Atheroscelerosis and Peripheral Vascular disease Tutorial Flashcards
What is atheroscelerosis involved in?
- Neurology (cerebrovascular disease)
- Acute medicine (Heart attack / stroke)
- Cardiology ( coronary disease)
- Cardiac surgery (revascularisation)
- Vascular surgery (revascularisation)
- Endocrinology (diabetes)
- Metabolic medicine (lipids)
What are modifiable risk factors?
- Smoking
- Lipid intake
- Blood pressure
- Diabetes
- Obesity
- Sedentary lifestyle
What are non-modifiable factors?
- Age
- Sex
- Genetic background
What happens to the risk factor increase?
multiplies risk
What has reduced over the last decade?
- Reduced hyperlipidaemia (statin treatment)
2. Reduced hypertension (antihypertensive treatment)
What has increased?
Increased obesity -> Increased diabetes
What type of treatments have improved?
New improvements in diabetes treatment have doubtful effect on macrovascular disease
Why is there changing pathology of coronary thrombosis?
related to altered risk factors
If risk factors are general why is atherosclerosis focal?
turbulence and aerodyanmic
Where do LDL deposits?
-Low density lipoproteins (LDL) deposit in the subintimal space -binds to matrix proteoglycans
What is the progression of atherosclerosis?
- Coronary artery at lesion-prone location
- Type II lesion
- Type III (preatheroma)
- Type IV (atheroma)
- Type V (fibroatheroma)
- Type VI (complicated lesion)
What happens at a coronary artery at lesion-prone lesion?
Adaptive thickening (smooth muscle) - intima thickens
What happens at a type II lesion?
macrophage foam cells
What happens at a type III lesion (preatheroma)?
small pools of extracellular lipid
What happens at a type IV lesion (atheroma)?
core of extracellular lipid (inflammatory)
What happens at a type V lesion (fibroatheroma)?
fibrous thickening
What happens at a type VI (complicated lesion)?
- thrombus
- fissure and hematoma
- Lipid core breakdown
What is the natural history of atheroscelerosis?
- Normal
- intermediate lesions
- Advanced lesions
- Complication (e.g. stenosis, plaque rupture)
When is there a window of opportunity for primary prevention?
-intermediate lesions
-Advanced lesions
(Life-style changes
Risk factor management)
What are the clinical interventions for complications?
- Secondary prevention
- Catheter based interventions
- Revascularisation surgery
- Treatment of heart failure
What is the function of vascular endothelial cells?
- Barrier function (e.g. to lipoproteins)
2. Leukocyte recruitment
What is the function of monocyte-macrophages?
- Foam cell formation
- Cytokine and growth factor release
- Major source of free radicals
- Metalloproteinases
What is the function of platelets?
- Thrombus generation (late)
2. Cytokine and growth factor release
What is the function of T lymphocytes?
Macrophage activation
What is the function of vascular smooth muscle cells?
- Migration and proliferation
- Collagen synthesis
- Remodelling & fibrous cap formation
What basis does atherosclerosis have?
inflammatory
What did the CANOS trial involve?
- Patients at high risk of atherosclerosis complications injected with antibodies to Interleukin -1 (IL-1) (so could be sued for treatment)
- Fewer major adverse cardiovascular events (MACE) mostly stroke and heart attacks in treated patients
What type of mechanisms connect lipids and inflammation in atherosclerosis?
Multiple mechanisms including cholesterol crystal formation
What happens if WBC are activated excessively or inappropriately?
injure host tissue
What are the main inflammatory cells in atherosclerosis?
macrophages, which are derived from blood monocytes
How are macrophage subtypes regulated?
d by combinations of transcription factors binding to regulatory sequences on DNA
What are the two main classes of macrophages?
- Inflammatory macrophages
- Resident macrophages
What do inflammatory macrophages do?
adapted to kill micro-organisms (germs)
What do resident macrophages do?
- Normally homeostatic - suppress inflammatory activity
- Alveolar resident macrophages - surfactant lipid homeostasis
- Osteoclasts - calcium and phosphate homeostasis
- Spleen - iron homeostasis
What are LDL?
- Synthesised in liver
2. Carries cholesterol from liver to rest of the body including arteries
What is the structure of LDLs?
- docking molecule ‘molecular addresses for fat delivery’
- lipid monolater (like cell membrane) but one molecule thick
- Cargo fat for fuel
What is HDL?
Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
What are oxidised LDLs?
- modified LDLs due to action of free radicals on LDL
- Not one single substance
- Families of highly inflammatory and toxic forms of LDL found in vessel walls
How are LDLs trapped?
- LDLs leak through the endothelial barrier
- Trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification
How are LDLs modified?
oxidation - represents partial burning
How do LDLs become oxidatively modified?
by free radicals
What happens to the oxidised LDLs?
phagocytosed by macrophages and stimulates chronic inflammation
What is the process of chronic inflammation from LDLs?
- LDLs
- LDL oxidation
- Phagocytosis by macrophages
- Macrophages now known as ‘foam cells’
- Chronic inflammation
What is familial hyperlipidemia (FH)?
- Autosomal genetic disease main form dominant with gene dosage)
- Massively elevated cholesterol (>20mmol/L)
- Failure to clear LDL from blood
- Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20
How is the LDL receptor expression regulated?
negatively regulated by intracellular cholesterol
How is cholesterol synthesis regulated?
negatively regulated by cellular cholesterol
How do you lower plasma cholesterol?
HMG-CoA reductase inhibitors (= “statins”)
What happens to cholesterol in LDLR-negative patients?
macrophages accumulate cholesterol
Where is there a second LDL receptor?
- not under feedback control
- in atherosclerotic lesions. -‘scavenger receptor’ since they hoover up chemically modified LDL
What are scavenger receptors?
family of pathogen receptors that ‘accidentally’ bind OxLDL
What are macrophage scavenger receptor A known as?
Known as CD204
What do CD204 bind to?
- oxidised LDL
- Gram-positive bacteria like Staphylococci & Streptococci
- dead cells
What is macrophage scavenger receptor B known as?
CD36
What does CD36 bind to?
- oxidised LDL
- malaria parasites
- dead cells
How are macrophages used in inflammation?
- Activation of ‘bug detector’ pathways
- Aterial Ox-LDL deposits
- Balance with homeostasis
How are macrophages used in homeostasis?
- Safe clearance
- Reverse cholesterol transport
- Aterial Ox-LDL deposits
- Balance with inflammation
