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Szakács Júlia M.D. Department of Pathophysiology Biomarkers in cardiac diseases FAINELLI Manon BOGÓ Ákos Numbers… Cardiovascular diseases The most frequent cause of death 7.5 millions of death/ year Important concerns in developed countries Cardiac diseases Ischemic diseases Stable angina Unstable angina Ischemic heart diseases: hypoxia or anoxia as a result of decrease or arrest of oxygen delivery ACS: obstruction of coronary arteries by a thrombus NSTEMI Acute coronary syndrome (ACS) STEMI Myocardial infarction (MI) Cardiovascular risk factors Age Genetics Smoking Arterial Hypertension Type II diabetes mellitus Inflammatory markers : CRP, endothelin… Protective factors: HDL-level Atherosclerosis Progressive complex chronic inflammatory disease accumulation of oxidized LDL inflammatory cells calcifications and of fibrosis leading to plaque formation this set modifies the intima of large and medium artery vessels Atherosclerosis Essentials of Pathophysiology: Concepts of Altered Health State; C. MATTSON PORTH and G.MATFIN Myocardial infarction (MI) Acute myocardial ischemia leading to myocardial necrosis Diagnosis Cardiac biomarker levels And at least of this items : Clinical symptoms of ischemia Modification of ST-segment Pathological Q waves Demonstration of loss cardiac muscle or function Thrombus into coronary artery Clinical classification Type 1: spontaneous MI due to ATS Type 2: secondary to an ischemic imbalance (e.g. coronary spasm, emboli, anemia) Type 3: sudden cardiac death when biomarkers value are not available with new ischemic ECG changes or new LBBB Type 4 and 5: MI related to revascularization procedures European Heart Journal (2012) 33, 2551–2567 Clinical symptoms of MI chest pain (>20min) not affected by position changing), not relieved by nitroglycerine radiation of pain to the lower jaw or the left-arm, even gastric pain. Less specific symptoms: nausea or vomiting, dyspnea, asthenia palpitations, sweating fainting European Heart Journal (2012) 33, 2551–2567 Heart failure abnormality of the structure or the function of myocardium, which prevents enough oxygen delivery to satisfy the metabolic needs of the tissues, at a normal filling blood pressure 2 categories Heart failure with Preserved Ejection Fraction (HF-PEF) Heart Failure with Reduced Ejection Fraction (HF-REF) Different states Asymptomatic Acute Chronic Compensated/Decompensated Congestive Clinical classification: NYHA European Heart Journal (2012) 33, 1787–1847 Clinical symptoms and signs of HF Clinical symptoms Breathlessness Orthopnea Paroxysmal nocturnal dyspnea Reduced exercise tolerance Asthenia Signs Elevated jugular venous pressure Hepatojugular reflux, hepatomegaly Gallop rhythm (3rd heart sound) Laterally displaced apical impulse Cardiac murmur Peripheral edema Pulmonary crepitations „Heart failure in a nutshell” (From: rickolddoc.wordpress.com) European Heart Journal (2012) 33, 1787–1847 BIOMARKERS Definition: -measurable and quantifiable biological parameter -suitable for early diagnosis, prognosis, follow-up and risk stratification -cardiospecific with enough released concentration levels -easily measurable (quick and adapted to emergency situations) -accurate -reproducible -cost-effective Chan D, Ng L.L. Biomarkers in acute myocardial infarction. BMC Med. 8:34 2010. Inflammation CRP Peak and return to the base line are too late Correlation with MI can help to stratify, to screen ischemic heart disease and seems to be a prognostic factor of acute or chronic HF But lack of specificity -> prentraxin-3 = treatment Other inflammatory proteins IL-6 and TNF-α: asymptomatic HF screening PaPPA: risk of cardiovascular death and future MI prediction Oxidative stress : indirect markers Plasmaoxidized low density lipoproteins 8-isoprostane urinary levels correlate with matrix metalloproteinases levels: predicting the risk of ventricular remodeling and more severe HF Myeloperoxidase: death caused by HF or MI Uric acids indicates detrimental prognosis in HF Neurohormones Activation of Sympathetic nervous system Renin-angiotensine-aldosterone system Norepinephrin ↑ Components ↑ Predictors of mortality Gerald W. Dorn II Circulation Research. 2011;108:1270-1283 Big Endothelin-1 Elevated level post-MI Predictor of death and hospitalization CTproET1 is in use for measurement Arginin Vasopressin Elevated level post-MI Persistently → heart failure / mortality For measurements: Copeptin (in combination with cTns) Biomarkers Copeptin is marked on this illustration post-MI Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:252-64. 2012 Myocyte injury Severe cardiac disease impairs the heart Injury of cardiac muscle → release of biomarkers Biomarkers reach the circulation with delays http://slideplayer.com/slide/258211/ Biomarkers Following Tissue Ischemia Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:252-64. 2012 Choline Component of cell membrane (not specific) Ischemia, necrosis, ACS Predictor of cardiac arrest or death H-FABP Cytosolic, low molecular weight protein Mainly expressed in myocardium Associated with MI, heart failure and death Combined with cTnI → higher sensitivity and NPV Ischemia modified albumin (IMA) Most frequent plasma protein Ischemia → not able to bind divalent ion albumin cobalt binding test Rapid elevation Contradictory results Hs-Tn High sensitivity troponin assays Biomarkers Following necrosis Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:252-64. 2012 Cardiac troponins (cTns) Complex of three regulatory proteins cTnI and cTnT is in use Specificity! Widest diagnostic window Preferred for MI detection and diagnosis Indicate poor prognosis The only biomarkers influencing the treatment Creatine kinase (CK-MB) BM isotype – specific for myocardium Former „gold standard” in MI diagnostics Predictor of hospitalization and death Less sensitive /specific Myoglobin Cytoplasmic heme protein Not specific! Earlier Early AMI detection (often in combination with cTns) Biomarkers Induced by myocyte stretch Kehl DW, Iqbal N, Fard A, Kipper BA, De La Parra Landa A, Maisel AS. Biomarkers in acute myocardial injury. Translational Research. 159:252-64. 2012 Myocyte stress N-terminal pro-B-type natriuretic peptide (NT-proBNP) Inactive by-product of pro-BNP cleavage MI, heart failure and possibly ACS too Others MR-proANP MR-proAdrenomedullin ST2 (plus IL-33) Conclusion Nowadays, no perfect biomarker Need more studies Leads to a multimarker strategies Thank you for your attention !