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การตรวจวินิจฉัยโรคทางแล็ป

Cardiac Markers:  
  
Troponin I/Troponin T
   Test
- Cardiac Troponins as 
  Markers of Myocardial Injury

Cardiac Markers:  
  
Myoglobin Test
  
Common Questions

CK-MB Test
 
Also known as: CK MB, CPK  
  MB
  Formally known as: Creatine 
  Kinase–MB

Cardiac Markers:  
  
CK, CPK Test
   Creatinine Kinase
   ครีเอตินีน ไคเนส

Cardiac Markers:  
   
LD, LDH Test
    Lactate Dehydrogenase
    แลคเตส ดีไฮโดรจิเนส


 รายละเอียดเรื่องโรคและอาการ
 ของโรคหัวใจขาดเลือด
 Myocardial infarction

   วิธีทดสอบ/วินิจฉัยทางแล็ป
 
     ( ห้องปฏิบัติการชันสูตร ) 
   
Reference test procedure

 
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  Cardiac Markers:      
Identification of patients presenting with chest pain under suspicion of an acute myocardial infarction (AMI) or minor myocardial damage (MMD) is a major problem even today. Differentiation between myocardial damage and non-cardiac syndromes with related symptoms has a major impact on the treatment strategy for each patient. Commonly used standard methods, such as ECG, and the measurements of enzymes, such as CK and CK-MB, allow no clear diagnosis in a high number of cases.

 It's Troponin T 
 The availability of troponin T assays for the specific detection of cardiac troponin T has enhanced diagnostic specificity, sensitivity and reliability in the diagnosis of myocardial damage.
 
Troponin T is part of the troponin complex which, in addition, comprises the subunit I and C (T for "tropomyosin binding", I for "inhibitory", and C for "calcium binding"). The complex is located on the thin filament of the contractile muscle apparatus and regulates the calcium mediated interaction of myosin and actin. Apart from their synergisms in the complex, troponin T, C and I are otherwise unrelated proteins.
 
Skeletal and cardiac troponin T isoforms differ from each other in amino acid sequence. Following myocardial damage, cardiac troponin T (cTnT) is released into blood within 2 to 6 hours after the event and can be detected with immunoassays based on specific antibodies.
 
 
 
 
All available Roche troponin T assays specifically detect the cardiac troponin T isoform by using monoclonal antibodies specific for the cardiac troponin T isoform.
 
The highly specific detection of all cardiac troponin T released into blood makes Roche troponin T assays a superior diagnostic tool for diagnosing myocardial damage.
 
 
 Index
 
Different troponin I assays are not directly comparable. This is due to the high variability of the analyte and the use of different antibodies in various assays. The analyte troponin I is not standardised!
 
Troponin T on the other hand is a stable analyte. cTnT assays are not affected by biochemical variations. The same antibodies are used in all assays to guarantee the same results and clinical interpretation.
 
Troponin T is a standardised parameter and all available troponin T assays are standardised and therefore comparable!

  1. Troponin T or troponin I?
 
There is a tendency to suggest that troponin T and troponin I are the same biochemically and that results can be used interchangeably. However, there are significant differences  in their biochemistry which suggest that this is not true:
There are several biochemical modifications of troponin I after its liberation.
 
Several complexes of troponin I with troponin C, I and T have been identified in blood circulation. These result in three different complex forms of troponin I (I, II, IC, and ICT) (Lavigne et al. [ref 23], Katrukha et al. [ref 17-21]). Troponin I can also be phosphorylated and oxidised. Furthermore, there is evidence of fragmentation of the troponin I molecule by proteolytic enzymes.
 
 
Grafik 02
 
 
Summary
 
Summary
 
 
Consequences of biochemical variation of troponin I:
 
All troponin assays use pairs of antibodies that recognise two different epitopes on the analyte. Different troponin I assays use different troponin I antibody pairs. In terms of standardisation and comparability of results, this causes a problem for troponin I assays:
 
The available troponin I assays differently detect the modified TnI molecules. For example, phosphorylation of troponin I may interfere with recognition of the epitope by different monoclonal TnI antibodies. Different assays using different antibodies may not identify some of the fragments, complexes or phosphorylated troponin I isoforms. As a consequence, results obtained with troponin I assays from different companies cannot be compared directly.
 
A.H.B. Wu et al. (ref 39). It was published recently in Clinical Chemistry that: "there are differences in absolute cTnI results due to a lack of mass standardisation and heterogeneity in the cross-reactivities of antibodies to various TnI forms."
 
In contrast, in cardiac troponin T assays, the antibody pair is well characterised and standardised across available measurement platforms (Point of Care and Laboratory). Troponin T assays are not affected by any biochemical variations after liberation into blood.
 
 
Grafik 3
 
 
Therefore, troponin T is a standardised parameter whilst troponin I is not!
 
In addition, more shortcomings of troponin I have been described:
 
a)
Instability of analyte: two different tests for troponin I may show increasing or decreasing levels of troponin I if a sample has been left at room temperature for some hours. (Waskiewicz et al. [ref 38]; Morjana et al. [ref 30])
 
b)
Unspecificity of troponin I:
 
(ref 4) Azzazy et al. found elevated cardiac troponin I in a patient with metastatic liver tumours without myocardial necrosis (autopsy).
 
(ref 29) Missov et al. also described elevated TnI levels in patients with various cancers not treated with cardiotoxic substances, such as doxorubicin.
 
(ref 10) Recently a false increase of cardiac troponin I with heterophilic antibodies in the sample has been described (Fitzmaurice et al. in Clin. Chem. 10/98).
 


  Testing for Troponin-T in Potential 

Myocardial Infarction Patients
By Daryl Shaw, Medical Student

The following is a synopsis of an article in the May/June issue of RETTUNGSMAGAZIN.     I have condensed and translated it and will include additions re: muscle/cardiological physiology for easier understanding.:

More than 250,000 persons suffer an AMI per year in Germany. Approx. 20% of these expire within 2 hours of ischamic begin. For this reason, it was of great importance that an objective test be found to confirm or indicate AMI in the preclinical (EMS) theater.

It was discovered that the cardial enzyme Troponin-T, a deciding factor in the Actin-Myosin contractile system typical to all muscles, especially striped muscle and, histologically related, cardial myocardial muscle. The component Troponin-T of the Actin strand is responsible, along with Tropomyosin, for the contraction in the individual muscle strand, in that they interact with calcium to allow or block the contraction cycle.

It has been determined that ischemia results in the release of Troponin-T from the damaged area of the myocard, whereby concentrations above 0.2 ng/ml blood are pathological and can be illustrated with the test.

The best situation for the use of the test is AMI suspect patients where ECG conformation is not definite or the symptomatic picture is "unappropriate". Dr. Motschwiller from Boehringer Mannheim stresses the fallicy of sole usage for AMI diagnosis, "The Tropt-Test should not be overestimated...(it) is primarily for the conformation of a suspected (AMI) diagnosis"(Due to individual cardiovascular kinetics and release rate, enzyme conformation may take up to 30 mins. after ischemia beginning.).

The test is composed of documentation card, test stick and syringe. 150 microliter anti-coagulated blood (i.e. from blood lab tube/Vacutainer) is put in window of test stick and covered with included flap. The stick is attached to the documentation card and the necessary information including start time is included. After "a few" (5) minutes a result can be visually registered; 1 stripe (control): negative , 2 stripes: positive. When negative, a waiting period of 20 minutes is advisable (kinetics). This test is only of qualitative value; a quantitive evaluation must be done in the treating facility. Due to the kinetics of release, a negative test result can occur up to 12 hours post ischemia.

Finally, there is the problem of storage; the test must be kept between 2 and 8 degrees celsius and only is good for a week at room temperature, hence the need for a cool storage area, i.e. a refridgerator.

The tests cost DM 179,98 for 10 sets or DM 100,40 for 5 Sets.

Contact Address:

Boeringer Mannheim
Dr. E. Motschwiller 
Sandhofer Strasse 116 
68298 Mannheim GERMANY

 

Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I
Authors Hamm C, Goldmann B, Heeschen C, Kreymann G, Berger J, Meinertz T.
Source New England Journal of Medicine. 337:1648-53. December 4, 1997. 
Institutions University Hospital Eppendorf, Hamburg, Germany
Support None indicated

Background

Myocardial injury, commonly assessed by CPK-MB levels, can be detected with greater sensitivity by assaying blood levels of the cardiac contractile proteins troponin T and I. These have been shown to have prognostic significance in the setting of acute ischemic syndromes, such as unstable angina. With the development of rapid bedside assays for these proteins, their use in the evaluation of chest pain in the emergency room becomes feasible. This study was designed to investigate the diagnostic and prognostic value of rapid bedside troponin testing in emergency room patients with chest pain and without ST-segment elevation on EKG. 

Methods

Patients

Patients were eligible if they presented to the emergency room of the University Hospital with less than 12 hours of anterior or left-sided chest pain, not explained by trauma or obvious abnormality on chest x-ray. 

Patients with ST-segment elevation or recent MI were excluded. 

Protocol

Troponin assays

Blood was obtained for troponin T and I assays within 15 minutes of arrival at the ER and again four hours later. For those patients who had arrived less than two hours after the onset of pain, a third sample was drawn 6 hours after the onset of pain (so that all patients had one sample drawn at least 6 hours after the onset of pain). 

A rapid, qualitative bedside assay for troponin T was performed on all samples and the results were immediately available to the treating physicians. 

Serum was centrifuged and frozen for quantitative troponin T measurement as well as for rapid qualitative and quantitative troponin I measurements. 

Other clinical data

Patients also had EKG's performed, blood drawn for CPK and MB fractions and history and physical examination recorded according to a protocol. 

After excluding patients with ST-segment elevation, the admission EKG was classified as: 

  • ST segment depression (with or without T-wave inversions) 
  • T-wave inversion only 
  • Nondiagnostic (paced or bundle branch block) 
  • Normal 
Follow-up and endpoints

MI at the time of admission was judged to be present if the CPK within 24 hours of admission was greater than twice the upper limits of normal with an elevated MB fraction. 

Patients were followed during hospitalization and for 30 days after discharge. Endpoints were death from cardiac causes and nonfatal MI (more than 24 hours after admission). 

Results

Patients and clinical diagnoses

870 eligible patients were screened between June, 1994 and March, 1996. There were 97 with ST-segment elevation, which left 773 study patients with chest pain but no ST-segment elevation. 

The final diagnoses were: 

  • Acute MI (by CPK): 47 patients 
  • Unstable angina: 315 
  • Stable angina: 121 
  • Heart failure: 15 
  • Pulmonary embolus: 12 
  • Myocarditis: 5 
  • No specific cardiovascular diagnosis: 258 
487 patients were admitted to the hospital (63%), 224 to the ICU. 
 

Qualitative and quantitative troponin tests

There was good correspondence between the rapid bedside assays and the quantitative assays -- 94.8% for troponin T and 98.7% for troponin I. There was only one false negative for troponin T and 5 for troponin I. 
 

Troponins and clinical diagnoses

Of the 773 patients, 16% had at least one positive troponin T result; 22% had at least one positive troponin I. Approximately 40% of patients with a positive test had a negative first sample. 

CPK-documented MI within the first 24 hours (47 patients): 

  • On admission, troponin T was positive in 51%, troponin I in 66%, CPK-MB was elevated in 53%. 
  • Four hours later, troponin T was positive in 94%, troponin I in 100%, CPK-MB in 91%
Unstable angina (315 patients): 22% had at least one positive troponin T; 36% had at least one positive troponin I; 5% had elevation of CPK-MB (presumably the total CPK did not rise enough to qualify for acute MI). 

Other diagnoses:

  • CHF: 1 positive troponin T, 5 positive troponin I 
  • PE: 1 positive troponin T, 2 positive troponin I 
  • myocarditis: 1 positive troponin T, 2 positive troponin I 
  • unexplained chest pain: 1 positive troponin I 
False positives

Seven patients had an elevated troponin T but normal troponin I; these were considered to be false positives. Six of these patients also had renal failure. 
 

EKG and troponins

  • Normal EKG was present in 331 patients (43%). At least one positive troponin test (both T and I) was present in 10% of these. One of the 47 myocardial infarctions on admission was in this group. 
  • Non-diagnostic EKG (paced or bundle branch block) was present in 87 patients (11%). The percentage of positive troponin T and I tests in this group was 32% and 47%, respectively. Of the 47 myocardial infarctions, 23 were in this group. 
  • ST-segment depression was present in 158 patients (20%). The percentage of positive troponin T and I tests was 32% and 56%. There were 8 myocardial infarctions in this group. 
  • T-wave inversions only were present in 197 patients (25%). Positive troponin T and I tests were present in 6% and 5%. There were 15 myocardial infarctions in this group. 
Troponin and events during follow-up

There were 20 deaths from cardiac causes during the follow-up period (11 in hospital and 9 after discharge). The troponin T test was positive in 16 out of these 20 patients; troponin I was positive in all but one. 

Myocardial infarction after admission occurred in 14 patients (9 in hospital, 5 after discharge). Troponin T was positive in 11 and negative in 3. Troponin I was positive in 13 and negative in 1. 

For the 34 total events, troponin I was positive in 32 and negative in 2. Troponin T was positive in 27 and negative in 7. The EKG was normal in 5 and abnormal or nondiagnostic in 29. 

In the 331 patients with a normal EKG, there were 5 events. Four of these had an abnormal troponin T, all 5 had an abnormal troponin I. 

The overall event rate for patients with negative troponin T was 1.1%, and for negative troponin I 0.3%. Troponin T and troponin I provided additional prognostic information, after EKG status and CPK-MB were taken into account. 

Author's discussion

The authors state that "the primary aim of this study was to demonstrate that two negative test results on admission and four hours later (or at least six hours from the onset of chest pain) allow safe early discharge". Patients with two normal troponin measurements had a low rate of cardiac events within 30 days (1.1% for troponin T; 0.3% for troponin I). 

They note that patients with one positive result should be admitted and evaluated further, and that a single test on admission is not sufficient. They feel that the slightly higher sensitivity of the troponin I test "may be related to different release kinetics and different limits of detection of the versions of the test that are currently available". They also feel that the six false positives seen in patients with renal failure may reflect a true difference between the troponin T and I assays. 

Editorial

In an accompanying editorial, Dr. Mark Hlatky from Stanford University reviews the problem of the evaluation of chest pain in the emergency room. He makes several important points about this article: 
  • Patients with a positive troponin test who were classified as unstable angina could also be classified as "small myocardial infarctions". 
  • Since no details about the clinical history were given, it is not possible to determine the risk of events in clinically high-risk subsets with negative troponin tests. 
  • The results obtained here only apply when at least two samples are obtained, with one sample at least 6 hours after the onset of chest pain. 
  • Among patients with ST-segment depression, the event rates with negative troponin T and I were 2.8% and 1.4%, not negligeable numbers. 
 

Comment

This was a study of 773 patients evaluated in an emergency room for chest pain without ST-segment evaluation. Patients underwent troponin T and I determination; the troponin T results were immediately available and all patients with a positive test were admitted. Patients with negative troponin tests had a good prognosis -- the event rate (cardiac MI or death) within 30 days was 1.1% for patients with a negative troponin T test and 0.3% for patients with a negative troponin I test. 

In addition to the limitations noted in Dr. Hlatky's editorial, there is another problem with the study that greatly limits its applicability, in my opinion. Of the 773 patients, 487 were admitted to the hospital, the vast majority with a diagnosis of unstable or stable angina. Overall, 123 patients had at least one positive troponin T test and 171 had a positive troponin I test. This means that at least 364 patients were admitted to the hospital with negative troponin T tests and at least 316 with negative troponin I tests. 

Thus, a large number of patients with negative troponin tests were admitted to the hospital, mainly with the diagnoses of unstable and stable angina, and presumably received treatment for this. Their good prognosis could be in part related to in-hospital therapy (such as heparin), not only to their negative troponin tests. 

Although we can conclude that patients who are appropriately treated (including hospitalization) have a good prognosis with negative troponins, we cannot conclude from this study that it is safe to discharge patients from the emergency room, even with normal EKG's and negative troponin tests, since so many patients in this study were, in fact, hospitalized. We do not know how they would have fared had they been discharged from the emergency room. 

The objective of this study, according to the authors, was to demonstrate that "two negative test results on admission and four hours later (or at least six hours from the onset of chest pain) allow safe early discharge". This has not yet been persuasively accomplished, in my opinion. 

December 20, 1997 


References
References related to this article
from the NLM's PubMed database. 

 

         Troponin I


 

 

 
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