AM L3 Thrombosis and diabetes Flashcards
What is plaque erosion?
focal areas of endothelium become denuded (stripped) and expose underlying connective tissue
MMPs are ____-dependent ____.
zinc dependent endopeptidases
Role of MMPs in plaque erosion?
degrade components of the extracellular matrix and basement membrane
2 main ways plaque erosion occurs?
- endothelial cell desquamation (scraping off) due to lysis of the extracellular matrix (caused by MMPs)
- endothelial cell death (including apoptosis)
MMPs subdivided into….
5 classes including collagenases, gelatinases and stromelysins
How does plaque erosion cause thrombosis?
The basement membrane is exposed, including collagen. This is prothrombotic. Platelet aggregation is trigger which can result in thrombosis.
Where does the thrombos lie in plaque erosion?
On top of the fibrous cap
Plaque rupture is….
a structural defect (gap) in the fibrous cap that separates the necrotic lipid core of an ATS plaque from the lumen, resulting in exposure of the necrotic core to the blood.
Trauma activates which clotting pathway
Extrinsic.
Activates VIIa.
The plaque expresses high levels of ….
tissue factor.
This results in the clotting cascade being activated when the legionis ruptured as large amounts are exposed.
Markers of vulnerable plaques
5
Large lipid core (>50% volume of plaque)
High density of macrophages
Low density of smooth muscle cells in the cap
High Tissue Factor content
Thin cap in which the collagen structure is disorganised
Why is high density of macrophages a risk factor?
Express tissue factor and MMPs.
Risky, particularly at the edges
If the thrombosis is in the surface of the plaque it is as a result of….
Superficial erosion
If the thrombosis is coming out of the necrotic lesion it is as a result of….
Rupture of the fibrous cap
Plaque rupture accounts for …. of fatal MI in men
Plaque erosion accounts for …. of MI in women
80%
50%
So basically it is very bad
What is a risk factor
something that changes your chances of having a disease.
May be modifiable or fixed
Modifiable risk factors in terms of LDL and HDL
Raised LDL
Low HCL
Modifiable risk factors include
Diabetes Obesity Hypertension Smoking Physical inactivity
Is homocysteine modifiable or fixed risk factor?
Elements of both - diet can change the level
What is the leading cause of mortality in diabetes?
CHD (50% of all deaths)
How does the body respond to an increase in blood glucose?
beta islet cells of the pancreas produce insulin
this causes adipocytes, liver and muscle to take up glucose
How does the body respond to a decrease in blood glucose?
Pancreatic alpha cells produce glucagon.
Causes liver to increase ketone synth, gluconeogenesis and glycogenolysis
What process is stopped in type 1 diabetes?
Pancreatic beta cells don’t produce insulin
What process is stopped in type 2 diabetes?
Response to circulating insulin
Diabetes causes ….(4)… thus increasing cardiovascular risk
increase endothelial dysfunction
increase blood viscosity
increase blood coagulation
secondary dyslipidemia
Most complications of diabetes arise from
damage to blood vessels
ATS is accelerated in diabetes particularly in what 3 arteries?
coronary, carotid and femoral
macrovascular damage
Microvascular damage of diabetes occurs where? (3)
Retina, kidney, nervous system
Hyperglycemia causes ….(4) … resulting in endothelial dysfuntion
Constriction
Growth promotion
Pro-thrombosis
Pro-inflammation
Endothelial dysfunction is…
imbalance between the production of vasoconstricting and vasorelaxing mediators
Sign of endothelial dysfunciton
decreased production of nitric oxide
enzyme that produces nitric oxide?
phosphorylated eNOS (endothelial nitric oxide synthase)
what is necessary to maintain the enzyme that makes NO
insulin is needed to activate AKt kinase
this phosphorylates eNOS to make it active
this produces NO
unphosphorylated eNOS causes….
endothelial dysfunction (via: reduced blood flow thrombosis inflammation neointima formation)
low NO also results in
more ROS more NADPH (precursor)
what happens in mice with insulin receptor knock out?
decreased eNOS and impaired endothelial vasodilator funciton.
Impaired NO bioavailability and defects in PI3kinase/Akt system, what ever that is ….
