Atherosclerosis and Coronary Heart Disease Flashcards by Meley Gdey

non modifiable risk factors of atherosclerosis or coronary heart disease

age
sex
genetics

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modifiable risk factors of atherosclerosis or coronary heart disease

smoking
lipids intake
blood pressure
diabetes
obesity
sedentary lifestyle

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Progression of atherosclerosis

adaptive thickening > type II lesion (macrophage foam cells) > type III (preatheroma) > type IV (atheroma: core of EC liquid) > type V (fibroatheroma: fibrous thickening) > type VI complicated lesions: thrombus, fissure, haematoma

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Primary prevention of atherosclerosis

lifestyle changes

risk factor management

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secondary prevention of atherosclerosis

Catheter based interventions
Revascularisation surgery
Treatment of heart failure

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role of endothelial cells in atherosclerosis

barrier fx

leukocyte recruitment

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role of platelets in atherosclerosis

thrombus generation

cytokine and growth factor release

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role of monocyte/macrophage in atherosclerosis

foam cell formation
cytokine and growth factor release
major source of free radicals
metalloproteinases

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role of T lymphocytes in atherosclerosis

macrophage activation

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role of VSMC in atherosclerosis

migration + proliferation
collagen synthesis
remodelling + fibrous cap formation

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Two main classes of macrophages

inflammatory (for fighting infection)

resident (homeostatic, alveolar, osteoclasts, spleen)

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LDL

role of monocyte/macrophage in atherosclerosis

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HDL

‘Good’ cholesterol

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

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Oxidised/modified LDL

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.

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Familial hyperlipidemia

Autosomal genetic disease, massively elevated cholesterol (20mmol/L). Failure to clear LDL from blood. Xanthomas and early atherosclerosis; if untreated fatal MI

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expression of LDL receptor is _______ regulated by ________

negatively

intracellular cholesterol

what are statins?

HMG-CoA reductase inhibitors

In LDLR-negative patients, macrophages ________ cholesterol.

accumulate

what are scavenger receptors?

second LDL receptor - not under feedback control - in atherosclerotic lesions that bind OxLDL

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

List oxidative enzymes macrophages have that can modify native LDL.

NADPH oxidase

myeloperoxidase

What are cytokines?

protein immune hormones that activate endothelial cell adhesion molecules

What are chemokines?

small proteins chemoattractant to monocytes

cytokines expressed by plaque macrophages to recruit monocytes

IL1 which upregulates VCAM 1 (adhesion molecule)

chemokines expressed by plaque macrophages to recruit monocytes

MCP1 which binds to CCR2 receptor

"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 are metalloproteinases?

Family of ~28 homologous enzymes. Activate each other by proteolysis. Degrade collagen. Catalytic mechanism based on Zn.

Effect of atherosclerotic plaque erosion/rupture

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

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

Macrophage apoptosis

OxLDL derived metabolites are toxic eg 7-keto-cholesterol > once protective macrophage systems overwhelmed > apoptosis > release factors in central death zone > material accumulates until rupture causes it to meet blood

What is NFkB?

transcription factor (nuclear factor kappa B)

NFkB activated by?

Scavenger receptors Toll-like receptors Cytokine receptors e.g. IL-1

NFkB activates?

Matrix metalloproteinases Inducible nitric oxide synthase Interleukin-1