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

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. 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 Atheroma - Lipid Metabolism

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?