1. Emerging Cardiac Risk Factors Jon W. Wahrenberger, MD FACC DHMC Cardiology Update Symposium 2003 December 1, 2003

2. Traditional Risk Factors Tobacco Exposure Hypertension Diabetes Mellitus Lipid Disorders Family History

3. Question: Traditional risk factors are present in what percentage of patients with coronary heart disease: A. Less than 50% B. Greater than 50% C. Conflicting data Audience Response Question 1

4. Total Cholesterol Distribution: CHD vs Non-CHD Population Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9. 35% of CHD Occurs in People with TC<200 mg/dL 150 200 Total Cholesterol (mg/dL) 250 300 No CHD CHD Framingham Heart Study—26-Year Follow-up

5. Prevalence of Risk Factors in Patients with Coronary Heart Disease Khot, et al. JAMA 2003;290:898-904

6. Prevalence of Risk Factors in CHD 0 1 2 3 4

7. Emerging Cardiac Risk Factors C-Reactive Protein Lipoprotein (a) Fibrinogen Homocysteine The Four Big Ones

8. Atherosclerosis Current Understanding

10. Endothelium Vessel Lumen Intima Foam Cell Monocyte Cytokines Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation Macrophage Atherosclerosis and Inflammation Ross R. N Engl J Med 1999;340:115-126.

11. LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Adhesion Molecules Foam Cell Intima Modified LDL Cytokines Cell Proliferation Matrix Degradation Growth Factors Metalloproteinases MCP-1MCP-1 Atherosclerosis and Inflammation

12. Anatomy of the Mature Plaque Lumen Lipid Core Fibrous cap Shoulder Intima Media Elastic laminæ Internal External

13. Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap Libby P. Circulation 1995;91:2844-2850. + + + + + + – Synthesis Breakdown Lipid core IL-1 TNF- MCP-1 M-CSF Fibrous cap IFN-  CD-40L Collagen-degradingProteinases Tissue Factor Procoagulant

14. Plaque Rupture with Thrombosis From A Slide Atlas Atherosclerosis Progression and Regression, Parthenon Publishing, 1999

15. Emerging Cardiac Risk Factors C-Reactive Protein Lipoprotein (a) Fibrinogen Homocysteine The Four Big Ones

16. Characteristics of an Ideal Screening Test Presence of reliable assay Independence from other risk factors Presence of populations norms to allow interpretation of test Clear statistical association of test and clinical endpoint Ability to improve prediction beyond traditional risk factors Ability to generalize results to other groups Acceptable cost for assay Circulation 2003;107:499-511

17. C-reactive Protein Circulating acute phase reactant Many-fold increase with injury & infection Synthesized in liver, induced primarily by interleukin-6 (IL-6) Stable levels in circulation, not affected by meals, no circadian levels Level – within normal range – predicts CVD risk

18. Hs-CRP predicts first events

19. hs-CRP and Risk of Future MI in Apparently Healthy Men Ridker PM et al. N Engl J Med 1997;336:973-979. 1 <0.055 Relative Risk of MI P = 0.03 Quartile of hs-CRP (range, mg/dL) 2 0.056–0.114 3 0.115–0.210 4 >0.211 P < 0.001 P Trend <0.001

20. hs-CRP and Risk of Future MI: Analysis Stratified by Smoking Status Ridker PM et al. N Engl J Med 1997;336:973-979. 1 Relative Risk of Future MI Quartile of CRP 234 All Patients Nonsmokers

21. CRP and Risk: Overview of 18 Studies Ridker PM. Circulation 2003;107:363-9

22. Danesh, et al. BMJ. 2000;321:199-204 C-Reactive Protein and CHD

23. CRP and Cardiovascular Risk MI Stroke Peripheral arterial disease Sudden cardiac death Recurrent ischemia and death in: Unstable Angina Myocardial Infarction Percutaneous intervention CRP will Predict:

24. hs-CRP and Risk of T2DM Pradhan, et al. JAMA 2001;286:327-34 P value for trend = 0.001

25. hs-CRP and Risk of Metabolic Syndrome Ridker, et al. Circulation 2003;107:391-7 P value for trend < 0.0001 ATP III Definition of the Metabolic Syndrome Three of the following five characteristics: Midline obesity Elevated TG Low HDL Hypertension Glucose Intolerance

26. CRP, Metabolic Syndrome and CV Events Ridker, et al. Circulation 2003;107:391-7

27. Elevated CRP Levels in Obesity: NHANES 1988-1994 Visser M et al. JAMA 1999;282:2131-2135. Normal Percent with CRP 0.22 mg/dL OverweightObese

28. Does CRP provide predictive information beyond existing global predictors?

29. CRP and Framingham Risk Score Ridker PM. Circulation 2003;107:363-9

30. CRP and LDL Cholesterol Ridker PM. Circulation 2003;107:363-9

31. Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study Relative Risk for Future MI 0 1.02.04.06.0 Lipoprotein(a) Homocysteine Fibrinogen tPA Antigen hs-CRP hs-CRP + TC/HDL-C Total Cholesterol TC:HDL-C Ridker PM. Ann Intern Med 1999;130:933-937.

32. CRP and Risk of MI: Rotterdam Study van der Meer, et al Arch Intern Med 2003;164:1323-8 P Trend = 0.50 Rotterdam Study: Prospective trial of 7093 apparently healthy men and women, age > 55, in which 157 with myocardial infarction were compared with 500 selected controls were compared in nested case control analysis based on baseline CRP levels. CRP compared with Framingham Risk Score (FRS): Receiver operating characteristic curve was not improved when hs-CRP was added FRS: AUC FRS: 0.745 AUC FRS + CRP = 0.748

33. Can intervention lower CRP levels? Statins? Yes Weight loss ?? Smoking cessation?? Physical activity?? No studies to date have shown CRP lowering in itself is associated with reduced event rates!

34. hs-CRP (mg/L) Effect of Statin Therapy on hs-CRP Levels at 6 Weeks Jialal I et al. Circulation 2001;103:1933-1935. 2001 Lippincott Williams & Wilkins. 65432106543210 Baseline * ** Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) *p<0.025 vs. Baseline

35. Routine screening with c-reactive protein?

36. CRP Limitations Most studies limited to North American and European population -- limited ability to extrapolate to Native American, African and South Asian Not good indicator of extent of disease burden Most studies have not adjusted for body-mass- index Strength of association lessoned in some studies when adjusting for other risk factors

38. AHA/CDC Consensus Panel Class I: None Class IIa: In primary prevention, CRP measurement may be useful in those at intermediate risk (10-20% 10-year CHD risk), to help direct further evaluation and treatment. In patients with stable CAD or ACS, CRP may be useful as an independent marker of recurrent events, including death, MI and restenosis following PCI. Circulation 2003;107:499-511 Hs-CRP Recommendations

39. Class IIa: Measurement should be done twice (two weeks apart) and results averaged. If level > 10 mg/L, test should be repeated and patient examined for sources of infection or inflammation Classify risk as follows: Low < 1 mg/L Average 1.0 – 3.0 mg/L High:> 3.0 mg/L Circulation 2003;107:499-511 AHA/CDC Consensus Panel Hs-CRP Recommendations

40. 1.Screening of the population as a whole is NOT recommended 2.Application of secondary prevention measures should not depend upon hs-CRP results 3.Application of management guidelines for acute coronary syndromes should not be dependent upon hs-CRP level 4.Serial CRP levels should not be used to monitor effects of treatment Circulation 2003;107:499-511 AHA/CDC Consensus Panel Hs-CRP Recommendations

41. Emerging Cardiac Risk Factors C-Reactive Protein Lipoprotein (a) Fibrinogen Homocysteine The Four Big Ones

42. Lipoprotein (a) LDL-like particle consisting of apolipoprotein moiety attached to apoB- 100 Levels under genetic control and don’t vary with diet or exercise Acute phase reactant, doubling in concentration after IL-6 stimulation Structural similarities to plasminogen

43. Lipoprotein (a) Danesh, et al. Circulation 2000;102:1082-5

44. Lipoprotein (a) Lp(a) levels not affected by usual lipid lowering drugs; lowered only by high-dose niacin No prospective trials showing reduction of cardiac endpoints with Lp(a) lowering Not recommended for general screening

45. Emerging Cardiac Risk Factors C-Reactive Protein Lipoprotein (a) Fibrinogen Homocysteine The Four Big Ones

46. Fibrinogen Circulating glycoprotein involved in final steps of coagulation Other actions: –Regulation of cell adhesion, chemotaxis and proliferation –Vasoconstriction at sites of vascular injury –Stimulation of platelet aggregation –Influence on blood viscosity

47. Fibrinogen Acute phase reactant, increasing up to 4-fold after infectious or inflammatory stimuli Levels also increased by: –Cigarette smoking –Diabetes –Hypertension –Obesity –Sedentary lifestyle Levels lowered with fibrates and niacin; no effect from statins or aspirin

48. Emerging Cardiac Risk Factors C-Reactive Protein Lipoprotein (a) Fibrinogen Homocysteine The Four Big Ones

50. Causes of elevated Homocysteine Homozygous homocysteinurias MTHFR mutations Others: –Renal failure –Hypothyroidism –Drugs interfering with folate metabolism (niacin)

51. Clinical Consequences of Elevated Homocysteine Clinical studies show increased risk of: –CHD –Stroke –Peripheral vascular disease

52. MTHFR Homozygous AbnormalGeneral Population Wald et al. BMJ 2002;325:1202-9

53. Homocyteine Meta-analysis PopulationOutcomeOdds Ratio Confidenc e Intervals MTHFR Mutation CHD1.211.06-1.31 General Population CHD1.231.14-1.32 General Population Stroke1.421.21-1.66 Wald et al. BMJ 2002;325:1202-9

54. Homocystine and Risk of CHD: ARIC Study ARIC Study. Circulation 1998;98:204-10 P Trend = 0.29 ARIC Study: Prospective trial of 15,792 men and women, age 45-64, in which 232 with incident CHD events 537 selected controls were compared in nested case control analysis based on baseline tHcy levels. Mean f/u 3.3 years.

55. Homocystine and Risk of CHD: ARIC Study ARIC Study. Circulation 1998;98:204-10 Plasma Homocysteine Dietary Folate Plasma PLP (B6) Dietary Vitamin B12 P = 0.24P = 0.14P = 0.001P = 0.29

56. Secondary Prevention with Homocysteine Lowering 593 patients with stable CAD (documented MI, > 60 lesion on cath, PCI/CABG) Prospective, open label Mean follow-up 24 months Leim, et al. J Am Coll Cardiol 2003:41:2105-13 Stable CAD Folate 0.5 mg Standard Care

57. Secondary Prevention with Homocysteine Lowering Leim, et al. J Am Coll Cardiol 2003:41:2105-13 Clinical Events

58. Secondary Prevention with Homocysteine Lowering Leim, et al. J Am Coll Cardiol 2003:41:2105-13 Survival Analysis

59. Homocysteine Reduction After PCI Prospective double-blind, placebo controlled trial 205 patients undergoing PCI randomized to receive: –Folate 1 mg, Vit. B12 400 mcg, Pyridoxine 10 mg OR –Placebo Primary endpoint: angiographic restenosis at 6 months Schnyder et al. NEJM 2001;345:1593-600

60. Folate Supplementation and Renstenosis Schnyder et al. NEJM 2001;345:1593-600 P < 0.001 P = 0.32 P = 0.01

61. Homocysteine Reduction After PCI Schnyder et al. NEJM 2001;345:1593-600

62. Problems with Homocysteine as a Vascular Disease Risk Factor Recent prospective studies in low risk populations have shown little or no risk association between tHcy and CVD Traditional risk factors are often associated with tHcy and may confound results Mutations of MTHFR cause a moderate elevation of tHcy but little or no increased CVD risk

63. AHA Science Advisory Widespread population screening not advised Selective screening should be considered in those with: –Strong family history –Suspected elevated risk Pending results of large clinical trials, treatment to lower homocysteine should be considered experimental

64. Conclusions The majority of those with CHD have traditional risk factors Novel risk factors add little to existing global risk predictors such a Framingham risk score CRP may provide useful information in those at intermediate risk Routine screening of homocysteine levels is not recommended Fibrinogen and Lp(a) screening not recommended