🫀🫁Cardio & Resp🫀🫁 - Atherosclerosis & Peripheral Vascular Disease Flashcards
What are the modifiable risk factors for atherosclerosis and coronary heart disease?
Smoking
Lipid intake
Blood pressure
Diabetes
Obesity
Sedentary lifestyle
What are the non-modifiable risk factors?
Age
Sex
Genetic background
How do risk factors interact when it comes to cardiovascular diseases?
Risk factor multiplication
How has the epidemiology of the risk factors for atherosclerosis and peripheral vascular disease changed over the last decade?
How was it proved that atherosclerosis has an inflammatory basis?
CANTOS trial
Patients at high risk of atherosclerosis complications injected with antibodies to Interleukin -1 (IL-1)
Fewer major adverse cardiovascular events (MACE) mostly stroke and heart attacks in treated patients
Multiple mechanisms including cholesterol crystal formation connect lipids and inflammation in atherosclerosis
What are the main cell types involved in atherosclerosis?
Vascular endothelial cells
Platelets
Monocyte-macrophages
Vascular smooth muscle cells
T lymphocytes
What is the involvement of vascular endothelial cells in atherosclerosis?
Barrier function
Leukocyte recruitment
What is the involvement of platelets in atherosclerosis?
Thrombus generation
Cytokine and growth factor release
What is the involvement of Monocyte-macrophages in atherosclerosis?
Foam cell formation
Cytokine and growth factor release
Major source of free radicals
Metalloproteinases
What is the involvement of vascular smooth muscle cells in atherosclerosis?
Migration and proliferation
Collagen synthesis
Remodelling and fibrous cap formation
What is the involvement of T lymphocytes in atherosclerosis?
Macrophage activation – CD4 Th1
Macrophage de-activation – CD4 Treg
Vascular smooth muscle cell death – CD8 CTL
B-cell / Antibody help – CD4 Th2
What are the main inflammatory cells in atherosclerosis?
Macrophages - derived from blood monocytes
What is LDL?
“Bad cholesterol”
Synthesised in liver
Carries cholesterol from liver to rest of the body including arteries
High levels associated with health issues
What is HDL?
“Good cholesterol”
Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
How happens to LDL in the pathogenesis of atherosclerosis?
Modification of subendothelial trapped LDL
LDLs leak through the endothelial barrier –likely due to endothelial activation in areas of vortex blood flow
LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification
What are oxidised and modified LDLs?
Chemical and physical modifications of LDL by free radicals, enzymes, aggregation
Families of highly inflammatory and toxic forms of LDL found in vessel walls
How are LDLs modified?
Best studied modification is oxidation – free radical attack from activated macrophages
LDL becomes oxidatively modified by free radicals. Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation
What is familial hyperlipidemia?
Autosomal genetic disease (main form dominant with gene dosage)
Massively elevated cholesterol (>~20 mmol/L). (effective ‘normal’ ~1-5 mmol/L)
Failure to clear LDL from blood.
Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20
How is cholesterol synthesis regulated?
Negatively regulated by cellular cholesterol
What family of drugs are HMG-CoA reductase inhibitors and what is their effect?
“statins”
Lower plasma cholesterol
What is the role of PCSK9?
LDLs enter a cell through the LDL receptor (LDLR)
PCSK9 degrades LDLRs, therefore stopping cholesterol from entering cells (i.e. keeping cholesterol in the blood plasma)
PCSK9 inhibitors used to supplement statins, allowing cells to uptake as much cholesterol as possible
LDLR removes cholesterol from blood and allows it to suppress cholesterol biosynthesis
PCSK9-deficient humans are protected from cardiovascular disease
What is reverse cholesterol transport?
Transport of cholesterol from cells to the liver for excretion - prevents cholesterol build up and atherosclerosis
How does cholesterol leave cells in reverse cholesterol transport?
Leaves via cholesterol export pumps ABCA1 and ABCG1
What happens to cholesterol after ABCA1 and ABCG1?
Apolipoprotein A (ApoA) found on HDL particles
ABCA1 and ABCG1 are selective for ApoA, which means they specifically interact with HDL particles
Cholesterol from the cell binds to HDL via ApoA, facilitated by ABCA1 and ABCG1 transporters
What happens to cholesterol in the artery walls once it has bound to HDL?
It is returned to the liver - undergoes excretion
Outline macrophage scavenger receptor A
Known as CD204
Binds to oxidised LDL
Binds to Gram-positive bacteria like Staphylococci & Streptococci
Binds to dead cells
Activation of ‘bug-detector’ pathways - leads to inflammation
What are the 2 possible fates of oxidised LDL?
Binds to either macrophage scavenger receptor A or B
Stimulates either the A pathway or B pathway
Outline macrophage scavenger receptor B
Known as CD36
Binds to oxidised LDL
Binds to malaria parasites
Binds to dead cells
Safe clearance - reverse cholesterol transport
Homeostasis
What happens to phagocytes that phagocytose oxidised/modified lipoproteins?
They become foam cells
What are foam cells?
Lipid-filled macrophages
Release pro-inflammatory substances
What do foam cells release?
Free radicals
Reactive oxygen species
Cytokines
Chemokines
What is the effect of free radicals?
Further oxidisation of lipoproteins
Outline the cytokines produced in the pathogenesis of atherosclerosis
Cytokines – protein immune hormones that activate endothelial cell adhesion molecules
IL-1 - triggers intracellular cholesterol crystals and NFkB. Coordinates multiple processes including cell death and cell proliferation; and elevated CRP
(Atherosclerosis is reduced in mice without IL-1 and humans with anti-IL-1 antibodies)
Outline the chemokines produced in the pathogenesis of atherosclerosis
Chemokines - small proteins chemoattractant to monocytes
Monocyte chemotactic protein-1 (MCP-1)
MCP-1 binds to a monocyte G-protein coupled receptor CCR2
(Atherosclerosis is reduced in MCP-1 or CCR2 deficient mice)
What is the role of macrophages in atherosclerosis (specifically plaque formation)?
“Wound healing”
Macrophages release growth factors to recruit VSMCs
This stimulates VSMCs to migrate, survive, proliferate, and deposit extracellular matrix (e.g., collagen), mimicking a wound healing process within the vessel wall
Which 2 growth factors do macrophages release that contribute to plaque formation?
Platelet derived growth factor
Transforming growth factor beta
What is the role of platelet derived growth factor?
VSMC chemotaxis
VSMC survival
VSMC division (mitosis)
i.e. Encourages VSMCs to:
Migrate to the lesion site
Survive in the atherosclerotic environment
Proliferate (divide) and contribute to plaque formation
What is the role of transforming growth factor beta?
Increased collagen synthesis
Matrix deposition
Strengthens the plaque structure but also increases rigidity
What is expressed by macrophages and endothelial cells (among others) that directly degrades tissue?
Metalloproteinases (MMPs)
What are metalloproteinases (MMPs)
Family of ~28 homologous enzymes
Activate each other by proteolysis
Degrade collagen
(Catalytic mechanism based on Zn)
What is the effect of MMPs?
Degradation of collagen
Tissue degradation
Weakens plaque, increased risk of rupture and possible thrombosis
What occurs upon foam cell death?
Release and subsequent accumulation of tissue factor and toxic oxidised-lipids
Briefly outline the atherosclerotic cycle
What are the characteristic of a vulnerable (to rupture) plaque?
Large, soft, eccentric lipid-rich necrotic core
Increased VSMC apoptosis
Reduced VSMC and collagen content
Thin fibrous cap
Infiltrate of activated
macrophages expressing MMPs
What are the signs/symptoms of atherosclerosis (specifically ruptured plaque leading to thrombosis)
Death of downstream tissues (heart and brain most significant)
Loss of function of one side of the body (major ischemic stroke)
Severe central crushing chest pain with fear, dizziness and nausea (myocardial infarction ‘heart attack)
Angina
Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood - subsequent effects
What is nuclear factor kappa B (NFkB) and what is its role in atherosclerosis?
A transcription factor that plays a critical role in the inflammatory response involved in atherosclerosis
A “Master regulator” of inflammation; predominant non-redundant highly connected network hub
Activated by numerous inflammatory stimuli
-Scavenger receptors
-Toll-like receptors
-Cytokine receptors e.g. IL-1
Switches on numerous inflammatory genes
-Matrix metalloproteinases
-Inducible nitric oxide synthase
-Interleukin-1
