Biomarkers of Cardiac Injury: Troponins and Creatine Kinase-MB
In its inactive state, cardiac muscle has the tropomyosin protein physically blocking the attachment site for the myosin crossbridge. The tropomyosin protein is related to three other proteins responsible for the regulation of this attachment, namely: (1) cardiac troponin C, cardiac troponin I, and cardiac troponin T. Together, these form the troponin-tropomyosin complex. For the muscle to contract, available calcium causes a conformational change to cardiac troponin C that removes the tropomyosin and frees up the attachment site for the myosin heads. Cardiac troponin I is an inhibitory protein responsible for the inhibition of ATPase activity, thereby increasing adenosine triphosphate levels to power muscle contraction. It also modulates calcium binding to cardiac troponin C. Cardiac troponin T is responsible for the attachment of the tropomyosin to the actin filament.
Cardiac troponins I and T are unique to the heart. Their untimely release into plasma occurs when there is pathologic degeneration of the actin and myosin filaments in the heart, because an inherent quality of these proteins is that they have early releasable pools. This is the reason why cardiac troponin I and T are very specific markers for disease entities that cause myocardial damage, such as myocardial infarction, pulmonary embolism with acute right heart overload, heart failure, and myocarditis.
Troponins and Acute Myocardial Infarction
The diagnosis of acute myocardial infarction depends on the presence of clinical and laboratory findings of chest pain, electrocardiogram changes, and elevations of biomarkers indicating cardiac injury. Eighty percent of patients with acute myocardial infarction will have a rise in cardiac troponin levels two to three hours after the event.1 Significant findings of cardiac injury from serum troponins should have a cut-off level at the 99th percentile of the upper normal range limit, with a rise or fall of at least 3 standard deviations between each reading of blood samples taken 6 hours apart.1
The delay in biomarker elevations after a cardiac event should not hinder the administration of reperfusion therapy to patients highly suspected of having experienced an acute ST-elevation myocardial infarction.2 However, in symptomatic patients with no ST elevation, rapid intervention is not a priority. When a patient has intermediate values of cardiac troponins and non-diagnostic ECG changes but there is clinical suspicion of myocardial ischemia or infarction, repeat serial biomarker testing can be performed after four to six hours or more. An elevated troponin in patients with chest pain and no ECG changes is associated with coronary artery disease, and these patients are prone to adverse cardiac events after one year.3 Studies show that both cardiac troponin T and I can prognosticate patients with ST elevation MI and non-ST elevation MI.4-9 A study showed that an increased cardiac troponin T of more than 0.47 ng/ml was associated with a 30-day mortality rate of 7.4%, compared to cardiac troponin T values of less than or equal to 0.01 ng/ml that were associated with an increase in the 30 day mortality rate of only 1.1%.10
Creatine kinase is composed of isoenzymes with M-chains and B-chains. Creatine kinase was formerly known as creatinine phosphokinase. Creatinine kinase (CK) facilitates the transfer of energy phosphates into and out of the mitochondria. It is present in many tissues, particularly skeletal muscles and heart muscles; however, more creatine kinase is seen in the skeletal muscles per gram of tissue as compared to the heart.11 The heart has high concentrations of creatine kinase-MB. Increased serum levels are seen with myocardial damage such as ischemia or infarction, other tissue destruction and even in vigorous exercise. Because of this, elevations in creatine kinase-MB lack specificity for cardiac damage. A two-fold increase in serum levels should be seen before making a diagnosis of myocardial infarction; however, this can be problematic for geriatric patients because of lower muscle mass.
An elevated creatine-kinase MB may be specific for myocardial injury in patients with clinical findings of ischemia, but only if skeletal damage is not present. It increases in plasma four to six hours after myocardial infarction but is not significantly elevated to diagnostic levels until after 12 hours.12-13 Elevations return to baseline 36 to 48 hours after the event.14
The Demise of the Creatine Kinase-MB
Cardiac troponins are more sensitive and specific for myocardial damage than creatine kinase-MB because more troponins are present per gram of myocardium, and a greater percentage arrives in the blood following injury.15 Also, troponin elevations are specific to cardiac injury while, as mentioned -above, creatine kinase-MB is not specific for cardiac injury. The only advantage of creatine kinase-MB over cardiac troponins is its lower cost.15 Cardiac troponin is the preferred biomarker for the diagnosis of myocardial infarction.2
- Macrae AR, Kavasak PA, Lustig V, et al. Assessing the requirement for the 6-hour interval between specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies. Clin Chem 2006; 52:812.
- O’Gara P, Kushner FG, Ascheim DD, wt al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140. doi:10.1016/j.jacc.2012.11.019
- deFilippi CR, Tocchi M, Parmar RJ, et al. Cardiac troponin T in chest pain unit patients without ischemic electrocardiographic changes: angiographic correlates and long-term clinical outcomes. J Am Coll Cardiol 2000; 35; 1827.
- Olatidoye AG, Wu AH, Feng YJ, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis. J Am Coll Cardiol 2001; 38: 478.
- Heidenreich PA, Alloggiamento T, Melsop K, et al. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol 2001; 38: 478.
- Heeschen C, Hamm CE, Goldmann B, et al. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet 1999; 354:1757.
- Giannitsis E, Muller-Bardoff M, Lenke S, et al. Admission troponin T level predicts clinical outcomes, TIMI flow, and myocardial tissue perfusion after primary percutaneous intervention for acute ST-segment elevation myocardial infarction. Circulation 2001; 104:630.
- Ottani F, Galvani M, Nicolini FA, et al. Elevated cardiac troponin levels predict the risk of adverse outcome in patients with acute coronary syndromes. Am Heart J 2000; 140:917.
- Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia.GUSTO IIA Inversigators. N Engl J Med 1996; 335:1333.
- James SK, Armstrong P, Barnathan E, et al. Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy. J Am Coll Cardiol 2003; 41:916.
- Neumeier D. Tissue specific and subcellular distribution of creatine kinase isoenzymes. In: Creatine Kinase Isoenzymes, Lang H (Ed), Springer-Verlag, Berlin/Heidelberg 1981. p. 85.
- Puleo PR, Guadagno PA, Roberts R, at al. Early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-MB. Circulation 1990; 82:759.
- Puleo PR, Meyer D, Wathen C, et al. Use of a rapid assay of subforms of creatine kinase-MB to diagnose or rule out acute myocardial infarction. N Engl J Med 1994; 331:561.
- Jaffe AS, Landt Y, Parvin CA, et al. Comparative sensitivity of cardiac troponin I and lactate dehydrogenase isoenzymes for diagnosing acute myocardial infarction. Clin Chem 1996; 42:1770.
- Saenger AK, Jaffe AS. Requiem for a heavyweight: the demise of creatine kinase-MB. Circulation 2008; 118:2200.