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Artery
Cholesterol particles
Buildup of cholesterol
in the lining of artery
Plaque forms
(atherosclerosis)

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dietary chol / trigs carried by apo-B-48 (intestine) chylomicrons  VLDL + remnants  carry trigs not very  atherogenic

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LDL transport by lipoproteins hydrophobic core Not soluble in water Apo B-100 made in liver deposit peripheral  membranes & hormones

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atherogenic = High LDL deposit in arteries attract macrophages  activate inflammatory cytokines – oxidize form epithelium damage nitric oxide / prostacyclin inhibited

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chol (75%) made de novo liver synthesis from acetyl-CoA LDL transport by  Apo B-100  rate limiting step is HMG CoA reductase  hydroxy methyl glutaryl treatment = inhibit HMG CoA

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HDL  removes cholesterol  peripheral arteries transfers  to LDL Lecithin cholesterol acyl transferase (LCAT)  esterfies CE HDL

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Cholesterol ester transfer protein CETP -  CE from HDL to VLDL/LDL apolipoprotein A-1 inhibited by smoking exercise / moderate alcohol prevents oxidation  foam cells

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Type 2  Type 1 Diabetes with microalbuminuria,  those with severe genetic lipid disorders   patients with a 10 yr risk of CHD of >20%

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Familial Hypercholesterolemia genetic low LDL-C receptors in liver Heterozygous Familial Hypercholesterolemia (HeFH)  one gene missing one normal Homozygous Familial  missing (HoFH) : Two FH genes

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Familial hyperlipoproteinemia high trig + LDL Familial Hypercholesterolemia heterozygous TC> 8.0mmol/L  CAD increased homozygous TC >25mmol/L

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Familial Hypertriglyceridaemia Severe (Usually Mixed Lipemia) trigs + VLDL high pancreatitis obesity / insulin resistance

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Total Cholesterol =
LDL + HDL + Triglycerides
LDL
Cholesterol =
= Low Density Lipoprotein
Lipid (fat)
Protein
HDL removes
cholesterol from plaque
LDL adds cholesterol to plaque
HDL High Density
Lipoprotein
— Protein
Lipid (fat)
O medmovie_corm

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cell lining
(eridOthelium)
Muscle layer
Vessel opening
Norrnal artery
Aorta
Right coronary
artery
Left coronary
artery
Pulmonary
artery
Area Of
occlusion
Area Of
muscle
damage
Early iniury
Beg inn i ng
cholesterol plaque
Adva n c ed
cholesterol plaque
Si
a
nificant
erosclerosis
Blood clot
Cornplete
blockage

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which diet low carb? low fat? French food? vegetarian?

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Red meat - a few times per
month in very small
amounts
A few times per week
Daily
Sweets
oultry
Fish
Mediterranean Diet Pyramid*
* Adapted from Consumer Repotts, Novg
Cheese and yogurt
Olive Oil
Beans,
Legumes
Nuts
Bread, pasta, rice, couscous, polenta, bulgar,
and potatoes

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Statins Fibrates cholestyramine Ezetimibe PCSK 9 inhibitors

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binds bile acid gut (cholesterol)  large –ve charged molecule not absorbed bile + resin = eliminated  liver synthesis new LDL receptors poorly tolerated

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binds GIT bile acids Increase hepatic LDL Receptors LDL  -  20% Tg    -  0 HDL = 0 used for  puritis  from bile acid  tastes like sea sand

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Acetyl Co A + Acetyl Co A 3 - hydroxy methyl glutaryl CoA mevalonic acid cholesterol

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Simvastatin   Pravastatin	-  Prava Fluvastatin	-  Lescol atorvastatin – Lipitor rosuvastatin – Crestor HMG CoA Reductase inhibitors

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atorvastatin      10mg simvastatin       20mg rosuvastatin      5mg dose limit          40-80mg

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well tolerated rhabdomyolisis  - fatal    myalgia liver problems – transient

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ezetemibe  (Ezetrol) blocks cholesterol uptake gut liver synthesizes LDL receptor decrease  LDL 20% well tolerated add on therapy to statins

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Proprotein convertase subtilisin/kexin type 9 (PCSK-9)  9th member of the proprotein convertase  activate  other  protein regulated by LDL-C levels up regulated as LDL-C drops PCSK-9 coronary artery disease

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PCSK-9 binds LDL-C hepatic degrades receptor  high statins = PCSK-9  as LDL-C receptors bind circulating LDL-C.  low LDL-C receptors = high LDL monoclonal antibody inhibits PCSK-9 allows LDL Receptors protected

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adjunct adults heterozygous familial hypercholesterolemia (HeFH)  Atherosclerotic cardiovascular disease (ASCVD),  lower  LDL-C plus other LDL-lower therapies  LDL apheresis, statins, ezetemibe in patients with homozygous familial hypercholesterolemia (HoFH)

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Administration: SC 2 weeks.  Alternative  once every 4 weeks  ADR:  nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. 5% of patients.				        $14,523 for 1 year of therapy

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bezafibrate  (Bezalip) gemfibrozil  (Lopid) lipoprotein lipase activity PPAR –peroxisome proliferative activated receptor -gamma

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decrease VLDL use in mixed dyslipidaemia  useful in type II diabetes? decreases LDL 10% decreases Trig's 	40% increases HDL	10%

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well tolerated rhabdomyolisis  fatal  drug interaction -statins  myalgia liver problems – transient CNS

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