Pathophysiology of atheroma Flashcards
What is the definition of atheroma/atherosclerosis ?
Formation of focal elevated lesions (plaques) in intima of large and medium sized arteries
What are potential outcomes of atheroma ?
Ischaemia in coronary arteries - atheromatous plaques narrowing lumen
Angina due to myocardial ischaemia
Complicated thromboembolism
What is the earliest significant lesion of atheroma ?
Fatty streak
What makes up the yellow linear elevation of intimal lining of a fatty streak ?
Comprises masses of lipid - laden macrophages
What is the clinical significance of fatty streaks ?
No clinical significance
Who often gets fatty streaks ?
Young children
Who often gets early atheromatous plaques ?
Young adults onwards
What is the histological appearance of early atheromatous plaques ?
Smooth yellow patches in intima
Lipid-laden macrophages
What can early atheromatous plaques progress to ?
Established plaques
What are the features of a fully developed atheromatous plaque ?
Central lipid core with fibrous tissue cap, covered by arterial endothelium
What is responsible for the collagen production in the cap ?
Smooth muscle cells
What is the function of the fibrous cap that sits on the central lipid core ?
Provides structural strength
What resides in the fibrous cap ?
inflammatory cells-
- Macrophages
- T-lymphocytes
- Mast cells
What is contained within the central lipid core ?
Cellular lipids/debris derived from macrophages which have died in the plaque
Often a rim of foamy thrombogenic macrophages
Why are some macrophages described as foamy ?
Due to the uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor
What marker in angiograms forms in late plaque development ?
Dystrophic calcification
What is dystrophic calcification ?
Dystrophic calcification (DC) is the calcification occurring in degenerated or necrotic tissue
What is a complicated atheroma ?
Haemorrhage into plaque causing plague rupture and potential thrombosis
What is the most important risk factor for atheroma ?
Hypercholesterolaemia
How does increased LDL cholesterol levels arise ?
Lack of cell membrane receptor for LDL
What is the epidemiology for the decreased functional receptor mutation ?
1/500 Caucasians
What are the signs of major hyperlipidaemia ?
Familial/ primary vs acquired/secondary (idiopathic?)
Biochemical evidence: LDL, HDL , total cholesterol, Triglycerides
Corneal arcus (premature)
Tendon xanthomata (knuckles, achilleas)
Xanthelasmata
Risk/premature/family history MI/atheroma
What are the risk factors for atheroma ?
Smoking Hypertension Diabetes Male Elderly Accelerate process of plaque formation driven by lipids
What are the less strong risk factors for atheroma ?
Obesity Sedentary lifestyle Low socio-economic status Low birthweight Role of micro-organisms
What is arteriosclerosis ?
Not atheromatous
Stiffening or hardening or the arterial walls which features smooth muscle hypertrophy, apparent reduplication of internal elastic laminae and intimal fibrosis leading to a decrease in vessel diameter
What does arteriosclerosis contribute to ?
High frequency of cardiac cerebral, colonic and renal ischaemia in elderly
Clinical effects most apparent when CVS further stressed by haemorrhage, major surgery, infection, shock
Who commonly suffers from arteriosclerosis ?
The elderly
What is the two step development process of atheromatous plaques ?
- Injury to endothelial lining or artery
- Chronic inflammation and healing repsonse of vascular wall to agent causing injury
Chronic/episodic exposure of arterial wall to these processes-> formation of atheromatous plaques
What is the steps of the pathogenesis of atherosclerosis ?
- Endothelial injury and dysfunction
- Accumulation of lipoproteins (LDL) in vessel wall
- Monocyte adhesion to endothelium-> migration into intima and transformation to foamy macrophages
- Platelet adhesion
- Factor release from activated platelets, macrophages -> smooth muscle cell recruitment
- Smooth muscle cell proliferation, extracellular matric production and T-cell recruitment
Lipid accumulation (extracellular and in foamy macrophages)
What are the possible causes of endothelial injury ?
Haemodynamic disturbances (turbulent flow)
Hypercholesterolemia:
- (chronic hypercholesterolaemia can directly impair endothelial cell function by
increasing local production of reactive oxygen species)
- (lipoproteins aggregate in intima and are modified by free radicals produced by
inflammatory cells → modified LDL accumulated by macrophages but not
completely
- degraded → foamy macrophages → toxic to endothelial cells plus release of growth
factors, cytokines
How are injured endothelial cells functionally altered ?
Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin)
High permeability for LDL
Increased thrombogenicity
Inflammatory cells, lipids-> intimal layer-> plaques
How does advanced plaques form ?
Large numbers macrophages, T-lymphocytes
Lipid-laden macrophages die through apoptosis-> lipid into lipid core
Response to injury= chronic inflammatory process: 1. inflammatory response 2. process of tissue repair
Growth factors (PDGF) -> proliferation intimal smooth muscle cells, subsequent synthesis in collagen, fibrous, mucopolysaccharide
Fibrous cap encloses lipid rich core
Growth factors secreted by platelets, injured endothelium, macrophages and smooth muscle cells
What is the consequence of progressive lumen narrowing due to high grade stenosis ?
Stenosis of >50-75% of vessel lumen-> critical reduction of blood flow in distal arterial bed-> reversible tissue ischaemia
E.g. Stenosed atheromatous cornonary artery-> stable angina
Very severe stenosis-> ischamic pain at rest (unstable angina)
E.g. Ileal, femoral, popliteal artery stenosis -> intermittent claudication (peripheral arterial disease)
Longstanding tissue ischemia -> atrophy of affected organ e.g. Atherosclerotic renal artery stenosis-> renal atrophy
What is the consequence of acute atherothrombotic occlusion ?
Major complications rupture of plaque-> acute event
Rupture exposes highly thrombogenic plaque contents (collagen, lipid, debris) to blood stream-> activation of coagulation cascade and thrombotic occlusion in very short time
Total occlusion -> irreversible ischemia-> necrosis (infarction) of tissues
E.g. Myocardial infarct (coronary artery)
E.g. Stroke (carotid, cerebral artery)
E.g. Lower limb gangrene (ileal, femoral, popliteal artery)
What is the consequence of embolization of the distal arterial bed ?
Detachment if small thrombus fragments from thrombosed atheromatous arteries-> embolise distal to ruptured plaque
Embolic occlusion of small vessels-> small infarcts in organs
E.g. Heart, dangerous small foci of necrosis-> life-threatening arrhythmias
E.g. Large ulcerating aortic plaques, lipid rich fragments of plaque-> cholestrol emboli in kidney, leg, skin
E.g. Carotid artery atheromatous debris, common cause stroke (cerebral infarct/ TIA)
What is the consequence of ruptured atheromatous abdominal aortic anuerysm ?
Media beneath atheromatous plauqes gradually weakened (lipid-related inflammatory activity in plaque)
-> gradual dilatation of vessel
Slow but progressive, seen in elderly, often asymptomatic
Sudden rupture-> massive retroperitoneal haemorrhage (high mortality)
Aneurysms >5cm diameter at high risk of rupture
Mural thrombus-> emboli in legs
What is the preventative and theraputic approaches to atheroma ?
Stop smoking Control blood pressure Weight loss Regular exercise Dietary modification
What are the secondary prevention measures of atheroma’s ?
Cholesterol lowering drugs, aspirin (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques
Surgical options
