41.4 Atherosclerosis Flashcards
What is atherosclerosis?
pathological build-up of fibrofatty lesions (in form of plaques) in tunica intima of major arteries.
How does sex affect the development of atherosclerosis?
Women are less likely to develop plaques against age-matched men
UNTIL MENOPAUSE = women equally as likely to get atherosclerosis-related diseases
What is the geographical distribution of atherosclerosis?
Leading cause of morbidity and mortality in the western world
Western diet is high in fat and salt
How does age affect the incidence of atherosclerosis?
increasing risk with age (as fatty deposits continue to build up throughout life
What are the 2 major epidemiological studies on atherosclerosis?
Framingham Heart Study (1948) + MRFIT (1973)
What environmental factors can predispose an individual to atherosclerosis?
*Smoking (increases oxidative stress and cytokines)
*Obesity
*Hypertension
*Hyperlipidaemia (more LDLs compared to HDLs) from obesity, PCOS and FH
*Increased oxidised LDL
How is cholesterol/ increased LDL associated with atherosclerosis?
LDL levels in plasma + duration of exposure to vessels → associated w/ graded ↑ in risk of dev atherosclerosis.
How does hypertension predispose to atherosclerosis?
Shear stress + physical damage to endothelium from ↑ pressure flow → endothelial dysfunction
How does smoking predispose to atherosclerosis?
↑ platelet activation, inflammatory environment, ↓ bioavailability of NO → loss of protective effect (vasodilation/ anti-platelet activity/ anti-inflammatory effects).
How does diabetes predispose to atherosclerosis?
Glycation of proteins → glycated end products → associated w/ accelerated disease progression
What genetic factors can predispose an individual to atherosclerosis?
Familial Hypercholesterolaemia
Sex (endocrine - oestrogen believed to be protective)
Diabetes
What is familial hypercholesterolaemia?
*Loss of function mutations in the gene encoding the LDL receptor (LDLR) or gain of function of PCSK9.
*LDLR mediated pathways metabolise around 2/3 of LDL particles, with the majority being found on hepatocytes which endocytose, and enzymatically degrade LDLs.
*Non-functional, both LDL and IDL uptake is reduced and more IDL remains in the blood where it is converted to LDLs = more taken up by scavenger receptors on macorphages = more foam cells
(PCSK9 degrades LDLRs)
Describe the appearance and structure of a mature atheroma?
core of foam cells, lymphocytes, OxLDLs and cholesterol crystals within the tunica intima, surrounded by a cap made of collagen and fibrin
What is a fatty streak?
The initial accumulation of lipids in the tunica intima, which is taken up by macrophages that become foam cells. Most of the lipid is intracellular.
*Lesions begin as sub-endothelial fatty streak formation → LDL accumulation + oxidation.
What is the fibro-fatty plaque?
The progressed form of a fatty streak, with increased infiltration of macrophages, smooth muscle cells and T-cells. Contains a core of extracellular lipids and some connective tissue.
What is the complicated lesion?
When the atheroma ruptures, leading to surface events such as thrombosis.
What happens during initiation of an atherosclerotic plaque?
1) Endothelial dysfunction. 2) inflammation. 3) Lipid accumulation.
What does damaged/ dysfunctional endothelium lead to?
*↑ LDL permeability.
*Expresses VCAM/ secretes CKs +MCP → recruit monocytes + lymphocytes → inflammation.
What happens to the recruited monocytes in atherosclerosis initiation?
- Recruited monocytes → enter subendothelial space via diapedesis → differentiate into macrophages (under influence of M-CSF → secreted by infiltrating T-lymphocytes)
- Macrophages –take up ox-LDL via scavenger Rs→ foam cells.
Exacerbate pathogenesis (secrete free radicals → further LDL oxidation)
- Macrophages –take up ox-LDL via scavenger Rs→ foam cells.
Although macrophages are initially protective, they become damaging. How?
*exacerbate progression
*produce free radicals
*act as chemoattractant (to recruit more immune cells) → ↑ inflammatory response.
What causes the formation of OxLDLs in the subendothelial space?
Body is under oxidative stress (diabetes, ageing and cancer)
Production of reactive oxygen species (ROS) which oxidise trapped LDLs into OxLDLs
What are the consequences of OxLDL accumulation in subendothelial space?
-Increased expression of adhesion molecules on endothelial surface (I-CAM and selectins)
-Production of inflammatory cytokines (prostaglandins and chenoattractants)
-Monocyte entry into intima and differentiation into macrophages
Outline the general stages of atheroma development?
Endothelial damage
Lesion
Fatty streak formation
Intermediate lesion
Atheroma
Fibrous cap formation (plaque) = stable if thick
Advanced/vulnerable plaque
How is the fibrous cap formed over the fatty streak?
Macrophages secrete inflammatory mediators (IL-1 and TNF-alpha) which further induce the expression of adhesion molecules and produciton of PDGF and FGF.
PDGF and FGF cause poliferation and migration of smooth muscle from media to intima, where they secrete proteoglycans, fibrin and collagen which forms a fibrous cap around the fatty plaque.
What happens when macrophages infiltrate the subendothelial space? What forms as a result?
Exponetially engulf OxLDLs using scavenger receptors and OxLDL accumulates inside of them and they become foam cells which reduces their cellular function.
Macorphages die, leaving behind a nectrotic lipid core in the subendothelial (intimal) region of the artery.
What is the ‘initial’ step in the development of atherosclerosis?
Endothelial injury and LDL accumulation
LDLs are endocytosed by LDLRs on endothelial cells (clathrin mediated endocytosis) and accumulate in to the subendothelial space
Which arteries does atherosclerosis occur in?
LARGE ARTERIES:
-Carotid
-Femoral
-Coronary
What is the difference between a stable and unstable plaque?
Stable → inflammation resolves
*Outward expansion of plaque into arterial lumen → flow-limiting lesions
Unstable → remain inflamed
*Large lipid core + thin fibrous cap → prone to rupture → arterial thrombosis
What can stenosis in the coronary arteries caused by a stable plaque lead to?
stable angina pectoris (restricted flow through coronary arteries)
*↑ myocardial demand (e.g. exercise) → ischaemia
What can stenosis in the femoral arteries caused by a stable plaque lead to?
intermittent claudication (pain in calf when ↑ O2 demand)
What are the clinical manifestations of atherosclerosis?
Angina pectoris, MI, Claudication, embolism, aneurysm, ischaemic stroke.
When do complications of atherosclerosis arise?
generally arise after decades (>50 years)
How is the fibrous cap formed over the fatty streak?
Macrophages secrete inflammatory mediators (IL-1 and TNF-alpha) which further induce the expression of adhesion molecules and produciton of PDGF and FGF.
PDGF and FGF cause poliferation and migration of smooth muscle from media to intima, where they secrete proteoglycans, fibrin and collagen which forms a fibrous cap around the fatty plaque.
How does unresolved inflammation in an unstable plaque lead to fibrous cap thinning?
*T-cells secrete mediators (e.g. IFN-gamma) → impair SMC’s ability to synthesise collagen + maintain fibrous cap overlying necrotic core.
*Activated macrophages –secrete→ matrix metalloproteinases → degrade interstitial collagen.
How do T cell and macrophage entry into plaques result in their rupture?
T cells: secrete IFN-gamma which inhibits collagen synthesis
Macrophages: secrete MMPs which degrade collagen in the fibrous cap
How can atherosclerosis lead to myocardial infarction?
Thrombosis on a ruptured lesion occludes coronary blood cessels resulting in ischaemia of the heart muscle and an MI
How may atherosclerosis reult in ischaemic stroke?
Rupture causes thrombus to develop and block arteries supplying the brain, resulting in a stroke
What are aneurysms?
Dilations of blood vessels or the heart
Occur as a result of reduced elasticity if the endothelium after the development of a fibrous cap around an atherosclerotic plaque
What will cause a plaque to rupture?
Erosion
Ulceration
Increased inflammation = increased T cell and macrophage
What is angina pectoris?
chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium)
What happens to the plaque after rupture>
exposure of plaque contents to blood → thrombus formation
*Complete occlusion of BV
*Dislodge → embolus occluding smaller vessels further down arterial tree
Cause ↑ly fatal acute ischaemic events (e.g. MI/ stroke).
