The 10 th International & 15 th National Congress on Quality Improvement in Clinical Laboratories

The 10 th International & 15 th National Congress on Quality Improvement in Clinical Laboratories

Cardiac biomarkers in atherosclerosis Najma Asadi MD-APCP

Ross and Colleagues in 1973: Response to Injury Hypothesis

Injury to endothelial tissue Infiltration of LDL into arterial intima oxidation

Adhesion molecules expressed on inflamed endothelium Lymphocyte and monocyte penetrate into the intima Produce inflammatory cytokines and chemokines Monocyte change to MQ and ingest oxidized LDL

Foam cells Plaque formation

Production of MMP Rupture of cap thrombosis Occulsion

Inflammatory Biomarkers

CRP Most promising indicator for vascular inflammation. Produce in liver and local site of inflammation or injury. Hs-CRP Vs CRP to detect small changes in CRP concentration.

CRP Higher predictive accuracy when combined with Framingham risk factors. High level of Hs-CRP lead to higher incidence of cardiovascular events. Hs-CRP influenced by infection, tissue damage, obesity, old age, HTN, DM, smoking.

Not all individuals with coronary heart disease have traditional risk factors 3 RF 9% 4 RF 1% 0 RF 19% 2 RF 28% 1 RF 43% Khot et al. JAMA 2003

The Detection Gap in CHD Despite many available risk assessment approaches, a substantial gap remains in the detection of asymptomatic individuals who ultimately develop CHD The Framingham and European risk scores emphasize the classic CHD risk factors. is only moderately accurate for the prediction of short- and long-term risk of manifesting a major coronary artery event Pasternak and Abrams et al. 34 th Bethesda conf. JACC 2003; 41: 1855-1917

Is there clinical evidence that novel risk markers predict future coronary events and provide additional predictive information beyond traditional risk factors?

CRP CRP is an acute-phase protein produced by the liver in response to cytokine production (IL-6, IL-1, tumor necrosis factor) during tissue injury, inflammation, or infection. Standard CRP tests determine levels which are increased up to 1,000-fold in response to infection or tissue destruction, but cannot adequately assess the normal range High-sensitivity CRP (hs-crp) assays (i.e. Dade Behring) detect levels of CRP within the normal range, levels proven to predict future cardiovascular events.

Relative Risk hs-crp Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MI 5.0 4.0 3.0 2.0 1.0 0.0 High Medium Low Low Medium High Total Cholesterol:HDL Ratio Ridker et al, Circulation. 1998;97:2007 2011.

Lipoprotein(a) Homocysteine IL-6 TC LDLC sicam-1 SAA Apo B TC: HDLC hs-crp hs-crp + TC: HDLC Risk Factors for Future Cardiovascular Events: WHS 0 1.0 2.0 4.0 6.0 Relative Risk of Future Cardiovascular Events Ridker et al, N Engl J Med. 2000;342:836-43

Is there clinical evidence that inflammation can be modified by preventive therapies?

Percent with CRP 0.22 mg/dl Elevated CRP Levels in Obesity: NHANES 1988-1994 25 20 15 10 5 0 Normal Overweight Obese

hs-crp (mg/dl) Effect of HRT on hs-crp: the PEPI Study 3.0 CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE 2.0 Placebo 1.0 0 12 36 Months Cushman M et al. Circulation 1999;100:717-722. 1999 Lippincott Williams & Wilkins.

Median hs-crp Concentration (mg/dl) Long-Term Effect of Statin Therapy on hs-crp: Placebo and Pravastatin Groups 0.25 Placebo 0.24 0.23 0.22 0.21-21.6% (P=0.004) 0.20 0.19 Pravastatin 0.18 Baseline 5 Years Ridker et al, Circulation. 1999;100:230-235.

AFCAPS/TEXCAPS showed statins to be effective in lowering risk in the setting of normal LDL-C, but only when inflammation was present AFCAPS/TexCAPS Low LDL Subgroups Low Low LDL, LDL, Low Low hscrp hscrp Low Low LDL, LDL, High High hscrp hscrp [A] [B] 0.5 0.5 Statin Statin Effective Effective 1.0 2.0 RR Statin Statin Not Not Effective Effective 1.0 2.0

[B] However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hscrp but low cholesterol was made on a post hoc basis. Thus, a large-scale 0.5 0.5 randomized trial of statin therapy was needed to directly test this hypotheses. Statin Effective [A] Ridker et al, New Engl J Med 2001;344:1959-65

AHA / CDC Scientific Statement Markers of Inflammation and Cardiovascular Disease: Applications to Clinical and Public Health Practice Circulation January 28, 2003 Measurement of hs-crp is an independent marker of risk and may be used at the discretion of the physician as part of global coronary risk assessment in adults without known cardiovascular disease. Weight of evidence favors use particularly among those judged at intermediate risk by global risk assessment.

Clinical Application of hs-crp for Cardiovascular Risk Prediction 1 mg/l 3 mg/l 10 mg/l >100 mg/l Low Risk Moderate Risk High Risk Acute Phase Response Ignore Value, Repeat Test in 3 weeks Ridker PM. Circulation 2003;107:363-9

Cytokines: HMW polypeptides, deliver signals in: Immunological response Inflammatory reaction Hematopoiesis IL6 and TNFα deeply involved in atherosclerosis

Ridker and Collegues Study: Follow up of 14916 healthy male adult for 6 years IL6 in those developed MI Health ABC cohort study: In 2225 aged 70-79 IL6 was correlated with ischemic cardiac disease, stroke and heart failure chemokines like IL8, interfron-inducible protein of 10KD (IP-10), MCP-1 atherosclerosis

Oxidized LDL as an effective biological indicator for atherosclerosis. LDL oxidation lead to formation of aldehyde products like malondialdehyde-modified LDL (MDA-LDL) is indicator for oxidized LDL. Recent study: circulating MDA-LDL show thin-cap fibroatheroma determined by optical coherence tomography.

Lectin-like oxidized LDL receptor-1 (LOX-1), a major receptor for oxidized LDL in many cells mediate plaque destabilization through apoptosis of smooth muscle cells and also MMP secrection by mature foam cells and also mediate thrombosis after plaque rupture.

LOX-1 express on cell surface of MQ and smooth muscle cell can be cleaved by protease transformed to soluble forms. rise of soluble LOX-1 is seen earlier than cardiac troponint.

Cell adhesion molecules

ICAM-1, VCAM-1, E selection, P-selection are increased in inflammation in atherosclerotic lesion. PECAM-1: A glycoprotectein increased in 3 hours after MI and unstable agina as compared with controls and exersional angina so useful in early diagnosis of acute coronary syndrom.

60 % of acute coronary syndrom caused by plaque rupture which do not necessarily involve significant stenosis. Vulnerable or unstable plaque show: Cholestrole abundance thinning of fibrous cap cap with prominent inflammatory cells necrotic core mild to moderate vasa vasarum neovascularization intraplaque hemorrhage MMP produced by MQ important in fibrous cap thinning and rupture.

MMP1, 3, 8 detected in shoulder region of unstable plaque and important in fibrous cap thinning. Those with acute coronary syndrom had increase level of MMP1, 2, 3, 9. Mortality rate increase in high plasma MMP-9.

MPO: Serum MPO is independent risk factor for coronary artery disease and predict cardiovascular event in emergency department presenting patient with chest pain.

Novel Prediction Markers

Pentraxin3 (PTX3): Acute phase reactant Member of pentraxin family that include CRP. More specific for cardiovascular inflammation. Reflect local inflammatory reaction. Produced by cells involved in atherosclerotic lesion (endothelial, smooth muscle, MQ, PMN, dendritic cells) in response to inflammatory mediators.

Detected in carotid atherosclerotic lesion and coronary with MI and thrombi. Increase concentration in unstable angina. No increase in stable angina with coronary stenosis in angiography. So PTX3 is more specific for coronary plaque instability than for atherosclerosis (produced by PMN penetrating into unstable coronary plaque). High concentration of PTX3 in patient with acute phase MI. More accurate predictor of cardiovascular event after MI than CRP, NT-Pro PNP and troponint But increase in vasculitis and heart failure.

Thank you for your attention