MoD session 6: atheroma

Question 1

Define atheroma

Answer 1

The accumulation of intracellular and extracellular lipid in the intima and media of medium and large sized arteries

Question 2

Define atherosclerosis

Answer 2

The thickening and hardening of arterial walls as a consequence of atheroma

Question 3

Define arteriosclerosis

Answer 3

Thickening of artery and arteriole walls, usually as a result of hypertension or diabetes

Question 4

Which arteries is atherosclerosis commonly found in?

Answer 4

Aorta (esp. abdominal), coronary, carotid, cerebral, leg

Question 5

What is the normal arterial structure, from inside to outside?

Answer 5

Lumen - endothelium - sub endothelial connective tissue - internal elastic lamina - muscular media - external elastic lamina - adventitia

Question 6

Describe the macroscopic morphology of atheroma

Answer 6

FATTY STREAK: lipid deposits in intima (yellow and raised). Precursor to atheroma

SIMPLE PLAQUE: raised yellow/white areas with irregular outline, widely distributed, will enlarge and coalesce

COMPLICATED PLAQUE: thrombosis and haemorrhage into plaque, often calcification, aneurysm may form

Question 7

Describe the microscopic changes that occur in atheroma

Answer 7

Early changes:

• smooth muscle proliferation
• accumulation of foam cells
• extracellular lipid

Later changes:

• fibrosis and necrosis
• cholesterol clefts (cholesterol dissolved out by tissue processing leaves shape of cholesterol crystals)
• inflammatory cells
• disruption of internal elastic lamina so altered compliance. Damage extends into media
• ingrowth of blood vessels (similar to granulation tissue)
• plaque fissuring: releases material that will promote thrombosis

Question 8

Ischaemic heart disease

Answer 8

Leads to:

• MI: necrosis of myocardium due to ischaemia, usually by blockage of coronary artery by a thrombus
• angina pectoris: chest pain at increased workloads due to ischaemia from narrowed coronary artery
• arrhythmias
• cardiac failure as heart chronically scarred
• sudden death

Question 9

Cerebral ischaemia

Answer 9

TIA (transient ischaemic attack): a brief episode of neurological dysfunction due to temporary ischaemia without infarction [seconds to minutes, complete recovery, may be a prelude to stroke]. Usually the result of micoemboli

Cerebral infarction (stroke): rapid onset cerebral deficit lasting >24hours/leading to death. Thrombosis/arterial stenosis/cardio-embolic/intracerebral haemorrhage/sub-arachnoid haemorrhage

Multi-infarct dementia: vascular dementia. Often if history of TIA. See widespread small vessel disease on MRI. Second most common dementia after Alzheimer’s

Question 10

Mesenteric ischaemia

Answer 10

Ischaemic colitis: inflammation and injury of large intestine (mucosa + submucosa). May lead to peritonitis
Malabsorption
Intestinal infarction: often due to thrombus or embolus in superior mesenteric artery

Question 11

Peripheral vascular disease

Answer 11

INTERMITTENT CLAUDICATION: pain in legs due to reduced blood supply, goes away when not walking initially but over time worsens until eventually getting pain at rest

LERICHE SYNDROME: aorto-iliac occlusive disease. Buttock claudication and impotence

GANGRENE: needs amputation, often multiple amputations as gangrene returns if the increased O2 demand post-surgery is not met

Question 12

Abdominal aortic aneurysm

Answer 12

Fusiform dilatation: bulge in whole of aorta. Abnormal flow + abnormal walls=2/3 of Virchow’s triad

Cause: degradation of elastic lamellae, leukocytic infiltrate, enhanced proteolysis, smooth muscle cell loss-affects all 3 layers of vessel wall

Rapidly fatal

Question 13

Define aneurysm

Answer 13

A permanent and irreversible dilatation of a blood vessel by at least 50% of the normal expected diameter. Majority abdominal; can be thoracic

Question 14

What is a pseudoaneurysm?

Answer 14

Blood leaks through arterial wall but is contained by the adventitia or surrounding perivascular tissue

Question 15

Describe the risk factors for atheroma

Answer 15

Age: increase risk as increase age because risk factors operate over years

Gender: women relatively protected pre-menopause, then evens out after

Hyperlipidaemia: high plasma cholesterol, high LDL levels most important and low HDL levels (protective function). Can be familial due to defect in apolipoprotein E; present with signs such as corneal arcus, tendon xanthoma and xanthelasma at a young age

Smoking: action unknown but affects coagulation system by decreasing PG12 and increasing platelet aggregation

Hypertension: endothelial damage caused by raised pressure maybe but uncertain cause

Diabetes mellitus: doubles IHD risk, also higher risk of cerebrovascular and peripheral vascular disease. Often related to hyperlipidaemia and hypertension

Alcohol: high consumption increases risk, moderate may be protective

Diet and exercise

Infection: chlamydia pneumoniae, helicobacter pylori, cytomegalovirus

Stress

Question 16

Briefly describe some historical hypotheses for atheroma genesis

Answer 16

1. 1852 Rokitnasky: thrombogenic theory (plaques formed by repeated thrombi, lipid derived, fibrous cap)
2. 1856 Virchow: endothelial injury, inflammation, increased permeability to lipid from plasma
3. 1972 Ross and Glomset: reaction to injury. Endothelial injury increases permeability and allows platelet adhesion, smooth muscle proliferates
4. Benditt and Benditt: monoclonal hypothesis. Each plaque is monoclonal, may represent abnormal growth control, is each plaque a benign tumour/viral aetiology?

Question 17

Outline the pathogenesis of atheroma

Answer 17

1. Thrombosis
2. Lipid accumulation
3. Production of intercellular matrix and interactions between cell types

Question 18

Describe the role of different cell types in atheroma

Answer 18

ENDOTHELIAL CELLS: haemostasis, altered permeability to lipoproteins and collagen production stimulates proliferation and migration of smooth muscle cells

PLATELETS: haemostasis, stimulate proliferation and migration of smooth muscle cells (due to PDGF)

SMOOTH MUSCLE CELLS: take up LDL for become foam cells. Synthesise collagen and proteoglycans–> different tissue consistency

LYMPHOCYTES: TNF may affect lipoprotein metabolism and stimulate proliferation and migration of smooth muscle cells

NEUTROPHILS: secrete proteases causing continued local damage and inflammation

Question 19

Describe the unifying hypothesis atheroma formation

Answer 19

1. Endothelial injury due to high LDL, hypertension, toxins (e.g. cigarette smoke), haemodynamic stress
2. Injury causes:
   - platelet adhesion, PGDF release and smooth muscle proliferation
   - insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
   - migration of monocytes into intima
3. Stimulated smooth muscle cells produce matrix material
4. Foam cells secrete cytokines causing:
   - more smooth muscle cell stimulation
   - recruitment of other inflammatory cells

Question 20

Prevention/intervention in atheroma

Answer 20

Smoking cessation
Decreased fat and alcohol intake
Treat hypertension and diabetes
Regular exercise/weight control
Aspirin
Lipid lowering drugs (e.g. statins)