Lecture 4.2 - Atherosclerosis

Images of blood vessels: Definitions: ◦Arteriosclerosis - hardening of the arteries. It includes three diseases: ‣ Atherosclerosis ‣ Arteriolosclerosis - kidneys ‣ Monkeberg's disease - formed by calcification of arteries Atherosclerosis: ◦Atherosclero...

Images of blood vessels: Definitions: ◦Arteriosclerosis - hardening of the arteries. It includes three diseases: ‣ Atherosclerosis ‣ Arteriolosclerosis - kidneys ‣ Monkeberg's disease - formed by calcification of arteries Atherosclerosis: ◦Atherosclerosis - the accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries doesn't affect veins or capillaries ◦Slowly progressive ◦A build-up of fat (cholesterol) within the artery wall ◦Characterised by intimal lesions called: atheroma, atheromatous or fibro-fatty plaques. Pathogenesis of atherosclerosis: ◦Current hypothesis - response to injury ‣ Initiated by endothelial dysfunction ◦Endothelial injury causes: ‣ Platelet adhesion, platelet derived growth factor release, smooth muscle cell (SMC) proliferation and migration ‣ Accumulation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages due to increase in permeability ‣ Migration of monocytes from media into intima ---> starts proliferation  ◦The main component of fibro-fatty plaque are: ‣ Lipid containing macrophages ‣ Extracellular matrix ‣ Cells, proliferating smooth muscle cells Response to injury hypothesis: ◦Injury to the endothelium (dysfunctional endothelium) ◦Chronic inflammatory response - presence of macrophages ◦Migration of SMC from media to intima ◦Proliferation of SMC in intima - growing of legion ◦Excess production of extracellular matrix (collagen and elastin) ◦Enhanced lipid accumulation Pathogenesis of atherosclerosis: Response to injury: ◦The two most important causes of endothelial dysfunction are: ‣ Hemodynamic disturbances (HTN - hypertension) ‣ Hypercholesterolemia ◦Inflammation is also an important contributor Atherosclerosis - macroscopic features: ◦Fatty streak - yellow discolouration with no bulging (small accumulation of macrophages with fat inside) ◦Simple plaque - raised yellow legion with irregular outline, large plaque present ◦Complicated plaque - can end up with calcification and hemorrhage  Atherosclerosis - microscopic features: ◦Early changes: ‣ Proliferation of smooth muscle cells ‣ Accumulation of foam cells ‣ Extracellular lipid ◦Later changes: ‣ Fibrosis ‣ Necrosis ‣ Cholesterol clefts ‣ +/- inflammatory cells ‣ Disruption of internal elastic lamina ‣ Damage extends into media ‣ Ingrowth of blood vessels ‣ Plaque fissuring Stable plaque and the vulnerable plaque concepts:  Common sites: ◦Abdominal aorta ◦Coronaries ◦Popliteal artery ◦The internal carotid arteries ◦The vessels of the circle of Willis Clinical complications: ◦Progressive lumen narrowing due to high-grade plaque stenosis ◦Acute atherothrombotic occlusion - due to the activation of the coagulation cascade ◦Thrombus embolisation into the distal arterial bed (fragmentation of thrombus, and then thrombus travels to another vessel and causes occlusion - could lead to myocardial infarction, stroke etc) ◦Ruptured abdominal atherosclerotic aneurysm - creates extra pressure on the walls of the vessels, causing blood to leave the vessel ◦Myocardial infarction (heart attack), ischaemic heart disease (IHD) ◦Cerebral infarction (stroke) ◦Aortic aneurysms ◦Mesenteric occlusion ◦Peripheral vascular disease (gangrene of the legs) Atherosclerosis - myocardial infarction:  Atherosclerosis - cerebral infarction: Atherosclerosis - intestinal infarction: Atherosclerosis - peripheral vascular disease: Atherosclerosis - abdominal aortic aneurysm: ◦Localised enlargement of the abdominal aorta ◦Cause no symptoms except when ruptured ◦Occasionally, abdominal, back or leg pain may occur Risk factors: ◦Non-modifiable risk factors: ‣ Age - slowly progressive throughout adult life ‣ Gender - women protected relatively before menopause ‣ Genetic predisposition: Genetically determined abnormalities of lipoproteins Lead to early development of atherosclerosis Associated physical signs ◦Modifiable risk factors: ‣ Hyperlipidaemia: High plasma cholesterol associated with atherosclerosis  LDL most significant HDL protective ‣ Cigarette smoking: Powerful risk factor for ischaemic heart disease (IHD) Mode of action uncertain: ◦Coagulation system ◦Increased platelet aggregation ‣ Alcohol: >5 units/day associated with increased risk of IHD Alcohol consumption often associated with other risk factors e.g. smoking and high BP but still an independent risk factor ‣ Infection: Chlamydia pneumoniae Helicobacter pylori Cytomegalovirus ‣ Hypertension: Mechanism uncertain Endothelial damage caused by raised pressure Atherosclerosis - diabetes mellitus: ◦DM also associated with high risk of cerebrovascular and peripheral vascular disease ◦Related to hyperlipidaemia and hypertension Other risk factors: ◦Lack of exercise ◦Obesity ◦Oral contraceptives ◦Stress and personality type? Atherosclerosis - the processes involved: ◦Lipid accumulation ◦Interactions between cell types ◦Production of intercellular matrix ◦Thrombosis Atherosclerosis - the cells involved: ◦Endothelial cells: ‣ Key role in haemostasis ‣ Altered permeability to lipoproteins ‣ Production of collagen ‣ Stimulation of proliferation and migration of smooth muscle cells ◦Platelets: ‣ Key role in haemostasis ‣ Stimulate proliferation and migration of smooth muscle cells ◦Smooth muscle cells:  ‣ Take up LDL and other lipid to become foam cells ‣ Synthesise collagen and proteoglycans ◦Macrophages: ‣ Oxidise LDL ‣ Take up lipids to become foam cells ‣ Secrete proteases which modify matrix ‣ Stimulate proliferation and migration of smooth muscle cells ◦Lymphocytes: ‣ Stimulate proliferation and migration of smooth muscle cells ◦Neutrophils: ‣ Secrete proteases leading to continued local damage and inflammation Atherosclerosis - prevention: ◦No smoking ◦Reduce fat intake ◦Treat hypertension ◦Not too much alcohol ◦Regular exercise/weight control ◦However, people will still develop atherosclerosis Atherosclerosis - intervention: ◦Stop smoking ◦Modify diet ◦Treat hypertension ◦Treat diabetes ◦Lipid lowering drugs