Cardiac enzymes. 2 – Non enzyme proteins The Troponins Dr Muhammad Ramzan

Cardiac Troponin – the definition A muscle protein Cardiac Troponins are the regulatory proteins that control the Calcium mediated interactions B/W Actin and Myosin Cardiac Troponin consists of 2 subunits and include Troponin I (cTnI) and Troponin T (cTnT)) www.merriam – Webster.com – J Clin Pathol.2004

Cardiac Troponins (cTn) – the background non enzyme proteins Troponin is a muscle protein of 3 subunits (cTnI, cTnT and TnC) and a part of native Tropomycin Cardiac Troponin are low/absent in smooth muscles Have different Amino acid sequence for their detection through Monoclonal antibody assay Troponins are released into the plasma in response to cardiac (MI) and skeletal muscle damage Alpert et al,2000 – www.emedicine.medscape.com

Cardiac Troponins – the properties bound and free floating cTn are coded by specific genes and are : Unique to Cardiac muscles Have shorter half life of 90 minutes appear 3-4 hours after symptoms Alpert et al,2000 (Tunstall- Paedo et al. 1994) – www.wikepedia.com

Cardiac Troponin – the properties cont. Majority of the cTn are bound to myofilaments but remainder is free floating in the cytoplasm This is in comparison to the CKMB which is fully Cytosolic cTn levels are normally too low to be detected in plasma or have no base line Alpert et al,2000 (Tunstall- Paedo et al. 1994) – www.wikepedia.com

cTn – Cytosolic and filamentous 2 peaks

Release of cTn – the mechanism injury to the cardiac Cell membrane Cardiac injury occurs when membrane of normal cardiac myocyte is damaged ( Ischaemia /MI) It results in the loss of Troponin; intracellular/ structural proteins like Troponins; Enzymes, blood and : Myoglobin into Extra cellular space – cardiac biomarkers The subsequent release is maintained by the degradation of the Actin and Myosin filaments www.emedicine.medscape.com

Release of cTn – the mechanism

Cardiac Troponin – 2 Types There are 2 types of Troponins, present in cardiac muscles with certain differences These are: Cardiac Troponin T - cTnT Cardiac Troponin I - cTnI

Cardiac Troponin – Pattern of rise and fall 2 Peaks and clearance cTn has 2 peaks – an early/Cytosolic and late/muscular Cytosolic pool is released first in the blood - 6- 12hrs Late peak is achieved in 24 hrs by muscle degradation cTn is cleared lately ( 2 wks), opposite to the CKMB which gets cleared in 3- 4 days cTn I value of >20ng/ml is diagnostic of 90% cases of MI Neumayr et al,2001- www.backmanscientific.com – www.emedicine.medscape.com

Elevation of Troponins in MI >20ng/ml – 90% MI

Causes of elevated cTn These are divided into 2 1. Cardiac /CAD causes – the commonest and major ones include Myocardial infarction or MI 2. Non CAD causes are variable and include ones that are not related to the cardiac ones

Elevated cTn – Non CAD conditions Elevated levels of cTn are also found in non coronary artery disease (CAD) related conditions Like: Critically ill patients with non CAD – 50% Tachycardia - 28% Pancreatitis/heavy exercise - 10% Heart failure - 5% Bakshi et al; 2002 – Korff et al;2006

Diagnostic value of cTn Detection and monitoring of the cTn is the new standard in the differential diagnosis of the : Unstable angina and non ST elevation MI 1 It is also significant in the following conditions: Acute MI and Myocardial re- infarction Post procedural MI and diagnosis of MI after non cardiac surgery 3 Braunwald et al;2000 -

Cardiac biomarkers - significance the features These are the molecules released into blood after myocardial damage and enhance the ability of the clinician: to manage the patient after chest pain. (blood, urine and tissues) The important cardiac biomarkers are : The Typical rise and gradual fall of cTn or : 1 A more rapid rise and fall in CKMB and others 2 Rama Chandran Vasan ;2006

Myocardial infarction (MI) - the definition It is the death of an area of myocardium as a result of sudden and complete obstruction of blood supply Most common cause of the MI is the occlusion of the coronary artery or one of its branches MI is evaluated by the history; Physical examination, cardiac biomarkers, ECG, cardiac imaging

Criteria for MI – 2 Classes Expert consensus document Criteria for the diagnosis of MI is divided into 2 according to the Expert Consensus Document (ECD) ECD was agreed upon by the experts from the : European Society of Cardiology (ESC), American College of Cardiology (ACC) and American Heart Association (AHA) 1. Criteria for an acute, evolving or recent MI 2. Criteria for the established MI

Diagnosis of MI by ECD criteria Following is the ECD criteria for the : 1 Acute, evolving or recent MI 2. Established MI

Diagnosis of acute /recent / evolving MI Diagnosis of acute /recent / evolving MI. (A) one of the biomarkers + ECG changes Either one of the following criteria, satisfies the diagnosis for acute/evolving/recent MI 1. Cardiac Biomarkers: Typical rise and gradual fall of cTn or More rapid rise and fall (CKMB) (one of cardiac bio markers- cTn – CKMB ) the

Diagnosis of acute/recent. B ECG changes/symptoms At least one of the followings: 1. Severe pain/pressure in the chest 2. Development of pathological Q wave on ECG, 3. ST segment elevation or depression 4. Coronary artery intervention angiography /angioplasty J Am Coll Cardiol Sep;36(3): 959- 69 –ESC/ACC/AHA

Normal Electrocardiogram - ECG

Pathological Q wave

MI – ST segment elevation

MI- ST segment depression

Criteria for the Established MI ECG and structural heart changes Any one of the following criteria satisfies the diagnosis for the established MI. 1 Development of fresh pathological Q waves on serial ECG 3. Findings of a healed/healing MI on Echo - Imaging Biomarkers may have been normalized (1. New patho.Q wave 2. echo +imaging of healed infarcts)

Difference B/W Cardiac Troponins (cTn) and Creatine Kinase (CK- CKMB) Serial NO Cardiac Troponins CKMB 1 Are non enzyme proteins Are enzyme proteins 2 Are specific to cardiac myosites Also present in skeletal muscles 3 Normal serum levels are too low to be detected, has no base line Normal serum levels are detected – has base line 4 Majority is bound to cardiac myofilaments Majority is unbound and fully Cytosolic 5 Rapid rise and gradual fall with Late clearance Rapid rise and fall in MI early clearance 6 Elevated levels Predicts the adverse out come in CAD No such property 7 Predicts the infarct size Do not predict

Cardiac biomarkers- the time table