Atherosclerosis Flashcards
Atherosclerosis risk factors
Smoking
HTN
diabetes
Hyperlipidaemia
Where does atherosclerosis occur more frequently?
Birfucation/bends in blood vessels
Turbulent flow -> damage
What mechanism underpins atherosclerosis
Inflammation of macrophages
(can be due to lipid accumulation)
What is oxidised LDL?
Physically modified LDL which are highly inflammatory
What does oxidised LDL bind to
Scavenger receptors on macrophages
Allow removal of cholesterol by HDL
What is secreted by overactive macrophages (due to lipid accumulation)
ROS- O2 free radicals
Cytokines
Chemokines
MMP - enzymes that breakdown tissue
Apoptotic factors - kill host cells (can form an abscess)
Growth factors - trigger formation of scar tissue
What are the two inflammatory factors that macrophages release, and what do they do?
Cytokines (promotes endothelial adhesion of inflammatory cells)
Chemokines (attract monocytes)
What is the purpose of growth factors release?
Wound healing
What are the functions of metalloproteinases?
Breakdown collagen and fibrous gap by activating proteolysis, can lead to plaque rupture
What is released upon the death of overactive macrophages
Tissue factor (clotting factor)
OxyLipids - toxic and can trigger clotting in bloodstream
What is the fatberg model of atherosclerosis
Fat buildup in the artery walls -> atherosclerosis
What is the inflammatory model of atherosclerosis
(Virchow’s)
Chronic inflammation due increase in blood lipids -> atherosclerosis
What are the oxidative enzymes that macrophage release?
NADPH Oxidase - forms superoxide O2-, also H2O2 which kills off melanocytes
Inducible nitric oxide synthase (iNOS) - prod ^ conc of NO which can bind and destroy proteins
Myeloperoxidase - forms HOCl (beach), HONOO (Peroxynitrite which releases NO)
How do transcription factors affect contribute to atherosclerosis
Turned on by LDL/OxLDL -> macrophage activation
What is an endothelial erosion lesion
Selective death of endothelial cells -> Thrombosis (typically non-occlusive)
Related to diabetes as opposed to lipids
Can cause N-STEMI
Lower raters of hyperlipidaemia/hypertension
Greater rates of obesity w
What is the main transcription factor that regulates inflammation?
Nuclear Factor Kappa B (all receptors report here, which in turns activates upregulation of MMPs/IL-1 etc.)
What are modifiable risk factors for coronary heart disease?
Smoking, Lipids, Blood Pressure, Diabetes, Obesity, Sedentary Lifestyle
What are non-modifiable risk factors for coronary heart disease?
Age, Sex, Genetic Predisposition
What are the two types of macrophages?
Inflammatory and Non-inflammatory
Macrophage functions?
Inflammatory - kill microorganisms
Non-Inflammatory - homeostasis like alveolar surfactant
What is LDL and what does it do?
Low Density Lipoprotein - carries cholesterol from liver to rest of the body
Explain the J curve
LDL cholesterol isn’t inherently bad, a small amount is necessary for normal function
High cholesterol levels = highest risk of CVD
Very low cholesterol levels > risk than moderate levels
What is HDL and what does it do?
High Density Lipoprotein - carries cholesterol from peripheral tissues back to liver
Reverse cholesterol transport
What are the functions of apoproteins?
Proteins on surface of LDL - dock molecule to the sites of delivery
bind lipids
How can subendothelial LDL lead to inflammation?
LDLs leak through endothelial barrier
Become oxidised
Phagocytosed by macrophages -> foam cells (fatty macrophage)
Chronic inflamm
What is a genetic disease that causes high cholesterol?
Familial Hyperlipidaemia - failure to clear LDL from blood
What are the signs of familial hyperlipidaemia?
Xanthomas (fat bumps in skin), Early Atherosclerosis
What is an enzyme involved in cholesterol production?
HMG-CoA-Reductase (targeted by statins)
Mechanism of Cholesterol export pumps
ABCA1, ABCG1
Identify apolipoprotein A on HDL
Export cholesterol to ApoAHDL for removal from tissues
What are the two macrophage scavenger receptors?
MSR A (CD204) // MCR B (CD36)
What does MSR A bind to?
gram positive bacteria,
oxidised LDL,
dead cells
What does MSR B bind to?
malaria parasites,
oxidised LDL,
dead cells
What are the homeostatic roles of macrophage scavenger receptors
Safe clearance of OxLDL
Reverse cholesterol transport
What is the main cytokine underpinning atherosclerosis
IL-1
triggers NFKb, cell death, prolif
What is the main chemokine underpinning atherosclerosis
Monocyte chemotactic protein-1 (MCP-1) which binds CCR2
What growth factors do macrophages release?
Platelet Derived Growth Factors
Transforming Growth Factor Beta
Role of Platelet Derived Growth Factors
PDGF
vascular smooth muscle cell chemotaxis/survival/mitosis
Role of Transforming Growth Factor Beta
TGFb
^ collagen synthesis
matrix deposition
Components of Virchow’s triad
Underpins thrombosis
1. Abnormal blood flow - stenosis
2. Abnormal blood - ^clotting factor
3. Abnormal vessel wall - exposed collagen due to plaque, and damage
Aspirin mechanism of action
- antiplatelet
Irreversibly blocks COX
.: platelets cannot make thromboxane A2 and aggregation is inhibited
Clopidogrel mechanism of action
Irreversibly blocks ADP receptor on platelets
Endothelial cells use of COX
Can make the prostacyclin PG12 which inhibits platelet aggregation
How do thrombolytic agents work
E.g. Tissue Plasminogen activator/Strepokinase
Breakdown of plasminogen -> plasmin
activated plasmin can breakdown fibrin mesh
Thrombosis signs and symptoms
Tissue necrosis
LOF on one side (Maj. ischaemic stroke)
Heart attack - severe chest pain w/ nausea
What is contained within ruptured plaques
lots of activated macrophages with xs lipid
