Atherosclerosis Flashcards
Atherosclerosis
Is the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
It’s also the thickening and hardening of arterial walls as a consequence of this build up of lipid
The thickening of the walls due to this lipid of arteries and arterioles usually is as a result of hypertension or diabetes mellitus (increased cholesterol and fat levels)
ATS macroscopic features
Fatty streak - Lipid deposits in intima
Yellow, slightly raised
Relationship to atherosclerosis somewhat debatable
Simple plaque - It’s raised and is yellow/white
It has an irregular outline
And is widely distributed
If there is enough then groups can enlarge and coalesce
Complicated plaque - Thrombosis forms when groups of simple plaques coalesce
This can lead to a haemorrhage into plaque
Which calcifies and an aneurysm forms
ATS - common sites
Aorta
Coronary arteries
Carotid arteries
Cerebral arteries
Leg arteries
Normal arterial structure
Endothelium
Sub endothelial connective tissue
Internal elastic lamina
Muscular media
External elastic lamina
Adventitia
ATS - microscopic features
Early changes -
proliferation of smooth muscle cells
accumulation of foam cells
formation and build up of extracellular lipid
Later changes - fibrosis necrosis cholesterol clefts \+/- inflammatory cells disruption of internal elastic lamina damage extends into media ingrowth of blood vessels plaque fissuring
ATS - clinical effects
Ischaemic heart disease, which can lead to - sudden death - heart stops
MI - large part of the heart cant get blood therefore dies via necrosis
angina pectoris - chest pains due to part of the heart being blocked
arrhythmias - abnormal (not sinus) rhythm due to lack of blood/dying parts of the heart
cardiac failure - heart cant pump enough blood to meet the bodies needs
Cerebral ischaemia - transient ischaemic attack - blood flow to part of the brain is temporarily blocked - could be due to a blood clot, narrowing of vessels - etc
cerebral infarction
multi-infarct dementia - loss of congitve functions due to lack of blood to the brain
Mesenteric ischaemia - ischaemic colitis - blood supply to bowel is compromised, therefore not enough blood for tissues in cell
malabsorption - occurs due to lack of oxygen to tissues of bowel
intestinal infarction - bowel starts to die due to lack of oxygen
Peripheral vascular disease - intermittent claudication - pain in legs after mild excursion, relieved after rest
Leriche syndrome - build up of plaque in your 2 iliac arteries
ischaemic rest pain - pain in feet when elevated
gangrene - tissue death due to lack of blood supply
Abdominal Aortic aneurysm - Weakening of aortic vessel walls, due to presence of ATS (causes damage to the elastic lamina therefore when stretched there is less recoil therefore abnormal dilation, which can lead to rupture)
ATS pathogenesis
Age - slowly progressive throughout adult life, risk factors operate over years
Gender - women protected relatively before menopause, presumed hormonal basis - after menopause they are at more risk
Hyperlipidaemia - high plasma cholesterol associated with atherosclerosis , increased LDL count is most significant, high HDL count is seen as protective
Cigarette smoking - Powerful risk factor for IHD, Risk falls after giving up, Mode of action for ATS is uncertain? - does it affect the coagulation system? reduce PGI2? Or increase platelet aggregation?
Hypertension - Strong link between IHD and high systolic/diastolic blood pressure, Mechanism uncertain? - endothelial damage caused by raised pressure?
Diabetes mellitus - DM doubles IHD risk, the protective effect in premenopausal women lost, DM is also associated with high risk of cerebrovascular and peripheral vascular disease, may be related to hyperlipidaemia and hypertension
Alcohol - >5 units /day associated with increased risk of IHD, Alcohol consumption often associated with other risk factors eg smoking and high BP but still an independent risk factor
Smaller amounts of alcohol have indicated a protective function
ATS - lipid metabolism
Lipid in the blood is carried on lipoproteins
Lipoproteins carry cholesterol and triglycerides (TG)
These lipoproteins contain a hydrophobic lipid core and a hydrophilic outer layer of phospholipid and apolipoprotein (A-E) - they come in different forms -
Chylomicrons - transport lipid from intestine to liver
LDL - rich in cholesterol, carry cholesterol to non liver cells
VLDL - carry cholesterol and TG from the liver, TG removed leaving LDL
HDL - carrry cholesterol from periphery back to liver
ATS and apolipoprotein E
Genetic variations in Apo E are associated with changes in LDL levels
Polymorphisms of the genes involved lead to at least 6 Apo E phenotypes
Polymorphisms can be used as risk markers for atherosclerosis
Familial hyperlipidaemia
Genetically determined abnormalities of lipoproteins
Lead to early development of atherosclerosis
Associated physical signs
arcus - blue/grey circle around the cornea of the eye
tendon xanthomas - build up of lipid underneath the skin causing a yellow patch
xanthelasma - an xanthoma but around the eye
Risk factors for ATS
Lack of exercise
Obesity
Oral contraceptives
Stress and personality type?
Genetic Predisposition - Familial predisposition well known
Possibly due to
variations in apolipoprotein metabolism
variations in apolipoprotein receptors
Processes and roles of cells in ATS
Processes that occur in ATS - Thrombosis Lipid accumulation Production of intercellular matrix Interactions between cell types
The role of Endothelial Cells in ATS - Key role in haemostasis
In ATS they have altered permeability to lipoproteins
In ATS they have increased production of collagen
And stimulation of proliferation and migration of smooth muscle cells occurs to the site of the plaque build up in the intima of the vessel
Role of Platelets - Key role in haemostasis
Stimulate proliferation and migration of smooth muscle cells (PDGF)
Role of Smooth Muscle Cells - Take up LDL and other lipid to become foam cells
Synthesise collagen and proteoglycans
Role of Macrophages - Oxidise LDL
Take up lipids to become foam cells
Secrete proteases which modify matrix
Stimulate proliferation and migration of smooth muscle cells
Role of Lymphocytes - TNF may affect lipoprotein metabolism
Stimulate proliferation and migration of smooth muscle cells
Role of Neutrophils - Secrete proteases leading to continued local damage and inflammation
ATS - a unifying hypothesis
Endothelial injury occurs in blood vessels due to - raised LDL ‘toxins’ eg cigarette smoke hypertension haemodynamic stress
This endothelial injury causes
platelet adhesion, PDGF release, smooth muscle cell proliferation and migration
accumulation of lipid, LDL oxidation, uptake of lipid by Smooth muscle cells and macrophages
migration of monocytes from the blood into intima
The smooth muscles cells that have been stimulated produce matrix material - such as collagen (this holds all the cells, lipids and inflammatory mediators in one place - forms the fibrous cap)
Foam cells that have formed secrete cytokines causing
further SMC stimulation
recruitment of other inflammatory cells
Once this fibrous cap gets too big it ruptures causing a bleed - which could lead to thrombosis and occulsion of the vessel
ATS - prevention and intervention
Prevention: No smoking Reduce fat intake Treat hypertension Not too much alcohol Regular exercise/weight control BUT some people will still develop atherosclerosis!
Atherosclerosis - Intervention: Stop smoking Modify diet Treat hypertension Treat diabetes Lipid lowering drugs
