W2 10 - Atherosclerosis Flashcards
What can atherosclerosis lead to?
Ischaemic heart disease, stroke, abdominal aortic aneurysm, gut ischaemia, peripheral vascular disease
Constituitional multi-factorial factors of atherosclerosis
Genetic abnormalities
Family history
Increasing age
Male gender
Modifiable factors causing atherosclerosis
Hyperlipidaemia, hypertension, cigarette smoking, diabetes, inflammation
How does atherosclerosis occur - what is the ‘response-to-injury’ hypothesis?
Atherosclerosis arises due to endothelial injury on a background of hypercholesterolaemia
What are the 4 stages of atherosclerosis pathogenesis?
Endothelial injury
Endothelial dysfunction
Inflammation
Repair
Give causes of endothelial injury
Turbulent blood flow (most important)
Hypercholesterolaemia
Toxins from cigarettes
Homocysteine
Viruses
Inflammation
How does turbulent blood flow explain the distribution of the disease atherosclerosis?
Atherosclerosis isn’t evenly distributed in blood vessels. Tends to occur at particular points. Arabises at Ostia, branch points and curvature of vessels (area of turbulence, which can damage the endothelium lining this areas contributing to development of atherosclerosis).
Where does atherosclerosis arise from (areas of turbulent flow)?
Ostia of infrarenal aorta, coronary arteries, internal carotid arteries, circle of willis
What does endothelial injury result in?
Increased permeability and altered expression of endothelial cell surface molecules
Endothelial dysfunction occurs. What does increased permeability and altered expression of endothelial cell surface molecules lead to? (Pg89)
Increase permeability leads to accumulation of oxidised LDL and cholesterol crystals in the intima
Altered expression of adhesion molecules by endothelial cells leads to localised inflammation and platelet adhesion
What does inflammation stage lead to in atherosclerosis?
Recruits macrophages to engulf oxidised LDL and cholesterol crystals. This triggers:
- activation of inflammasome/IL1 signalling and further inflammation
- production of ROS that causes further LDL oxidation
(Pg89 image)
What happens in the repair stage of atherosclerosis?
Smooth muscle cells are recruited to the intima by growth factors (PDGF, FGF, TGF-a), which produce collagen and other ECM proteins. (Pg89 image)
What are the 3 components of an atherosclerotic plaque? (Pg90)
Cells: smooth muscle cells, macrophages, lymphocytes
Extracellular matrix
Lipid
PAGE90 IMAGE OF ATHEROSCLEROTIC PLAQUE COMPONENTS
Fibrous cap - smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularisation
Necrotic centre - cell debris, cholesterol crystals, foam cells, calcium
What are the consequences of atherosclerosis?
Critical stenosis
Thrombosis - thrombus forming on plaque can cause stenosis or complete occlusion
Aneurysm formation
What is critical stenosis?
Occurs when the atherosclerotic plaque obstructs blood flow to the organs to the extent that oxygen delivery/supply can’t meet the demand of the organ.
(in coronary arteries it occurs at about 70% occlusion)
What does critical stenosis result in?
Cardiac ischaemia (stable angina)
How can a thrombus form over an atherosclerotic plaque?
In a stable plaque there is a lipid core in the middle with fibrous cap over top. Fibrous cap prevents the thrombogenic lipid core from being exposed to the haemostatic substances present in the blood. If this ruptures, the lipid cortriade is exposed to these substances, and a thrombus forms on top of the atherosclerotic plaque.
What factors increase risk of plaque rupture?
Plaque structure - a thin fibrous cap, large lipid core, inflammation
Extrinsic factors - hypertension, adrenergic stimulation
What is an aneurysm?
The abnormal dilation of a blood vessel
How do atherosclerotic plaques increase risk of aneurysm?
Aneurysm forms due to damage to the media. Damage can be mediated by pressure from the necrotic core, ischaemia or inflammation. These changes can damage the smooth muscle cells and weaken the integrity of the wall of the vessel. Under high arterial pressures as the media becomes weakened, the diameter of the vessel increased, leading to the formation of an aneurysm.
Where are plaques in relation to the layers of the blood vessels?
Plaque is in the intima of the blood vessel. Media is beneath, adventitia is beneath this.
What are the 4 clinical syndromes of ischaemic heart disease?
Angina pectoris
Acute myocardial infarction
Chronic ischaemic heart disease
Sudden cardiac death
What is the pathogenesis of stable angina?
Occlusion of coronary artery lumen by >70% = critical stenosis
Perfusion to cardio myocytes cannot meet demand at times of exertion
Causes pain on exertion, relieved by rest
What is the pathogenesis of unstable angina?
Plaque disruption, thrombosis, vasospasm
Causing increasingly frequent pain at rest
What is acute myocardial infarction!
Necrosis of heart muscle resulting from ischaemia (following coronary artery disease)
What is the pathogenesis of acute myocardial infarction?
Generally mediated by plaque rupture, thrombosis and vasospasm causes complete occlusion of a coronary artery.
Loss of aerobic glycolysis, decreased ATP and accumulation of lactic acid causes cytoplasmic swelling of cardiac myocytes (reversible injury). Na/K ATPase pumps cease working properly. Cells will start swelling up due to osmosis of fluid.
Progresses to ischaemic necrosis in 20-40>8<$ unless perfusion is re-established.
How does acute myocardial infarction progress?
Necrosis begins in the subendocardial region and spreads outwards to become transmural. Pg93 image.
When do transmural infarcts occur?
Transmural infarcts happen when there is complete occlusion of one of the coronary arteries
Transmural infarcts - what will occlusion of the left anterior descending branch cause?
Necrosis of the anterior part of the heart
Transmural infarcts - what will occlusion of the left circumflex branch?
Will affect the free wall of the left ventricle
Transmural infarcts - what will occlusion of the posterior descending branch of right coronary artery?
Will affect the posterior part of the heart and the interventricular septum
Why might non-transmural infarcts occur?
- transient or partial obstruction
- global hypotension, during severe hypotension episode
- disease to the small vessels
Non-transmural infarct - what will a transient or partial obstruction cause?
Will preferentially effect the subendocardial zone. May be a pattern of subendocardial necrosis, with sparing of the epicardial region.