Leicester Warwick Medical School Atheroma Dr Mark Bamford
Leicester Warwick Medical School Atheroma Dr Mark Bamford Department of Pathology
Atheroma - Objectives 1 Definition of atheroma l Macroscopic appearances l Microscopic appearances l Effects l
Atheroma - Objectives 2 l Mechanisms of atherogenesis encrustation l insudation l monoclonal l response to injury l Epidemiology l Prevention/Intervention l
Atheroma l Definition Atheroma is the accumulation of intracellular and extracellular lipid in the intima of large and medium sized arteries
Atherosclerosis l Definition The thickening and hardening of arterial walls as a consequence of atheroma
Arteriosclerosis l Definition The thickening of the walls of arteries and arterioles usually as a result of hypertension or diabetes mellitus
Atheroma - Macroscopic Features Fatty streak l Simple plaque l Complicated plaque l
Atheroma - The Fatty Streak Lipid deposits in intima l Yellow, slightly raised l Relationship to atheroma somewhat debatable l
Atheroma - The Simple Plaque l l Raised yellow/white Irregular outline Widely distributed Enlarge and coalesce
Atheroma - The Complicated Plaque l l Thrombosis Haemorrhage into plaque Calcification Aneurysm formation
Atheroma - Common Sites Aorta - especially abdominal l Coronary arteries l Carotid arteries l Cerebral arteries l Leg arteries l
Normal Arterial Structure Endothelium l Sub-endothelial c. t. l Internal elastic lamina l Muscular media l External elastic lamina l Adventitia l
Atheroma - Microscopic Features l Early changes proliferation of smooth muscle cells l accumulation of foam cells l extracellular lipid l
Endothelium Smooth muscle cell Lipid Matrix
Atheroma - Microscopic Features l Later changes fibrosis l necrosis l cholesterol clefts l +/- inflammatory cells l
Atheroma - Microscopic Features l Later changes disruption of internal elastic lamina l damage extends into media l ingrowth of blood vessels l plaque fissuring l
Atheroma - Coronary Artery
Atheroma - Clinical Effects l Ischaemic heart disease sudden death l myocardial infarction l angina pectoris l arrhythmias l cardiac failure l
Atheroma – myocardial infarction
Atheroma – myocardial infarction
Atheroma - Clinical Effects l Cerebral ischaemia transient ischaemic attack l cerebral infarction (stroke) l multi-infarct dementia l
Atheroma – cerebral infarction
Atheroma - Clinical Effects l Mesenteric ischaemia ischaemic colitis l malabsorption l intestinal infarction l
Atheroma – intestinal infarction
Atheroma - Clinical Effects l Peripheral vascular disease intermittent claudication l Leriche syndrome l ischaemic rest pain l gangrene l
Atheroma – peripheral vascular disease
Atheroma – Abdominal Aortic Aneurysm
Atheroma - Pathogenesis l l l l Age Gender Hyperlipidaemia Cigarette smoking Hypertension Diabetes mellitus Alcohol Infection
Atheroma l Age slowly progressive throughout adult life l risk factors operate over years l l Gender women protected relatively before menopause l presumed hormonal basis l
Atheroma l Hyperlipidaemia high plasma cholesterol associated with atheroma l LDL most significant l HDL protective l
Atheroma - Lipid Metabolism Lipid in the blood is carried on lipoproteins l Lipoproteins carry cholesterol and triglycerides (TG) l Hydrophobic lipid core l Hydrophilic outer layer of phospholipid and apolipoprotein (A-E) l
Atheroma - Lipid Metabolism l Chylomicrons l l l transport lipid from intestine to liver LDL l l VLDL l l carry cholesterol and TG from liver TG removed leaving LDL l rich in cholesterol carry cholesterol to nonliver cells HDL l carry cholesterol from periphery back to liver
Atheroma and Apolipoprotein E Genetic variations in Apo E are associated with changes in LDL levels l Polymorphisms of the genes involved lead to at least 6 Apo E phenotypes l Polymorphisms can be used as risk markers for atheroma l
Familial Hyperlipidaemia Genetically determined abnormalities of lipoproteins l Lead to early development of atheroma l Associated physical signs l arcus l tendon xanthomas l xanthelasma l
Xanthelasma
Atheroma - Cigarette Smoking Powerful risk factor for IHD l Risk falls after giving up l Mode of action uncertain l u coagulation system u reduced PGI 2 u increased platelet aggregation
Atheroma - Hypertension Strong link between IHD and high systolic/diastolic blood pressure l Mechanism uncertain l ? endothelial damage caused by raised pressure l
Atheroma - Diabetes Mellitus DM doubles IHD risk l Protective effect in premenopausal women lost l DM also associated with high risk of cerebrovascular and peripheral vascular disease l ? related to hyperlipidaemia and hypertension l
Atheroma - Alcohol Consumption >5 units /day associated with increased risk of IHD l Alcohol consumption often associated with other risk factors eg smoking and high BP but still an independent risk factor l Smaller amounts of alcohol may be protective l
Atheroma-Infection Chlamydia pneumoniae l Helicobacter pylori l Cytomegalovirus l
Atheroma - Other Risk Factors Lack of exercise l Obesity l Soft water l Oral contraceptives l Stress l
Atheroma - Genetic Predisposition Familial predisposition well known l Possibly due to l variations in apolipoprotein metabolism l variations in apolipoprotein receptors l
Atheroma - Pathogenesis Thrombogenic theory l Insudation theory l Monoclonal hypothesis l Reaction to injury hypothesis l
Atheroma - Thrombogenic Theory l 1852 Karl Rokitansky plaques formed by repeated thrombi l lipid derived from thrombi l overlying fibrous cap l
Atheroma - Insudation Theory l 1856 Rudolf Virchow endothelial injury l inflammation l increased permeability to lipid from plasma l
Atheroma - Reaction to Injury Hypothesis l 1972 Ross and Glomset u plaques form in response to endothelial injury u hypercholesterolaemia leads to endothelial damage in experimental animals u injury increases permeability and allows platelet adhesion u monocytes penetrate endothelium u smooth muscle cells proliferate and migrate
Atheroma - Reaction to Injury Hypothesis l 1986 Ross endothelial injury may be very subtle and be undetectable visually l LDL, especially oxidised, may damage endothelium l
Atheroma - The Monoclonal Hypothesis l Benditt and Benditt crucial role for smooth muscle proliferation l each plaque is monoclonal l might represent abnormal growth control l is each plaque a benign tumour? l could atheroma have a viral aetiology? l
Atheroma - The Processes Involved Thrombosis l Lipid accumulation l Production of intercellular matrix l Interactions between cell types l
Atheroma - The Cells Involved Endothelial cells l Platelets l Smooth muscle cells l Macrophages l Lymphocytes l Neutrophils l
Atheroma - Endothelial Cells Key role in haemostasis l Altered permeability to lipoproteins l Secretion of collagen l Stimulation of proliferation and migration of smooth muscle cells l
Atheroma - Platelets Key role in haemostasis l Stimulate proliferation and migration of smooth muscle cells (PDGF) l
Atheroma - Smooth Muscle Cells Take up LDL and other lipid to become foam cells l Synthesise collagen and proteoglycans l
Atheroma - Macrophages Oxidise LDL l Take up lipids to become foam cells l Secrete proteases which modify matrix l Stimulate proliferation and migration of smooth muscle cells l
Atheroma - Lymphocytes TNF may affect lipoprotein metabolism l Stimulate proliferation and migration of smooth muscle cells l
Atheroma - Neutrophils l Secrete proteases leading to continued local damage and inflammation
Atheroma - A Unifying Hypothesis 1 l Endothelial injury due to raised LDL l ‘toxins’ eg cigarette smoke l hypertension l haemodynamic stress l
Atheroma - A Unifying Hypothesis 2 l Endothelial injury causes platelet adhesion, PDGF release, SMC proliferation and migration l insudation of lipid, LDL oxidation, uptake of lipid by SMC and macrophages l migration of monocytes into intima l
Atheroma - A Unifying Hypothesis 3 Stimulated SMC produce matrix material l Foam cells secrete cytokines causing l further SMC stimulation l recruitment of other inflammatory cells l
Atheroma and Apolipoprotein E Genetic variations in Apo E are associated with changes in LDL levels l Polymorphisms of the genes involved lead to at least 6 Apo E phenotypes l Polymorphisms can be used as risk markers for atheroma l
Atheroma - Prevention No smoking l Reduce fat intake l Treat hypertension l Not too much alcohol l Regular exercise/weight control l l BUT some people will still develop atheroma!
Atheroma - Intervention Stop smoking l Modify diet l Treat hypertension l Treat diabetes l Lipid lowering drugs l
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