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CDL301 > Atherosclerosis > Flashcards

Atherosclerosis Flashcards

1
Q

Where does atherosclerosis come from?

A

Greek- athero= paste
sclerosis= hardness
Coat thickens so much as to close up and stop blood movement

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2
Q

Why can atherosclerosis result in?

A

Heart attack, stroke and gangrene

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3
Q

Initially thought of and what is it now known as?

A

Initially- lipid storage disease

now- chronic inflammatory disease influenced by many factors= inflammatory cells and cytokines

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4
Q

Main problem with atherosclerosis

A

If the plaque ruptures- thrombosis formation and death

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5
Q

Pathogenesis

A

Lifestyle choices, medical conditions and haemodynamic of blood flow
begin at birth but develops over lifetime
often remains symptomless for majority of life until advanced

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6
Q

Risk factors

A

Modifiable- physical inactivity, stress, obesity, diabetes, dyslipidaemia, hypertension, smoking
Non- modifiable- genetics, gender, age, inflammation, family history

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7
Q

Distribution of atherosclerotic plaque

A

Found within the peripheral and coronary arteries
focal distribution along the artery length
-may be governed by haemodynamics= changes in tuburlance/flow
- alter gene expression
- areas prone to atherosclerosis

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8
Q

Atherosclerosis is composed of what

A 
Complex lesion consisting of:
lipids 
necrotic core 
connective tissue 
fibrous cap- made from SMC and ECM
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9
Q

What happens if the plaque occludes

A

restrict blood flow- angina

or it may rupture- thrombus formation/ death

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10
Q

Response to injury hypothesis of atherosclerosis

A

First suggested in 1856- Rudolph Virchow and updated by Russell ross in 1993/9
indicated by an injury in the endothelial cells which leads to endothelial dysfunction

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11
Q

What does healthy endothelium produce to protect against atheroma?

A

NO and other mediators which protect
alter NO biosynthesis- affects BP control, regional blood flow, predisposes to atherosclerosis
send signals to inflammatory cells which accumulate and migrate into the vessel, leading to inflammation

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12
Q

Stimulus adhesion

A

Chemoattractants
chemicals that attract leukocytes are released from the site of injure and a concentration gradient is produced
damaged EC also express adhesion molecules

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13
Q

the adhesion cascade

A 
Capture 
rolling 
slow rolling 
firm adhesion 
transmigration - following down vessel wall and migrate through by chemoattractant
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14
Q

LDL passing though and out of the arterial wall- When?

A

when in excess, accumulate in the arterial wall- deliver cholesterol

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15
Q

What generate free radicals

A

Macrophages and EC

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16
Q

LDL is oxidised by and what happens?

A 
free radicals (oxLDL)- engulfed by macrophages to form foam cells 
release more proinflammatory cytokines
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17
Q

Cytokines found in plaques

A

IL-1,6,8,IFN-g, TGF-b, MCP-1 and PDGF

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18
Q

Progression of atherosclerosis 1- fatty streaks, what happens?

A
  • earliest lesion of atherosclerosis
  • appear at very early age
  • accumulation of lipid laden macrophages (foam cells) and T lymphocytes within the intimal layer of the vessel wall form fatty streaks
  • damage endothelium- allow macrophages in
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19
Q

progression of atherosclerosis 2- intermediate lesions?

A

layers composed of:

  • foam cells
  • VSMC
  • EC lipids and cholesterol
  • T lymophocytes
  • adhesion and aggregation of platelets to vessel wall
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20
Q

progression of atherosclerosis 3- protective mechanism

A

reverse cholesterol transplant

  • pathway for plaque reduction involving HDL
  • HDL contain apo-A1 interact with foam and collect cholesterol
  • mature HL travels to liver and releases cholesterol
  • HDL then recirculates back
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21
Q

progression of atherosclerosis 4- fibrous plaque or advanced lesion

A
  • thought to need an added impetus= another risk factor or area of disturbed flow
  • cytokine release cells cause SMC proliferation and deposition of connective tissue
  • leads to dense fibrous cap
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22
Q

What is fibrous cap composed of?

A

ecm- collagen (strength) and elastin (flexibility)

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23
Q

Lipid core

A

Necrotic and apoptotic debris, smc, foam cells, macrophages, t lymphocytes

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24
Q

Cap and core=

A

Artheromatous plaque

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25
Q

What does the Artheromatous plaque do?

A

may be calcified
impedes blood flow
prone to rupture
bigger the plaque= more narrowing and pain

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26
Q

Cyles of vascular inflammation and LDL results in formation of necrotic cap

A
  1. LDL enters vessel wall
  2. macrophage engulf and LDL become foam cells
  3. LDL lysed, cholesterol released crystalizes
  4. crystals in the foam cells induce apoptosis
  5. extracellular lipid pool within the arterial wall
  6. further attraction of macrophages
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27
Q

Human coronary atherosclerotic plaque looks like

A

Yellow core
lipids separated from lumen by fibrous cap
opposite plaque is an arc of normal vessel wall

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28
Q

Progression of atherosclerotic plaque 5- plaque rupture

A

Plaque constantly growing and receding
fibrous cap- resorbed and redoposited in order to be maintained
increase VMSC and matrix proteins to stabalise

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29
Q

What does a large number of macrophages predispose the plaque to?

A

Rupture
increase matrix metalloproteinases and gelatinase- cap becomes weak and rupture provides a substrate for thrombus formation and vessel occlusion

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30
Q

Rupture can be induced by

A

Cholesterol crystallization

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31
Q

Large necrotic plaque can rupture with

A

Haemorrhage

plaque lap is tonr and leads to rupture

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32
Q

Small necrotic plaque rupture

A

Erosion - wearing away

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33
Q

plaque disruption

A

The torn cap projects into the lumen of the artery and thrombus is contained with the plaque core

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34
Q

Plaque rupture- why it happens?

A 
thin fibrous cap 
collagen poor fibrous cap 
large lipid cap 
many macrophages 
fibrin rich thrombus
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35
Q

How does erosion happen?

A 
prosteoglycan glycosaminoglycan rich 
little or no lipid core 
neutrophils and NETS
many smooth muscle cells 
platelet rich thrombus
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36
Q

Mechanism of erosion

A
  1. resting endothelial cell
  2. activated endothelial cell
  3. sloughed endothelial cells
  4. resting platelet and grammalogue
  5. activated platelet and granulocyte
  6. rich platelet thrombosis
    * disturbed flow
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37
Q

Lipoproteins

A

Lipids are transported around the body as these

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38
Q

General structure of lipoproteins

A

central core is hydrophobic lipid (triglyceride cholesterol) surrounded by hydrophilic (free cholesterol, phospholipids, apolipoproteins)

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39
Q

Lipids classification

A

According to density

  • chylomicrons= ApoB-48, diameter 100-1000nm
  • LDL- ApoB-100, diameter 20-30nm
  • Very low density lipoproteins- ApoB-100 diameter 30-80nm
  • HDL- APOA1/A2, diameter 7-20nm
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40
Q

Lipids transport by 3 pathways

A
  1. Exogenous- gut to liver, dietary
  2. endogenous- liver to cells
  3. reverse- cells to liver
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41
Q

Exogenous pathway

A
  1. Lipids are digested
  2. lipids assemble with apoplipoproteins B-48 into nascent chylomicrons
  3. chylomicrons move into liver and bloodstream, HDL donate apopliporteins C-11 and E- mature chylomion. AC-11 can only bind adipose and ApoE cannor bind hepatocytes
  4. LDL catalyses hydrolysis reaction releasing glycerol and fatty acid from chylomicrons- absorbed into tissue
  5. remnants are endocytosed and hydrolysed within lysosomes and this releases glycerol and fatty acid in the cell
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42
Q

Endogenous pathway

A
  1. triclylglycerol and cholesterol are assembled with apolipoprotein
  2. HDL donates apolipoprotein C-II and E
  3. Apolipoprotein C-II activates LDL, causing hydrolysis of VDL particles and the release of glycerol and fatty acids- these can be absorbed by adipose tissue and muscle
  4. the hydrolysed VLDL particles are now called IDL
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43
Q

IDL

A

Contain multiple AoE binding LDLR with high affinity

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44
Q

LDL binds

A

Tissue via ApoC endocytosed, hydrolysed with lysosome release cholesterol
or
LDLR on liver via ApoB 100 removed from circulation

45
Q

What is the lipoprotein reverse cholesterol pathway?

A

removes cholesterol from peripheral tissues and returns to liver

46
Q

Mechanism of Reverse cholesterol

A

ApoA1 of HDL bind to transport protein ABC-A1 or ABC-G1 in macrophages/ foam cells and absorb cholesterol
- HDL then transports cholesterol via liver

47
Q

What are the 2 pathways HDL transports cholesterol back to the liver?

A
  1. indirect pathway- cholesterol esters transfer to VLDL and LDL particles via cholesterol ester transport protein (CETP), LDL bines to LDLR on liver
  2. Direct pathway- APOA1 of HDL bind SRB1 receptor on liver. Cholesterol transfer to liver . HDL recirculates
    * Cholesterol in liver processed and secreted in bile or transported to intestine via ABC-G5/G8 for excretion
48
Q

Dyslipidaemia

A

Imbalance of lipid transport- atherosclerosis

an abnormal amount of lipids in the blood

49
Q

Hyperlipidaemia

A

Elevation of lipids in the blood

50
Q

Primary cause of hyperlipidaemia

A

due to combination of diet and genetic, usually polygenic (involve multiple genes). can be monogenic (one gene)

51
Q

Secondary causes of hyperlipidaemia

A

consequence of other conditions
diabetes, alcoholism, renal failure, liver disease and drugs
secondary forms are treated where possible by correcting underlying cause

52
Q

How is primary dyslipidaemia classified

A

According to lipoprotein uptake
Six phenotype
the higher the LDL and lower then HDL the higher the risk of

53
Q

Type IIa

A

Familial hypercholesterolaemia

  • LDL receptor deficiency
  • increased LDL lipoprotein
  • high risk of atherosclerosis
  • 1:500 (heterozygous)
54
Q

Treatment for IIa

A

bile acid resins
statins
niacin

55
Q

Familial hypercholesterolaemia

A

genetic disorder causing very high LDL levels in the blood and early cardiovascular disease
mutations are rare but exist

56
Q

FH mutations in

A
  1. LDLR gene (encodes the LDL receptor protein, which removed LDL from the circulation)
  2. Apdiopoprotein B (ApoB) which is part of LDL that binds with the receptor
57
Q

Heterozygous and homozygous FH

A

Hetero- LDLR gene defect may have been premature CVD at the age of 30-40, 1:500
homozygous- LDLR gene defect may cause severe CVD in childhood, rarer 1 in a million

58
Q

How are heterozygous and homozygous treated?

A

Hetero- statins, bile acid or lipid lowering agents that lower cholesterol levels
homo- does not respond to medical therapy and may require other treatments, including LDL apheresis or liver transplant

59
Q

Treating dyslipidaemia or atherosclerosis

A
  • statins
  • fibrates
  • inhibitors of cholesterol absorption
  • PCSK9 inhibitor
60
Q

What are statins?

A
  • HMG-CoA reductase= rate limiting enzyme in cholesterol synthesis
  • regulate cholesterol levels by targeting HMG-CoA
  • specific reversible competitive inhibitor
61
Q

Short acting statins

A
  • given orally at night to reduce cholesterol early morning
  • deferentially absorbed and extracted by liver
  • subject to extensive presystemic metabolism via cytochrome P450 and glucuronidation pathway
62
Q

Mechanism of statins

A

cholesterol synthesis in liver causes LDL receptor synthesis
LDLR causes LDL clearance from plasma to liver
statins reduce plasma LDL and increase HDL

63
Q

Pleiotropic effects

A

products of the melovonate pathway are involved in lipidation ie react with protein to add a hydrophobic group

  • fatty group anchors to localise the protein in organelles
  • important membrane bound enzyme are modified by that way by inhibiting melavonate pathway- statins also affect lipidation
64
Q

What can the pleiotropic effect cause?

A
  • improved endothelial function
  • reduced vascular inflammation
  • reduced platelet aggregability
  • increased revascularisation in ishaemic tissue
  • increase circulating endothelial progenitor cells
  • stabilisation of atherosclerotic plaque
  • antithrombic plaque
  • enhanced fibrinolysis
  • inhibition of germ cell migration
  • immune suppression
  • protection against sepsis
65
Q

What is the primary prevention of atherosclerosis?

A

arterial disease in “at risk” patients elevated serum cholesterol conc +/- for atherosclerosis

66
Q

What is secondary prevention of atherosclerosis

A

MI or stroke inpatients with symptomatic disease (have had angina, MI or stroke)

67
Q

What does atorvastatin do?

A

lowers serum cholesterol in patients with homozygous familial hypercholesterolaemia

68
Q

What is heterozygous FH

A

serve drug resistant dyslipidaemia statin treatment is combined with other drugs

69
Q

What can statins not be used?

A

During pregnancy

HMG-CoA reductase guides migrating primordial germ cells

70
Q

What are the adverse effects of statins?

A 
Muscle pain 
GI disturbance 
rash 
raised conc of liver enzymes in plasma 
insomnia 
skeletal muscle damage- rare dose related, more common in patients with low lean body mass or uncorrected hypothyroidism
71
Q

Controversy around statins

A

A lower treatment threshold is proposed by NICE so that millions more people are at a lower risk of heart attack or stroke
Low risk patients- 99.3 % of patients see no benefit

72
Q

Effectiveness in high risk patients

A

side effects are neligable compared to the benefits in cutting the risk of having a heart disease
statins increase the risk of developing diabetes by 1% in women

73
Q

Why might not all data about statins side effects/ effectiveness be available?

A

Industry funded studies
not all data made available by researchers
industry/ non industry often show different results

74
Q

Interaction of statins with other medication or lifestyle

A

statin users consume more, exercise less, increase weight

75
Q

Names of fibrates

A 
benzofibrate 
cipofibrate 
gemfabrazil 
fenofibrate 
clofibrate
76
Q

Names of statins

A 
Simvastatin 
Atorvastatin 
fluxastatin 
pravastatin 
rosuvastatin 
pituvastatin
77
Q

What do fibrates do?

A

active PPAR especially PPARa

78
Q

What is PPAR

A

peroxisome proliferator activated receptor

intracellular receptors that modulate carbohydrate and fat metabolism and adipose tissue differentiation

79
Q

What does activating PPAR do?

A

induces the transcription of a number of genes that facilitate lipid metabolism

80
Q

Fibrates metabolised by

A

Cytochrome P450 3A4

81
Q

cyp3A4

A

enzyme, mainly found in the liver and intestine. oxidised small foreign organic molecules such as toxin or drugs so that they can be removed from the body

82
Q

Effects of fibrates

A

decrease circulation VLDL
decrease triglyceride levels
* modest (10%) decrease in LDL and increase in HDL

83
Q

Clinical use of fibrates

A

Rarely used
only when statins and ezetamide are not tolerated
can be combined with other lipid lowering drugs in patients with severe treatment resistant dyslipidaemia

84
Q

Adverse effects of fibrates

A
  • Mild stomach upset and myopathy (muscle pain)
  • clofibrate increase risk for gallstones
  • combination of statin and fibrate increases risk of muscle damage
  • should not be taken by patients with advanced kidney disease
  • fibrates should not be taken by alcoholics
85
Q

What is Ezetimibe

A

Inhibitor of cholesterol absorption

one of a group of azetmide cholesterol absorption inhibitors

86
Q

Action of ezetimibe?

A

Block intestinal absorption of cholesterol by blocking a transport protein (NPCIL1) in the brush border of enterocytes
Does not affect absorption of fat soluble vitamins, triglycerides or bile acids

87
Q

Facts about ezetimibe?

A
  • Does not affect absorption of fat soluble vitamins, triglycerides or bile acids
  • has high potency= 10mg/reduced LDL cholesterol by 17-19%
  • combination of statin = 25% reduction
88
Q

Pharmacology of ezetimibe

A

administered by mouth
absorbed into intestinal epithelial cells and localises to the brush border
extensively metabolised to active metabolite (80%)
enterohepatic recycling results in slow elimination- half life approx. 22hrs

89
Q

Advantages and disadvantages of ezetimibe

A

Advantages

  • low potential to interact with other medications
  • convenience of taking single tablet 10mg a day

Disadvantages
- expensive

90
Q

Who is ezetimibe given to

A

Patients with side effects from high dose statins

supplementary to statins

91
Q

Side effects of ezetimibe

A 
Mild diarrhoea 
abdominal pain 
headache 
rash 
angioedema
92
Q

What are resins

A

inhibitor of cholesterol absorption

1st cholesterol lowering drug to be used clinically

93
Q

Names of resins

A

colestryamine, colestipol, colesvelan

94
Q

How are they taken and pharmacology

A

Oral

  • remain in intestinal tract and bind bile acid= preventing their absorption into their blood stream
  • liver compensates by increasing metabolism of endogenous cholesterol into bile acids= increases expression of LDL receptors and clearance of LDL from blood= decrease LDL plasma conc
95
Q

Side effects resin

A

bloating
diarrhoea
nasusea
constipation

96
Q

What do resins interfere with the absorption of ?

A 
Fat soluable vitamins 
digoxin 
diuretics 
warfarin 
thyroid hormones 
bb and ca blockers
97
Q

How are resins taken

A

Oral
taken 1 hour after or 4-5 hours before food
rarely used

98
Q

Plant sterols/stanols

A

Isolated from wood pulp

stanol ester- hydrolysed into stanols and fatty acids

99
Q

how do sterols/stanols work

A

incorporated into mixed micelles replacing cholesterol
or
activate transporter proteins with enterocytes= increase movement from enterocytes back into the intestinal lumen and excreted

100
Q

What is the result of using sterols

A 
reduce cholesterol (40-45%) absorption into blood stream 
reduced serum total and ldl conc lower
101
Q

Optimal efficacy

A

plant stanols taken with meal

retain efficacy long term

102
Q

With and without plant stenol

A

without- 50% absorbed

with- 20% absorbed

103
Q

PSCK9 inhibitor

A

evolucumob
raopatha- human monoclonal antibody (IgG2) to proprotein convertase subtilism/ kexin type 9
* negative regulator of LDLR

104
Q

Mechanism for PSCK9 action

A

binds LDLR
complex internalises receptor undergoes lysosomal degradation
LDL continues to circulate

105
Q

Evolocumab mechanism of action

A

binds PSCK9 preventing from binding to LDLR- prevents PSCK9 mediated LDLR degradation

106
Q

What happens when LDL binds LDLR

A

internalises LDL releases
LDLR recycles back to the liver surface
increase the number of LDLR available to clear LDL from the blood, lowering LDL

107
Q

Pharmacology of Rapatha

A

injection
140mg/2 weeks
adjunct to diet and statin for adult with HeFH or clinical CVD

108
Q

Adverse effects of rapatha

A

back pain
reactions
nasopharyngitis

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