Atherosclerosis Flashcards
Normal structure of arteries (general)
a) tunica intima
b) tunica media
c) tunica adventitia
a) consists of endothelial cells (flattened cells linked by tight junctions) lying on a basement membrane. Endothelial cells perform many functions including - containment of the blood, selective transport of fluids, gases, ions and proteins into tissues, control of haemostasis, and regulation of blood pressure. Endothelial cells lining healthy adult blood vessels have a long life (>5 years) and only rarely divide. However they retain the latent capacity to proliferate (angiogenesis)
b) consists of layers perforated elastic laminae with smooth muscle cells in between. The intimal side of the media is bound by the internal elastic lamina and the adventitial side by the external elastic lamina
c) consists of connective tissue, and contains fibroblasts, leukocytes (mainly macrophages) and nerves, in addition to the lymphatic and blood vessels (vasa vasorum) supplying the artery wall
Normal structure of arteries (specific)
a) large arteries
b) medium-sized and small arteries
c) what is meant by the the vessel walls as a system
a) (eg aorta, common carotid, common iliac) have prominent eleastic laminae in their media, between the internal and external elastic laminae. This leads to their classification as elastic arteries. They are exposed to high pulsatile pressures, Their elastic recoil assists the maintenance of continuous flow
b) (eg coronary arteries) classified as muscular arteries since their media is composed largely of smooth muscle cells with fewer elastic fibres. Separate internal and external elastic laminae are visible. Contraction of the smooth muscle cells in the tunica media assists in the regulation of blood pressure
c) multiple cell types in the vessel wall continually communicate to regulate one another’s fate and function, meaning that the function of the entire vessel wall is more than the sum of its parts
Normal structure of arteries (specific)
a) large arteries
b) medium-sized and small arteries
c) what is meant by the the vessel walls as a system
a) (eg aorta, common carotid, common iliac) have prominent eleastic laminae in their media, between the internal and external elastic laminae. This leads to their classification as elastic arteries. They are exposed to high pulsatile pressures, Their elastic recoil assists the maintenance of continuous flow
b) (eg coronary arteries) classified as muscular arteries since their media is composed largely of smooth muscle cells with fewer elastic fibres. Separate internal and external elastic laminae are visible. Contraction of the smooth muscle cells in the tunica media assists in the regulation of blood pressure
c) multiple cell types in the vessel wall continually communicate to regulate one another’s fate and function, meaning that the function of the entire vessel wall is more than the sum of its parts
Normal structure of arteries (specific)
a) large arteries
b) medium-sized and small arteries
c) what is meant by the the vessel walls as a system
a) (eg aorta, common carotid, common iliac) have prominent eleastic laminae in their media, between the internal and external elastic laminae. This leads to their classification as elastic arteries. They are exposed to high pulsatile pressures, Their elastic recoil assists the maintenance of continuous flow
b) (eg coronary arteries) classified as muscular arteries since their media is composed largely of smooth muscle cells with fewer elastic fibres. Separate internal and external elastic laminae are visible. Contraction of the smooth muscle cells in the tunica media assists in the regulation of blood pressure
c) multiple cell types in the vessel wall continually communicate to regulate one another’s fate and function, meaning that the function of the entire vessel wall is more than the sum of its parts
Normal structure of arteries (specific)
a) large arteries
b) medium-sized and small arteries
c) what is meant by the the vessel walls as a system
a) (eg aorta, common carotid, common iliac) have prominent eleastic laminae in their media, between the internal and external elastic laminae. This leads to their classification as elastic arteries. They are exposed to high pulsatile pressures, Their elastic recoil assists the maintenance of continuous flow
b) (eg coronary arteries) classified as muscular arteries since their media is composed largely of smooth muscle cells with fewer elastic fibres. Separate internal and external elastic laminae are visible. Contraction of the smooth muscle cells in the tunica media assists in the regulation of blood pressure
c) multiple cell types in the vessel wall continually communicate to regulate one another’s fate and function, meaning that the function of the entire vessel wall is more than the sum of its parts
Normal structure of arteries (specific)
a) large arteries
b) medium-sized and small arteries
c) what is meant by the the vessel walls as a system
a) (eg aorta, common carotid, common iliac) have prominent eleastic laminae in their media, between the internal and external elastic laminae. This leads to their classification as elastic arteries. They are exposed to high pulsatile pressures, Their elastic recoil assists the maintenance of continuous flow
b) (eg coronary arteries) classified as muscular arteries since their media is composed largely of smooth muscle cells with fewer elastic fibres. Separate internal and external elastic laminae are visible. Contraction of the smooth muscle cells in the tunica media assists in the regulation of blood pressure
c) multiple cell types in the vessel wall continually communicate to regulate one another’s fate and function, meaning that the function of the entire vessel wall is more than the sum of its parts
a) define atherosclerosis
b) define arteriosclerosis
c) acquired positive risk factors for atherosclerosis
d) constitutive positive risk factors for atherosclerosis
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a) disease of the intima of large and medium sized arteries. Lesions are focal thickenings of the intima called plaques, which are deposits of fibrous tissue, lipids and cells
b) not the same as atherosclerosis. Implies loss of elasticity and physical hardening of the arterial wall from any cause
c) i) dyslipidaemia ii) cigarette smoking iii) hypertension (both systolic and diastolic pressures important iv) diabetes mellitus (via dyslipidaemia, elevated PAI-1 and other factors)
d) i) genetics (a positive family history is a strong predictor of atherosclerotic disease. Inheritance is usually polygenic, involving genes affecting factors related to atherogenesis like blood pressure, blood glucose regulation, inflammatory response. Some single gene disorders also increase risk, eg mutations of the LDL receptor in familial hypercholesterolaemia) ii) advancing age iii) male gender (pre-menopausal females are protected, possibly by oestrogens)
Lipoproteins in atherosclerosis
a) what are lipoproteins
b) Two types (which is a positive risk factor for atherosclerosis)
c) How do LDLs transfer the lipids they carry
d) define dyslipoproteinaemia
e) what types of dysliportoeinaemia increase the risk of atherosclerosis
a) Consist of a lipid core (triglycerides, cholesterol, cholesterol esters, phospholipids) surrounded by apoliproteins. Carry hydrophobic lipids in the aqueous environment of the plasma and are powerful risk moderators for atherosclerosis
b) Low density lipoproteins (LDL) - deliver cholesterol to peripheral tissues
High-density lipoproteins (HDL) - transport cholesterol from peripheral tissues to the liver for excretion in the bile
c) Using two receptor systems. i) the native LDL receptor pathway, which is responsible for cholesterol breakdown. Under-activity of this pathway leads to hypercholesterolaemia. ii) the scavenger receptor pathway, used by macrophages to take up lipoproteins that have been modified (oxidised). The pathway leads to uncontrolled accumulation of cholesterol, after which the macrophages are known as foam cells
d) Abnormality in the constitution/concentration of lipoproteins in the blood. May be inherited (familial hypercholesterolaemia) or secondary to other diseases (diabetes mellitus)
e) Increased levels of cholesterol, low density lipoproteins or lipoprotein α. Decreased levels of high density lipoproteins
Lipoproteins in atherosclerosis
a) What are high levels of blood cholesterol linked to
b) What are high levels of blood HDL linked to
c) What is obesity linked to
a) Diets high in cholesterol, saturated fats, trans-fats
b) Exercise, modest alcohol consumption (2 units/day)
c) Lower levels of HDL, increases levels of triglycerides, hypertension and diabetes mellitus
Pathogenesis of atherosclerosis (atherogenesis)
a) overview of what occurs in atherogenesis
b) Changes in vessel walls - endothelial cell injury and dysfunction
a) cellular components of the vessel wall system are disrupted in a prolongued response to injury of endothelial cells. This leads to a chronic inflammatory process
b) Key initiator to atherosclerosis. Endothelial injury leads to altered endothelial cell gene expression, which produces multiple dysfunctional changes in the intima
Cause of injury - i) change in haemodynamic forces (hypertension, branch points, posterior abnormal aorta) ii) chemical injury (cigarette smoke, oxidised lipoproteins) iii) pro-inflammatory cytokines (IL-1, TNFα)
How injury casues dysfunction - i) Increased permeability (so lipid infiltration) ii) Increased adhesion molecule expression (P- and E-selectin, VCAM1, ICAM1) iii) Increased expression of inflammatory mediators (cytokines, eicosanoids) iv) Increased macrophage and T cell entry v) Increased thrombosis
Pathogensis of atherosclerosis (atherogenesis)
a) overview of monocyte migration into the plaque and maturation into macrophages
b) pathway of activation and effects activation has
c) smooth muscle cell activation
a) circulating monocytes (recruited by chemotatic factors) adhere to endothelial cells and enter the lesion, where they mature into macrophages. In the lesion the macrophages phagocytose oxidised lipoproteins to become foam cells. Macrophage activation induces mulitple changes that contribute to atherogenesis
b) see image
c) Macrophages, platelets and endothelial cells produce growth factors (PDGF, FGF) and reactive oxugen intermediates that activate smooth muscle cells. Once activated, the smooth muscle cells proliferate, migrate into the intima, change from a contractile phenotype to a synthetic phenotype. They secrete ECM and release enzymes that assist matrix remodelling (like collagenase)
Pathogenesis of atherosclerosis (atherogenesis)
a) lipoprotein infiltration (support for how we know the importance of oxidised lipoproteins in atherosclerosis
b) T-lymphocyte migration into the plaque
c) Platelet adherence
a) Lipoproteins, especially LDL, become modified (oxidised) in plaques by reactive oxygen species and enzymes released by macrophages, endothelial cells and platelets.
Oxidised lipoproteins: i) are chemoattractant for monocytes ii) are phagocytosed by macrophages, which become foam cells iii) induce dysfunction/apoptosis in smooth muscle, macrophages and endothelium iv) stimulate release of cytokines and growth factors from smooth muscle, macrophages and endothelium v) may be immunogenic vi) inhibit plasminogen activation
In support of the importance of oxidised lipoproteins in atherosclerosis, cholesterol-lowering drugs (statins, which reduce liver synthesis of cholesterol) decrease the frequency of coronary artery atherosclerosis
b) T-lymphocytes may recognise antigens (eg oxidised lipoproteins) and subsequently activate immune responses and cytotoxic killing of cells in the plaque
c) In early lesions, there is evidence that platelets adhere transiently to the injured or dysfunctional endothelial cells and release platelet-derived growth factor (PDGF), which can activate smooth muscle.
In advanced lesions, platelets are also involved in thrombosis secondary to plaque ulceration or rupture
Spectrum of intimal lesions (and severity)
a) Isolated monocytes/macrophages
b) Fatty streaks or fatty dots
c) Fibro-fatty atherosclerotic plaques
d) Complicated plaques
a) Can be found in the intima soon after birth. (not very severe)
b) By second decade of life these lesions can be found throughout the vascular tree, especially at branch points. Macroscopically they are pale yellow streaks or dot. Microscopically they are clusters of lipid-laden smooth muscle cells and macrophages, foam cells. (Cause no significant pathological effects themselves, controversial if they relate to atherosclerosis)
c) Principally seen in abdominal aorta, coronary arteries, circle of Willis in the braina nd arterial branch points. Often appear in 30s/40s in men, later in women. Macroscopically they are raised white/yellow plaques that may coalesce. Microscopically, the media may appear thinned, atrophic. In the intima there are three regions: i) fibrous cap - on extreme intimal surface of the plaque, composed of collagen, smooth muscle cells, macrophages and T-lymphocytes ii) lipid core - contains foam cells, and in more advanced lesions necrotic debris and extracellular lipid, especially cholesterol iii) the shoulder of the cap - contains foam cells, smooth muscle cells, T-lymphocytes and new blood vessels, angiogenesis (moderately severe)
d) Plaques may become calcified. Plaques may expand due to haemorrhage of new vessels. Plaques may ulcerate/rupture, partially if they are rich in leukocytes or show haemorrhage. May lead to thrombisis and embolisation of plaque fragments. An aneurysm is localised abnormal dilatation of an artery or cardiac chamber. Atherosclerosis causes an increased diffusion distance between the arterial lumen and the arterial wall, leading to thinning of the media and fragmentation of the elastic laminae (very severe)
Consequences of atherosclerosis (+ clinical sequels to atherosclerosis)
Atherosclerosis and its complications account to ~50% deaths in western world. Usually clinically silent until it reaches the stage when it causes symptoms and signs. Often symptoms appear suddenly due to rupture, haemorrhage or thrombosis. In smaller arteries, atherosclerosis causes gradual narrowing of the lumen (stenosis) or occlusion due to plaque progression, hamorrhage, rupture or thrombosis. In larger arteries embolisation of the thrombus formed on the plaque and aneurysm formation are common consequences of atheroma.
Clinical sequels - i) ischaemic heart disease, leading to angina, myocardial infarction and heart failure ii) peripheral vascular disease, leading to gangrene iii) cerebrovascular disease, leading to cerebral infarction/stroke
