1. UNDERSTANDING CHOLESTEROL DR M J NIENKEMPER VERGELEGEN MEDICLINIC 2014/11/19

2. Objectives for Presentation To review importance of the history of cholesterol and other lipids as risk factors for heart disease To review cholesterol metabolism To review cholesterol pathogenesis To understand the tests for total cholesterol and its different lipoprotein components Treatment of lipid disorders

3. Cholesterol has important functions in the human body Necessary part of cell walls Precursor chemical for steroid hormones: - hydrocortisone, aldosterone, estrogens, etc. Formation of bile acids for digestion The Liver is the major organ for synthesis and metabolism of cholesterol.

4. LIPID HYPOTHESIS “The outstanding characteristic of atherosclerosis is the presence of cholesterol deposits in the walls of the arteries”

5. PAST, PRESENT and FUTURE IT IS ESTIMATED THAT 50% OF THE AMERICAN POPULATION HAVE UNHEALTHY LIPID PROFILES INCIDENCE OF HEART DISEASE REFLECT THIS ROLE OF CHOLESTEROL IN HEART DISEASE WAS REJECTED FOR DECADES DO STATINS BENEFIT ALL PATIENT POPULATIONS EQUALLY?

6. HORUS STUDY 137 mummies from Egypt, Peru were examined (4000-2000 BC) Atherosclerosis was detected in 37%, looking similar than modern day coronary problems although not exposed to modern lifestyle and fast foods Most mummies were younger than 40yrs

7. HISTORY LIPID HYPOTHESIS 1900: ANITSCHKOW: showed that by feeding rabbits pure cholesterol led to atherosclerosis (rabbits are herbivores) 1913: VIRCHOW: studied arterial plaques and assumed blood cholesterol leads to deposits in blood vessels

8. GOFMAN 1940: rekindled Anitschkow’s hypothesis that cholesterol causes vascular problems Identified different forms of cholesterol: HDL and LDL Again many years lapsed

9. Fredrickson: described the lipoproteins as cholesterol carriers Goldstein/Brown: Nobel Prize in1985 for their work on the genetic regulation of cholesterol production which led to the discovery of the regulating enzyme, HMG CoA reductase, which in turn led to the development of the STATIN GROUP of drugs.

12. 1. Framingham heart study in 1948 and ongoing: smoking, hypertension and CHOLESTEROL (1961 and 1988) 2. Seven countries study in 1958: lifestyle, diet and heart disease 3. Cholesterol reported as a heart disease risk factor 1961

13. “Eliminating saturated fats and replacing them with unsaturated fats has a cholesterol lowering effect.” FIRST DIETERY ADVICE GIVEN Oslo study 1966 VA study 1969

15. Serum Cholesterol and CHD in 361,662 U.S. Men Martin M. Lancet 1986;11:933-936 6 Year CHD Death Rate per 1,000 Men Serum Cholesterol mg/dL 18 16 14 12 10 8 6 4 2 0 140160180200220240260280300

16. CHOLESTEROL METABOLISM

17. IS ATHEROSCLEROSIS A METABOLIC DISEASE? … when considering its pathogenesis, it is important to remember that the best documented initiating factor in atherogenesis is still hypercholesterolemia and that additional factors, of which there are many, should whenever possible be considered in the context of how they relate to the processes initiated by hypercholesterolemia

18. LIVER The liver is the central regulator in cholesterol metabolism Synthesizes cholesterol for export to - cells for cellular membranes - hormone production - removes cholesterol by producing bile acids in the intestine Produces lipoproteins for cholesterol transport Chol production in the liver is under negative feedback When cellular chol concentration ↑, HMG CoA Reductase↓ HMG CoA reductase is the rate limiting enzyme and also the site where the Statins act

20. Lipoprotein lipase Free fatty acids Adipose tissue, muscle Exogenous Pathway ApoE B-100 IDL Plasma LCAT (lecithin cholesterol acyl transferase HDL ApoA-I A-II Dietary Cholesterol Endogenous Cholesterol Endogenous Pathway LDL VLDL ApoE C-II B-100 ApoE B-48 ApoE C-II B-48 Lipoprotein lipase Free fatty acids Adipose tissue, muscle RemnantsChylomicrons ApoB -100 LDL-R Extra Hepatic Tissue Liver Dietary fat LDL-R Remnant Receptor Bile acids and Cholesterol Intestine

21. Major Lipoproteins and their function Classified according to lipid content and density Chylomicrons: – Chylomicrons transport triglycerides from intestine Low Density Lipoproteins (LDL) – LDL result from metabolism of VLDL and IDL and carry cholesterol. Used by cells for cell membranes and hormone production. LDL is an important cause of heart disease High Density Lipoproteins (HDL) – HDL is “good” cholesterol. It removes LDL cholesterol and protects against heart disease

23. HIGH DENSITY LIPOPROTEIN HDL is produced by the liver and secreted into the bloodstream It scavenges LDL cholesterol and transports it back to the liver by removing it from cells and blood High HDL protects and Low HDL ?

24. BAD IS STILL BAD BUT IS GOOD STILL GOOD?

26. CHOLESTEROL PATHOGENESIS

27. Development of an atherosclerotic lesion © Michael Palmer 2014

28. Progression Of Atherosclerosis

29. Microscopic appearance of atherosclerotic lesions © Michael Palmer 2014

30. CHOLESTEROL LOWERING MEDICATION

31. Lowering LDL cholesterol: Therapeutic principles ● Inhibition of cholesterol synthesis ● Inhibition of cholesterol uptake ● Inhibition of cholesterol ester transfer protein ● Inhibition of bile acid reuptake ● LDL apheresis

32. STATINS: Block HMG COA-reductase that is an enzyme in the production of cholesterol. EZETIMIBE: Prevents intestinal cholesterol reabsorption. NIACIN: LDL↓; HDL↑; Triglycerides↓ FIBRATES: ↓Triglycerides NEWER DRUGS in development

33. Complementary Mechanisms of Action Lead to Broader Lipid Control DIETARY CHOLESTEROL BILIARY SECRETION INTESTINE Excretion VLDL LDL Absorption synthesis IDL Statins Cholesterol Absorption Inhibition

35. The effects of early statin treatment on absolute risk reduction in 1-year mortality for hospital survivors of acute MI Fonarow G. C. Chest 2005;128:3641-3651 ©2005 by American College of Chest Physicians Observational study

36. Coronary Mortality: PLACEBO vs STATIN 42% Risk Reduction p<0.00001 Number of deaths The Lancet, Vol 344, November 19, 1994

37. ACC/AHA GUIDELINES: Benefits of statins outweigh the risk 1.Clinically evident CVD 2.LDL > 4.9mmol/L 3.Diabetes (type I and II) and LDL > 1.8 (40-75 yrs) 4.Patients with a 10 yr risk ≥ 7.5% and LDL > 1.8.(risk prediction)

38. What is wrong with New Guidelines? THE GOOD, THE BAD and THE UGLY

43. Statins are the largest selling prescription drugs worldwide (soon OTC) Benefits derived from LDL lowering The greater LDL lowering, the greater the reduction in CVS mortality The pleiotropic effects of statins contribute to risk reduction It is unclear if different statins act differently (class effect).

44. Benefits in “healthy people” with normal/near normal LDL JUPITER STUDY: Rosuvastatin 40mg vs placebo - ↓/normal – LDL and ↑ hsCRP - 47% ↓ CVS risk(?pleiotropic effects)

45. SIDE-EFFECTS: 1.Statin related myopathy (10-20%) 2.Liver toxicity 3.Inhibits Co-enzyme Q10: part of the heart’s energy cycle. 4.Risk of diabetes with Statin use (1/500)

46. STATINS ARE NOT AN INSURANCE POLICY

47. HEALTHY LIFESTYLE IS THE FOUNDATION FOR CARDIOVASCULAR HEALTH.

48. Measurement of Cholesterol Total Cholesterol is the sum of cholesterol contained in the different lipoproteins Fasting not required Measured in millimoles per Liter (mmol/L) – Measured in milligrams per deciliter in US – 5.17 mmol/L = 200 mg/dL

50. Values for Cholesterol Total Cholesterol < 5.1 mmol/L = Good 5.1-6.1 = Borderline High > 6.20 = High

51. Values for Low Density Lipoprotein (LDL) < 2.8 = Good 2.8-3.3 = Near Normal 3.3- 4.1 = Borderline High 4.1-4.8 = High > 4.8 = Very High

52. Values for High Density Lipoprotein (HDL) < 1.03 mmol/L = LOW (Increased Risk) > 1.55 mmol/L = HIGH (Lower Risk)

53. Triglycerides Measured in mmol/l Levels: < 1.7 mmol/l = normal 1.7-2.24 = borderline high 2.3-5.6 = high > 5.6 = very high

54. Disorders of Cholesterol and Lipoproteins 3 Categories Specific Familial/Genetic Disorders – These comprise a small minority of patients Secondary to other Diseases – Diabetes, Hypothyroid, Nephrotic syndrome, Renal Failure, Lupus Dietary/Polygenic --(most common) – This is the great majority of patients with elevated cholesterol/LDL

55. Familial hypercholesterolemia is due to a gene defect in the LDL receptor © Michael Palmer 2014

56. FAMILIAL HYPERCHOLESTEROLAEMIA Familial hypercholesterolaemia is a common genetic disorder with a prevalence of 1/500 in America and Europe. Within South Africa, the prevalence is very high in particular population groups. Thus, in the Afrikaner population a prevalence rate of 1/72 has been reported whilst in the Ashkenazi Jewish population the prevalence is 1/67. It has also been stated that the Gujerat Indian community of South Africa has a high disease prevalence, although rates have not been published.

57. Afrikaner community The high prevalence of FH in the Afrikaner community of South Africa is probably due to a founder effect. The original colonists who gave rise to the present Afrikaner population came from Holland, France and Germany and numbered around 2000. Within this small community there was, by chance, a high prevalence of subjects carrying LDL receptor gene mutations. The prevalence of FH is far higher in the Afrikaner population than in the European populations from which these subjects were descended. Ninety per cent (90%) of cases of familial hypercholesterolaemia in the Afrikaner community are due to 3 separate LDL receptor mutations termed FH Afrikaner-1, -2 and –3.7 The coloured population also carry these same 3 mutations plus a fourth mutation that has been called FH Cape Town-28, 9.

58. Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder which results in patients having significantly increased levels of serum total cholesterol and low density lipoprotein (LDL) cholesterol. The high cholesterol levels are caused by a deficiency or a defect in the LDL receptor which results in severe and premature coronary artery disease. Clinicians are able to diagnose this disorder by the clinical signs found on examination such as arcus and tendinous xanthomata, and the high cholesterol levels measured in the laboratory. Early and aggressive therapy using drugs and diet aims at decreasing the levels of cholesterol and thereby inhibiting the progression of coronary artery disease.

66. AHA American Heart Association urged the reduction in saturated fat intake with the following results…..

67. The Obesity Epidemic Started When The Low-Fat Guidelines Were Published

68. HOW TO OPTIMIZE YOUR CHOLESTEROL LEVELS 1.Reduce carbohydrate intake. - Obesity leads to insulin resistance and worsens lipid profile. 2. Increase intake of healthy fats a) HARMFUL (SOLID FATS) - Animal fats b) HEALTHY (LIQUID FATS) - MUFA - PUFA - Omega(Ω)- 3 3. Optimize your vit D levels (independent risk factor) 4. Exercise daily (lifestyle-statin interaction) 5. Avoid smoking/excessive alcohol intake 6. Get enough sleep

69. QUO VADIS