Cardio - Ischaemic Heart Disease Flashcards
What are the 2 types of Coronary Heart Disease?
Ischaemic Heart Disease
What is Ischaemic Heart Disease?
CHD affecting coronary arteries
What is cerebrovascular disease?
CHD affecting carotid arteries
What are the modifiable risk factors?
→ smoking → lipids intake → blood pressure → diabetes → obesity → sedentary lifestyle
What are the non-modifiable factors?
→ age
→ sex
→ genetic background
What is the treatment for lipids intake?
→ statins
→ anti-hyperlipidemic agents
→ antibodies against PCSK9
What is the treatment protocol for BP?
→ ACE inhibitors
→ beta blockers
→ conducting enzyme inhibitors
→ diuretics
What is risk factor multiplication?
when multiple risk factors multiply your chances of getting a disease
What are the changes in epidemiology?
→ 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
→ SGLT-2 inhibitors can reduce CVD effects +
Where do plaques commonly occur?
→ bifurcations in arteries
→ areas of turbulent flow
Where does LDL deposition occur?
in the sub-intimal space and binds to matrix proteoglycans
What do LDLs bind to?
matrix proteoglycans
What is the Type II lesion of atherosclerosis?
macrophage foam cells
What is the Type III lesion of atherosclerosis?
→ preatheroma
→ small pools of extracellular
What is the Type IV of atherosclerosis?
→ atheroma
→ core of extracellular lipid
What is the Type V of atherosclerosis?
→ fibroatheroma
→ fibrous thickening
What is the Type VI of atherosclerosis?
→ thrombus
→ fissure + hematoma
What can be done as primary prevention?
→ life-style changes
→ risk factors management
What can be done as clinical intervention?
→ secondary prevention
→ catheter based interventions
→ revascularisation surgery
→ treatment of heart failure
What are the main cells involved?
→ vascular endothelial cells → platelets → monocyte-macrophages → vascular smooth muscle cells → T lymphocytes
What is the role of vascular endothelial cells?
→ barrier function (e.g. to lipoproteins)
→ leukocyte recruitment
What are the roles of platelets?
→ thrombus generation
→ cytokine + growth factor release
What are the roles of monocyte-macrophages?
→ foam cell formation
→ cytokine + growth factor release
→ major source of free radicals
→ metalloproteinases
What are the roles of vascular smooth muscle cells?
→ migration and proliferation
→ collagen synthesis
→ remodelling + fibrous cap formation
What is the role of T lymphocytes?
→ macrophage activation
What is a huge basis in atherosclerosis?
inflammation
What was given to high risk atherosclerosis patients in a trial? Why?
→ Interleukin-1
→ to understand how important inflammation is in atherosclerosis
What was the result of the trial?
→ 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
How did IL-1 help?
x
What are the 2 main classes of macrophages?
→ Inflammatory macrophages
→ Resident macrophages
What is the purpose of inflammatory macrophages?
adapted to kill microorganisms (germs)
What is the purpose of resident macrophages?
→ normally homeostatic - suppress inflammatory activity
→ alveolar resident macrophages - surfactant lipid homeostasis
→ osteoclasts - calcium + phosphate homeostasis
→ splenic red pulp macrophages - iron homeostasis
What are LDLs?
→ ‘Bad’ cholesterol
→ Synthesised in liver.
→ Carries cholesterol from liver to rest of the body including arteries
What are the structural points of LDLs?
→ docking molecule “molecular addresses for fat delivery”
→ lipid monolayer (like cell membrane) but one molecule thick
→ cargo fat for fuel
What are HDLs?
→ ‘Good’ cholesterol
→ Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
What are oxidised LDLs?
→ Due to action of free radicals on LDL. (see later)
→ Not one single substance.
→ Families of highly inflammatory and toxic forms of LDL found in vessel walls.
How do LDLs become modified into oxLDLs?
→ LDLs leak through the endothelial barrier by uncertain mechanisms.
→ LDL is trapped by binding to sticky matrix carbs (proteoglycans) in the sub-endothelial layer and becomes susceptible to modification.
→ Best studied modification is oxidation - represents partial burning
→ LDL becomes oxidatively modified by free radicals.
→ Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation
How do oxLDLs promote foam cell formation?
→ LDLs become oxidised
→ phagocytosis by macrophages
→ macrophages now known as “foam cells”
→ goes back to chronic inflammation
What is FH?
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
What receptor do FH patients lack? What are the features of this receptor?
LDL receptor
- negatively regulated by intercellular cholesterol
Why was a second LDL receptor deduced?
In LDLR-negative patients, macrophages accumulate cholesterol
- therefore there must be a second LDL receptor, not under negative feedback regulation so that macrophages can still ingest LDLs.
What are the secondary LDL receptors called?
Macrophage scavenger receptors
What are the 2 types of macrophage scavenger LDL receptors?
Macrophage scavenger receptor A = CD204
Macrophage scavenger receptor B = CD36
What do CD204 do?
Binds to oxidised LDL
Binds to Gram-positive bacteria e.g. staph + strep
Bind to dead cells
What do CD36 do?
Binds to oxLDLs
Binds to malaria parasites
Binds to dead cells
What do macrophages in plaques do to worsen + propagate atherosclerosis?
- generate free radicals to further oxidise LDLs
- phagocytose modified LDLs + become foam cells
- express cytokine mediators to recruit monocytes
- express chemo-attractants + growth factors for VSMC
- express proteinases that degrade tissue
How do macrophages generate free radicals that further oxidise LDLs?
Macrophages have oxidative enzymes that modify LDLs
- NAPDH oxidase
- myeloperoxidase
What cytokines do macrophages produce?
- IL-1 upregulates vascular cell adhesion molecule VCAM-1
- VCAM-1 mediates tight monocyte binding
What chemokines do macrophages produce?
- monocyte chemotactic protein-1 (MCP-1)
- MCP-1 binds to monocyte G-protein coupled receptor CCR2
Why is it a vicious cycle of inflammation ?
Positive feedback loop + vicious cycle that leads to self-perpetuating inflammation
What chemo-attractants + growth factors do macrophages produce for VSMC? What do they promote?
Platelet derived growth factor (PDGF) - VSMC chemotaxis - VSMC survival - VSMC division Transforming growth factor beta (TGF-b) - increased collagen synthesis - matrix deposition
Why do macrophages release these growth factors in atherosclerosis?
“Wound healing” role of the macrophage in atherosclerosis - Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix
What is the difference between atherosclerotic VSMCs compared to normal ones?
What are metalloproteinases?
Family of 28 homologous enzymes
Activate each other in proteolysis
Degrade collagen
Catalytic mechanism based on zinc
What is the effect of plaque erosion + rupture?
blood coagulation at site of rupture may lead to an occlusive thrombus + cessation of blood flow
What are the characteristics of a vulnerable + unstable plaque?
→ large soft eccentric lipid rich necrotic core
→ increased VSMC apoptosis
→ reduced VSMC + collagen content
→ thin fibrous cap
→ infiltration of activated macrophages expressing MMPs
What is the process of macrophage apoptosis?
What is Nuclear Factor kappa B (NFkB)?
Transcription factor
Master regulator of inflammation
What can NFkB be activated by?
Numerous inflammatory stimulation
- scavenger receptors
- toll-like receptors
- cytokine receptors e.g. il-1
What does NFkB do?
Switches on numerous inflammatory genes
- matrix metalloproteinases
- Inducible nitric oxide synthase
- interleukin-1
What is the positive feedback involved with NFkB?
Interleukin-1 activates it, it also causes release of IL-1
What is a summary of atherosclerosis?
