Atherosclerosis and Coronary Heart Disease Flashcards
non modifiable risk factors of atherosclerosis or coronary heart disease
age
sex
genetics
modifiable risk factors of atherosclerosis or coronary heart disease
smoking lipids intake blood pressure diabetes obesity sedentary lifestyle
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
Primary prevention of atherosclerosis
lifestyle changes
risk factor management
secondary prevention of atherosclerosis
Catheter based interventions
Revascularisation surgery
Treatment of heart failure
role of endothelial cells in atherosclerosis
barrier fx
leukocyte recruitment
role of platelets in atherosclerosis
thrombus generation
cytokine and growth factor release
role of monocyte/macrophage in atherosclerosis
foam cell formation
cytokine and growth factor release
major source of free radicals
metalloproteinases
role of T lymphocytes in atherosclerosis
macrophage activation
role of VSMC in atherosclerosis
migration + proliferation
collagen synthesis
remodelling + fibrous cap formation
Two main classes of macrophages
inflammatory (for fighting infection)
resident (homeostatic, alveolar, osteoclasts, spleen)
LDL
role of monocyte/macrophage in atherosclerosis
HDL
‘Good’ cholesterol
Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
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.
Familial hyperlipidemia
Autosomal genetic disease, massively elevated cholesterol (20mmol/L). Failure to clear LDL from blood. Xanthomas and early atherosclerosis; if untreated fatal MI
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
