Scene 1

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

Scene 20

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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Scene 22

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?

Scene 27

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

Scene 28

Statins Fibrates cholestyramine Ezetimibe PCSK 9 inhibitors

Scene 29

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

Scene 40

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

Scene 41

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

Scene 42

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)

Scene 45

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%

Scene 49

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

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