Lecture 6.1: Atherosclerosis Flashcards
What is Atherosclerosis?
The thickening, narrowing and hardening of the walls of large and medium sized arteries as a consequence of atheroma and arteries become clogged with fatty substances called plaques, or atheroma
What Arteries are affected by Atherosclerosis?
Large Arteries (Aortas)
Medium Arteries (Coronary, Renal, Cerebral, Mesenteric, Popliteal)
What is Atheroma?
An accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries
What is Arteriosclerosis?
The thickening and hardening of the walls of arteries and arterioles, from ANY CAUSE
What is the Macroscopic Appearance of Atherosclerosis?
• Fundamental lesion is the plaque
What are the 3 Stages of Plaque Developments?
1) Fatty streak
2) Simple plaque
3) Complicated plaque
3 Stages of Plaque Developments: Features of Fatty Streak (4)
• Can be seen in children
• Lipid deposits in intima
• Yellow, slightly raised
• No disturbance to blood flow
3 Stages of Plaque Developments: Features of Simple Plaque (8)
• Raised yellow/white
• Approximately 1cm in diameter
• Irregular outline
• Widely distributed
• Often occur around ostia
• Turbulent blood flow
• Enlarge and coalesce
• Impinge on vessel lumen
3 Stages of Plaque Developments: Features of Complicated Plaque (5)
• Calcification
• Thrombosis
• Haemorrhage into plaque
• Weakening of the wall
• Aneurysm formation
What is the Early Microscopic Appearance of Atherosclerosis? (4)
• Accumulation of foam cells
• Proliferation of smooth muscle cells
• Extracellular lipid deposition
• Scattered T lymphocytes
What is the Later Microscopic Appearance of Atherosclerosis? (8)
• Fibrosis
• Necrosis
• Cholesterol clefts
• Calcification
• Disruption of internal elastic lamina
• Damage extends into media
• Ingrowth of blood vessels
• Plaque fissuring & rupture
What are the Most Common Sites for Atherosclerosis?
• Aorta - especially abdominal aorta
• Coronary arteries
• Carotid arteries
• Cerebral arteries
• Arteries of the legs
Damage to Heart in Atherosclerosis Disease: Where? Effects?
• Coronary Arteries
• Ischaemic Damage/ Ischaemic Heart Disease
• Myocardial Infarction
• Angina Pectoris
• Chronic Congestive Cardiac Failure (CHF)
• Sudden death from Arrythmia
Damage to Brain in Atherosclerosis Disease: Where? Effects? How?
• Cerebral Arteries
• Atherosclerosis of carotid arteries
• Thrombus forms over plaque
• Thromboembolism to cerebral arteries
• Stroke (Cerebral Infarction)
• Transient Ischaemic Attack
• Multi-Infarct Dementia
Damage to Aorta in Atherosclerosis Disease: Where? Effects?
• Subdiaphragmatic Part
• Aneurysm Rupture
Damage to Peripheral Arteries in Atherosclerosis Disease: Where? Effects?
• Mainly the legs
• Distal Gangrene
Mechanism of IHD in Acute Myocardial Infarction
Acute severe coronary obstruction
Mechanism of IHD in Angina Pectoris
Chronic obstruction plus excess demand on heart causes, attacks of chest pain caused by reduced blood flow to your heart
Mechanism of IHD in Chronic Heart Failure
Chronic obstruction with multiple small infarct damage accumulation
Mechanism of IHD in Sudden Cardiac Death
Old infarct scar triggering acute LV arrhythmia
When is flow in an artery considered ‘significantly reduced’?
Until lumen is reduced by 70- 80% = <1mm diameter
What is an AAA? Structure?
• Abdominal Aortic Aneurysm
• A bulge or swelling in the aorta, the main blood vessel that runs from the
heart down through the chest and tummy
• It can rupture and cause fatal bleeding
• Lined/filled by thrombus
What is the size of an AAA?
Can be 10-15cm in diameter
What is an Aneurysm?
• Local dilatation of an artery due to weakening of the wall
• May rupture
• Can produce emboli
Why are aneurysms caused in large arteries (most common reason)?
Due to Atherosclerosis
What is Peripheral Vascular Disease?
PVD is a common condition where a build-up of fatty deposits in the arteries restricts blood supply to leg muscles
Effects of PVD (4)
• Intermittent claudication
• Ischaemic rest pain
• Gangrene
• Leriche syndrome
What is Intermittent Claudication?
Pain affecting the calf, and less commonly the thigh and buttock, that is induced by exercise and relieved by rest
Due to reduced blood flow to legs due to PAD/PVD
What is Ischaemic Rest Pain?
Severe pain in the legs and feet while a person is not moving, or non-healing sores on the feet or legs
It is due to reduced blood flow to legs due to atherosclerosis of blood vessels in the legs
What is Dry Gangrene?
A serious condition where a loss of blood supply causes body tissue to die
What is Leriche Syndrome?
• Aka aortoiliac occlusive disease
• Caused by severe atherosclerosis
• Affects: distal abdominal aorta, iliac arteries, and femoro-popliteal vessel
• Presents with triad of claudication, impotence & absence of femoral pulses
Effects of Mesenteric Ischaemia & Bowel Infarction
• Superior Mesenteric Artery Disease
• Ischaemic Colitis
• Malabsorption
• Intestinal Infarction
What is Superior Mesenteric Artery Disease?
What is Ischaemic Colitis?
What is Malabsorption?
What is Intestinal Infarction?
Pathogenesis of Atheroma: What is the Reaction to Injury Hypothesis?
Atherogenesis becomes an inflammatory, macrophage and smooth muscle cell
response process, involving both lipid and absorbed thrombus on the intima or arteries
What are 5 Cellular Events that Lead to Atherosclerosis?
1) Chronic Endothelial Injury (LDL, toxins, hypertension, haemodynamic stress)
2) Endothelial Dysfunction (T-Cell attraction to area, platelet adhesion, PDGF)
3) Smooth muscle emigration from media into intima
4) Macrophages & smooth muscle cells engulf accumulated, oxidised lipid and
form foam cells
5) Smooth muscle proliferation in response to cytokines and growth factors,
collagen and matrix deposition, neovascularistaion
What Cells are involved in Atherogenesis?
• Endothelial Cells
• Platelets
• Smooth Muscle Cells
• Macrophages
• Lymphocytes
• Neutrophils
Process of Atherogenesis
What happens when plaque ruptures?
Exposure of tissue triggers both the intrinsic & extrinsic coagulation pathways and a blood clot forms following plaque rupture, which limits blood flow
Cells Involved in Atherogenesis: Endothelial Cells
• Key role in haemostasis
• Altered permeability to lipoproteins
• Secretion of collagen
• Stimulate proliferation and migration of smooth muscle cells
Cells Involved in Atherogenesis: Platelets
• Key role in haemostasis
• Altered permeability to lipoproteins
• Secretion of collagen
• Stimulate proliferation and migration of smooth muscle cells
Cells Involved in Atherogenesis: Smooth Muscle Cells
• Take up LDL and other lipids to become foam cells
• Synthesise collagen and proteoglycans
Cells Involved in Atherogenesis: Macrophages
• Oxidise LDL
• Take up lipids to become foam cells
• Secrete proteases which modify matrix
• Stimulate proliferation and migration of smooth muscle cells
Risk Factors for Atherosclerosis (12)
• Age (non-modifiable)
• Gender (non-modifiable)
• Hyperlipidaemia (increased LDL significant)
• Smoking
• Hypertension
• Impaired glucose tolerance and diabetes mellitus
• Alcohol
• Geography – Civilisation & Diet
• Lack of exercise/ Obesity
• Soft water
• Oral contraceptive pill
• Possibly stress and personality type (type ‘A’)
Lipid Metabolism
• Lipid in the blood is carried in lipoproteins
• Lipoproteins carry cholesterol and triglycerides (TG)
• Hydrophobic lipid core
• Hydrophilic outer layer of phospholipid and apolipoprotein (A-E)
Chylomicrons in Lipid Metabolism
Transport lipid from intestine to liver
VLDL in Lipid Metabolism
• Carry cholesterol and TG from liver to muscle and fat
• TG removed leaving LDL
LDL in Lipid Metabolism
• Rich in cholesterol
• Carries cholesterol to non-liver cells
HDL in Lipid Metabolism
Carry cholesterol from periphery back to liver
What is the primary function of LDL?
The primary function of LDL is to provide cholesterol from liver to peripheral
tissues
How is LDL absorbed by peripheral cells?
Peripheral cells express LDL receptor and take up LDL via process of receptor mediated endocytosis
Why is LDL not efficiently cleared by the Liver?
• LDL do not have apoC or apoE
• Liver LDL-Receptor has a high affinity for apoE
What clinic relevance of the half-life of LDL?
• Half life of LDL in blood is much longer than VLDL or IDL
• Making LDL more susceptible to oxidative damage
How are Foam Cells formed? Clinic Relevance of Foam Cells?
• Oxidised LDL taken up by macrophages can transform to foam cells
• Contribute to formation of atherosclerotic plaques
What is the function of HDL? Why is this important?
• HDL can remove cholesterol from cholesterol laden cells & return it to liver
• Important process for blood vessels as it reduces likelihood of foam cell and
atherosclerotic plaque formation
What protein within cells facilitates transfer of cholesterol to HDL?
ABCA1
What is cholesterol converted to after it is taken by HDL?
Cholesterol then converted to cholesterol ester by Lecithin–cholesterol acyltransferase (LCAT)
Familial Hyperlipidaemia as a Risk Factor for Atherosclerosis
• Genetically determined abnormalities of lipoproteins
• Lead to early development of atherosclerosis
Physical Signs associated with Hyperlipdaemia (3)
• Corneal Arcus
• Tendon Xanthomas
• Xanthelasma
Smoking as a Risk Factor for Atherosclerosis
• Powerful risk factor for ischaemic heart disease and atherosclerosis
• Risk falls after giving up smoking
• Mode of action uncertain but it is a procoagulant
• Reduced prostacyclin (which is a platelet activation inhibitor) and therefore
increased platelet aggregation
Hypertension as a Risk Factor for Atherosclerosis
• Strong link between ischaemic heart disease and high systolic & diastolic
blood pressure
• Mechanism uncertain, perhaps endothelial damage caused by raised
pressure
Impaired Glucose Tolerance/Diabetes Mellitus as a Risk Factor for Atherosclerosis
• Cardiovascular disease accounts for 80% deaths in DM type 2
• DM patients have at least 3 times greater incidence of death from CVD
compared to non-DM
• Protective effect in premenopausal women is lost if they are diabetic
• Diabetes mellitus associated with high risk of cerebrovascular and peripheral
vascular disease
Alcohol as a Risk Factor for Atherosclerosis
• More than 5units/day associated with increased risk of ischaemic heart
disease
• Smaller amounts of alcohol may be protective (increase HDL levels)
Prevention of and Interventions in Atherosclerosis (8)
• No smoking
• Decrease fat intake
• Treat hypertension
• Aspirin
• Sensible alcohol intake
• Regular exercise and control of weight control
• Good glycaemic control in diabetes mellitus
• Lipid lowering drugs, e.g., statins, where needed
Apolipoprotein E (Apo E) Genotype and Atherosclerosis
• 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
Impaired Glucose Tolerance/DM and Atherosclerosis: AGEs
• Formation of advanced glycation end products (AGE – amino acids of
proteins which have reacted with glucose derivatives)
• Crosslinks collagen in large vessels → ↓elasticity predisposes to endothelial
injury
• Changes protein properties which results in ↑LDL trapping and enhances
cholesterol deposition in intima
• React with plasma proteins, leading to interaction with endothelial cells and
release of inflammatory markers
• Increase procoagulant activity of endothelial cells
Impaired Glucose Tolerance/DM and Atherosclerosis: Activation of Protein Kinase C
• Caused by intracellular hyperglycaemia
• Increases production of procoagulants (PAI-1) → ↓fibrinolysis
• Production of proinflammatory cytokines by vascular endothelium
Lymphocytes in Atherosclerosis
• TNF (Tumor Necrosis Factor) may affect lipoprotein metabolism
• Stimulate proliferation and migration of smooth muscle cells
Neutrophils in Atherosclerosis
• Secrete proteases leading to continued local damage and inflammation
