Coronary Heart Disease Flashcards by Dean Whaley

What are modifiable risk factors for Atherosclerosis?

Smoking - Smoking cessation
Lipids intake - Statins, injection with pcsk9 antibody
Blood pressure - ABCDE
Diabetes - Dietary advice, weight loss, Metformin
Obesity - Dietary advice, Gastric surgery
Sedentary lifestyle - advice.
Risk factors multiply.

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What are non-modifiable risk factors for Atherosclerosis?

Age
Sex
Genetic Background

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What is the ABDCE approach in treating blood pressure?

Ace inhibitors first followed by,
Beta blockers
Converting enzyme inhibitors
Diuretics

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What have been the epidemiological change in coronary heart disease?

Reduced hyperlipidemia
Reduced hypertension
Increased Obesity - Diabetes
New improvements in diabetes treatment have a doubtful effect on macro vascular disease.

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What would happen if you inhibited the endothelium?

Rise in blood pressure

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What are the stages of Atherosclerosis?

Type II - Macrophage foam cells
Type III - Macrophages die, forming small pool of lipids.
Type IV - Atheroma, lipids coalesce to form a big core
Type V - fibro-atheroma, Inflammatory reaction that triggers smooth muscles to form fibrous thickening.
Type VI - complicated lesion, collagen becomes weaker, breaks allowing formation of a thrombus, fissure & hematoma

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At what point is the window for primary intervention (Lifestyle changes, risk factor management)?

Intermediate lesions

Advanced lesions

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At what point is there need for clinical intervention?

Stenosis, plaque rupture.

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What is the role of vascular endothelial cells?

Barrier function via lipoproteins

Leukocyte recruitment

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What is the role of platelets

Coronary, cerebral artery thrombosis.
Carotid embolism,
Activation means a lot of cytokine secretion

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What is the role of Monocytes & Macrophages?

Lipid rapping - foam cell formation.
Secrete cytokines & growth factors.
Major source of free radicals and Metalloproteinases ( enzymes that degrade collagen).

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What is the role of vascular smooth muscle cells?

Migrate from the media into the plaque, strengthening it through collagen synthesis as well as narrowing the lumen slightly. However this protects you from getting an MI.

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What is the role of T-Lymphocytes?

Macrophage activation

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Why are patients at high risk of atherosclerosis complications injected with antibodies to Interleukin-1?

Atherosclerosis has an inflammatory basis.

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What are the two main classes of Macrophages?

Inflammatory Macrophages

Resident Macrophages

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What is the role of Inflammatory macrophages?

Adapted to kill microorganisms

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What are the roles of Resident Macrophages?

Homeostasis - suppress inflammatory activity
Alveolar resident macrophages - surfactant lipid homeostasis.
Osteoclast - Calcium and phosphate homeostasis
Spleen - iron homeostasis

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What is LDL?

‘Bad’ cholesterol - Synthesised in liver.

Carries cholesterol from liver to rest of the body, including arteries.

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What is HDL?

‘Good’ cholesterol

Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”

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How is LDL modified in atherosclerosis?

LDL’s leak through endothelial barrier & bind to proteoglycans, making them susceptible to modification. Modification involves oxidation (partial burning). Free radicals oxidise LDL.
Oxidised LDL is phagocytosed by macrophages, which form foam cells that lead to chronic inflammation

What happens in 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 does increased LDL in the liver do?

switches off cholesterol synthesis in a negative feedback loop.The enzyme that is the rate limiting step in cholesterol synthesis is the same one that is regulated by cholesterol itself. HMG-CoA reductase inibitors - statins.

What is Macrophage scavenger receptor A?

Known as CD204
Binds oxidised LDL
Binds to gram positive bacteria, e.g. staphylococci & Streptococci.
Bind to dead cells

What in Macrophage scavenger receptor B?

Known as CD36
Bind to oxidised LDL
Binds to malaria parasites
Binds to dead cells

Why are macrophages with activated oxLDL deposits double faced?

On the one hand they activate inflammation through bug detector pathways, but also reverse cholesterol transport & safe clearance via Homeostasis.

What is the structure of LDL?

Lipid monolayer

What are Macrophages effect on LDL?

Can activate NADPH Oxidase (superoxidase), Myeloperoxidase (hypochlorous acid-bleach), which modify LDL.

Why is hypochlorous acid (bleach) bad for arteries?

It further oxidises the LDL's and damages the inside of the artery, allowing the plaques to fall apart.

What are cytokines?

Protein immune hormones that activate endothelial cell adhesion.

What is the role of VCAM-1 in atherosclerosis?

Vascular adhesion molecule, mediates tight monocyte binding. Plaque macrophages secrete IL-1 which upregulates them. Positive feedback loop

What are chemokines?

Small proteins chemoattractant to monocytes.

What does Monocyte chemotactic protein 1 MCP-1 do?

Chemical smell macrophages can hone in on and track down the site of infection. Too much fat can do the same thing. MCP-1 binds to a monocyte G-Protein coupled receptor, CCR2. Positive feedback loop

Which mice is atherosclerosis reduced in?

``` Mice deficient in; IL-1 VCAM-1 MCP-1 CCR2 ```

What is the wound healing role of Macrophages in atherosclerosis?

Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix

What are the 2 types of protein growth factors released by macrophages?

Platelet derived growth factor | Transforming growth factor beta

What is the role of transforming growth factor beta?

Increased collagen synthesis | Matrix deposition

What is the role of Platelet derived growth factor?

Vascular smooth muscle cell chemotaxis Vascular smooth muscle cell survival Vascular smooth muscle cell division (mitosis)

What happens to the contractile vascular smooth muscle cell under the effect of PDGF & TGF-beta?

Lose contractile control | move into the endothelium where the facts and plaques are. Make a lot of matrix.

What do macrophages do to degrade tissue?

Express proteinases; 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 plaque erosion?

Rupture - Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation of blood flow.

What are the Characteristics of vulnerable and stable plaques?

``` Large soft eccentric lipid-rich necrotic core Increased VSMC apoptosis Reduced VSMC & collagen content Thin fibrous cap Infiltrate of activated macrophages expressing MMPs ```

What does Anteroseptal myocardial infarction show as on an ECG?

ST elevation | T wave inversion on anterior myocardial leads

How does Macrophage apoptosis take place?

OxLDL derived metabolites are toxic eg 7-keto-cholesterol. Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading. 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.

What is Nuclear Factor Kappa B?

Transcription factor that is a master regulator of inflammation.

What activates NF-kappa-B?

Activated by numerous inflammatory stimuli Scavenger receptors Toll-like receptors Cytokine receptors e.g. IL-1

What does NF-kappa-B switch on?

Switches on numerous inflammatory genes Matrix metalloproteinases Inducible nitric oxide synthase Interleukin-1

How does NF-kappa-B work?

NF-kappa-B directs multiple genes in concert after being activated by multiple different inflammatory stimuli including IL-1 & cholesterol crystals.