HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY

1. HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY Gary A. Lopez, M.D. Makati Medical Center Asian Hospital and Medical Center

2. Cardiovascular disease is the most frequent cause of mortality in the Philippines , the U.S., and many parts of the world. • Most events caused by acute coronary events from coronary artery disease

3. ATHEROTHROMBOSIS LEADS TO CARDIAC AND VASCULAR EVENTS

4. COEXISTENCE OF ATHEROSCLEROTIC VASCULAR DISEASE

5. Pathology of Acute Coronary Syndrome Plaque Rupture Plaque Erosion Calcified Nodules Luminal Thrombosis Acute Coronary Syndrome

6. Virnani et al., JACC vol. 47, no. 8, 2006

7. FORMATION OF THE FIBROFATTY PLAQUE

8. FORMATION OF THE YOUNG ATHEROSCLEROTIC LESION

9. MATURATION OF THE ATHEROSCLEROTIC PLAQUE

12. AVERAGE COMPOSITION OF ADVANCED CORONARY PLAQUE

14. High-Risk, Vulnerable and Thrombosis-Prone Plaque - synonyms to describe a plaque that is at increased risk of thrombosis and rapid stenosis progression • Inflamed Thin-cap Fibroatheroma - an inflamed plaque with a thin cap covering a lipid-rich, necrotic core. Suspected to be a high risk/vulnerable plaque. • Vulnerable patient - a patient at high risk (vulnerable/prone) to experience a cardiovascular ischemic event due to a high atherosclerotic burden, high risk/vulnerable plaques, and/or thrombogenic blood.

15. NON-INVASIVE TESTS TO IDENTIFY HIGH-RISK CORONARY DISEASE (>10% 1-YEAR RISK OF CARDIAC EVENTS) 1. MRI of the coronary arteries 2. Multislice (64-slice) CT angiography of the coronary arteries with calcium scoring 3. Myocardial perfusion imaging using radionuclide techniques. 4. Positive emission tomography.

16. CORONARY ANGIOGRAPHY • An invasive cardiac diagnostic procedure using catheterization techniques and fluoroscopic visualization. • Should be performed in asymptomatic high-risk patients. • Provide risk stratification to alter therapy.

19. C- REACTIVE PROTEIN • A circulating pentraxin • Produced predominantly in the liver as part of the acute phase response • Expressed in smooth muscle cells within diseased atherosclerotic arteries • Plays a major role in human innate immune response • Provides a stable plasma biomarker for low-grade systemic inflammation

20. C-REACTIVE PROTEIN • Composed of five 23 kD subunits • Has a half-life of 19 hours • Neither consumed nor produced during the reaction. • Ideally 2 assays, averaged, fasting or nonfasting, and optimally 2 weeks apart, provide a more stable level of this marker.

21. C-REACTIVE PROTEIN • Stable for over long periods of time • Has no circadian rhythm • Not affected by food intake • Therefore screening can be done on an outpatient basis at the time of cholesterol evaluation.

22. Cost of high-sensitivity C-reactive protein at Makati Medical Center = 925.00 pesos

23. MECHANISMS OF HSCRP ELEVATION IN RELATION TO ATHEROTHROMBOTIC EVENTS • Unknown • Theories 1. Inflammation of atherosclerotic plaques leading to HSCRP elevation 2. HSCRP may contribute to pathogenesis of atherosclerosis due to interaction with lipids, lipoproteins, complement and coagulation 3. HSCRP is detected in atherosclerotic plaques

24. C-REACTIVE PROTEIN • Mechanisms of influencing direct vascular vulnerability: 1. increased expression of endothelial PAI-1. 2. enhanced expression of adhesion molecules 3. reduced endothelial nitric oxide bioactivity. 4. altered LDL uptake by macrophages 4. colocalization with complement within atherosclerotic lesions. 5. inhibition of intrinsic fibrinolysis

25. THE INFLAMMATORY PATHWAY

26. USES OF ELEVATED HSCRP • Neonatal medicine - infection • Atherosclerotic and coronary heart disease • Osteoarthritis

27. CONDITIONS ASSOCIATED WITH MAJOR ELEVATION OF SERUM CRP • Infections • Allergic complications of infection Rheumatic fever Erythema nodosum leprosum • Inflammatory disease Rheumatoid arthritis Juvenile chronic arthritis Ankylosing spondylitis Psoriatic arthritis Systemic vasculitis Polymyalgia rheumatica Reiter’s disease Crohn’s disease Familial Mediterranean fever • Necrosis Myocardial infarction Tumour embolization Acute pancreatitis Trauma • Surgery Burns Fracrures • Malignant neoplasia Lymphoma, Hodgkin’s disease Carcinoma, sarcoma

28. ROLE OF INFECTION IN ATHEROTHROMBOSIS 1. Clamydia , Helicobacter, Herpes simplex virus and Cytomegalovirus -- lead to systemic inflammation. -- lead to increased risk of cardiovascular events. 2. Clamydia and viral species have been identified in atheromatous lesions.

29. Need 2-3 weeks to check HSCRP in patients with injury or infection due to marked degree of inflammation.

30. Hormonal replacement therapy may augment levels of HSCRP Cushman et al, Citculation 100:717-722;1999

31. NON-PHARMACOLOGIC METHODS TO REDUCE HSCRP 1. WEIGHT REDUCTION 2. EXERCISE

33. VALUE OF HSCRP MEASUREMENTS • Conventional CRP assays cannot quantify serum proteins less than 5 mg/l.

34. HSCRP > 2.5 mg/liter • Two to five-fold increased risk of suffering a coronary event in the future in patients with angina or in healthy normal adult population. • May predict progression of atherothrombotic events in cerebrovascular and peripheral vascular disease.

35. HSCRP > 3 mg/liter • Poor outcome in patients with severe unstable angina ( increased risk of death, acute myocardial infarction, or need for urgent revascularization intervention). • Predicts early reocclusion in patients undergoing PCI.

36. “Your blood pressure and cholesterol are fine, but your hsCRP… “

37. USE OF HSCRP IN PRIMARY AND SECONDARY PREVENTION • More than 24 prospective epidemiologic primary prevention studies evaluated the role of hsCRP as a determinant of vascular risk – all reported positive findings. • 10 of these studies were powered to evaluate the risk prediction role of hsCRP beyond that associated with traditional factors included in global assessment algorithms such as the Framingham Risk Score.

38. HSCRP HAS STRONG PREDICTIVE VALUE IN: 1. currently healthy men 2. currently healthy women 3. elderly people 4. high-risk smokers 5. stable and unstable angina 6. prior myocardial infarction

39. ADDITIVE VALUE OF HSCRP AFTER ADJUSTMENT FOR RISK FACTORS

40. RELATIVE RISKS OF FUTURE CV EVENTS ACCORDING TO BASELINE LEVELS OF HSCRP

41. PROSPECTIVE STUDIES RELATING BASELINE HSCRP LEVELS TO THE RISK OF FIRST CV EVENTS

42. ADDITIVE VALUE OF HSCRP OVER TOTAL CHOLESTEROL, HDL-C AND APO B:APO A RATIO

43. Ridker et al, Women’s Health Study , NEJM, 2002; 347; 1557-65

44. Ridker et al,Clinical application of CRP for CV disease detection and prevention,Circulation 107:363,2003

45. GUSTO IV ACS Trial

47. PROGNOSTIC UTILITY OF HSCRP, TROPONIN, AND BNP IN ACUTE CORONARY ISCHEMIA

48. Baseline levels of HSCRP associate with increased risk of developing Type 2 diabetes mellitus. • Prediction of vascular events is beyond the components of the metabolic syndrome or presence of frank diabetes.

49. NATIONAL HEALTH AND NUTRITION EVALUATION SURVEY (NHANES)

50. Rotterdam Scan Study • Higher HSCRP levels are associated with the presence and progression of cerebral white matter lesions in the periventricular and subcortical regions. • Data implies small vessel disease progression. Van Dijk EJ et al, Circulation, 2005;112:900-5