1. Cholesterol and Heart Disease

2. 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

3. Deaths from cardiovascular disease(United States: 1900–2006 preliminary). Source: NCHS and NHLBI.

4. 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.

5. Annual rate of first heart attack by age, sex and race. (ARIC Surveillance:1987-2004). Source: NHLBI.

6. 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.

7. 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

8. 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)

9. 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.

10. 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

11. Acetyl-CoA-> HMG CoA reductase -> cholesterol Liver Cholesterol Diet Bile Acids Cholesterol Cholesterol

12. 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

13. 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.

14. 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

15. 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 -/-

16. 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