1. Atherosclerosis D S O’Briain April 2007

2. Atherosclerosis Arteriosclerosis (hardening of the arteries) 3 types: 1.Atherosclerosis (athero=porridge) plaques of lipid and fibrous tissue in vessel wall Less important forms of arteriosclerosis 2. Medial calcification (Monckeberg) 3. Small vessel (arteriolosclerosis) hyaline or hyperplastic

3. Atheromatous Plaque, Macroscopic Distribution: Abdominal aorta> coronary > popliteal > descending thoracic >internal carotid > circle of Willis. Spared: upper extremities, renal, mesenteric (except ostia). Fibrous cap (white), deeper portion (grumous, yellow). 3 - 15 mm diameter, raised, coalesce. Scanty to numerous

4. Atheromatous Plaque Histology Fibrous cap: Smooth muscle, WBC, connective tissue, collagen, elastic, proteoglycan. Core: lipid debris, cholesterol, cholesterol esters, foam cells ( smooth muscle and macrophage), fibrin, plasma proteins, T-cells. Periphery: neovascularisation, chronic inflammation.

5. Effects of Atheromatous Plaque Different effects in narrow (coronary) and wide (aorta) vessels Clinically silent Most plaques have no effect. Calcification: Identify on imaging. Complicated plaques Fissure Ulcerate: atheroemboli. Thrombose: occlude, embolise Haemorrhage: occlude. Consequences Stenose: Ischaemia, atrophy. Occlude (by thrombus or haemorrhage): Infarct. Aneurysm: pressure effects, leak (rupture)

6. Fatty streak Possible precursor of atheroma. Spot (1mm), Streak (1x10mm). Composition: Macrophages filled with lipid (foam cells) later smooth muscle cells with lipid droplets, extracellular lipid, T-lymphocytes, proteoglycans, collagen, elastin. Incidence: More frequent with high milk/fat diet: 10% first decade, 30% third decade, May recede, persist or convert to fibrous plaque Distribution: Aorta - unlike atheroma, Coronary arteries - like atheroma.

7. Intimal Cushion White areas of diffuse intimal thickening composed of intimal smooth muscle and matrix (little collagen, no lipid), gelatinous lesion. Degenerate effect of blood pressure and time. But occur at ostia (atheroma sites).

8. Monckeberg’s Calcific Medial Sclerosis Calcification of medium or small arteries Both sexes, over 50 Arteries: Femoral, radial, ulnar, genital. Cause: vasotonic factors, adrenaline, nicotine. Effect: none, visible in imaging

9. Arteriolosclerosis Hyaline change in vessel walls. Pathogenesis - plasma leakage, smooth muscle matrix. Associations - hypertension, diabetes, age. Benign - hyaline narrowing. Hyperplastic - onion skin (fibrinoid necrosis). Sites: Kidney, gall bladder, intestine, periadrenal, pancreatic.

10. Theories of Atherogenesis Virchow - imbibation –(lipid theories) Rokitansky - encrustation –(thrombotic theories)

11. Atherosclerosis Risk Factors Hyperlipidemia.LDL (low density lipoprotein) Hypertension: 160/95 V s 140/90,- Risk X 5. Increases: Atheroma, IHD, CVD. Risk decreases with therapy. Cigarettes: More AS, more sudden death, Risk increased by 70-200%. Decreases after cessation. Diabetes: More AS, MI x 2, Increased CVD, PVD risk increased x 8-150. Other: Physical activity, stress, obesity, oral contraceptives, hyperuricemia, high carbohydrate intake, male, age, family history, homocystinemia. Multiple Factors:More than additive. NOTE: IHD ischaemic heart disease, CVD cerebrovascular disease, PVD peripheral vascular disease AS atherosclerosis, MI myocardial infarction,

12. Role of lipid in Atherosclerosis 1. Found in plaque 2. Experimentally raised lipid -> AS 3. Hyperlipidemias -> AS 4. Populations with high lipids -> high AS rate 5. Treat hyperlipidemia - decrease AS.

13. Risk of Atherosclerosis High: Raised LDL (70% cholesterol), triglyceride and VLDL. Low: Raised HDL. Risk increases with increased cholesterol level (risk x 5 with cholesterol increase 220 to 265) Increased intake cholesterol and triglycerides - increases serum cholesterol. Omega 3 fatty acids (fish) protective

14. How Hyperlipidemia may damage intima More serum LDL, more cellular penetration. LDL with proteoglycan - avid uptake. LDL modified - lysosomal uptake. LDL - directly damages endothelial cell. Oxidised lipoproteins: Endothelial injury, smooth muscle injury, foam cells - scavenger receptor, chemotactic.

15. Intimal dysfunction Cause: Mechanical, Haemodynamic stress, Immune complex, Radiation, Chemotherapy. Association: Hypertension, Stress, Cigarettes. Effect: Increased intimal permeability, adhesion, smooth muscle proliferation, atheroma (if hyperlipidemia )

16. Macrophage Family: Monocyte, histiocyte, macrophage, epithelioid cell, giant cell, granuloma Monocytes adhere, migrate, phagocytose Have scavenger receptor - modified VLDL receptor (Lipid internalised, hydrolysed, esterified -> lipid droplet). Monocytes produce: IL-1, TNF (increased adhesion), chemotaxis factors, toxic O 2, PDGF, TGF beta -> smooth muscle

17. Smooth muscle proliferation Origin: From media (or myointima) Stimulus: PDGF (from platelets, macrophages, endothelial and smooth muscle cells), FGF, EGF, TGF. Inhibit: Heparin, TGF-B. Result: Smooth muscle cells produce extracellular matrix and foam cells (atheroma)

18. Arterial Injury Permeability increases. Adhesion of platelets, monocytes Factors released Smooth muscle migrates to intima, proliferates and produces extracellular matrix, collagen, elastin, proteoglycans Monocytes - phagocytose Lipid deposited

19. Other Theories of Atherogenesis Primary smooth muscle proliferation: monoclonal growth (as a form of leiomyoma) Cause: Exogenous (hydrocarbon, virus), endogenous (cholesterol) Experimentally: Plaques in Marek chicken virus, anthracycline, herpes mRNA in plaque

20. Ischaemic Heart Disease Epidemic Causes 80% of cardiac mortality Peaked in US in 1960s, 40% decline since Different patterns in some Western countries Cause of decline: Changing lifestyle (diet, smoking, exercise) Better therapy (CCU, thrombolysis, arrhythmia therapy, CABG, angioplasty)

21. Atherosclerotic Coronary Artery Disease: Clinical Syndromes Silent Infarct Angina Pectoris Myocardial Infarct Chronic Ischaemic Heart Disease Sudden Death

22. Atherosclerotic Coronary Artery Disease: Clinical Syndromes Silent Infarct Angina Pectoris Myocardial Infarct Chronic Ischaemic Heart Disease Sudden Death

23. Aneurysms Localised abnormal dilation of vessel. Types: Saccular, fusiform, cylindroid, dissection. Complications: Pressure, thrombus, rupture. Aetiology: Atherosclerosis, cystic medial necrosis, syphilis, trauma (arteriovenous aneurysm), PAN, infections, (mycotic), congenital (berry).

24. Atherosclerotic Aneurysm Males of 50+, frequently (50%) hypertensive Abdominal aorta (between renal artery and aortic biforcation). (Thoracic aorta, renal, mesenteric arteries) Complications; Rupture (if >6 cm, 50% rupture in 10 years) surgical mortality 50% (unruptured 5%) Compression - ureter, vertebrae Occlusion (thrombus, pressure) Embolism Abdominal mass

25. Atherosclerosis Peripheral vascular disease Pain (claudication) Ischaemic changes Gangrene General atheroma risk factors But 100 times more frequent in diabetes

26. Atherosclerosis Mesenteric ischaemia Coeliac, superior mesenteric artery) Aymptomatic Intestinal angina (pain after food) Intestinal ischaemia Bloody diarrhoea Infarction/gangrene obstruction

27. Athersclerosis Cerebrovascular disease Thrombosis (embolism, haemorrhage are other import factors in stroke) Sites of thrombotic occlusion:carotid bifurcation, middle cerebral and basilar arteries) Transient ischaemic attack (TIA), cerebrovascular accident (CVA), (stroke)