Atherosclerosis : Pathophysiology of Atheroma Flashcards
<p>What is the definition of atheroma/atherosclerosis?</p>
<p>•Formation of focal elevated lesions (plaques) in intima of large and medium-sized arteries</p>
<p>What are potential outcomes of atheroma?</p>
<p>Ischaemia in coronary arteries - atheromatous plaques narrowing lumen</p>
<p>Angina due to myocardial ischaemia</p>
<p>Complicated thromboembolism</p>
<p>What is arteriosclerosis?</p>
<p><strong>Stiffening or hardening or the arterial walls</strong> which features smooth muscle hypertrophy, apparent reduplication of internal elastic laminae and intimal fibrosis leading to a decrease in vessel diameter.</p>
<p>When is the difference between arteriosclerosis and atherosclerosis?</p>
<p>Atherosclerosis is a type of arteriosclerosis</p>
<p>When are the effects of arteriosclerosis most apparent?</p>
<p>When the CVS is further stressed by haemorrhage, major surgery , infection or shock</p>
<p>Who commonly suffers from arteriosclerosis?</p>
<p>Elderly</p>
<p>What is the earliest significant lesionof atheroma?</p>
<p>Fatty streak</p>
<p>What makes up the yellow linear elevation of intimal lining?</p>
<p>Comprises masses of lipid - laden macrophages</p>
<p>Who often gets early atheromatous plaques?</p>
<p>Young adults onwards - fatty streaks are present in children although they may disappear</p>
<p>What does early atheromatous plaque progress to?</p>
<p>Established plaques</p>
<p>What are the structural features of a fully developed atheromatous plaque?</p>
<p>Central lipid core with fibrous tissue cap - covered by arterial endothelium</p>
<p></p>
<p>What is responsible for the collagen production in the cap?</p>
<p>Smooth muscle cells</p>
<p>What is the function of the fibrous cap that sits on the central lipid core?</p>
<p>Provides structural strength</p>
<p>What resides in the fibrous cap?</p>
<p>Inflammatory cells - macrophages, T lymphocytes and mast cells - recruited from the arterial endothelium</p>
<p>What is contained within the central lipid core?</p>
<p>Cellular lipids/debris derived from macrophageswhich have died in the plaque</p>
<p>Often a rim of foamy thrombogenic macrophages</p>
<p>Why are some macrophages described as foamy?</p>
<p>Due to the uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor</p>
<p>What marker in angiograms forms in late plaque development?</p>
<p>Dystrophic calcification</p>
<p>What is dystrophic calcification?</p>
<p>Dystrophic calcification(DC) is thecalcification occurring in degenerated or necrotic tissue</p>
<p>Where does atheroma normally occur?</p>
<p>•Form at arterial branching points/bifurcations (turbulent flow)</p>
<p>What is meant by a complicated atheroma?</p>
<p>Haemorrage into plaque causing plague rupture and potential thrombosis</p>
<p>Define haemorrhage</p>
<p>an escape of blood from a ruptured blood vessel.</p>
<p>What is the most important risk factor for atheroma?</p>
<p>Hypercholesterolaemia</p>
<p>How may increased LDL cholesterol levels arise?</p>
<p>•lack of cell membrane receptors for LDL</p>
<p>What are signs of major lipidaemia?</p>
<p>Familial</p>
<p>Biochemical evidence (•LDL, HDL, total cholesterol, triglycerides)</p>
<p>•Corneal arcus (premature)</p>
<p>•Tendon xanthomata (knuckles, Achilles)</p>
<p>•Xanthelasmata – fatty lumps on the eyelid</p>
<p>What are the risk factors for atheroma?</p>
<p>•Smoking</p>
<p>•Hypertension</p>
<p>•Diabetes mellitus</p>
<p>•Male</p>
<p>•Elderly</p>
<p>•Accelerate process of plaque formation driven by lipids</p>
<p>What are the less strong risk factors?</p>
<p>•Obesity</p>
<p>•Sedentary lifestyle</p>
<p>•Low socio-economic status</p>
<p>•Low birthweight</p>
<p>•?role of micro-organisms</p>
<p>What is the two step development process of athermoatous plaques?</p>
<p>•1. injury to endothelial lining of artery</p>
<p>•2. chronic inflammatory and healing response of vascular wall to agent causing injury</p>
<p>•Chronic/episodic exposure of arterial wall to these processes → formation of atheromatous plaques</p>
<p>What is the step by step process of development of atheromatous plaques?</p>
<p>Endothelial injury</p>
<p>LDL accumulation in vessel wall</p>
<p>Monocyte adhesion to endothelium</p>
<p>Migration of monocytes to intima and transformation into foamy macrophages</p>
<p>Platelet adhesion</p>
<p>Activated platelets release factors causing macrophage recruitment to smooth muscle cell</p>
<p>Smooth muscle cell proliferation - extracellular matrix production and T-cell recruitment</p>
<p>Lipid accumulation (extracellular and in foamy macrophages)</p>
<p>What are the possible causes of atheromatous plaques?</p>
<p>•haemodynamic disturbances (turbulent flow)</p>
<p>•hypercholesterolaemia</p>
<p> (chronic hypercholesterolaemia increases production of reactive oxygen species)</p>
<p> (lipoproteins aggregate in intima and are modified by free radicals produced by inflammatory cells → modified LDL is gathered by macrophages but not completely degraded forming foamy macrophages → partly broken down LDL is toxic to endothelial cells plus release of growth factors, cytokines</p>
<p>How are injured endothelial cells functionally altered?</p>
<p>Enhanced expression of cell adhesion molecules•(ICAM-1, E-selectin)</p>
<p>•High permeability for LDL – normally LDL wouldn’t be able to cross the barrier</p>
<p>Increased thrombogenicity</p>
<p></p>
<p>How do lipid laden macrophages die?</p>
<p>Through apoptosis - lipid into lipid core</p>
<p>What is the effect of PDGF? (Platelet derived growth factor)</p>
<p>Results in proliferation of intimal smooth muscle cells and subsequent synthesis of collagen, elastin and mucopolysaccharide</p>
<p>Where are growth factors secreted?</p>
<p>Platelets, injured endothelium, macrophages and smooth muscle cells</p>
<p>Where do microthrombi form?</p>
<p>Denuded area of the plaque surface</p>
<p>How are microthrombi organised?</p>
<p>•By same repair process (smooth muscle cell invasion and collagen deposition) - repeated cycles eventually increase plaque volume</p>
<p>What is normally the level of occlusion resulting in•reversible tissue ischaemia</p>
<p>Stenosis of > 50-75% of vessel lumen → critical reduction of blood flow in distal arterial bed</p>
<p>What causes stable angina?</p>
<p>stenosed atheromatous coronary artery</p>
<p>What causes ischaemic pain at rest?</p>
<p>Very severe stenosis - unstable angina</p>
<p>What causes intermittant claudication?</p>
<p>ileal, femoral, popliteal artery stenosis</p>
<p>What is the effect ofLongstanding tissue ischaemia?</p>
<p>•atrophy of affected organ e.g. atherosclerotic renal artery stenosis → renal atrophy</p>
<p>What are the immediate events following the rupture of a plaque?</p>
<p>•exposes highly thrombogenic plaque contents (collagen, lipid, debris) to blood stream → activation of coagulation cascade and thrombotic occlusion in very short time</p>
<p>What is the effect of total occlusion?</p>
<p>Irreversible ischaemia - necrosis (infarction of tissues)</p>
<p>•E.g. myocardial infarct (coronary artery)</p>
<p>•E.g. stroke (carotid, cerebral artery)</p>
<p>•E.g. lower limb gangrene (ileal, femoral, popliteal artery)</p>
<p>Where do detatchments of small thrombus fragments from thrombosed atheromatous arteries embolise?</p>
<p>Distal to the ruptured plaque</p>
<p>What is the result of emolic occlusion of small vessels?</p>
<p>•small infarcts in organs</p>
<p>•E.g. heart, dangerous small foci of necrosis → life-threatening arrhythmias</p>
<p>•E.g. large ulcerating aortic plaques, lipid rich fragments of plaque → cholesterol emboli in kidney, leg, skin</p>
<p>•E.g. carotid artery atheromatous debris, common cause stroke (cerebral infarct/TIA)</p>
<p>What causes an atheromatous abdominal aortic aneurysm?</p>
<p>Weakened media beneath atheromatous plaques - causing the gradual dilation of the vessel</p>
<p>What is the result of a ruptured abdominal aortic annyeurism?</p>
<p>•massive retroperitoneal haemorrhage (high mortality)</p>
<p>•Aneurysms > 5cm diameter at high risk of rupture</p>
<p>•Mural thrombus → emboli to legs</p>
<p>Define mural thrombus</p>
<p>A thrombus in a large blood vessel that decreases blood flow through that vessel</p>
<p>What plaques have a high risk of developing thrombitic complications?</p>
<p>•Typically thin fibrous cap, large lipid core, prominent inflammation</p>
<p>What is the effect of pronounced inflammatory activity?</p>
<p>Degradation and weakening of plaque</p>
<p>Increased risk of rupture</p>
<p>What do inflammatory cells release that increase the risk of rupture and cause degradation?</p>
<p>Secretion of proteolytic enzymes, cytokines and reactive oxygen species</p>
<p>Which plaques are less likely to rupture?</p>
<p>Highly stenotic plaques with large fibrocalcific component, little inflammation</p>
<p>What are the preventative and therapeutic options?</p>
<p>•Stop smoking</p>
<p>•Control blood pressure</p>
<p>•Weight-loss</p>
<p>•Regular exercise</p>
<p>•Dietary modifications</p>
<p></p>
<p>•Secondary prevention:</p>
<p>•Cholesterol lowering drugs, aspirin (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques)</p>
<p>•</p>
<p>•Surgical options</p>
