Atherosclerosis: Pathology, Diagnosis & Treatment Flashcards
Outline the epidemiology of atherosclerosis related diseases (3).
- Increase from a minor in world disease in 1990 to 32% of global deaths in 2020
- Developing world approaching developed world for control of infections and for diet and lifestyle
- Increasing levels of obesity and diabetes globally
Increase from a minor in world disease in 1990 to 32% of global deaths in 2020
* Reduced hyperlipidaemia (statin treatment)
* Reduced hypertension (antihypertensive treatment)
* Increased obesity -> Increased diabetes
* New improvements in diabetes treatment have doubtful effect on macrovascular disease
* Changing pathology of coronary thrombosis possibly related to altered risk factors
What are the risk factors of atherosclerosis divided into?
- Modifiable Factors
- Non-modifiable Factors
What are the modifiable risk factors of atherosclerosis divided into (6)?
- Smoking
- Lipids Intake
- Blood Pressure
- Diabetes
- Obesity
- Sedentary Lifestyle
What are the non-modifiable risk factors of atherosclerosis divided into (3)?
- Age
- Sex
- Genetic background
Outline the pathogenesis of atherosclerosis (6).
- Adaptive thickening of smooth muscle at lesion-prone location in an artery
- Type II lesion: Inflammation of the endothelium attracts macrophages to migrate there
- Type III lesion (Preatheroma): Small pools of extracellular lipids form
- Type IV lesion (Atheroma): The pools of lipids fuse to form a core of extracellular lipid
- Type V lesion (Fibroatheroma): Fibrous thickening of the core of extracellular lipid
- Type VI lesion (Complicated lesion): Part of the fibrous extracellular lipid breaks of to form a thrombosis
What cells are involved in the pathogenesis of atherosclerosis (5)?
Vascular endothelium cells:
* Barrier function (e.g. to lipoproteins)
* Leukocyte recruitment
Platelets:
* Thrombus generation
* Cytokine and growth factor release
T-lymphocytes:
* Macrophage activation
Vascular smooth muscle cells (SMC):
* Migration and proliferation
* Collagen synthesis
* Remodelling and fibrous cap formation
Macrophages:
* Foam cell formation
* Metalloproteinases
* Cytokine & growth factor release
* Major source of free radicals
Main classes of macrophages:
* Inflammatory macrophages:
* Adapeted to kill microorganisms
* Resident macrophages:
* Normally homeostatic - supress inflammatory activity
* Alveolar resident macrophages - surfactant lipid homeostasis
* Osteoclasts - calcium & phosphate homeostasis
* Spleen - iron homeostasis
What is the role of leukocyte recruitment in the pathogenesis of atherosclerosis (3 steps)?
- Leukocytes adhere to activated (damaged) vascular endothelium of large arteries & get stuck in the subendothelial space
- Monocytes migrate into the subendothelial space
- Monocytes differentiate into macrophages and then become foam cells
-
Normally (non-atherosclerotic): Recruitment and adhesion of leukocytes to the endothelium of post-capillary venules & transmigrate into tissues during inflammation
- Post capillary venule: Structure similar to capillaries but more pericytes
What is the role of permeability in the pathogenesis of atherosclerosis?
- Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space
- Normally (non-atherosclerotic): Endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
At which point of the arterial system do plaques develop and what is the role of stress to that?
Atherosclerosis plaques occur preferentially at bifurcations & curvatures of the vascular tree, because the flow pattern and haemodynamic forces are not uniform in the arterial system.
What does laminar blood flow (high sheer stress) in the arterial system promote (4)?
- Stimulation of anti-inflammation and anti-thrombotic factors
- Endothelial survival
- Inibition of smooth muscle cell (SMC) proliferation
- Nitric Oxide (NO) production
What does disturbed blood flow (low sheer stress) in the arterial system promote (4)?
- Thrombosis & inflammation (leukocyte adhesion)
- Endothelial apoptosis
- Smooth muscle cell (SMC) proliferation
- Loss of nitric Oxide (NO) production
What are the productive effects of Nitric Oxide (NO) on the arterial endothelium (6)?
- Reduces oxidation of LDL cholesterol
- Reduces release of superoxide radicals
- Reduces proliferation of SMC in the vessel wall
- Dilates blood vessels
- Reduces platelet activation
- Inhibits monocyte adhesion
What is the role of angiogenesis in the pathogenesis of atherosclerosis?
Janus Paradox:
* Adverse effect: Promotes plaque growth
* Therapeutic effect: Prevents post-ischaemic damage
What is the role of subendothelial trapped LDL in the pathogenesis of atherosclerosis (4 steps)?
- LDLs leak through the endothelial barrier – likely due to endothelial activation in areas of vortex
- LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification
- LDL becomes oxidatively modified by free radicals
- Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation
Low density lipoprotein (LDL):
* ‘Bad’ cholesterol - Synthesised in liver.
* Carries cholesterol from liver to rest of the body including arteries.
High density lipoprotein (HDL):
* ‘Good’ cholesterol
* Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
Oxidised LDL(s), modified LDL(s):
* Chemical and physical modifications of LDL by free radicals, enzymes, aggregation
* Families of highly inflammatory and toxic forms of LDL found in vessel walls.
What is the role of macrophages in the pathogenesis of atherosclerosis (6 steps / 3rd step divided into 3 points)?
- Macrophages have oxidative enzymes that can modify native LDL
- Phagocytose modified lipoproteins & become foam cells
- Express cytokine mediators that recruit monocytes AND Express chemo-attractants & growth factors for VSMC AND Express proteinases that degrade tissue
- Once overwhelmed, macrophages die via apoptosis
- Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
- Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood
Macrophage scavenger receptor A:
* Known as CD204
* Binds to oxidised LDL
* Binds to Gram-positive bacteria like Staphylococci & Streptococci
* Binds to dead cells
Macrophage scavenger receptor B:
* Known as CD36
* Binds to oxidised LDL
* Binds to malaria parasites
* Binds to dead cells
What oxidative enzymes do macrophages release (3)?
- NADPH Oxidase i.e. superoxide O2-
- Myeloperoxidase i.e. HOCl hypochlorous acid (bleach) from ROS + Cl- / HONOO Peroxynitrite
- Generation of H2O2
What cytokine and chemokine do macrophages release (1 / 1)?
- Immunosuppression a big problem as a side effect
- Positive feedback loop / vicious cycle leading to self-perpetuating inflammation
- Monocyte chemotactic protein-1 (MCP-1)
- Interleukin-1 (IL-1)
Cytokines – protein immune hormones that activate endothelial cell adhesion molecules:
* Interleukin-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
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 chemo-attractants and growth factors do macrophages release (2)?
- Platelet derived growth factor
- Transforming growth factor beta
Platelet derived growth factor:
* Vascular smooth muscle cell chemotaxis
* Vascular smooth muscle cell survival
* Vascular smooth muscle cell division (mitosis)
Transforming growth factor beta:
* Increased collagen synthesis
* Matrix deposition
What proteinase do macrophages release?
Metalloproteinases
Metalloproteinases (=MMPs)
* Family of ~28 homologous enzymes.
* Activate each other by proteolysis.
* Degrade collagen.
* Catalytic mechanism based on Zn
Outline the pathophysiology of atherosclerosis (7 steps).
- Macrophages in plaque secrete inflammatory cytokines and chemokines
- Phagocytose, process and export cholesterol to reverse cholesterol transport (HDL)
- Secrete oxidants that damage cells and LDL
- Accumulate cholesterol and become sick and activated by cholesterol overload
- Release macrophage tissue factors and toxic lipids into the ‘central death zone’ called lipid necrotic core
- Secrete matrix metalloproteinases which degrade fibrous cap collagen
- Initiate death of vascular smooth muscle cells
How would a patient with atherosclerosis present (location dependent) (1 / stroke 1 / MI 4)?
- Death (ischemia) of the downstream tissues (heart and brain)
- 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
Which of the following statement is CORRECT for atherosclerosis?
* It is decreasing globally due to improved lifestyle
* It is an inflammatory disease of arteries characterised by macrophage inflammatory cells
* It is characterised by proliferation of pericytes, which drive the disease via IL-15
* Anti-inflammatory treatments such as anti-IL-1 have no effect as it is solely driven by ageing and telomere shortening
* It only affects coronary arteries making it the specialty interest of cardiologists
It is an inflammatory disease of arteries characterised by macrophage inflammatory cells
Which of the following statement is CORRECT for atherosclerotic risk factors?
* Are expected to decrease globally leading to a decrease in cardiovascular disease worldwide
* Include high blood pressure, diabetes, hyperlipidaemia, smoking, age, and anatomically localising branches and bends
* Are not worth treating since atherosclerosis is fundamentally a degenerative disease
* Do not modify vascular and leukocyte cell functions because they promote arterial thickening by the fatberg mechanism (passive deposition at branches and bends)
* Do not interact in any meaningful way, consequently integrated risk factor management is without any basis
Include high blood pressure, diabetes, hyperlipidaemia, smoking, age, and anatomically localising branches and bends
Which of the following statement is CORRECT for Low density lipoproteins?
* Is decreased in familial hypercholesterolemia
* May be modified in vessel wall to a form that activates macrophages like a pathogen would
* Is formed in vessel walls and carries cholesterol back to the liver
* Is characterised by the presence of a lipid bilayer
* Is not measured clinically since there are no worthwhile ways to reduce its level
May be modified in vessel wall to a form that activates macrophages like a pathogen would
Which of the following is known to significantly increase cardiovascular risk by acting as an atherosclerotic risk factor?
* Higher level of high density lipoprotein cholesterol (but less than 2.5mmol/L)
* High level of low density lipoprotein cholesterol in familial hypercholesterolemia (>5mmol/L)
* Hepatitis B infection
* Malaria
* Blood pressure lowering medication
* Clotting Factor VIII deficiency
High level of low density lipoprotein cholesterol in familial hypercholesterolemia
Which of the following statement is CORRECT for ruptured plaques?
* Have an excess of structurally strong collagen synthesised by an excess of vascular smooth muscle cells
* Have excess of activated macrophages containing excess lipid
* Are safe since they do not cause thrombosis or myocardial infarction
* Are mechanically stabilised due to insufficient expression of proteases by macrophages
Have excess of activated macrophages containing excess lipid
