Updated: Jan 08, 2017 Madscape

 Author: Donald Schreiber, MD, CM; Chief Editor: Barry E Brenner, MD, PhD, FACEP  more...

Cardiac Troponins

The troponins are regulatory proteins found in skeletal and cardiac muscle. Three subunits have been identified: troponin I (TnI), troponin T (TnT), and
troponin C (TnC). The genes that encode for the skeletal and cardiac isoforms of TnC are identical; thus, no structural difference exists between them.
However, the skeletal and cardiac subforms for TnI and troponin TnT are distinct, and immunoassays have been designed to differentiate between them.

Two different reference ranges are used in troponin assays. The upper percentile reference limit gives the upper limit of what can be expected in a normal,
healthy, adult population, while the coefficient of variation (CV) is the percent variation in assay results that can be expected when the same sample is
repeatedly analyzed.

According to European Society of Cardiology (ESC)/American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/ World
Heart Federation (WHF) guidelines, MI refers specifically to myocardial necrosis due to myocardial ischemia. However, although elevations in the serum
levels of TnI, TnT, and CK-MB indicate the presence of injury-associated necrosis of myocardial cells, such elevations do not point to the underlying
mechanism of the necrosis. While myocardial necrosis occurs in MI, it can also be a product of predominantly nonischemic myocardial injury, as occurs in
association with heart failure, arrhythmia, myocarditis, renal failure, pulmonary embolism, and percutaneous or surgical coronary procedures. [14]

Troponin adalah protein regulator yang ditemukan pada otot rangka dan jantung. Tiga subunit telah
diidentifikasi: troponin I (TnI), troponin T (TnT), dan troponin C (TnC). Gen yang menyandikan isoform
rangka dan jantung dari TnC identik; Dengan demikian, tidak ada perbedaan struktural di antara keduanya.
Namun, subform kerangka dan jantung untuk TnI dan troponin TnT berbeda, dan immunoassay telah dirancang
untuk membedakannya.
Dua rentang referensi berbeda digunakan dalam uji troponin. Batas referensi persentil ke atas memberi
batas atas apa yang dapat diharapkan pada populasi normal, sehat, dewasa, sedangkan koefisien variasi
(CV) adalah variasi persen dalam hasil uji yang dapat diharapkan saat sampel yang sama dianalisis
berulang kali.
Menurut pedoman European Society of Cardiology (ESC) / American College of Cardiology Foundation
(ACCF) / American Heart Association (AHA) / World Heart Federation (WHF), MI secara khusus mengacu pada
nekrosis miokard karena iskemia miokard. Namun, meskipun peningkatan tingkat serum TnI, TnT, dan CK-MB
menunjukkan adanya nekrosis terkait cedera pada sel miokard, elevasi semacam itu tidak mengarah pada
mekanisme dasar nekrosis. Sementara nekrosis miokard terjadi di MI, ini juga dapat menjadi produk dari
cedera miokard yang sebagian besar nonischemic, seperti yang terjadi terkait dengan gagal jantung,
aritmia, miokarditis, gagal ginjal, emboli paru, dan prosedur koroner perkutan atau bedah. [14]

The sensitivity, specificity, and precision of the different commercially available troponin assays vary considerably. These differences are related to a lack
of standardization, the use of different monoclonal antibodies, the presence of modified TnI and TnT in the serum, and variations in antibody cross-
reactivity to the various detectable forms of TnI that result from its degradation.

Only one manufacturer produces the TnT assay, and its 99th percentile cutoffs and the 10% CV are well established. However, up to 20-fold variation has
occurred in results obtained with the multitude of commercial TnI assays currently available, each with their own 99th percentile upper reference limits and
10% CV levels.

In the GUSTO IV study, a relatively insensitive point-of-care TnI assay was used to screen patients for study eligibility. In a subsequent study, the blood
samples were reanalyzed using the 99th percentile cutoff of a far more sensitive central laboratory TnT assay. The more sensitive 99th percentile cutoff of
this TnT assay identified an additional 96 (28%) of 337 patients with a positive TnT result but negative point-of-care TnI; these patients had higher rates of
death or MI at 30 days. [15]

In a similar reanalysis of the TACTICS-TIMI 18 trial, 3 different TnI cutoffs were compared on 1821 patients to evaluate the 30-day risk of death or MI:
the 99th percentile, 10% CV, and the World Health Organization (WHO) acute MI cutoffs. (The WHO cutoffs define acute MI using CK-MB and report
troponin levels as either a higher “acute MI level” or a lower “intermediate level” that is correlated with “leak” or “minor myocardial injury.”)

Using the 10% CV cutoff identified, an additional 12% more cases were identified relative to the WHO acute MI cutoff. The 99th percentile cutoff
identified an additional 10% of cases relative to the 10% CV cutoff, as well as a 22% increase in the number of cases over the WHO acute MI cutoff.
Nevertheless, the odds ratios for the adverse cardiac event rates of death or MI at 30 days were similar for all 3 cutoffs, suggesting that the lower cutoffs
detected more patients with cardiovascular risk without sacrificing specificity. [16, 17]

The National Academy of Clinical Biochemistry (NACB) working with the ACC/ESC guidelines has recommended adoption of the 99th percentile upper
reference limit as the recommended cutoff for a positive troponin result. Ideally, the precision of the assay at this cutoff level should be measured by a CV
that is less than 10%.
However, most TnI assays are imprecise at the 99th percentile reference limit. [18] Some have therefore recommended that the cutoff level be raised to the
slightly higher 10% CV level instead of the 99th percentile reference limit to ensure adequate assay precision.

In addition, studies have shown that populations within the 99th percentile reference limit include patients with low troponin levels who nevertheless have
an elevated cardiac risk, and that the true 99th percentile cutoff for a healthy patient population is actually a factor of 10-50 lower. Accordingly, these
investigations suggest that higher sensitivity or ultrasensitive troponin assays are necessary. [17] The advantage of ultrasensitive troponins is based on the
premise that lower cutoff levels achieve higher sensitivity that will allow earlier diagnosis, often within 90 minutes of presentation.

To optimize the assay’s use in the ED, it is important to be familiar with the particular troponin assay available in the laboratory and to know whether the
cutoff is set at the 10% CV level or the 99th percentile upper reference limit.

Point-of-care assays

NACB recommendations specify that cardiac markers be available on an immediate basis 24 h/d, 7 d/wk, with a turnaround time of 1 hour. [19] Point-of-care
(POC) devices that provide rapid results should be considered in hospitals whose laboratories cannot meet these guidelines.

POC assays for CK-MB, myoglobin, and the cardiac troponins TnI and TnT are available. Only qualitative TnT assays are available as POC tests, but both
quantitative and qualitative POC TnI assays are currently marketed.

Rekomendasi NACB menentukan bahwa spidol jantung tersedia segera 24 jam, 7 d / minggu, dengan waktu
penyelesaian 1 jam. [19] Perangkat point-of-care (POC) yang memberikan hasil cepat harus dipertimbangkan
di rumah sakit yang laboratoriumnya tidak dapat memenuhi panduan ini.
Tes POC untuk CK-MB, mioglobin, dan troponin jantung TnI dan TnT tersedia. Hanya tes TnT kualitatif yang
tersedia sebagai tes POC, namun tes POC TnI kuantitatif dan kualitatif saat ini dipasarkan.
Dalam percobaan multisenter, waktu untuk positif secara signifikan lebih cepat untuk perangkat POC
daripada laboratorium lokal (2,5 h vs 3,4 jam).

In a multicenter trial, the time to positivity was significantly faster for the POC device than for the local laboratory (2.5 h vs 3.4 h). [20]

In another multicenter study, which evaluated the i-STAT POC TnI assay in comparison with the central laboratory in 2000 patients with suspected ACS,
POC testing reduced the length of stay by approximately 25 minutes for patients who were discharged from the ED. [21, 22] The sensitivity of current POC
assays coupled with the benefit of rapid turnaround time make the POC assays attractive clinical tools in the ED.
Dalam percobaan multisenter, waktu untuk positif secara signifikan lebih cepat untuk perangkat POC
daripada laboratorium lokal (2,5 h vs 3,4 jam). [20]
Dalam studi multisenter lain, yang mengevaluasi pengujian i-STAT POC TnI dibandingkan dengan
laboratorium pusat pada tahun 2000 pasien dengan dugaan ACS, pengujian POC mengurangi lama tinggal
sekitar 25 menit untuk pasien yang dipulangkan dari ED. [21, 22] Sensitivitas tes POC saat ini ditambah
dengan manfaat waktu penyelesaian yang cepat membuat POC menguji alat klinis yang menarik di ED

Prognostic value of troponin

In addition to its use in the diagnosis of MI, an elevated troponin level can identify patients at high risk for adverse cardiac events. [23, 24] Specifically, data
from a meta-analysis indicated that an elevated troponin level in patients without ST-segment elevation is associated with a nearly 4-fold increase in the
cardiac mortality rate. [25] In patients without ST-segment elevation who were being considered for thrombolytic therapy, initial TnI levels on admission
correlated with mortality at 6 weeks, but CK-MB levels were not predictive of adverse cardiac events and had no prognostic value. [23]

Other studies revealed that an elevated troponin level at baseline was an independent predictor of mortality, even in patients with chest pain and acute MI
with ST-segment elevation who were eligible for reperfusion therapy. [26, 27]

Data from the ARTEMIS study, comprising 1137 diabetic patients with stable coronary artery disease (CAD) and 649 normoglycemic patients, found that
high levels (≥14 ng/L) of highly sensitive TnT (hs-TnT) was an independent strong predictor of cardiac death or hospitalization for heart failure in patients
with diabetes and CAD (as were B-type natriuretic peptide, highly sensitive C-reactive protein [hs-CRP], and soluble suppressor of tumorigenicity-2 [sST2]
in a multivariate analysis). [28] In the nondiabetic group, only hs-CRP and sST2 were predictive for these outcomes.

Data from the Acute Decompensated Heart Failure National Registry (ADHERE) involving information from 23,696 patients hospitalized with acute heart
failure showed that increased levels of troponin and creatinine were the strongest predictors of in-hospital worsening heart failure. [29]

Finally, the TIMI IIIB, GUSTO IIa, GUSTO IV ACS, and FRISC trial all demonstrated a direct correlation between the level of TnI or TnT and the
mortality rate and adverse cardiac event rate in ACS. [23, 26, 30, 31, 32]

Creatine Kinase–MB
Prior to the introduction of cardiac troponins, the biochemical marker of choice for the diagnosis of acute MI was the CK-MB isoenzyme. The criterion
most commonly used for the diagnosis of acute MI was 2 serial elevations above the diagnostic cutoff level or a single result more than twice the upper
limit of normal. Although CK-MB is more concentrated in the myocardium, it also exists in skeletal muscle and false-positive elevations occur in a number
of clinical settings, including trauma, heavy exertion, and myopathy.

Creatine Kinase-MB
Sebelum diperkenalkannya troponin jantung, penanda biokimia pilihan untuk diagnosis MI akut adalah
isoenzim CK-MB. Kriteria yang paling umum digunakan untuk diagnosis MI akut adalah 2 peningkatan serial
di atas tingkat cutoff diagnostik atau hasil tunggal lebih dari dua kali batas atas normal. Meskipun CK-
MB lebih terkonsentrasi pada miokardium, itu juga ada pada otot rangka dan elevasi positif palsu terjadi
di sejumlah setting klinis, termasuk trauma, tenaga berat, dan miopati.

CK-MB first appears 4-6 hours after symptom onset, peaks at 24 hours, and returns to normal in 48-72 hours. Its value in the early and late (>72 h)
diagnosis of acute MI is limited. However, its release kinetics can assist in diagnosing reinfarction if levels rise after initially declining following acute MI.

In the CRUSADE registry, a review of almost 30,000 patients revealed that discordant troponin and CK-MB results occurred in 28% of patients. However,
patients who were troponin negative but CK-MB positive had in-hospital mortality rates that were not significantly increased from patients who were
negative for both biomarkers. [33]

CK-MB pertama kali muncul 4-6 jam setelah onset gejala, mencapai puncak pada 24 jam, dan kembali normal
dalam 48-72 jam. Nilainya dalam diagnosis MI akut akut dan awal (> 72 h) terbatas. Namun, kinetika
pelepasannya dapat membantu dalam mendiagnosis reinfarction jika tingkat meningkat setelah awalnya
menurun setelah MI akut.
Dalam registrasi CRUSADE, sebuah tinjauan terhadap hampir 30.000 pasien mengungkapkan bahwa troponin
sumbang dan hasil CK-MB terjadi pada 28% pasien. Namun, pasien yang mengalami troponin negatif namun CK-
MB positif memiliki angka kematian di rumah sakit yang tidak meningkat secara signifikan dari pasien
yang negatif untuk kedua biomarker. [33]

Similarly, in a report of more than 10,000 patients with ACS from the multicenter GRACE registry, in-hospital mortality was highest when both troponin
and CK-MB were positive, intermediate in troponin-positive/CK-MB-negative patients, and lowest in patients in whom both markers were negative and in
those who were troponin-negative/CK-MB-positive. [34] Thus, an isolated CK-MB elevation has limited prognostic value in patients with a non-ST elevation
ACS.

Demikian pula, dalam laporan lebih dari 10.000 pasien dengan ACS dari registri GRACE multisenter, angka
kematian di rumah sakit paling tinggi bila troponin dan CK-MB positif, menengah pada pasien troponin-
positif / CK-MB-negatif, dan terendah di pasien di mana kedua spidol tersebut negatif dan pada mereka
yang menderita troponin-negatif / CK-MB-positif. [34] Dengan demikian, peningkatan CK-MB yang terisolasi
memiliki nilai prognostik terbatas pada pasien dengan ACS non-ST.

CK-MB/CK relative index

The relative index calculated by the ratio of CK-MB (mass) to total CK can assist in differentiating false-positive elevations of CK-MB arising from
skeletal muscle. A ratio of less than 3 is consistent with a skeletal muscle source, while ratios greater than 5 are indicative of a cardiac source. Ratios
between 3 and 5 represent a gray zone. No definitive diagnosis can be established without serial determinations to detect a rise.

The CK-MB/CK relative index was introduced to improve the specificity of CK-MB elevation for myocardial infarction. However, sensitivity for acute MI
falls when concurrent cardiac injury and skeletal muscle injury is present. In an ED-based study to evaluate the CK-MB relative index compared with the
absolute CK-MB, specificity was increased, but with a loss of sensitivity. [35]

Indeks relatif yang dihitung dengan rasio CK-MB (massa) terhadap total CK dapat membantu dalam
membedakan elevasi positif-negatif dari CK-MB yang timbul dari otot rangka. Rasio kurang dari 3
konsisten dengan sumber otot skeletal, sedangkan rasio yang lebih besar dari 5 mengindikasikan sumber
kardiak. Rasio antara 3 dan 5 mewakili zona abu-abu. Tidak ada diagnosis pasti yang dapat ditetapkan
tanpa penentuan serial untuk mendeteksi kenaikan.
Indeks CK-MB / CK diperkenalkan untuk meningkatkan spesifisitas elevasi CK-MB untuk infark miokard.
Namun, kepekaan untuk MI akut turun saat terjadi cedera jantung bersamaan dan cedera otot skelet. Dalam
sebuah penelitian berbasis ED untuk mengevaluasi indeks relatif CK-MB dibandingkan dengan CK-MB mutlak,
spesifisitas meningkat, namun dengan hilangnya sensitivitas. [35]
The CK-MB/CK relative index is useful if patients have only an MI or only skeletal muscle injury, but not if they have both. Therefore, in the combined
setting of acute MI and skeletal muscle injury (rhabdomyolysis, heavy exercise, polymyositis), the fall in sensitivity is significant.

Note that the diagnosis of acute MI must not be based on an elevated relative index alone, because the relative index may be elevated in clinical settings
when either the total CK or the CK-MB is within normal limits. The relative index is only clinically useful when both the total CK and the CK-MB levels
are increased.

ndeks CK-MB / CK relatif berguna jika pasien hanya memiliki MI atau hanya cedera otot skeletal, tapi
tidak jika keduanya memiliki keduanya. Oleh karena itu, dalam rangkaian gabungan MI akut dan cedera otot
skeletal (rhabdomyolysis, latihan berat, polymyositis), penurunan sensitivitas signifikan.
Perhatikan bahwa diagnosis MI akut tidak boleh didasarkan pada indeks relatif tinggi saja, karena indeks
relatif mungkin meningkat dalam pengaturan klinis bila CK atau CK-MB berada dalam batas normal. Indeks
relatif hanya bermanfaat secara klinis bila total CK dan CK-MB meningkat.

CK-MB isoforms

The CK-MB isoenzyme exists as 2 isoforms: CK-MB1 and CK-MB2. Laboratory determination of CK-MB actually represents the simple sum of the
isoforms CK-MB1 and CK-MB2. CK-MB2 is the tissue form and initially is released from the myocardium after MI. It is converted peripherally in serum
to the CK-MB1 isoform rapidly after symptom onset.

Normally, the tissue CK-MB1 isoform predominates; thus, the CK-MB2/CK-MB1 ratio is typically less than 1. A result is positive if the CK-MB2 is
elevated and the ratio is greater than 1.7.

CK-MB2 can be detected in serum within 2-4 hours after onset and peaks at 6-9 hours, making it an early marker for acute MI. Two large studies evaluating
its use revealed a sensitivity of 92% at 6 hours after symptom onset, compared with 66% for CK-MB and 79% for myoglobin. [36, 37] The major disadvantage
of this assay is that it is relatively labor intensive for the laboratory.

Myoglobin
Myoglobin is a heme protein found in skeletal and cardiac muscle that has attracted considerable interest as an early marker of MI. Its low molecular weight
accounts for its early release profile: myoglobin typically rises 2-4 hours after onset of infarction, peaks at 6-12 hours, and returns to normal within 24-36
hours.

Rapid myoglobin assays are available, but overall, they have a lack of cardiospecificity. Serial sampling every 1-2 hours can increase the sensitivity and
specificity; a rise of 25-40% over 1-2 hours is strongly suggestive of acute MI. However, in most studies, myoglobin only achieved 90% sensitivity for
acute MI, so the negative predictive value of myoglobin is not high enough to exclude the diagnosis of acute MI

Myoglobin
Myoglobin adalah protein heme yang ditemukan pada otot rangka dan jantung yang telah menarik perhatian
besar sebagai penanda awal MI. Berat molekulnya rendah untuk profil pelepasan awalnya: mioglobin
biasanya naik 2-4 jam setelah onset infark, mencapai puncak pada 6-12 jam, dan kembali normal dalam
waktu 24-36 jam.
Tes mioglobin yang cepat tersedia, namun secara keseluruhan, mereka kekurangan kardiospesifikitas.
Sampling serial setiap 1-2 jam dapat meningkatkan sensitivitas dan spesifisitas; kenaikan 25-40% selama
1-2 jam sangat menandakan MI akut. Namun, pada kebanyakan penelitian, myoglobin hanya mencapai
sensitivitas 90% untuk MI akut, sehingga nilai prediksi negatif mioglobin tidak cukup tinggi untuk
menyingkirkan diagnosis MI akut

The original studies that evaluated myoglobin used the WHO definition of acute MI that was based on a CK-MB standard. With the adoption of a troponin
standard for acute MI in the ACC/ESC definition, the sensitivity of myoglobin for acute MI is substantially reduced. This significantly diminishes its utility,
and a number of studies have indicated that contemporary cardiac troponin assays render the use of myoglobin measurements unnecessary. [8, 10]

Studi asli yang mengevaluasi mioglobin menggunakan definisi WHO tentang MI akut yang didasarkan pada
standar CK-MB. Dengan adopsi standar troponin untuk MI akut pada definisi ACC / ESC, sensitivitas
mioglobin untuk MI akut berkurang secara signifikan. Ini secara signifikan mengurangi kegunaannya, dan
sejumlah penelitian telah mengindikasikan bahwa tes troponin kardiovaskular kontemporer membuat
penggunaan pengukuran mioglobin tidak perlu dilakukan. [8, 10]

Testing Strategy
In patients with definite or possible ACS, serial evaluation of cardiac markers is essential to diagnosing acute MI.

The American College of Emergency Physicians (ACEP) recommends 3 different testing strategies for ruling out NSTEMI in the ED. [38] One strategy is to
use a single negative CK-MB, TnI, or TnT measured 8-12 hours after symptom onset.

Another strategy is to use negative myoglobin in conjunction with a negative CK-MB mass or negative TnI measured at baseline and at 90 minutes in
patients presenting less than 8 hours after symptom onset.

A third approach is to use a negative 2-hour delta CK-MB in conjunction with a negative 2-hour delta TnI in patients presenting less than 8 hours after
symptom onset.

Note that ACEP does not specify whether to use the 99th percentile cutoff, the 10% CV cutoff, or the WHO acute MI cutoffs for troponin.

Pada pasien dengan ACS yang pasti atau mungkin, evaluasi serial penanda jantung sangat penting untuk
mendiagnosis MI akut.
American College of Emergency Physicians (ACEP) merekomendasikan 3 strategi pengujian berbeda untuk
mengesampingkan NSTEMI di ED. [38] Salah satu strategi adalah menggunakan CK-MB negatif tunggal, TnI,
atau TnT yang diukur 8-12 jam setelah onset gejala.
Strategi lain adalah menggunakan mioglobin negatif bersamaan dengan massa CK-MB negatif atau negatif
yang diukur pada awal dan pada 90 menit pada pasien yang mengalami kurang dari 8 jam setelah onset
gejala.
Pendekatan ketiga adalah menggunakan delta CK-2 negatif jam kerja bersamaan dengan delta TnI negatif 2
jam pada pasien yang hadir kurang dari 8 jam setelah onset gejala.
Perhatikan bahwa ACEP tidak menentukan apakah akan menggunakan cutoff persentil ke-99, cutoff CV 10%,
atau cutoff MI akut WHO untuk troponin.

The 90-minute rule-out with myoglobin recommended by ACEP was based on a study that used myoglobin in conjunction with either CK-MB or TnI. [39]
The CK-MB/myoglobin protocol yielded a sensitivity of 92% at 90 minutes, and the myoglobin/TnI combination yielded a sensitivity of 97% at 90 minutes.

ACEP acknowledges the relative lack of specificity for myoglobin and that many of the myoglobin studies did not define MI per the ACC/ESC guidelines.
Nevertheless, it is difficult to comprehend the ACEP clinical policy that accepts a missed MI rate of 3-8%.
ACEP’s recommendations on the use of delta CK-MB and delta TnI are based on determining the change in the level of TnI or CK-MB on samples drawn 2
hours apart. However, the delta TnI evaluation is partially based on the use of older TnI assays and outdated WHO acute MI cutoffs in a retrospective study.
Therefore, ACEP’s recommendation to use a delta TnI in conjunction with a delta CK-MB may not be generalizable to other commercially available
troponin assays. Caution must be used when using ACEP’s recommendations in ED patients with chest pain and suspected ACS.

The following table outlines the recommended sampling frequency after ED admission for the different cardiac markers.

Aturan 90 menit dengan mioglobin yang direkomendasikan oleh ACEP didasarkan pada penelitian yang
menggunakan mioglobin bersamaan dengan CK-MB atau TnI. [39] Protokol CK-MB / myoglobin menghasilkan
sensitivitas 92% pada 90 menit, dan kombinasi myoglobin / TnI menghasilkan sensitivitas 97% pada 90
menit.
ACEP mengakui kurangnya kekhususan untuk mioglobin dan bahwa banyak penelitian mioglobin tidak
mendefinisikan MI sesuai pedoman ACC / ESC. Namun demikian, sulit untuk memahami kebijakan klinis ACEP
yang menerima tingkat MI yang tidak terjawab yaitu 3-8%.
Rekomendasi ACEP tentang penggunaan delta CK-MB dan delta TnI didasarkan pada penentuan perubahan
tingkat TnI atau CK-MB pada sampel yang diambil 2 jam terpisah. Namun, evaluasi delta TnI sebagian
didasarkan pada penggunaan tes TnI yang lebih tua dan pengurangan MI MI akut yang sudah ketinggalan
zaman dalam penelitian retrospektif. Oleh karena itu, rekomendasi ACEP untuk menggunakan delta TnI
bersamaan dengan delta CK-MB mungkin tidak dapat digeneralisasikan ke tes troponin lain yang tersedia
secara komersial. Perhatian harus digunakan saat menggunakan rekomendasi ACEP pada pasien DE dengan
nyeri dada dan suspensi ACS.
Tabel berikut menguraikan frekuensi sampling yang disarankan setelah penerimaan ED untuk berbagai spidol
jantung.

Table 1. Sampling Frequency of Cardiac Markers (Open Table in a new window)

  Baseline 3-4 h 6-9 h 12-24 h >24 h

CK-MB isoforms, myoglobin X X X    
CK-MB, TnI, TnT X X X X  
 (only if very high risk)

Late presenters

        X
(TnI, TnT)

The sample time at 3-4 hours is useful in the ED or chest pain observation unit where rapid triage and early diagnosis are essential. In other patients
admitted for ACS, biomarkers drawn at the 3- to 4-hour interval are not as important as they are at the 6- to 9-hour mark. The ACC/AHA guidelines for the
treatment of patients with unstable angina and NSTEMI recommend a baseline sample upon ED arrival and a repeat sample 6-9 hours after presentation.

Few studies on the "time to positivity" have been performed, but serial samples that become positive in the 12- to 24-hour window are considered unlikely,
unless the patient has ongoing symptoms of ischemia after admission. Acute MI can therefore be ruled out in patients with negative serial marker results
through the 6- to 9-hour period after presentation.

Cardiac Markers in Therapeutic Management

Clinical trials have demonstrated the benefits of using cardiac markers as an indicator for specific therapeutic interventions in ACS. However, this use
remains investigational; currently, no validated therapeutic algorithms are based on an isolated positive marker result in the absence of other clinical or
ECG findings.

Subgroup analysis of trials with low molecular weight heparin (LMWH) showed a decreased cardiac event rate in patients with a positive result for TnT and
who were treated with an LMWH. [40, 41]
Similarly, in the PRISM trial, patients with an elevated TnI who were treated with the glycoprotein (GP) IIb/IIIa inhibitor tirofiban (Aggrastat)
demonstrated a significant decrease in cardiac events compared with patients without an elevated TnI level. No significant difference in outcomes was seen
in patients without TnI elevations who were treated with tirofiban when compared with placebo. [42]

In the PURSUIT trial, patients who were treated with the GP IIb/IIIa inhibitor eptifibatide (Integrilin) within 6 hours of symptom onset obtained the greatest
benefit, and subgroup analysis showed that patients with an elevated troponin level also had better responses to therapy than did those whose troponin result
was negative. [43]

Finally, in the TACTICS-TIMI 18 trial, patients with elevations in TnI or TnT had a significant reduction in death, MI, or rehospitalization for ACS within
6 months after being treated with early invasive therapy consisting of aspirin, heparin, tirofiban, and catheterization/revascularization within 4-48 hours. [44,
45]
Subset analysis noted that an elevation of CK-MB did not benefit the early invasive group when compared with the conservative management group.
However, early invasive therapy did benefit the subgroup of patients with elevated troponin levels but normal CK-MB levels. [46]

These studies suggest that a positive troponin result alone is an independent predictor of high risk for adverse cardiac events, and that therapy with LMWHs
and/or GP IIb/IIIa inhibitors appears to confer the most benefit on patients with elevated cardiac troponins levels.

Troponins in CRF

Patients with chronic renal failure (CRF) who are on hemodialysis are at increased risk of coronary artery disease and acute ACS, and cardiovascular
disease accounts for about 50% of deaths in these patients. Early studies revealed a high prevalence of elevated cardiac troponin levels in patients with
CRF, and especially of TnT. However, the clinical significance of an elevated TnT level is unclear.

Biochemical studies have demonstrated that the troponin elevation originates from the myocardium and is not related to the myopathy associated with renal
failure. Yet, patients with CRF frequently have chronic congestive heart failure (CHF) and hypertension, which may independently elevate the troponin
level. In addition, data suggest that elevated troponin levels in asymptomatic patients may reflect subclinical microinfarctions that are clinically distinct
from ACS.

Large prospective studies have confirmed the association between TnT elevation and cardiac mortality in patients with CRF. The GUSTO IV ACS trial
showed that patients with renal insufficiency and an elevated TnT had the highest overall risk of the composite endpoint of death or acute MI, [47] and 2 other
prospective studies reported that an elevated TnT—but not TnI—increased the risk of long-term mortality. [48, 49] Whether elevated TnT increases cardiac risk
in the short term (ie, 30 d) is unclear, but patients without short-term risk may not require hospitalization and potentially could be managed on an outpatient
basis.
It has been suggested that chronically elevated troponin levels represent chronic structural cardiovascular disease, such as prior MI, chronic CHF, or
hypertension in the setting of CRF. If true, these patients are at higher cardiac risk compared with the normal, healthy patient population and troponin
remains a useful marker in the setting of CRF. [50, 51]

Note that dialysis does not affect TnT or TnI levels; predialysis and postdialysis levels are essentially unchanged. CK-MB, however, is dialyzable, and
levels are decreased postdialysis. Therefore, a single elevated TnT level in patients with CRF and possible ACS is nondiagnostic for acute MI in the
absence of other findings. Serial determinations are usually required, with a focus on a rise in the troponin level.

Ascertaining whether an elevated troponin in patients with CRF represents true acute MI or a false-positive result can be difficult. In patients with cardiac
risk factors who are deemed clinically to be at moderate-high risk for ACS, the prudent approach would be to observe and perform serial cardiac markers
over 6-9 hours. In low-risk asymptomatic patients and in the absence of any other findings indicative of ACS, the elevated troponin result is more likely to
be false positive for acute MI.

Troponins in Nonischemic Heart Disease

A number of studies have demonstrated that TnT can be used for risk stratification of patients with CHF without ischemia. Specifically, elevated cardiac
troponins are associated with decreased left ventricular ejection fraction and poor prognosis in patients with CHF and are related to the severity of heart
failure. [52]

Isolated studies have shown evidence of MI and elevated TnI levels in patients with subarachnoid hemorrhage. [53] Vasoactive peptides released during acute
subarachnoid hemorrhage induce deep T-wave inversions on ECG that indicate myocardial injury. Similarly, TnT has been shown to be an independent
predictor of outcome in patients with pulmonary embolism; right ventricular strain or infarction from acute pulmonary hypertension causes the elevated
troponin level.

Elevated troponin levels have also been documented in other nonischemic cardiac disease states, such as tachyarrhythmias, hypertension, myocarditis, and
myocardial contusion.

Emerging Markers

Investigations into emerging cardiac markers are focusing on increasing diagnostic sensitivity and specificity and on improving prognostic capability.

B-type natriuretic peptide

B-type natriuretic peptide (BNP) is secreted primarily by the ventricular myocardium in response to wall stress, including volume expansion and pressure
overload. Multiple studies have demonstrated that BNP may also be a useful prognostic indicator in ACS. The TIMI study group performed several

Investigasi terhadap marka jantung yang muncul berfokus pada peningkatan sensitivitas dan spesifisitas
diagnostik dan pada peningkatan kemampuan prognostik.
Peptida natriuretik tipe B
Peptida peptida natriuretik B-tipe ini disekresi terutama oleh miokardium ventrikel sebagai respons
terhadap tekanan dinding, termasuk perluasan volume dan kelebihan tekanan. Beberapa penelitian telah
menunjukkan bahwa BNP mungkin juga merupakan indikator prognostik yang berguna di ACS. Kelompok studi
TIMI melakukan beberapa

investigations showing that the BNP level predicted cardiac mortality and other adverse cardiac events across the entire spectrum of ACS. The mortality
rate nearly doubled when both TnI and BNP levels were elevated.

Peptida natriuretik tipe B

Peptida peptida natriuretik B-tipe ini disekresi terutama oleh miokardium ventrikel sebagai respons
terhadap tekanan dinding, termasuk perluasan volume dan kelebihan tekanan. Beberapa penelitian telah
menunjukkan bahwa BNP mungkin juga merupakan indikator prognostik yang berguna di ACS. Kelompok studi
TIMI melakukan beberapa penyelidikan yang menunjukkan bahwa tingkat BNP memperkirakan mortalitas jantung
dan kejadian kardiak merugikan lainnya di seluruh spektrum ACS. Tingkat kematian hampir dua kali lipat
ketika tingkat TnI dan BNP meningkat.

In the TACTICS-TIMI 18 trial, an elevated BNP level was associated with tighter culprit stenosis, higher corrected TIMI frame count, and left anterior
descending artery involvement. [44] These data suggest that increased BNP levels may correlate with greater severity of myocardial ischemia and could
partially explain the association between increased BNP levels and adverse outcomes.

Data from OPUS-TIMI 16 and TACTICS-TIMI 18 demonstrated that baseline elevations of TnI, C-reactive protein (CRP), and BNP levels in patients with
NSTEMI were independent predictors of the composite endpoint of death, MI, or CHF. [54] The PROMPT-TIMI 35 trial demonstrated that transient
myocardial ischemia during exercise testing was associated with an immediate rise in BNP levels. [55] In addition, the severity of ischemia was directly
proportional to the elevation in BNP.
Dalam uji coba TAKTIK-TIMI 18, tingkat BNP yang meningkat dikaitkan dengan stenosis pelakunya yang lebih
ketat, jumlah kerangka TIMI yang dikoreksi lebih tinggi, dan menyebabkan turunnya arteri anterior. [44]
Data ini menunjukkan bahwa peningkatan kadar BNP dapat berkorelasi dengan tingkat keparahan iskemia
miokard yang lebih parah dan sebagian dapat menjelaskan hubungan antara tingkat BNP yang meningkat dan
hasil buruk.
Data dari OPUS-TIMI 16 dan TACTICS-TIMI 18 menunjukkan bahwa kenaikan awal tingkat TnI, C-reactive
protein (CRP), dan BNP pada pasien dengan NSTEMI adalah prediktor independen dari titik akhir komposit
kematian, MI, atau CHF. [54] Uji coba PROMPT-TIMI 35 menunjukkan bahwa iskemia miokard sementara selama
pengujian latihan dikaitkan dengan peningkatan segera tingkat BNP. [55] Selain itu, tingkat keparahan
iskemia berbanding lurus dengan elevasi di BNP.

The presence of acute CHF in patients with ACS is a well-known predictor of adverse cardiac events and higher risk. Therefore, it is not surprising that an
elevated BNP level, as a marker of CHF, is also predictive of adverse cardiac events in patients with ACS. Although BNP has been validated as a diagnostic
marker for CHF, insufficient data are available to evaluate the use of BNP as a diagnostic cardiac marker for ACS in the ED.

Preinterventional levels of mid-regional (MR) pro-adrenomedullin (MR-proADM), MR-pro-A-type natriuretic peptide (MR-proANP), and N-terminal pro-
natriuretic peptide (NT-proBNP) also appear to have potential prognostic utility for adverse events within 1 year of patients with severe aortic valve
stenosis who undergo transcatheter aortic valve implantation (TAVI). [56] In a prospective study of 100 consecutive patients with aortic stenosis who were
treated with TAVI, preintervention levels of these markers as well as highly sensitive troponin T (hs-TnT) were not predictive of 30-day outcome but were
associated with cardiovascular events and all-cause mortality at 1 year.

Kehadiran CHF akut pada pasien dengan ACS adalah prediktor terkenal dari kejadian kardiak yang merugikan
dan risiko yang lebih tinggi. Oleh karena itu, tidak mengherankan bahwa tingkat BNP yang meningkat,
sebagai penanda CHF, juga memprediksi kejadian kardiak yang merugikan pada pasien dengan ACS. Meskipun
BNP telah divalidasi sebagai penanda diagnostik untuk CHF, data yang tidak mencukupi tersedia untuk
mengevaluasi penggunaan BNP sebagai penanda jantung diagnostik untuk ACS di ED.
Tingkat praintervensi pro-adrenomedullin (MR-proADM), peptida natriuretik MR-pro-A tipe MR-pro-A, MR-
proANP, dan peptida pro-natriuretik N-terminal (NT-proBNP) tampaknya juga memiliki utilitas prognostik
potensial untuk kejadian buruk dalam waktu 1 tahun pasien dengan stenosis katup aorta berat yang
menjalani implantasi katup aorta transkatheter (TAVI). [56] Dalam sebuah penelitian prospektif terhadap
100 pasien berturut-turut dengan stenosis aorta yang diobati dengan TAVI, tingkat prapenuaan penanda ini
dan juga troponin T yang sangat sensitif (hs-TnT) tidak memprediksi hasil 30 hari namun dikaitkan dengan
kardiovaskular. kejadian dan semua penyebab kematian pada 1 tahun.

C-reactive protein

C-reactive protein (CRP), a nonspecific marker of inflammation, is considered to be directly involved in coronary plaque atherogenesis. Extensive studies
beginning in the early 1990s showed that an elevated CRP level independently predicted adverse cardiac events at the primary and secondary prevention
levels.

Data indicate that CRP is a useful prognostic indicator in patients with ACS, as elevated CRP levels are independent predictors of cardiac death, acute MI,
and CHF. In combination with TnI and BNP, CRP may be a useful adjunct, but its nonspecific nature limits its use as a diagnostic cardiac marker for ACS
in the ED.

Protein C-reaktif (CRP), penanda nonspesifik peradangan, dianggap terlibat langsung dalam aterosklerosis
plak koroner. Studi ekstensif yang dimulai pada awal tahun 1990an menunjukkan bahwa tingkat CRP yang
meningkat secara independen memperkirakan kejadian kardiak yang merugikan pada tingkat pencegahan primer
dan sekunder.
Data menunjukkan bahwa CRP adalah indikator prognostik yang berguna pada pasien dengan ACS, karena
tingkat CRP yang meningkat adalah prediktor independen kematian jantung, MI akut, dan CHF. Dalam
kombinasi dengan TnI dan BNP, CRP mungkin merupakan tambahan yang berguna, namun sifat nonspesifiknya
membatasi penggunaannya sebagai tanda diagnostik jantung untuk ACS di ED.

Myeloperoxidase

Myeloperoxidase (MPO) is a leukocyte enzyme that generates reactant oxidant species and has been linked to prothrombotic oxidized lipid production,
plaque instability, lipid-laden soft plaque creation, and vasoconstriction from nitrous oxide depletion. Early studies showed significantly increased MPO
levels in patients with angiographically documented coronary artery disease [57] ; these findings spurred further investigation into MPO as a novel cardiac
marker.
In 604 sequential patients presenting to the ED with chest pain, elevated MPO levels independently predicted increased risk for major adverse cardiac
events, including MI, reinfarction, need for revascularization, or death at 30 days and at 6 months. [58] Among the patients who presented to the ED with
chest pain but who were ultimately ruled out for MI, an elevated MPO level at presentation predicted subsequent major adverse cardiovascular outcomes. In
a subgroup of patients with negative baseline TnT, MPO levels were significantly elevated at baseline, even within 2 hours after symptom onset.

Myeloperoxidase (MPO) adalah enzim leukosit yang menghasilkan spesies oksidan reaktan dan dikaitkan
dengan produksi lipid anti-oksidasi prothrombotic, ketidakstabilan plak, pembuatan plak lembut lipid,
dan vasokonstriksi dari penipisan oksida nitrat. Studi awal menunjukkan tingkat MPO meningkat secara
signifikan pada pasien dengan penyakit arteri koroner didiagnosis secara angiografi [57]; Temuan ini
mendorong penyelidikan lebih lanjut terhadap MPO sebagai penanda jantung baru.
Pada 604 pasien berurutan yang hadir ke DE dengan nyeri dada, tingkat MPO yang meningkat secara
independen memperkirakan peningkatan risiko kejadian jantung merugikan utama, termasuk MI, reinfarction,
kebutuhan revaskularisasi, atau kematian pada 30 hari dan 6 bulan. [58] Di antara pasien yang
dipresentasikan ke ED dengan nyeri dada tapi yang pada akhirnya dikesampingkan untuk MI, tingkat MPO
yang meningkat pada presentasi memprediksi hasil kardiovaskular utama yang merugikan berikutnya. Dalam
subkelompok pasien dengan tingkat dasar TnT yang negatif, tingkat MPO meningkat secara bermakna pada
awal, bahkan dalam waktu 2 jam setelah onset gejala.

MPO may be a useful early marker in the ED based on its ability to detect plaque vulnerability that precedes ACS. However, further validation studies on
MPO in the general ED chest pain population are needed to determine its sensitivity and specificity, as well as its negative and positive predictive values. [59,
60]

MPO mungkin merupakan penanda awal yang berguna di ED berdasarkan kemampuannya untuk mendeteksi
kerentanan plak yang mendahului ACS. Namun, studi validasi lebih lanjut pada MPO pada populasi nyeri
dada ED umum diperlukan untuk menentukan sensitivitas dan spesifisitasnya, serta nilai prediksi negatif
dan positifnya. [59, 60]

Ischemia modified albumin

Ischemia modified albumin (IMA) is a novel marker of ischemia that is produced when circulating serum albumin contacts ischemic heart tissues. IMA can
be measured by the albumin cobalt binding assay that is based on IMA’s inability to bind to cobalt. [61] A rapid assay with a 30-minute laboratory turnaround
time has been developed and marketed as the first commercially available US Food and Drug Administration (FDA)–approved marker of myocardial
ischemia.

Based on investigations of myocardial ischemia induced by balloon inflation during percutaneous coronary intervention, IMA levels rise within minutes of
transient ischemia, peak within 6 hours, and can remain elevated for as long as 12 hours.

Studies on the use of IMA in patients with chest pain in the ED found sensitivities that ranged from 71-98% and specificities of 45-65%, with a negative
predictive value of 90-97% for ACS. [62]

Iskemia dimodifikasi albumin

Ischemia modified albumin (IMA) merupakan penanda baru iskemia yang dihasilkan saat beredar kontak
albumin serum jaringan jantung iskemik. IMA dapat diukur dengan uji ikatan kobalt albumin yang
didasarkan pada ketidakmampuan IMA untuk mengikat kobalt. [61] Uji cepat dengan waktu perumusan
laboratorium 30 menit telah dikembangkan dan dipasarkan sebagai penanda iskemia miokard yang pertama
kali diberikan oleh Food and Drug Administration (FDA) yang disetujui secara komersial.
Berdasarkan penyelidikan iskemia miokard yang disebabkan oleh inflasi balon selama intervensi koroner
perkutan, tingkat IMA meningkat dalam beberapa menit setelah iskemia transien, puncak dalam 6 jam, dan
dapat tetap meningkat selama 12 jam.
Studi tentang penggunaan IMA pada pasien dengan nyeri dada di DE menemukan sensitivitas yang berkisar
antara 71-98% dan spesifisitas 45-65%, dengan nilai prediksi negatif 90-97% untuk ACS. [62]

A multimarker approach in one study, using a combination of ECG findings, TnT levels, and IMA levels, achieved a sensitivity of 95% for ACS, [63] while a
second study calculated that the combination of IMA, myoglobin, CK-MB, and TnI increased the sensitivity to 97% for detecting myocardial ischemia. [64]

However, IMA levels are also elevated in patients with cirrhosis, certain infections, and advanced cancer, which reduces the specificity of the assay. Further
validation and outcome studies are required to evaluate IMA’s use in the ED diagnosis of ACS when the ECG and cardiac troponins levels are
nondiagnostic.

pendekatan multimarker dalam satu studi, dengan menggunakan kombinasi temuan EKG, tingkat TnT, dan
tingkat IMA, mencapai sensitivitas 95% untuk ACS, [63] sementara studi kedua menghitung bahwa kombinasi
IMA, myoglobin, CK-MB, dan TnI meningkatkan sensitivitas menjadi 97% untuk mendeteksi iskemia miokard.
[64]
Namun, tingkat IMA juga meningkat pada pasien dengan sirosis, infeksi tertentu, dan kanker lanjut, yang
mengurangi spesifisitas uji. Penelitian validasi dan hasil lebih lanjut diperlukan untuk mengevaluasi
penggunaan IMA dalam diagnosis DE ACS saat kadar ECG dan troponin jantung tidak didiagnostik.