Transcript Cholesterol and Heart Disease

Cholesterol and Heart Disease
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
Deaths in Thousands
1200
1000
800
600
400
200
0
00
10
20
30
40
50
60
70
80
90
00
06
Years
Deaths from cardiovascular disease
(United States: 1900–2006 preliminary). Source: NCHS and NHLBI.3
100
85.9
Percent of Population
90
80
73.3
72.6
79.3
70
60
50
37.9 38.5
40
30
20
10
15.9
7.8
0
20-39
40-59
60-79
Men
80+
Women
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.
4
16
Per 1,000 Persons
14
12
10
8
6
4
2
0
35-44
White Men
45-54
Black Men
55-64
White Women
65-74
Black Women
Annual rate of first heart attack by age, sex and race. (ARIC
Surveillance:1987-2004). Source: NHLBI.
5
15.1
16
Prevalence (%)
14
11.4
12
10.4
10
8.3
8
6
5.1
7.9
8.6
6.2
5.6 5.1
3.6
4
2.2
2
0
All
1971-75
Women
1976-1980
1988-1994
Men
1999-2002
Prevalence of low CHD risk, overall and by sex, ages 25-74
(NHANES :1971-2002). Source:Personal communication with NHLBI
6/28/07. “Low risk” is defined as SBP <120 mm Hg and DBP<80 mm Hg;
cholesterol < 200 mg/dL and BMI <25 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
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)
LDLR
PDB 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.
LDL receptors
• Liver normally clears
out 75% of cholesterol
to bring the level down
through a regulatory
process
• It also produces
cholesterol
– Acetic acid -> HMG CoA
reductase -> cholesterol
Acetyl-CoA-> HMG CoA
reductase -> cholesterol
Cholesterol
Liver
Bile Acids
Cholesterol
Diet
LDL
extracellular space
cytosol
receptor-mediated
endocytosis
LDL
receptor
Cholesterol
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
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.
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
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 don’t benefit are FH -/-
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