Atherosclerosis and CHD

Question 1

What is cerebrovascular disease?

Answer 1

atherosclerosis/AS in carotid artery

Question 2

What is the leading killer?

Answer 2

ischaemic heart disease

Question 3

What are risk factors for AS?

Answer 3

MODIFIABLE
smoking, lipid intake, BP, diabetes, obesity, sedentary lifestyle

NON
age, sex, genetics (50% total risk)

risk factors multiply as risk of CHD with hypertension, smoking, high cholesterol x16

Question 4

What are the epidemiological changes in CHD?

Answer 4

less hyperlipidaemia (statins)
less hypertension (antihypertensives)
increase obesity and diabetes

Question 5

What is the tunica intima?

Answer 5

interstitial matrix between endothelial and subendothelium

endothelial risk factors increase endothelial permeability causing more LDLs to deposit in subintimal space and bind to matrix proteoglycans causing inflammation

Question 6

Describe the different types of lesion

Answer 6

coronary artery is at a lesion prone location where there is increased subintimal space
TYPE…
2 - macrophage foam cells
3 - some macrophages die and form pools of extracellular lipid (preatheroma)
4 - pools and macrophages coalesce to form core of lipid and necrotic core (atheroma)
5 - inflammation triggers fibrotic thickening and scarring (fibroatheroma)
6 - if not enough thickening fibrous cap opens and thrombus forms that may block coronary artery and cause MI (complicated lesion)
stratified appearance = stepwise formation of plaque and growth with age

Question 7

Treatment for different lesions?

Answer 7

intermediate and advanced = primary prevention
lifestyle changes, risk factor management

complications (stenosis and plaque rupture) - clinical intervention/secondary prevention
catheter based, revascularisation surgery, treat heart failure
PCI - percutaneous coronary intervention

Question 8

What is the function of vascular endothelial cells?

Answer 8

barrier function

leukocyte recruitment

Question 9

What is the function of platelets?

Answer 9

thrombus generation

cytokine and GF release to affect plaque growth

Question 10

What is the function of monocyte and macrophages?

Answer 10

foam cell formation
cytokine/GF release
source of free radicals
metalloproteinase source - degrade fibrous cap using catalytic site with Zn

Question 11

What is the function of VSMC?

Answer 11

migration and proliferation
collagen synthesis (thinner cap)
remodelling and fibrous cap formation

Question 12

What is the function of T lymphocytes?

Answer 12

macrophage activation

Question 13

What regulates macrophage subtypes?

Answer 13

transcription factors binding to DNA
NFkB
- activated by inflammation stimuli by scavenger/toll like/cytokine receptors
- turns of inflammation genes, matrix metallproteinase, NO synthase

Question 14

What are 2 types of macrophage?

Answer 14

inflammatory - kill macrophages

resident - normal homeostatic to suppress inflammatory activity

Question 15

What are the functions of macrophages in AS?

Answer 15

1 - generate free radicals to oxidise lipoproteins via oxidative enzymes
NADPH oxidase - superoxide O2-
myeloperoxidase - takes in superoxide derived oxidants (H2O2) to form HOCl, HONOO Peroxynitrite (from nitrogen peroxide)

2 - phagocytose modified lipoproteins to form foam cells
- lipid overload cause release of debris into lipid necrotic core

3 - express cytokine mediators to recruit monocytes
(with positive feedback)
cytokines = activated endothelial cell adhesion molecules
IL1 upregulates VCAM1 to made cells sticky and mediated tight monocyte binding
chemokines = attract monocytes (MCP-1 bind to monocyte GPCR)

4 - wound healing, express chemoattractants and GFs for VSMCs

• macrophages release GF to recruit VSMC and stimulate them to proliferate and deposit ECM
• platelet derived GF (VSMC chemotaxis,, survival and division)
• transforming GFB (increase collagen synthesis and matrix deposition to thicken fibrous cap)

5 - express proteinases that degrade tissue
- MMPs activate each other by proteolysis and degrade collagen
plaque erosion
rupture
coagulation lead to occlusive thrombosis and stop blood flow causing MI (plaque full of procoagulant factors)

= VULNERABLE PLAQUE

• large soft lipid rich necrotic core
• lots of VSMC apoptosis, decrease VSMC and collagen content
• infiltrate of macrophages expressing MMP
• thin fibrous cap

6 - apoptosis
foam cells protected against toxic OxLDL derived metabolites but overwhelmed so apoptose and release TFs and lipids into core
rupture
thrombosis

Question 16

What are the 2 outcomes for arterial OX-LDL deposits?

Answer 16

haemostasis - safe clearance, reverse chol transport by interacting with HDL

inflammation - activate WBCs

Question 17

Describe the transformation of VSMCs?

Answer 17

normal medial
- more contractile fragments and less matrix deposition genes

to atherosclerotic

Question 18

What colour are MI areas of heart?

Answer 18

pale grey

myoglobin needed

Question 19

What is the role of HDL, LDL and OxLDL?

Answer 19

LDL - made in liver, carry chol to body (bad over 5mmol)
HDL - reverse cholesterol transport from tissue to liver
OxLDL - highly inflammatory/toxic LDL in vessel wall due to free radicals

Question 20

What is the role of LDLs in AS?

Answer 20

excess leak through endothelial barrier
trapped by binding to stick matrix carbs (proteoglycans) and can be modified - oxidised by free radicals
phagocytosed by macrophages to form foam cells
stimulate chronic inflammation

Question 21

What is familial hyperlipidaemia?

Answer 21

autosomal recessive/dominant (typically LDL receptor)
very high chol (20mmol/l)
cannot remove LDl from blood to liver to fatty deposits in skin (XANTHOMA) and arteries (FOAM CELLS)

is a paediatric disease as can cause MI before 20 if untreated

Question 22

Describe the action of the LDL receptor

Answer 22

expression decreases with increased intracellular cholesterol
decrease cholesterol synthesis increases intracellular cholesterol
LDLR -ve patients have macrophages that accumulate cholesterol via scavenger receptors not under feedback control (bind to OxLDL rather than pathogens)

Question 23

What is the effect of statins?

Answer 23

HMG-CoA inhibitors

lower plasma cholesterol