1. Leicester Warwick Medical School Department of Pathology
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 Epidemiology
encrustation
insudation
monoclonal
response to injury
Epidemiology
Prevention/Intervention

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 Gender 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
>5 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

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