Leicester Warwick Medical School

1
Leicester Warwick Medical School
Atheroma Dr Mark Bamford Department of Pathology
2
Atheroma - Objectives 1

• Definition of atheroma
• Macroscopic appearances
• Microscopic appearances
• Effects

3
Atheroma - Objectives 2

• Mechanisms of atherogenesis
• encrustation
• insudation
• monoclonal
• response to injury
• Epidemiology
• Prevention/Intervention

4
(No Transcript)
5
Atheroma

• Definition
• Atheroma is the accumulation of intracellular
  and extracellular lipid in the intima of large
  and medium sized arteries

6
Atherosclerosis

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

7
Arteriosclerosis

• Definition
• The thickening of the walls of arteries and
  arterioles usually as a result of hypertension or
  diabetes mellitus

8
Atheroma - Macroscopic Features

• Fatty streak
• Simple plaque
• Complicated plaque

9
Atheroma - The Fatty Streak

• Lipid deposits in intima
• Yellow, slightly raised
• Relationship to atheroma somewhat debatable

10
Atheroma - The Simple Plaque

• Raised yellow/white
• Irregular outline
• Widely distributed
• Enlarge and coalesce

11
Atheroma - The Complicated Plaque

• Thrombosis
• Haemorrhage into plaque
• Calcification
• Aneurysm formation

12
Atheroma - Common Sites

• Aorta - especially abdominal
• Coronary arteries
• Carotid arteries
• Cerebral arteries
• Leg arteries

13
Normal Arterial Structure

• Endothelium
• Sub-endothelial c.t.
• Internal elastic lamina
• Muscular media
• External elastic lamina
• Adventitia

14
Atheroma - Microscopic Features

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

15

• Endothelium
• Smooth muscle cell
• Lipid
• Matrix

16
Atheroma - Microscopic Features

• Later changes
• fibrosis
• necrosis
• cholesterol clefts
• /- inflammatory cells

17
Atheroma - Microscopic Features

• Later changes
• disruption of internal elastic lamina
• damage extends into media
• ingrowth of blood vessels
• plaque fissuring

18
Atheroma - Coronary Artery
19
Atheroma - Clinical Effects

• Ischaemic heart disease
• sudden death
• myocardial infarction
• angina pectoris
• arrhythmias
• cardiac failure

20
Atheroma myocardial infarction
21
Atheroma myocardial infarction
22
Atheroma - Clinical Effects

• Cerebral ischaemia
• transient ischaemic attack
• cerebral infarction (stroke)
• multi-infarct dementia

23
Atheroma cerebral infarction
24
Atheroma - Clinical Effects

• Mesenteric ischaemia
• ischaemic colitis
• malabsorption
• intestinal infarction

25
Atheroma intestinal infarction
26
Atheroma - Clinical Effects

• Peripheral vascular disease
• intermittent claudication
• Leriche syndrome
• ischaemic rest pain
• gangrene

27
Atheroma peripheral vascular disease
28
Atheroma Abdominal Aortic Aneurysm
29
Atheroma - Pathogenesis

• Age
• Gender
• Hyperlipidaemia
• Cigarette smoking
• Hypertension
• Diabetes mellitus
• Alcohol
• Infection

30
Atheroma

• Age
• slowly progressive throughout adult life
• risk factors operate over years
• Gender
• women protected relatively before menopause
• presumed hormonal basis

31
Atheroma

• Hyperlipidaemia
• high plasma cholesterol associated with atheroma
• LDL most significant
• HDL protective

32
Atheroma - Lipid Metabolism

• Lipid in the blood is carried on lipoproteins
• Lipoproteins carry cholesterol and triglycerides
  (TG)
• Hydrophobic lipid core
• Hydrophilic outer layer of phospholipid and
  apolipoprotein (A-E)

33
Atheroma - Lipid Metabolism

• Chylomicrons
• transport lipid from intestine to liver
• VLDL
• carry cholesterol and TG from liver
• TG removed leaving LDL

• LDL
• rich in cholesterol
• carry cholesterol to non-liver cells
• HDL
• carry cholesterol from periphery back to liver

34
Atheroma 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
  atheroma

35
Familial Hyperlipidaemia

• Genetically determined abnormalities of
  lipoproteins
• Lead to early development of atheroma
• Associated physical signs
• arcus
• tendon xanthomas
• xanthelasma

36
Xanthelasma
37
Atheroma - Cigarette Smoking

• Powerful risk factor for IHD
• Risk falls after giving up
• Mode of action uncertain
• coagulation system
• reduced PGI2
• increased platelet aggregation

38
Atheroma - Hypertension

• Strong link between IHD and high
  systolic/diastolic blood pressure
• Mechanism uncertain
• ? endothelial damage caused by raised pressure

39
Atheroma - Diabetes Mellitus

• DM doubles IHD risk
• Protective effect in premenopausal women lost
• DM also associated with high risk of
  cerebrovascular and peripheral vascular disease
• ?related to hyperlipidaemia and hypertension

40
Atheroma - Alcohol Consumption

• gt5 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 may be protective

41
Atheroma-Infection

• Chlamydia pneumoniae
• Helicobacter pylori
• Cytomegalovirus

42
Atheroma - Other Risk Factors

• Lack of exercise
• Obesity
• Soft water
• Oral contraceptives
• Stress

43
(No Transcript)
44
Atheroma - Genetic Predisposition

• Familial predisposition well known
• Possibly due to
• variations in apolipoprotein metabolism
• variations in apolipoprotein receptors

45
Atheroma - Pathogenesis

• Thrombogenic theory
• Insudation theory
• Monoclonal hypothesis
• Reaction to injury hypothesis

46
Atheroma - Thrombogenic Theory

• 1852 Karl Rokitansky
• plaques formed by repeated thrombi
• lipid derived from thrombi
• overlying fibrous cap

47
Atheroma - Insudation Theory

• 1856 Rudolf Virchow
• endothelial injury
• inflammation
• increased permeability to lipid from plasma

48
Atheroma - Reaction to Injury Hypothesis

• 1972 Ross and Glomset
• plaques form in response to endothelial injury
• hypercholesterolaemia leads to endothelial damage
  in experimental animals
• injury increases permeability and allows platelet
  adhesion
• monocytes penetrate endothelium
• smooth muscle cells proliferate and migrate

49
Atheroma - Reaction to Injury Hypothesis

• 1986 Ross
• endothelial injury may be very subtle and be
  undetectable visually
• LDL, especially oxidised, may damage endothelium

50
Atheroma - The Monoclonal Hypothesis

• Benditt and Benditt
• crucial role for smooth muscle proliferation
• each plaque is monoclonal
• might represent abnormal growth control
• is each plaque a benign tumour?
• could atheroma have a viral aetiology?

51
Atheroma - The Processes Involved

• Thrombosis
• Lipid accumulation
• Production of intercellular matrix
• Interactions between cell types

52
Atheroma - The Cells Involved

• Endothelial cells
• Platelets
• Smooth muscle cells
• Macrophages
• Lymphocytes
• Neutrophils

53
Atheroma - Endothelial Cells

• Key role in haemostasis
• Altered permeability to lipoproteins
• Secretion of collagen
• Stimulation of proliferation and migration of
  smooth muscle cells

54
Atheroma - Platelets

• Key role in haemostasis
• Stimulate proliferation and migration of smooth
  muscle cells (PDGF)

55
Atheroma - Smooth Muscle Cells

• Take up LDL and other lipid to become foam cells
• Synthesise collagen and proteoglycans

56
Atheroma - Macrophages

• Oxidise LDL
• Take up lipids to become foam cells
• Secrete proteases which modify matrix
• Stimulate proliferation and migration of smooth
  muscle cells

57
Atheroma - Lymphocytes

• TNF may affect lipoprotein metabolism
• Stimulate proliferation and migration of smooth
  muscle cells

58
Atheroma - Neutrophils

• Secrete proteases leading to continued local
  damage and inflammation

59
Atheroma - A Unifying Hypothesis 1

• Endothelial injury due to
• raised LDL
• toxins eg cigarette smoke
• hypertension
• haemodynamic stress

60
Atheroma - A Unifying Hypothesis 2

• Endothelial injury causes
• platelet adhesion, PDGF release, SMC
  proliferation and migration
• insudation of lipid, LDL oxidation, uptake of
  lipid by SMC and macrophages
• migration of monocytes into intima

61
Atheroma - A Unifying Hypothesis 3

• Stimulated SMC produce matrix material
• Foam cells secrete cytokines causing
• further SMC stimulation
• recruitment of other inflammatory cells

62
Atheroma 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
  atheroma

63
Atheroma - Prevention

• No smoking
• Reduce fat intake
• Treat hypertension
• Not too much alcohol
• Regular exercise/weight control
• BUT some people will still develop atheroma!

64
Atheroma - Intervention

• Stop smoking
• Modify diet
• Treat hypertension
• Treat diabetes
• Lipid lowering drugs

65
(No Transcript)