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HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY Gary A. Lopez, M.D. Makati Medical Center Asian Hospital and Medical Center 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 ATHEROTHROMBOSIS LEADS TO CARDIAC AND VASCULAR EVENTS COEXISTENCE OF ATHEROSCLEROTIC VASCULAR DISEASE Pathology of Acute Coronary Syndrome Plaque Rupture Plaque Erosion Luminal Thrombosis Acute Coronary Syndrome Calcified Nodules Type of Vulnerable Plaque Frequency Plaque Rupture 55 – 60% Plaque Erosion 30 – 35% Calcified Nodule 2 – 7% Pathological Findings Numerous neutrophils, Macrophages and monocyte infiltration of thrombus Few or absent macrophages and lymphocytes Fibrin in between bony spicules along with osteoclasts and inflammatory cells Virnani et al., JACC vol. 47, no. 8, 2006 FORMATION OF THE FIBROFATTY PLAQUE FORMATION OF THE YOUNG ATHEROSCLEROTIC LESION MATURATION OF THE ATHEROSCLEROTIC PLAQUE AVERAGE COMPOSITION OF ADVANCED CORONARY PLAQUE High-Risk, Vulnerable and ThrombosisProne 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. 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. 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. 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 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. 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. Cost of high-sensitivity C-reactive protein at Makati Medical Center = 925.00 pesos 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 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 THE INFLAMMATORY PATHWAY USES OF ELEVATED HSCRP Neonatal medicine - infection Atherosclerotic and coronary heart disease Osteoarthritis 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 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. Need 2-3 weeks to check HSCRP in patients with injury or infection due to marked degree of inflammation. Hormonal replacement therapy may augment levels of HSCRP Cushman et al, Citculation 100:717-722;1999 NON-PHARMACOLOGIC METHODS TO REDUCE HSCRP 1. WEIGHT REDUCTION 2. EXERCISE VALUE OF HSCRP MEASUREMENTS Conventional CRP assays cannot quantify serum proteins less than 5 mg/l. 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. 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. “Your blood pressure and cholesterol are fine, but your hsCRP… “ 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. 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 ADDITIVE VALUE OF HSCRP AFTER ADJUSTMENT FOR RISK FACTORS RELATIVE RISKS OF FUTURE CV EVENTS ACCORDING TO BASELINE LEVELS OF HSCRP PROSPECTIVE STUDIES RELATING BASELINE HSCRP LEVELS TO THE RISK OF FIRST CV EVENTS ADDITIVE VALUE OF HSCRP OVER TOTAL CHOLESTEROL, HDL-C AND APO B:APO A RATIO Ridker et al, Women’s Health Study , NEJM, 2002; 347; 1557-65 Ridker et al,Clinical application of CRP for CV disease detection and prevention,Circulation 107:363,2003 GUSTO IV ACS Trial PROGNOSTIC UTILITY OF HSCRP, TROPONIN, AND BNP IN ACUTE CORONARY ISCHEMIA 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. NATIONAL HEALTH AND NUTRITION EVALUATION SURVEY (NHANES) 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 Recent observations 1. Statins lower CRP in a manner largely independent of LDL-C reduction. 2. Efficacy of statin therapy may be related to the underlying level of vascular inflammation as detected by HS-CRP. CHOLESTEROL AND RECURRENT EVENTS (CARE) TRIAL Risk reduction with Pravastatin was greater in patients with elevated HSCRP Pravastatin significantly reduced elevated HSCRP levels over a 5-year period PRAVASTATIN OR ATORVASTATIN EVALUATION AND INFECTION THERAPY-THROMBOLYSIS IN MYOCARDIAL INFARCTION 22 TRIAL (PROVE IT-TIMI 22) 1. level of HS-CRP achieved after initiation of statin therapy is as important as LDL-C for subsequent vascular events. 2. best overall survival was seen not only with patients whose LDL-C was lowered to <70 mg/dl but also whose HS-CRP lowered < 2 mg/l. 3. this result was present regardless of statin regimen used. 4. measuring and monitoring of HS-CRP following initiation of statin therapy may be required to maximize benefit similar to use of LDL-C. Ridker et al, NEJM, 2005; 352: 20-8 PROVE IT - TIMI 22 – CUMULATIVE RATE OF RECURRENT M.I. OR DEATH AMONG STATIN-TREATED PATIENTS ACCORDING TO ACHIEVED LEVELS OF LDL-C AND HSCRP PROVE IT - TIMI 22 – RATE OF RECURRENT M.I OR DEATH AMONG STATIN-TREATED PATIENTS ACCORDING TO LDL-C AND HSCRP AFTER 30 DAYS REVERSAL study Patients were randomized to moderate lipid lowering with Pravastatin 40 mg or intensive lipid lowering with Atorvastatin 80 mg for 18 months. Measurement of atherosclerotic burden by IVUS was carried out during baseline catheterization and at study completion. 502 patients completed the trial, 249 on Pravastatin and 253 for Atorvastatin. The 2 treatment groups were well matched: ave. age was 56 yrs, about 70% were male, and 20% were diabetic. Baseline LDLcholesterol was 150 mg/dl in both groups, triglycerides 197 mg/dl, and C-reactive protein (CRP) approximately 3 mg/dl. By the end of the treatment group, LDL-chol was significantly lower among patients who had been randomized to the Atorvastatin group. REVERSAL STUDY : Secondary Endpoints Endpoints Pravastatin ( n=249) Atorvastatin ( n=253) P value, Pravastatin vs. Atorvastatin Change in total Atheroma Volume (mm3) + 4.4 -0.9 .02 * P value vs baseline .01 ** .72 ** -- Change in % obstructive Volume (%) +1.6 +0.2 .0002 * P value vs baseline .0001 ** .18 ** -- Change in hsCRP (%) -5.2 -36.4 * Wilcoxon signed rank test **Wilcoxon rank sum test ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL MARKERS OF CV RISK Marker Assay conditions standardized? Prospective studies consistent? Additive to total cholesterol and HDL-C? Additive to Framingham risk? Lipoprotein (a) - +/- +/- - Homocysteine + + +/- - Tissue plasminogen activator and PAI-1 +/- + +/- - Lipoprotein density - +/- - - Fibrinogen - + + - Highsensitivity CRP + + + + Ridker et al, Risk Factors for Atherothrombotic Disease, 2005, 939-54 ACC/AHA CLASSIFICATIONS Class 1 Conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective. Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa Weight of evidence/opinion is in favor of usefulness/efficacy Class IIb Usefulness/efficacy is less well established by evidence/opinion. Class III Conditions for which there is evidence and/or general agreement that a procedure /treatment is not useful/effective and in some cases may be harmful. ACC/AHA GUIDELINES FOR THE MANAGEMENT OF PATIENTS WITH UNSTABLE ANGINA AND NON-ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION Nov, 2002 II. Initial evaluation and Management B. Early Risk Stratification Recommendations Class IIb 1. C-reactive protein (CRP) and other markers of inflammation should be measured. CENTERS FOR DISEASE CONTROL AND PREVENTION / AMERICAN HEART ASSOCIATION MARKERS OF INFLAMMATION AND CARDIOVASCULAR DISEASE: A STATEMENT FOR HEALTHCARE PROFESSIONALS It is reasonable to measure HSCRP as an adjunct to the major risk factors to further assess absolute risk for coronary disease primary prevention – optional. HSCRP measurement appears to be best employed to detect enhanced absolute risk in persons in whom multiple risk factor scoring projects a 10-year CHD risk in the range of 10% to 20% - intermediate risk. Pearson et al, Circulation, 2003; 107:449 CDC/AHA ISSUES ON HSCRP 1. When and in whom should HSCRP be used? 2. What is the purpose for its measurement and the likelihood that further diagnostic and therapeutic plans change on the basis of tests results? 3. No clinical trials have been completed in which a population has been randomly allocated to HSCRP screening and both groups followed up prospectively to determine the benefits and harms of the screening. 4. Few data on the cost-effectiveness of screening with HSCRP, taking into account further testing and treatment of persons classified as being at low risk. CDC/AHA RECOMMENDATIONS 1. HSCRP > 3.0 mg/L (high risk) – may allow intensification of medical therapy to further reduce the risk and to motivate patients to improve their lifestyle or comply with medications prescribed to lower their risk. 2. Low risk individuals (<10% in 10 years) will unlikely to have a high risk (>20%) identified thru HSCRP testing. 3. High risk individuals (>20% in 10 years) or with established atherosclerotic disease generally should be treated intensively regardless of their HSCRP levels. (limited use of HSCRP in secondary prevention). CDC/AHA RECOMMENDATIONS 4. In patients with stable coronary disease or acute coronary syndromes, HSCRP measurement may be useful as an independent marker for assessing likelihood of recurrent events, including death, myocardial infarction, or restenosis after PCI. 5. Secondary preventive interventions with proven efficacy should not be dependent on HSCRP levels. 6. Serial testing of HSCRP should not be used to monitor effects of treatment. The CDC/AHA Workshop identified CRP as the current analyte of choice , but do not support its use in risk prediction or patient management at this point in time. ISSUES ON HS-CRP No firm data to date that lowering CRP levels per se will lower vascular risk. It remains controversial whether CRP plays a direct causal role in atherogenesis. CONCLUSION Data for high-sensitivity C-reactive protein provides evidence that biomarkers beyond those taditionally used for vascular risk detection and monitoring can play important clinical roles in prevention and treatment. Thank You