Case 5 Flashcards
(48 cards)
What is shear stress? How does it cause damage to endothelium?
Shear stress is the force of flowing blow against the endothelium
Turbulent blood flow causes low shear stress. This promotes apoptosis of endothelium and secretion of mediators of vasoconstriction and coagulation
What is the initial trigger in the formation of an atherosclerotic plaque?
Endothelial dysfunction
Outline the three main causes of endothelial dysfunction
Low shear stress due to turbulent blood flow
ROS (smoking)
Elevated LDL
In which part of the blood vessel wall is vascular smooth muscle found?
Tunica media
In which part of the blood vessel wall does the initial fatty streak formation take place?
Tunica intima
What receptor do macrophages use to phagocytose oxidised LDL?
Scavenger receptors
What cytokines are relased by endothelial cells and smooth muscle cells in response to vascular damage that results in the migration of smooth muscle cells to the tunica intima?
IL1 and TNFa
What is the name given to macrophages that have phagocytosed oxidised LDL?
Foam cells
The next stage on from fatty streak development is the formation of a fibro-fatty lesion. What is this?
Calcified and fibrosed fatty streak
What is the fibrous cap of the plaque made from?
SMC that have undergone apoptosis
What protease is responsible for the eventual rupture of the plaque? From what cells is it secreted?
Matrix metaloprotease (MMP)
Foam cells secrete in response to oxidised LDL
What are the consequences of fibrous cap rupture
Subendothelial layer exposure
Platelet adhesion
Thrombosis
Summarise the main events in the formation and rupture of an atherosclerotic plaque (7 stages)
Endothelial dysfunction LDL migration, oxidisation and entrapment Foam cell formation Leukocyte adhesion Fibro-fatty lesion formed Cap formation Rupture
What molecule is responsible for the oxidation of LDL in the tunica intima?
Where is the molecule produced?
ROS
Produced by endothelium, macrophages and smoking
What protein binds LDL in the tunica intima to cause entrapment?
Proteoglycans
In normoxic conditions, what process facilitates the majority of ATP production?
Mitochondrial TCA cycle
What is the metabolic building block produced by glycolysis that can produce lactate anaerobically?
Pyruvate
ATP is essential for cardiac muscle function. Specifically what are the two main functions of ATP within the cardiomyocyte?
SERCA pump function to remove Ca2+ from cytosol
Myosin ATPase to induce muscle contraction
How is ATP produced in the absence of oxygen?
Anaerobic glycolysis
Phosphocreatine
How is ischaemia different to hypoxia in terms of myocardial metabolic responses?
In a hypoxic environment anaerobic glycolysis can continue indefinitely as lactate can be removed from the cardiomyocytes
Ischaemia is lack of flow and O2 delivery meaning lactate builds up and damages tissue
What are the eventual consequences of myocardial ischaemia?
Phosphocreatine and glycogen store depletion
Rise in lactate and intracellular pH
Fall in ATP
What are the two main consequences of depleted ATP stores on cardiomyocytes?
Myosin ATPase dysfunction (hence no contraction)
Ion pump dysfunction (meaning membrane potential disturbance)
In addition to membrane potential disturbance, what is the additional effect of elevated Ca2+ levels within cardiomyocytes?
Apoptosis induction
What is reperfusion injury?
When the reinstatement of blood supply following ischaemia results in inflammation and oxidative damage
