
3- It is caused by slowing and turbulence of blood flow in the region of the plaque and ulceration of the plaque.

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13
Q

13- Describe plaque evolution

12

A

1- Stable plaques
2- Vulnerable plaques
formation of calcified scar tissue.
If damaged, platelets from the plaque, stick to damaged area and a blood clot forms (thrombus). consequences, heart attack.

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14
Q

14- Explain the mechanisms that causes atheros

14

A

1- Endothelial injury with leukocyte ( lymphocyte and monocyte) adhesion and platelet adherence
2- Smooth muscle cell migration and proliferation
3- Lipid engulfment of activated macrophages
4- Subsequent development of an atherosclerotic plaque with lipid core

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15
Q

15- Mechanism: hypothesis of the reaction of injury

16

A

1- Atheros as a chronic inflammation and healing response to the endothelial injury

2- Inflammation of blood vessels due to endothelial damage caused by:

1) Hemodynamic disturbances (turbulent flow activates endothelium)
2) Hyperlipidemia, particularly LD with its high cholestrol content
3) products associated with smoking, immune mechanisms, mechanical stress (hypertension)

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16
Q

16- Explain the earliest mechanism of elevated cholestrol levels

(17)

A
  • One of the earliest responses to elevated
    cholesterol levels is the attachment of monocytes to the endothelium.
  • The monocytes emigrate through the cell to cell attachments of the endothelial layer intothe subendothelial spaces, where they are transformed into macrophages.
  • Activated macrophages release free radical
    that oxidize LDL.
  • Oxidized LDL
    It has a chemotacti effect on lymphocytes and monocytes
    It has chemotactic effect on smooth muscle cells from the arterial media and stimulates production of GM-CSF, cytokines, adhesion molecules in the endothelium
    It stimulates specific immune system (production of antibodies against oxidized LDL)
17
Q

17- Explain the mechanisms of complicated lesions

19

A

1- OxLDL is toxic to the endothelium, causing endothelial loss and exposure of the subendotheilal tissue to blood components
2- Endothelial disruption leads to platelet adhesion and aggregation and fibrin deposition
3- Platelets and activated macrophages release various factors that are thought to promote growth factors that modulate proliferation of smooth muscle cells and deposition of ECM in the lesions: elastins, collagen , proteoglycans
4- Activated macrophages also ingest oxidized LDL to become foam cells, which are present in all stages of atherosclerotic plaque fromation
5- Lipids released from necrotic foam cells accumulate to form lipid core of unstable plaques
6- Connective tissue synthesis determines stiffness, calcium fixation and further ulceration of artheromatous plaque.

18
Q

18- Types of risk factors related to atheros

21

A

1- Modifiable risk factors

2- Non modifiable risk factors

19
Q

19-Describe Non Modifiable risk factors

22

A

1) Age
2) Male gender
- men are at greater risk than premenopausal women due to the protective effects of estrogen
3) Hereditary
- several genetically determined alterations in lipoproteins and cholestrol metabolism have been identified

20
Q

20- Describe modifiable risk factors

23

A 
1) Hyperlipidemia
20 C)garette smoking
3) Hypertension
4) Diabetes mellitus
5) Insufficient physical activity
6)a stressful lifestyle
7) obesity
21
Q

21- Complications of atheros

21

A

1) Calcification
- Renal artery stenosis
- Angina
- Peripheral vascular disease
2) Rupture
- Myocardial infarction
- Thrombotic stroke
3) Hemorrhage
4) Embolization Distal sites
- Embolic stroke
5) Aneurysm
- AAA

22
Q

23- Cosequences of Atheros plaque

24

A

Aneurysm and rupture

  • Mural thrombosis
  • Embolization
  • Wall weakening

2) Occlusion by thrombus
- Plaque rupture
- Plaque erosion
- Plaque hemorrhage
- Mural thrombosis
- Embolization

3) Critical stenosis
- Progressive plaque growth

23
Q

24- Evidences of the role of hypercholestrolemia in atherogenesis

(28)

A
  • Cholesterol and cholesterol esters are the dominant lipids in atheromatous plaques.
  • Genetic defects causing hyperlipoproteinemia are associated with accelerated atherosclerosis. Homozygous familial hypercholesterolemia (defective LDL receptors and inadequate hepatic LDL uptake) can lead to myocardial infarction before age 20 years. Similarly, accelerated atherosclerosis occurs in animal models with engineered deficiencies in apolipoproteins or LDL receptors.
  • Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature therosclerosis.
  • Significant correlation between the severity of atherosclerosis and the levels of total plasma cholesterol or LDL.

• 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.

24
Q

24- Explainthe correlation of inflammation and atheros

29

A

1- Observations of-the-inflammatory nature-of- therosclerotic plaques made-by- Rudolf-Virchow in-1858
2- Immune-cells dominate-early lesions
3- Inflammation mediators accelerate-the-progression of-the-lesion
4- Activation of-inflammation stimulates acute-coronary syndromes
5-Inflammation present in-all the-aterosclerotic process

25
Q

25- Explain the relationship of immune system cells and plaque rupture

(33)

A

1- Rupture occurs when the coating is fibrous and thin
2- Immun cells are abundant at the site of the rupture
3- Immune cells produce inflammatory mediators and proteolytic enzymes that weaken coating, activate cells in the core by transforming a stable plaque to vulnerable
4- Important role of metallo proteases. MMPs

26
Q

26- Explain the clinical impact of inflammation on atherosclerosis

(34)

A

1- Plasma levels of inflammatory biomarkers including hs CRP and IL-6 robustly predict first and recurrent cardiovascular events, independent of lipid levels
2- Statins are both lipid lowerinf and anti inflammatory, and the gtreatest benefits of statin therapy accure to those who not only lower LDLC, but who also hs CRP.
3- JUPITER (justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin trial).

27
Q

27- What are the inplication of CRP

35

A

1- they are acutre-phase proteins
2- Marker of systemic inflammation
3- Functions: Opsonizing bacteria and activating complement.
4- Strong and independently predictor of myocardial infacrtion risk

28
Q

28- Explain targeting inflammation with old drugs

36

A

1- NSAIDs (non-steroidal antiinflammatory drugs) COXIB
- associated with an increase risk of MI

2- Methotrexate (MTX- anti-inflammatory drug)
- for the treatment of chronic inflammatory disorderes such as rheumatoid arthritis and psoriasis) associated with lower rosk of CVD

3- TNF inhibitors
- reduces the risk oof CV events in rheumaotid arthritis

4- IL-1 receptor antagonist (IL-1ra)
- reduces hsCRP and IL-6 levels

29
Q

29 - Explain the secondary prevention of atheros

37

A

Clinicians can now distinguish between patients with “residula cholestrol risk” and those with ‘residual inflammaotry risk’

Known Cardiovascular DIsease
LDL- 150 mg/dL
hsCRP 4.5 mg/L
(high intensity statin)

Residual Cholesterol Risk
LDL 110 mg/dl
hsCRP 1.8 mg/L
(Additional LDL reduction)

Residual Inflammatory Risk
LDL 70 mg/dL
hsCRP 3.8 mg/L
(additional inflammation reduction)

30
Q

30- Explain CANTOS

38

A

CANTOS - Canakinumab Anti-Inflammatory Thrombosis Outcomes Study

  • more thab 10,000 patients
  • with previious history of MI and lvl os hsCRP>2mh/L
  • treated with canakinuima, an antibody that binds and blocks selectivelt the IL-1 beta receptor (NOVARTIS)
  • Placebo group was included in the study
31
Q

31- The CANTOS Study and the proof of concept

44

A

1- Atherosclerosis is a inflammatory disease which can be targeted by a specific anti-inflammatory therapy

2- But the drug to use remains still undefined

3- Canakinumab cant be used for 2 reaseons

  1. Increase of death from infections
  2. The price of this therapy is still not easily affordable
32
Q

32- Conclusion of CANTOS

47

A

1- CANTOS demonstrates that targeting the IL-1B to IL-6 pathway of innate immunity with Canakinumab

  1. reduces cardiovascular event rates
  2. potentially reduces rates of incident lung cancer and lung cancer mortality

2- inflammation inhibition in the absence of lipid lowerinf :

  1. Can improve atherothrombotic outcomes
  2. and potentially alter the progression of some fatal cancers
33
Q

33- Accurate general simple defintion of Atherosclerosis

49

A

Atherosclerosis is an inflammatory disease in which immune mechanisms interacct with metabolic risk factors to initiate, propagate and activate lesions in the arteries.

Vascular Pathology (5 decks)

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