lipoproteins Flashcards
what does the secondary prevention of CVD include? patients with disease
lifestyle changes: smoking cessation
drugs: ACE inhibitor, beta blocker to reduce post-MI mortality
aspirin and clopidogrel to reduce CVD recurrence and mortality
statins to reduce CVD recurrence and mortality
what is the mainstay of primary prevention?
life style change:
aim for BMI 225kg/m2
reduce EtOH
aerobic exercise
diet: reduce sat fat, simple carbs, salt
how to decide whether patients need drugs in primary prevention? patients without disease but high risk
decision to treat: potential benefit vs side effect
estimating CV risk: easy for extreme risk factors like very high LDL-C in familial hypercholesterolaemia or severe hypertension
usually CV risk is product of several risk factors so use a risk calculator: ASSIGN, QRISK2
“high risk groups”: DM >40 years, famililal hypercholesterolaemia, CKD then treat
if not “high risk”, then use risk calculator recommended in all >40
treatment: lifestyle advice +- statin
what are the effects of lipid lowering drugs? (3)
statins: reduce LDL-C- lowers risk of coronary heart disease, 1st choice lipid-lowering drug class for CVD prevention
ezetimibe: reduce LDL-C, lower risk of coronary heart disease, usually adjunct
fibrates: reduce LDL-C & Trigs, increase HDL-C, only beneficial where low HDL-C and high trigs- T2DM, usually adjunct to statin
how does statins work?
HMG-CoA reductase inhibitor
inhibit rate limiting step of cholesterol synthesis
intra-cellular cholesterol depletion leads to LDL uptake
how does ezetimibe work?
inhibits cholesterol absorption at small intestine
binds to NPC1L1 (nieman-pick C1 like 1) protein, critical mediator of cholesterol absorption in GI epithelial cells
how do fibrates work?
stimulates PPARalpha - nuclear transcription factor
causes increase LPL activity, hepatic fatty acid oxidation
enhanced IDL, LDL uptake, reduced VLDL synthesis
what is the next generation of lipid lowering drugs?
PCSK9-inhibitors
monoclonal antibodies delivered by fortnightly s/c injection
capable of around 60% reduction of LDL-C (as adjunct to statin)
what is PCSK9 and how can it be targeted to reduce cholesterol levels?
proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation preventing uptake from blood into cell
therefore, new drugs that inhibit PCSK9 produced to prevent this degradation from cell surface
new drug approved that is siRNA and prevents translation of protein in liver
what is the first step of lipid driven CV disease happen?
formation of fatty streaks: LDL + monocytes + o free radicals
hypertension/ glycation/ O free radicals damage the endothelium
O free radicals produced by glycation reactions (diabetes), toxins from cigarette smoke, macrophages
monocytes attracted by damaged endothelium
LDLs oxidised by O-free radicals consumed by macrophages, macrophages laden with LDL are known as foam cells, fatty streak is a collection of foam cells within arterial wall
what is the second step of lipid-driven CV disease?
atheromatous plaque formation:
smooth muscle cells are stimulated by macrophages to migrae, proliferate and differentiate
SMCs differentiate into fibroblasts which produce a fibrous collagen cap
foam cells undergo necrosis or apoptosis to leave a pool of extracellular cholesterol
atheroma is a cholesterol pool beneath a fibrous cap within the arterial wall
what is the third step of lipid driven CV disease?
plaque rupture
cholesterol rich lesions lead to plaque rupture and thrombosis
total lumen obstruction
tissue ischaemia and myocardial infarctions
if they are fibrous lesions as opposed to cholesterol ones, less liable to rupture and reduces blood flow: stable angina
what is familial hypercholesterolaemia?
autosomal dominant
mutation in LDL receptor
causes high LDL-C levels
statin treatment reduces CVD risk
what are the signs of familial hypercholesterolaemia?
tendon xanthoma
corneal arcus
xanthelasma
how is LDL calculated?
specialist labs can measure concentrations of lipoproteins (ultracentrifugation) and apolipoproteins
routine lab measurements of lipids: total cholesterol, HDL cholesterol, triglycerides
LDL-C is calculated not measured
friedewald equation: assumes fasting sdample so no chylomicrons
