Coronary Vascular Pathophysiology Flashcards
What is the immediate cause of coronary arterial occlusion?
thrombosis
Coronary arterial occlusion results in the following
myocardial infarction or heart attack
What are the two principal components of a thrombus?
Fibrin and platelets
Fibrin is formed via the clotting cascade–which of the two pathways is more important?
extrinsic
What happens when the intrinsic and extrinsic pathways converge?
Prothrombin gets converted to thrombin
What are the two principal functions of thrombin?
- conversion of fibrinogen to fibrin
2. activation of platelets in a collagen/vWF-independent manner
What is the job of fibrin?
Polymerizes to form a mesh, allows platelets to be stimulated and aggregated
3 step process of platelet stimulation:
- adhesion
- activation
- aggregation
Platelet adhesion
binding to collagen and vWF to subendothelial part of vessel wall
Platelet activation
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
Platelet aggregation
expression of glycoprotein IIb/IIIa receptors on activated platelets will bind to RGD amino acid sequences of fibrin
In the platelet activation process, the receptors for thrombin, ADP, Epinephrine, serotonin and thromboxane are what type of GPCR? What do they stimulate?
Gq, stimulate phospholipase C
Thromboxane is platelet (stimulating/inhibiting)
platelet-stimulating
Prostacyclin is platelet (stimulating/inhibiting)
platelet-inhibiting
These two prostaglandins are formed as a result of breakdown of arachidonic acid to prostaglandin G2 via ____
thromboxane and prostacyclin
via cyclooxygenase
Artherogenesis
Development of atherosclerosis, takes long time to develop
Artherogenesis consists of these 3 mains steps:
- Lipoproteins (LDL) accumulate and adhere to proteoglycans of ECM in arterial intima
- leukocyte (mostly monocytes) adhere to endothelial cells
- formation of foam cells (macrophages)
In step 2 of artherogenesis, how do leukocytes adhere to the endothelial cells?
via binding to adhesion molecules such as VACM-1, ICAM, p-selectin
Once leukocytes adhere to endothelial, what do they do?
They take up modified LDL via scavenger receptors and become resident macrophages
When luekocytes becomes resident macrophages, what do they release? Effect?
Release cytokines (IL-1, TNF-alpha), which:
- induce expression of adhesion molecules on endothelial cells
- stimulate production of pro-inflammatory cytokines (monocyte chemoattractant protein-1 or MCP-1)
What do pro-inflammatory cytokines stimulate release of?
Growth factors (PDGF, FGF), which stimulate vascular smooth muscle migration, proliferation and production of ECM (main part is collagen, becomes part of plaque)
This marker of inflammation is made in the liver and is an independent risk factor for MI and coronary event
C-Reactive Protein (CRP)
Role of tissue-type plasminogen activator (tpa), streptokinase, urokinase
endogenous enzymes break down thrombus clots.
they convert plasminogen to plasmin that in turn cause the break up of fibrin in the clot (fibrinolysis)
Role of plasminogen activator inhibitor (PAI) and alpha2 antiplasmin
inhibit fibrinolysis
Two mechanisms of vasodilation
- NO
2. beta2 adrenergic or adenosine receptors –>
Explain mechanisms of NO as vasodilator
- 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
Explain mechanism of beta2 adrenergic and adenosine receptors as vasodilator
stimulate Gs–> increase adenylyl cyclase –> increase cAMP –> increase PKA activity –> inhibits MLCK –> relaxes smooth muscle –> vasodilation
2 Principle mechanisms for vasoconstriction
- Gq –> phospholipase C –> IP3 –> Ca2+ release from SR –> activates MLCK –> phosphorylates MLC –> cross-bridge cycling –> smooth muscle contraction
- RhoA kinase pathway –>inhibits myosin phosphatase –> more MLCK –> smooth muscle contraction
In general, which predominates? Contraction-enhanced effect or NO release
NO release
but in the absence of intact endothelium, any agent stimulating Gq –> PLC pathway will cause vasoconstriction
Thrombosis
clot formation
If you block thrombin, you can have an effective ____
anticoagulant – blood thinner
recall thrombin involved in converting fibrinogen to fibrin (clotting cascade).
Three main molecules involved in anticoagulation (antithrombin)
- Protein C – inactivates 8 and 5
- Protein S –helps Protein C
- Thrombomodulin – binds with thrombin to activate Protein C
You are shoveling in the winter and a fibrous capping is disrupted (plaque breaks). What happens?
- 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
anything that increases coronary vascular resistance will (increase/decrease) coronary blood flow
decrease
Pressure = flow x resistance flow = pressure / resistance
What activates NO synthase?
calcium and calmodulin
