Coronary Vascular Pathophysiology

Question 1

What is the immediate cause of coronary arterial occlusion?

Answer 1

thrombosis

Question 2

Coronary arterial occlusion results in the following

Answer 2

myocardial infarction or heart attack

Question 3

What are the two principal components of a thrombus?

Answer 3

Fibrin and platelets

Question 4

Fibrin is formed via the clotting cascade–which of the two pathways is more important?

Answer 4

extrinsic

Question 5

What happens when the intrinsic and extrinsic pathways converge?

Answer 5

Prothrombin gets converted to thrombin

Question 6

What are the two principal functions of thrombin?

Answer 6

1. conversion of fibrinogen to fibrin

2. activation of platelets in a collagen/vWF-independent manner

Question 7

What is the job of fibrin?

Answer 7

Polymerizes to form a mesh, allows platelets to be stimulated and aggregated

Question 8

3 step process of platelet stimulation:

Answer 8

1. adhesion
2. activation
3. aggregation

Question 9

Platelet adhesion

Answer 9

binding to collagen and vWF to subendothelial part of vessel wall

Question 10

Platelet activation

Answer 10

via action of thrombin, ADP, epinephrine, serotonin, and thromboxane. Fully activated platelets will now express new protein: GpIIb/IIIa put on cell surface for recognition and binding

Question 11

Platelet aggregation

Answer 11

expression of glycoprotein IIb/IIIa receptors on activated platelets will bind to RGD amino acid sequences of fibrin

Question 12

In the platelet activation process, the receptors for thrombin, ADP, Epinephrine, serotonin and thromboxane are what type of GPCR? What do they stimulate?

Answer 12

Gq, stimulate phospholipase C

Question 13

Thromboxane is platelet (stimulating/inhibiting)

Answer 13

platelet-stimulating

Question 14

Prostacyclin is platelet (stimulating/inhibiting)

Answer 14

platelet-inhibiting

Question 15

These two prostaglandins are formed as a result of breakdown of arachidonic acid to prostaglandin G2 via ____

Answer 15

thromboxane and prostacyclin

via cyclooxygenase

Question 16

Artherogenesis

Answer 16

Development of atherosclerosis, takes long time to develop

Question 17

Artherogenesis consists of these 3 mains steps:

Answer 17

1. Lipoproteins (LDL) accumulate and adhere to proteoglycans of ECM in arterial intima
2. leukocyte (mostly monocytes) adhere to endothelial cells
3. formation of foam cells (macrophages)

Question 18

In step 2 of artherogenesis, how do leukocytes adhere to the endothelial cells?

Answer 18

via binding to adhesion molecules such as VACM-1, ICAM, p-selectin

Question 19

Once leukocytes adhere to endothelial, what do they do?

Answer 19

They take up modified LDL via scavenger receptors and become resident macrophages

Question 20

When luekocytes becomes resident macrophages, what do they release? Effect?

Answer 20

Release cytokines (IL-1, TNF-alpha), which:

1. induce expression of adhesion molecules on endothelial cells
2. stimulate production of pro-inflammatory cytokines (monocyte chemoattractant protein-1 or MCP-1)

Question 21

What do pro-inflammatory cytokines stimulate release of?

Answer 21

Growth factors (PDGF, FGF), which stimulate vascular smooth muscle migration, proliferation and production of ECM (main part is collagen, becomes part of plaque)

Question 22

This marker of inflammation is made in the liver and is an independent risk factor for MI and coronary event

Answer 22

C-Reactive Protein (CRP)

Question 23

Role of tissue-type plasminogen activator (tpa), streptokinase, urokinase

Answer 23

endogenous enzymes break down thrombus clots.

they convert plasminogen to plasmin that in turn cause the break up of fibrin in the clot (fibrinolysis)

Question 24

Role of plasminogen activator inhibitor (PAI) and alpha2 antiplasmin

Answer 24

inhibit fibrinolysis

Question 25

Two mechanisms of vasodilation

Answer 25

1. NO

2. beta2 adrenergic or adenosine receptors –>

Question 26

Explain mechanisms of NO as vasodilator

Answer 26

• NO synthase converts L-arginine to NO in endothelial cell
• NO diffuses to vascular smooth muscle just below the endothelial cells
• activates cytoplasmic guanylyl cyclase
• increases cGMP
• relaxes smooth muscle
• causes vasodilation

Question 27

Explain mechanism of beta2 adrenergic and adenosine receptors as vasodilator

Answer 27

stimulate Gs–> increase adenylyl cyclase –> increase cAMP –> increase PKA activity –> inhibits MLCK –> relaxes smooth muscle –> vasodilation

Question 28

2 Principle mechanisms for vasoconstriction

Answer 28

1. Gq –> phospholipase C –> IP3 –> Ca2+ release from SR –> activates MLCK –> phosphorylates MLC –> cross-bridge cycling –> smooth muscle contraction
2. RhoA kinase pathway –>inhibits myosin phosphatase –> more MLCK –> smooth muscle contraction

Question 29

In general, which predominates? Contraction-enhanced effect or NO release

Answer 29

NO release

but in the absence of intact endothelium, any agent stimulating Gq –> PLC pathway will cause vasoconstriction

Question 30

Thrombosis

Answer 30

clot formation

Question 31

If you block thrombin, you can have an effective ____

Answer 31

anticoagulant – blood thinner

recall thrombin involved in converting fibrinogen to fibrin (clotting cascade).

Question 32

Three main molecules involved in anticoagulation (antithrombin)

Answer 32

1. Protein C – inactivates 8 and 5
2. Protein S –helps Protein C
3. Thrombomodulin – binds with thrombin to activate Protein C

Question 33

You are shoveling in the winter and a fibrous capping is disrupted (plaque breaks). What happens?

Answer 33

• plaque consists of vascular smooth muscle cells, foam cells, extracellular matrix and lipids
• soft plaque more susceptible to break
• if this ruptures, collagen is exposed, and leads to thrombus formation
• clot is formed inside arterial wall
• fibrin activation
• myocardial infarction

Question 34

anything that increases coronary vascular resistance will (increase/decrease) coronary blood flow

Answer 34

decrease

Pressure = flow x resistance
flow = pressure / resistance

Question 35

What activates NO synthase?

Answer 35

calcium and calmodulin