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Cardiovascular Block > L7 - Athersclerosis pathophysiology > Flashcards

L7 - Athersclerosis pathophysiology Flashcards

1
Q

What is contained in the media of a BV?

A

SMC and ECM

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2
Q

What is contained in the adventitia of a BV?

A

nerves, lymphatics, BV

- nourishes cells of arterial wall

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3
Q

Describe role of normal endothelium?

A
  1. Produces anti-thrombotic molecules, preventing clotting
  2. Produces NO & prostacyclin which enter circulation
  3. Secretes substances that modulate SMC contraction
  4. Endothelial cells can modulate immune response
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4
Q

Compare and contrast a normal and an activated endothelial cell?

A

Normal

  • impermeable to large molecules
  • anti-inflammatory
  • resist leukocyte adhesion
  • resist thrombosis

Activated

  • increased permeability
  • increased inflammatory cytokines
  • increased leukocyte adhesion molecules
  • decreased vasodilators
  • decreased anti-thrombotics
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5
Q

Compare and contrast a normal smooth muscle cell with an activated smooth muscle cell?

A

Normal

  • normal contractile function
  • maintains ECM
  • contained in medial layer

Activated

  • increased inflammatory cytokines
  • increased ECM
  • increased migration and proliferation into subintima
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6
Q

Describe how smooth muscle cells may promote leukocyte proliferation

A
  • secrete IL-6, TNF-a
  • promote leukocyte proliferation
  • inducing endothelial expression of leukocyte adhesion molecules
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7
Q

Describe the ECM in healthy arteries?

A
  • fibrillar collagen, proteoglycan, elastin

- native fibrillar collagen can inhibit SMC proliferation in vito

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8
Q

In an atherosclerotic wall, vascular endothelial and smooth muscle cells will react to?

A

inflammatory mediators such as IL-1 & TNF-a

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9
Q

Summarise the atherosclerotic inflammatory process?

A
  • endothelial dysfunction
  • accumulation of lipids in intima
  • recruitment of leukocytes and SMC to vessel wall
  • formation of foam cells
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10
Q

Evolution of the atheroslclerotic plaque

long answer, sorry!

A
  1. Lipoprotein accumulation intima
  2. Lipoprotein modification - darker aar of oxidation
  3. Oxidative stress and constituents of mLDL will induce local cytokine elaboration
  4. Increased expression of adhesion molecules which bind leukocytes. Increased expression of chemoattractants, monocyte chemoattractant protein 1 (MCP-1) which directs leukocyte migration into intima.
  5. After entering intima: blood monocytes encoutner stimulti such as macrophage colony stimulating factor (M-CSF) which augments their expression of scavenger receptors
  6. Scavenger receptor: increase lipoprotein uptake, promote development of foam cells
  7. Macrophage foam cell: addition cytokine source
  8. SMC migrate into intima from media
  9. Intimal SMC, divide, elaborate ECM - promotes matrix accumulation in growing athersclerotic plaque
  10. Increase intimal thickness, fatty streak develops and evolves into a fibro fatty lesion
  11. Calcification, fibrosis, SMC death
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11
Q

Role of scavenger receptors

How do they differ to classic LDL receptors

A
  • mediate uptake of modified lipoprotein particles
  • promote development of foam cells
  • classic LDL receptors do not recognise chemically altered mLDL,
  • hence macrophages rely on scavenger receptors that preferentially bind and internalise mLDL.
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12
Q

What response to endothelial cells have in response to injury?

A

secrete chemokines

- will attract WBC to area

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13
Q

Summarise stages of plaque development

A
  1. Fatty streak
  2. Plaque progression
  3. Plaque disruption
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14
Q

Formation of fatty streak

A
  • endothelial dysfunction
  • lipoprotein entry and modification
  • leukocyte recruitment
  • foam cell formation
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15
Q

Plaque progression

A
  • SMC migration into intima
  • will divide and elaborate ECM
  • altered matrix synthesis and degradation
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16
Q

Plaque disruption

A
  • disrupted plaque integrity
  • haemodynamic stresses and degradation of ECM
  • increase susceptibility of fibrous cap to rupture
  • allowing superimposed thrombus formation
17
Q

Fatty streak presents as..

A

Areas of yellow discoloration on the arteries inner surface

18
Q

Endothelial dysfunction is the primary event in plaque in plaque initiation - how does this occur?

A
  1. Physical and chemical stresses alter the normal endothelium
  2. Will allow lipids entry into the subintima and promote inflammatory cytokine release
  3. Cytokine + lipid rich environment promotes recruitment of leukocytes to the subintima
  4. Once in subintima, leukocytes will become foam cells
  5. foam cells are a prominent inflammatory participant
19
Q

Describe endothelial dysfunction as a result of exposure to a toxic chemical environment?

e.g. smoking, diabetes, circulating lipids

A
  • increase endothelial production of reactive oxygen species, superoxide anion (v.constrictor)
  • cells promote local inflammation
  • activated endothelium: permeable, no longer barrier to lipids
20
Q

Disadvantage of an activated epithelium

A
  • increased endothelial permeability
  • allows entry of LDL into intima
  • LDL accumulates in subendothelial space by binding to a component of ECM known as proteoglycans
  • LDL trapped within vessel wall for longer
  • hence lipoprotein will undergo chemical modification
  • contributing to development of athersclerotic lesion
21
Q

Apoprotein

A
  • directing lipoprotein to specific tissue receptors and mediating enzymatic reactions
22
Q

Foam cell formation

A
  1. monocytes adhere, penetrate intima
  2. m.cyte –differentiates–> phagocytic m.phage
  3. m.phage imbibe proteins to form foam cells
23
Q

M-LDL

A

modified low density lipoprotein

24
Q

Describe a plaque that has been developing for many years

A
  • typical athersclerotic plaque acquires a distinct thrombogenic lipid core that underlies a protective fibrotic cap
25
Q

Describe early plaque growth effects on arterial wall

A
  • compensatory outward remodelling of the arterial wall
  • preserves the diameter of lumen
  • permits plaque accumulation
26
Q

How might tissue ischaemic arise from plaque growth?

A
  • later plaque growth can outstrip the compensatory arterial enlargement, restricting vessel lumen
27
Q

Symptoms of tissue ischaemia

A
  • angina pectoris
  • intermittent claudication of the extremities
    - -> pain, cramping
28
Q

Summarise 4 stages of a plaque?

literally, 4 words

A
  • calcification
  • rupture
  • haemorrhage
  • embolisation
29
Q

How might fibrous plaque lead to aneurysm?

A
  • medial layer at increased pressure due to fibrous plaque
  • may provoke atrophy, loss of elastic tissue
  • subsequent expansion of artery
  • forming an aneurysm
30
Q

Rupture or ulceration of atherosclerotic plaque would lead to…

A
  • exposure of procoagulants within plaque circulating blood
  • causing thrombus to form at site
  • thrombus may occlude vessel resulting in infarction of the involved organs.
31
Q

Physiological response of VSMC to hypoxia

A
  • peripheral vessels dilatation
  • BV of pulmonary vasculature constrict to
  • shunting of blood from poorly ventilated region
32
Q

How would myocyte constriction occur?

A
  • inhibition of some K+ channels, which set membrane potential
  • resulting depolarisation
  • VG(Ca2+) channels activated
  • cystolic [Ca2+] increases
  • myocyte constriction.
33
Q

Incase of intact endothelium. give examples of following stimuli for vasodilation?

A
  • mechanical stimulation by increased blood flow

- catecholamines, bradykinin, platelets, released serotonin which stimulates specific receptors

34
Q

what leads to the paradoxical vasoconstriction of the arterial wall?

A
  • direct vasoconstrictor action of the stimuli on the VSMC outweighs the endothelium dependent vasodilator effect
  • leads to paradoxical vasoconstriction
35
Q

Diapedesis

A

Passage of blood cells through intact walls of the capillaries, typically accompanying inflammation

36
Q

Role of macrophage foam cells

A
  • additional source of cytokines

- e.g. effector molecules, matrix metallopeptidases 9

37
Q

Describe the process of how a thrombus will finally occlude the arterial lumen

Detailed pathophysiology

A
  1. IFN-y induces macrophage matrix metallopeptidase 9 (MMP) expression
  2. IFN-y inhibits VSMC proliferation and collagen synthesis which further weakens the cap
  3. VSMC undergoes apoptosis
  4. After plaque ruptures the area is exposed its interior to blood
  5. Interior of plaque is highly thrombogenic , small molecular weight glycoprotein (tissue factor) initiates the extrinsic clotting cascade
  6. Tissue factor complexes with factor VII/VIIa, factor IX and X are activated
  7. Platelets are activated and thrombus forms quickly on the surface of a ruptured plaque
  8. Thrombus completely occludes the arterial lumen
  9. Can cause tissue necrosis , myocardial infarction or brain stroke

Cardiovascular Block (16 decks)

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