Cardiac Enzymes


Article Author:
Saikrishna Patibandla


Article Editor:
Khalid Alsayouri


Editors In Chief:
Casey Ciresi


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/3/2019 8:49:48 AM

Introduction

Cardiac enzymes have been in use since the mid 20th century in evaluating patients with suspected acute myocardial infarction (MI). The biomarkers used back then are not clinically relevant today as more sensitive and specific biomarkers have replaced them. Troponins are the most widely recognized and important cardiac enzymes used in the diagnosis of acute myocardial ischemia in modern medicine. The majority of patients with an acute MI will have elevation in troponins within 2 to 3 hours of arrival at the emergency department, versus 6 to 12 hours with creatine kinase.

Diagnostic Tests

The first biomarker used to aid in the diagnosis of acute MI was aspartate aminotransferase (AST). In 1954, Ladue et al. proposed that AST released from cardiomyocytes undergoing necrosis would be useful in diagnosing acute MI.[1] AST increases in the blood 3 to 4 hours after an acute MI, peaks at 15 to 28 hours and returns to baseline within 5 days. In current clinical practice, AST has fallen out of favor for diagnosing acute MI because it is not a specific marker for cardiac myocytes. AST levels in the blood elevate in hepatic disease (e.g., hepatitis, hepatic congestion), pericarditis, pulmonary embolism, and shock and as a result, is not used in the diagnosis of acute MI anymore.

After discovering that AST was released from ischemic cardiac myocytes, lactate dehydrogenase (LDH) emerged as another potential biomarker for detecting myocardial ischemia. LDH increases in the blood 6 to 12 hours after an acute MI, peaks within 24 to 72 hours and normalizes within 8 to 14 days. In the past, a ratio of LDH1 (an isoform found in the heart) to LDH2 greater than 1 was considered to be specific for an acute MI.[2] Since it is not a specific marker for cardiac myocytes, and its levels can also increase in many other conditions, LDH is no longer used in the diagnosis of myocardial infarction. Nowadays, the only usage for LDH in the evaluation of acute MI is to differentiate acute from subacute MI in patients with elevated troponin levels and normal creatine kinase (CK) and CK-MB levels.[3] Blood LDH levels are still valuable for detecting erythrocyte hemolysis and for evaluating the management and prognosis of certain tumors such as testicular germ cell tumors.[4] 

Myoglobin is a heme protein found in cardiac and skeletal muscle tissue. Due to its low molecular weight, myoglobin can be detected in the blood 1 hour after myocardial injury, peaks within 4 to 12 hours, and then immediately return to baseline levels.[5] As a result, it had some diagnostic value alongside CK-MB for faster detection of acute MI. Although troponins have largely replaced myoglobin in the detection of acute MI, myoglobin is still valuable in the evaluation of skeletal muscle injury due to rhabdomyolysis.

Heart-type fatty acid-binding protein (H-FABP) is a protein involved in fatty acid metabolism in cardiac myocytes. In a study by Kabekkodu et al., the sensitivity of H-FABP in detecting acute MI in patients who present within 4 hours of the onset of symptoms was 60%, which was significantly higher than that of troponin (18.8%) and CK-MB (12.5%). The sensitivity of H-FABP in detecting acute MI between 4 to 12 hours after symptom onset was 86.96%, which was comparable to troponin (90.9%) and higher than CK-MB (77.3%).[6] However, it is also important to note that the specificity of H-FABP in detecting acute MI was less than that of troponin and CK-MB.[6] Despite its high sensitivity in detecting myocardial ischemia, H-FABP is not clinically used in the United States and has yet to undergo rigorous testing against high sensitivity troponin assays. (hs-TnT). Thus, H-FABP is not suitable as a stand-alone test for diagnosing acute MI but may have some value as an adjunctive test in specific patient populations.

CK-MB still holds some diagnostic value in cardiac and non-cardiac conditions. CK-MB is detected in the serum 4 hours after myocardial injury, peaks by 24 hours, and normalizes within 48 to 72 hours. CK-MB is a useful biomarker for detecting acute MI as it has a relative specificity for cardiac tissue but can still become elevated in non-cardiac conditions such as skeletal muscle injury, hypothyroidism, chronic renal failure, and severe exercise. The ratio of CK-MB2 to CK-MB1 greater than or equal to 1.5 and a CK-MB relative index (CK-MB/total CK x 100) greater than or equal to 2.5 improve specificity for cardiac tissue and are indicative of acute MI.[7] Since CK-MB normalizes 48 to 72 hours after myocardial ischemia (vs. troponins, which can persist for days), it can be useful in detecting re-infarction if levels rise again after declining.

Cardiac troponin is currently the first-line test for evaluating patients with suspected acute MI. Troponin is a protein found in both cardiac and skeletal muscles that play a role in muscle contraction. It is comprised up of three subunits, troponin C, troponin I and troponin T. Troponin I and troponin T in the heart are structurally different than the ones found in skeletal muscle, making them specific and sensitive biomarkers of cardiac myocyte injury. As a result, the European Society of Cardiology and American College of Cardiology guidelines released in September 2000, defined acute MI as an elevation in serum troponin greater than the level that expected from the 99 percentile of a healthy reference population supported by signs and symptoms of cardiac ischemia.[8] This was also corroborated by the 2007 World Task Force definition of MI, which stated that acute MI is accurately determined based on at least one troponin value over the 99th percentile of the upper reference limit in tandem with signs and symptoms of cardiac ischemia, electrocardiogram changes, and/or imaging findings suggestive of wall motion abnormalities or the loss of viable myocardium.[9] Troponin T and troponin I levels in the blood rise as early as 4 hours from the onset of acute MI symptoms, peaks in 24 to 48 hours, and remain elevated for multiple days thereby making them useful for detecting initial ischemic events but not reliable to detect re-infarction.[10] High-sensitivity troponin assay (hs-TnT), a test developed to detect troponin at much lower concentrations than what the conventional troponin tests can detect, allows for more rapid diagnosis in patients admitted to the hospital suspected to have acute MI. In a Japnese multicenter study, hs-TnT was found to have superior diagnostic value, compared to other cardiac biomarkers, in diagnosing acute MI within the first 3 hours of admission in patients with negative initial troponin T levels. Researchers also noted that this test had 100% sensitivity and negative predictive value in diagnosing acute MI, but the specificity was limited.[11]

Interfering Factors

Cardiac troponins are the standard, first-line blood test used to diagnose acute MI. However, cardiac troponins may be elevated in cases unrelated to cardiac ischemia. Elevated levels of cardiac troponins can occur due to open-heart surgery, post percutaneous coronary intervention, acute pulmonary embolism, end-stage renal disease, pericarditis, myocarditis, Stanford A aortic dissection, acute or chronic heart failure, strenuous exercise, cardiotoxic chemotherapy, radiofrequency catheter ablation of arrhythmias, cardioversion of atrial fibrillation or atrial flutter, defibrillation for ventricular fibrillation or tachycardia, amyloidosis, cardiac contusion from blunt chest wall trauma, sepsis, and rhabdomyolysis.[12] Another study has shown that aortic valve disease, apical balloon syndrome, bradyarrhythmia, endomyocardial biopsy, hypertrophic cardiomyopathy, tachyarrhythmias and non-cardiac causes such as acute pulmonary edema, chronic obstructive pulmonary disease, pulmonary hypertension, stroke, and subarachnoid hemorrhage can also cause cardiac troponins to become elevated in the blood.[7] These conditions may increase cardiac troponin concentration in the blood due to a mismatch between cardiac oxygen supply and demand even in the absence of coronary artery disease. 

The diagnosis of myocardial infarction requires that cardiac troponin levels must be above the 99 percentile upper reference limit for the assay in use and that there is clinical evidence of myocardial ischemia. Thus an elevated cardiac troponin level in the blood without clinical evidence of myocardial ischemia (e.g., symptoms of acute MI, ECG abnormalities, wall motion abnormalities) should prompt a search for other underlying conditions.

Results, Reporting, Critical Findings

Current recommendations recommend that troponin testing should be available in all hospitals 24/7 with a turnaround time of 60 minutes.

In addition to its application as a diagnostic marker for MI, elevated levels of troponin also have prognostic significance; high levels suggest an elevated risk for adverse cardiac events. Further, data show that increasing levels of troponin and creatinine are strong predictors of worsening of congestive heart failure.

Clinical Significance

Cardiac troponins are specific and sensitive biomarkers of cardiac ischemia, and they are the preferred blood test in the evaluation of patients suspected to have acute MI. There are sensitive and highly sensitive assays to detect cardiac troponin levels in the blood. The highly sensitive troponin assay obtained approval for use in the USA in 2017. Although CK-MB has a high sensitivity for cardiac myocytes, it should not be used as a first-line diagnostic test if cardiac troponin assays are available. In the absence of cardiac troponin assays, CK-MB can be useful in the evaluation of acute MI, but it is far less sensitive and specific than cardiac troponins. Since cardiac troponin levels remain elevated in the blood for multiple days after an acute MI, they are not useful in evaluating for re-infarction of cardiac myocytes (another MI). CK-MB levels normalize 48 to 72 hours after an acute MI, so a rising level in the blood after normalization can confirm that another MI has occurred.

Clinicians need to understand that cardiac markers are not mandatory in patients who present with acute chest pain mimicking angina and ECG evidence of ST-segment elevation. These individuals are candidates for primary coronary intervention or thrombolytic therapy. One should not delay treatment waiting for cardiac markers because their sensitivity is not high in the early hours after an infarct.

Enhancing Healthcare Team Outcomes

The correct diagnosis of acute MI requires an interprofessional team of healthcare professionals that includes laboratory technologists, nurses, and physicians. Measuring the blood levels of cardiac troponins is one of the first steps in reaching a diagnosis. Swift diagnosis of acute MI is crucial, as the less the time from symptom onset to reperfusion therapy is vital for improved long-term outcome of heart function.[13] The path to diagnosing acute MI starts with the physician ordering a cardiac troponin blood test, the nurses drawing blood and sending it to the appropriate laboratory and the laboratory technologists accurately measuring blood titers of cardiac troponins and posting the result on the electronic medical records.


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Cardiac Enzymes - Questions

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A 60-year-old female with a past medical history of hypertension and type 2 diabetes presents to the emergency room with pressure like discomfort in her lower chest and upper abdomen. She states that it started 1 hour ago with an initial episode lasting 30 minutes. It wasn’t worsened by lying down. She took an antacid and aspirin, and tried to sleep but was awoken from sleep by a repeat episode that was worse than the first episode. An initial ECG in the emergency room was done, and it showed horizontal ST depressions, tall wide R waves, upright T waves in V1-V3 with an R/S ratio > 1 in V2. Which laboratory results would be expected?



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A 55-year-old female is brought in by EMS with her daughter after feeling shortness of breath with chest discomfort, and a STEMI alert is called in the emergency room. An EKG is done and shows mild ST elevation changes in the precordial leads. The patient is given aspirin, and upon physical exam, it is noted that she has a right-sided weakness. Labs are drawn at this time. A CT scan of the head is done to evaluate for acute stroke and is negative for intracranial bleeding. The patient is given tissue plasminogen activator. An echocardiogram was done and showed wall motion abnormalities of the left ventricular apex with ballooning noted. Her lab results are notable for a troponin I level moderately elevated at 2.7 ng/ml. She again mentions chest discomfort and a repeat EKG shows a resolution of the ST elevations seen on the prior ECG and T wave inversions in leads V2-V4. The patient is crying and distressed, which her daughter attributes to a history of previous emotional grief. Which of the following is the next best step in the management of this patient?



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A client presents with acute chest pain radiating to the left arm and diaphoresis. Only a small amount of blood could be drawn from the client. Which of the following initial laboratory tests are the MOST appropriate based on this presentation? Select all that apply.



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A 75-year-old male with a history of hypertension, coronary artery disease, and hyperlipidemia presents to the emergency department with a complaint of a midline, retrosternal, squeezing and pressure-like chest pain that began 30 minutes ago while he was actively exercising at home. No aggravating or alleviating factors are mentioned. His vital signs are stable. An ECG shows non-specific changes. His initial troponin as 0.02 ng/mL. His troponin and ECG are repeated six hours later and later show a level of 0.98 ng/mL and ST elevations in V1-V3. At this time, he is medically optimized and is urgently taken to the cardiac catheterization lab. An 80% occlusion of the proximal LAD is found on angiography, and the patient receives a stent after which he is started on dual antiplatelet therapy with aspirin and ticagrelor and monitored. Four days after his myocardial infarction, he again complains of some substernal chest discomfort. Which of the following is the most appropriate test to evaluate for cardiac chest pain at this time?



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A 70-year-old male with a past medical history of hypertension and hyperlipidemia is brought to the emergency department by for complaints of left-sided weakness and numbness. He states that he passed out after having some beers and cigarettes and woke up two hours later with left-sided weakness. A CT scan of the head without contrast shows no evidence of hemorrhage. The patient is given IV TPA. His initial lab work was positive for an initial troponin of 2.96 ng/ml, and his second troponin is 3.55 ng/ml. His ECG shows a 0.5mm T-wave inversion in lead V2 and nonspecific ST-T wave changes in other precordial leads. What is the most likely causes of the elevated troponins and what medication(s) should be started next?



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A 55-year-old male with a pertinent past medical history of hypertension, hyperlipidemia, and diabetes mellitus was brought to the emergency department by his daughter from home with substernal chest pain for the past 15 minutes that is radiating to his left jaw and shoulder. When asking the daughter for more information, she mentions that he was drinking lots of alcohol recently because he was feeling depressed about his wife passing away after having a heart attack at the same age. The patient’s daughter is concerned that her father might also be having a heart attack. Which of the following cardiac enzymes is least likely to be helpful at this moment?



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Cardiac Enzymes - References

References

LADUE JS,WROBLEWSKI F,KARMEN A, Serum glutamic oxaloacetic transaminase activity in human acute transmural myocardial infarction. Science (New York, N.Y.). 1954 Sep 24;     [PubMed]
Schmiechen NJ,Han C,Milzman DP, ED use of rapid lactate to evaluate patients with acute chest pain. Annals of emergency medicine. 1997 Nov;     [PubMed]
Yun DD,Alpert JS, Acute coronary syndromes. Cardiology. 1997 May-Jun;     [PubMed]
Jialal I,Sokoll LJ, Clinical utility of lactate dehydrogenase: a historical perspective. American journal of clinical pathology. 2015 Feb;     [PubMed]
Mair J,Artner-Dworzak E,Lechleitner P,Morass B,Smidt J,Wagner I,Dienstl F,Puschendorf B, Early diagnosis of acute myocardial infarction by a newly developed rapid immunoturbidimetric assay for myoglobin. British heart journal. 1992 Nov;     [PubMed]
Kabekkodu SP,Mananje SR,Saya RP, A Study on the Role of Heart Type Fatty Acid Binding Protein in the Diagnosis of Acute Myocardial Infarction. Journal of clinical and diagnostic research : JCDR. 2016 Jan;     [PubMed]
Aydin S,Ugur K,Aydin S,Sahin İ,Yardim M, Biomarkers in acute myocardial infarction: current perspectives. Vascular health and risk management. 2019;     [PubMed]
Alpert JS,Thygesen K,Antman E,Bassand JP, Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Journal of the American College of Cardiology. 2000 Sep;     [PubMed]
Thygesen K,Alpert JS,White HD,Jaffe AS,Apple FS,Galvani M,Katus HA,Newby LK,Ravkilde J,Chaitman B,Clemmensen PM,Dellborg M,Hod H,Porela P,Underwood R,Bax JJ,Beller GA,Bonow R,Van der Wall EE,Bassand JP,Wijns W,Ferguson TB,Steg PG,Uretsky BF,Williams DO,Armstrong PW,Antman EM,Fox KA,Hamm CW,Ohman EM,Simoons ML,Poole-Wilson PA,Gurfinkel EP,Lopez-Sendon JL,Pais P,Mendis S,Zhu JR,Wallentin LC,Fernández-Avilés F,Fox KM,Parkhomenko AN,Priori SG,Tendera M,Voipio-Pulkki LM,Vahanian A,Camm AJ,De Caterina R,Dean V,Dickstein K,Filippatos G,Funck-Brentano C,Hellemans I,Kristensen SD,McGregor K,Sechtem U,Silber S,Tendera M,Widimsky P,Zamorano JL,Morais J,Brener S,Harrington R,Morrow D,Lim M,Martinez-Rios MA,Steinhubl S,Levine GN,Gibler WB,Goff D,Tubaro M,Dudek D,Al-Attar N, Universal definition of myocardial infarction. Circulation. 2007 Nov 27;     [PubMed]
Newby LK,Goldmann BU,Ohman EM, Troponin: an important prognostic marker and risk-stratification tool in non-ST-segment elevation acute coronary syndromes. Journal of the American College of Cardiology. 2003 Feb 19;     [PubMed]
Kitamura M,Hata N,Takayama T,Hirayama A,Ogawa M,Yamashina A,Mera H,Yoshino H,Nakamura F,Seino Y, High-sensitivity cardiac troponin T for earlier diagnosis of acute myocardial infarction in patients with initially negative troponin T test--comparison between cardiac markers. Journal of cardiology. 2013 Dec;     [PubMed]
Korff S,Katus HA,Giannitsis E, Differential diagnosis of elevated troponins. Heart (British Cardiac Society). 2006 Jul;     [PubMed]
Zughaft D,Harnek J, A review of the role of nurses and technicians in ST-elevation myocardial infarction (STEMI). EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2014 Aug     [PubMed]

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