Cholesterol and Heart Disease

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Cholesterol and Heart Disease
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Plaques

• Buildup in arteries is composed of proteins,
  lipids, and cholesterol
• When blood vessels are plugged up, you get heart
  attacks or strokes.
• 1.5 million deaths per year from heart attacks
• 600,000 deaths from cancer

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Deaths from cardiovascular disease(United
States 19002006 preliminary). Source NCHS and
NHLBI.
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Prevalence of CVD in adults age 20 and older by
age and sex (NHANES 2005-2006). Source NCHS and
NHLBI. These data include coronary heart
disease, heart failure, stroke and hypertension.
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Annual rate of first heart attack by age, sex and
race. (ARIC Surveillance1987-2004). Source
NHLBI.
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Prevalence of low CHD risk, overall and by sex,
ages 25-74 (NHANES 1971-2002). SourcePersonal
communication with NHLBI 6/28/07. Low risk is
defined as SBP lt120 mm Hg and DBPlt80 mm Hg
cholesterol lt 200 mg/dL and BMI lt25 kg/m2 and
currently not smoking cigarettes and no prior MI
or DM.
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Cholesterol

• What is it used for?
• Lipid bi-layer half of all lipids in your cell
  membranes are cholesterol, half of all your
  cholesterol in your body is in cell membranes
• You liver uses it to create bile that helps
  digest fats
• Where does it come from?
• Diet eggs, butter, etc
• Endogenous synthesis your liver makes it

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Cholesterol

• Cholesterol is too waxy to move through the
  blood, so it is esterified
• Low density lipoproteins (LDL)
• Very large particles
• 220 angstroms
• 1600 cholesterols
• High density lipoprteins (HDL)
• Very low density lipoproteins (VLDL)

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LDLRPDB code 1N7D

• The low-density lipoprotein receptor mediates
  cholesterol homeostasis through endocytosis of
  lipoproteins.
• Mutations in this gene cause the autosomal
  dominant disorder, familial hypercholesterolemia.
• The LDL receptor gene is located on the short arm
  of chromosome 19, and the protein is composed of
  860 amino acids.

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LDL receptors

• Liver normally clears out 75 of cholesterol to
  bring the level down through a regulatory process
• It also produces cholesterol
• Acetic acid -gt HMG CoA reductase -gt cholesterol

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Acetyl-CoA-gt HMG CoA reductase -gt cholesterol
Liver
Cholesterol
Diet
Bile Acids
Cholesterol
Cholesterol
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Familial Hypercholesterolemia

• Hypercholesterolemia too much cholesterol in
  the blood
• Familial transmitted in families
• / normal people 150mg/deciliter
• Heart att
• /- you got the mutation from one of your parents
  300 mg/deciliter
• -/- you got the mutation from both of your
  parents 600 mg/deciliter

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Background

• In 1972, Michael S. Brown and Joseph L. Goldstein
  hypothesized that surmised that cholesterol
  overproduction results from defect in the control
  mechanisms that normally regulate cholesterol
  biosynthesis.
• In 1974, Brown and Goldstein demonstrated that
  the lesion in FH cells is a defect in LDL binding
  to a receptor on the surface.

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What is your solution

• Reduce cholesterol in diet
• If reduce drastically, you only get a 10
  reduction in -/- patients
• Your body is more efficient at using cholesterol
• Your liver produces more when the level decreases
• Feed people bile acid-binding resins
• Your liver will then up regulate its LDL
  receptors, and use more cholesterol from the
  blood stream
• Get 20-25 reduction, but liver still increases
  production

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Solutions?

• You could give them HMG CO-A reductase inhibitors
  that stop the liver from producing cholesterol
• Statin drugs inhibit pathway to producing
  cholesterol
• When combined with diet and bile acid-binding
  resins /- patients are reduced to normal levels
• This same strategy helps people that arent FH
• The only people who dont benefit are FH -/-

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What about FH -/-

• Gene therapy
• Since the liver regenerates quickly, you can take
  out some cells, fix the mutation and inject them
  back and they will have the correct receptor