To evaluate the diagnostic value of Copeptin as a novel biomarker in early diagnosis of Acute Myocardial Infarction. 56 patients with acute Myocardial Infarction (STEMI) and 25 healthy controls who were admitted to the Cardiology and Clinical Pathology Departments, national heart institute (NHI) from October 2015 to April 2016. The kit used a double-antibody sandwich enzyme-linked immune-sorbent assay (ELISA) to assay the level of Human Copeptin in samples. As regard copeptin, the median range of copeptin level was 242.5pg/ml in patient group and 75pg/ml in control group. The comparative study between the two groups shows a significant difference (p < 0.05) Conclusion: Copeptin is a reliable diagnostic tool in patients with AMI (STEMI) with sensitivity 85.7%, specificity 86.7%, PPV 96% and NPV 61.9%.

1. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
IJCCR
Copeptin as a Novel Biomarker in the Diagnosis of Acute
Myocardial Infarction
*Eman Said Al Kishk1, El Sayed Abd El Khalik El Darky2, Mohammed Abd El Kader Ilian3, Saed
Fawzy Tawfik4, Ahmed Gamal El Nakeeb5
1,2,3,4,5
Cardiology Department, Faculty of Medicine, Benha University, Egypt
To evaluate the diagnostic value of Copeptin as a novel biomarker in early diagnosis of Acute
Myocardial Infarction. 56 patients with acute Myocardial Infarction (STEMI) and 25 healthy
controls who were admitted to the Cardiology and Clinical Pathology Departments, national heart
institute (NHI) from October 2015 to April 2016. The kit used a double-antibody sandwich enzyme-
linked immune-sorbent assay (ELISA) to assay the level of Human Copeptin in samples. As regard
copeptin, the median range of copeptin level was 242.5pg/ml in patient group and 75pg/ml in
control group. The comparative study between the two groups shows a significant difference (p
< 0.05) Conclusion: Copeptin is a reliable diagnostic tool in patients with AMI (STEMI) with
sensitivity 85.7%, specificity 86.7%, PPV 96% and NPV 61.9%.
Keywords: Copeptin; Myocardial infarction; Troponin; cardiac biomarkers
INTRODUCTION
Cardiovascular diseases are the leading cause of death in
industrializing countries. ST segment elevation myocardial
infarction (STEMI) is one of the most frequent
manifestations of acute coronary syndrome despite
advances in medical and interventional treatment mortality
and morbidity still high. (Libby P et al., 2001) Myocardial
infarction (MI) can be recognized by clinical features,
including electrocardiographic (ECG) findings, elevated
values of biochemical markers (biomarkers) of myocardial
necrosis, and by imaging, or may be defined by pathology
(Thygesen et al., 2012).
Ruling out AMI is expensive and time consuming.
Sometimes, doctors cannot fully rely on clinical findings
and ECG examination, since one quarter to one third of
patients with AMI present without significant ECG
changes. Current guideline recommends the
measurement of cardiac biomarkers (Troponin) for
differentiation between unstable angina and myocardial
infarction (NSTEMI, STEMI). (Mills et al., 2011) The
delayed rise of troponin after AMI warrants doctors to
monitor their patients in the emergency room for a longer
period of time. Not only this approach cause overcrowding
in the emergency department, but also a waste of time and
money. Therefore, rapid and reliable way to diagnose AMI
is required. In the absence of typical findings of AMI and
without any increase of classic cardiac biomarkers such as
troponin and CK-MB, it is helpful to have other biomarkers
to assist doctor in making clinical judgment and to
determine patient's prognosis. (Mills et al., 2011) Copeptin
is a strong marker for mortality and morbidity in patients
with heart failure after an acute MI. It is released very early
during the onset of an acute myocardial infarction (AMI),
raising the question of its potential value in the diagnosis
of AMI and particularly in ruling-out AMI. Indeed, copeptin
is released much earlier than Troponin making the
interpretation of their complementary kinetics a useful tool
to rule-out AMI (Maisel et al., 2013)
*Corresponding Author: Eman Said Al Kishk, Cardiology
Department, Faculty of Medicine, Benha University, Egypt.
Tel.: +201022080606; E-mail: husseine86@gmail.com;
emansaeid6767@yahoo.com
International Journal of Cardiology and Cardiovascular Research
Vol. 4(2), pp. 072-078, September, 2018. © www.premierpublishers.org, ISSN: 3102-9869
Research Article

2. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
Al-Kishk et al. 073
PATIENTS AND METHODS
Study Population
Our study included 56 patients with acute Myocardial
Infarction (STEMI) who were admitted to the Cardiology
and Clinical Pathology Departments, national heart
institute (NHI) from October 2015 to April 2016. We
included in our study Patients who have been already
diagnosed as Myocardial Infarction (STEMI) by Clinical
Manifestations of M.I. 12 leads E.C.G., CK-T and Cardiac
Troponin T (hs) Exclusion criteria included patients with
cardiomyopathy, HOCM, aortic dissection, aortic
aneurism, rheumatic heart disease and pericardial
diseases. We also enrolled 25 healthy control subjects (15
males and 10 females: mean age 52±11 years) from our
database for normal subjects. The Ethics Committee of the
hospital approved the protocol and informed consent was
obtained in every subject.
Demographic Data and Physical Examination
We obtained full medical history for all patients in this study
including age, gender, risk factors (DM, HTN, dyslipidemia
and smoking) and full medical history.
Laboratory investigations
A-cardiac biomarkers for myocardial necrosis (CK-T and
cardiac troponin T)
B- Copeptin: Venous blood samples withdrawn on
admission (Within 4 hours of onset of chest pain). We
measured copeptin in serum and plasma samples from
healthy individuals and from critically ill patients with Acute
Myocardial Infarction.
Test principle
The kit used a double-antibody sandwich enzyme-linked
immunosorbent assay (ELISA) to assay the level of
Human Copeptin in samples. Copeptin added to
monoclonal antibody Enzyme which is precoated with
Human Copeptin monoclonal antibody, incubation; then,
added Copeptin antibodies labeled with biotin, and
combined with Streptavidin-HRP to form immune complex,
then incubation and washing again to remove the
uncombined enzyme. Then added Chromogen Solution A,
B, the color of the liquid changes into the blue, and at the
effect of acid, the color finally becomes yellow. The chrome
of color and the concentration of the Human Substance
Copeptin of sample were positively correlated.
Specimen requirements
1-Extraction was done as soon as possible after collection
and according to the relevant literature, if it was not
possible; specimens were kept in -20 c to preserve it.
2-serum- coagulation at room temperature 10-20mins，
centrifugation 20-minat the speed of 2000-3000 r.p.m.
supernatant removed, If precipitation appeared,
Centrifugal again.
STATISTICAL METHODS
Data were analyzed using IBM© SPSS© Statistics version
23 (IBM© Corp., Armonk, NY, USA), MedCalc© version 15
(MedCalc© Software bvba, Ostend, Belgium). Normality of
numerical data distribution was examined using the
D‘Agostino-Pearson test. Skewed numerical variables
were presented as median and interquartile range and
intergroup differences were compared using the Mann-
Whitney test. Normally distributed numerical variables
were presented as mean ± SD and intergroup differences
were compared using the unpaired t test. Categorical
variables were presented as number and percentage, and
intergroup differences were compared using fisher‘s exact
test. Receiver-operating characteristic (ROC) curve
analysis was used to examine the value of total CK, hs-
cTnT, or copeptin for discrimination between cases with
STEMI and controls. The area under the various ROC
curves (AUC) was compared using the Delong method.
Correlations among numerical variables were tested using
the Spearman rank correlation. Backward multivariable
binary logistic regression analysis was used to identify
independent predictors of STEMI. A two-sided p-value
<0.05 was considered statistically significant.
RESULTS
This Prospective Comparative Analytical cohort study
included 56 patients with Patients with acute Myocardial
Infarction (STEMI) and 25 healthy controls who were
admitted to the Cardiology and Clinical Pathology
Departments, national heart institute (NHI) from October
2015 to April 2016.
Demographic characteristics and history: As shown in
(Table 1) (figure 1):
The mean age was 56 ± 9 years in patient group and 51 ±
9 years in control group. The comparative study between
the two groups shows a non-significant difference (p >
0.05).
Of the fifty-six patients in group I, 41 (73.2%) were males
and 15 (26.8%) were females; whereas out of the twenty-
five healthy controls in group II, 15 (60%) were males and
10 (40%) were females. The comparative study between
the two groups shows no significant difference (p > 0.05).
As regard smoking, of the fifty-six patients in group I, 26
(46.4%) were non-smokers and 30 (53.6%) were smokers;
whereas out of the twenty-five healthy controls in group II,
22 (88%) were non-smokers and 3 (12%) were smokers.
The comparative study between the two groups shows
significant difference (p < 0.05).
Regarding diabetes mellitus, of the fifty-six patients in
group I, 31(55.4%) were non-diabetic and 24 (44.6%) were
diabetic; whereas out of the twenty-five healthy controls in
group II, 22 (88%) were non-diabetic and 3 (12%) were
diabetic. The comparative study between the two groups
shows significant difference (p< 0.05).

3. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
Int. J. Cardiol. Cardiovasc. Res. 074
As regard dyslipidemia, of the fifty-six patients in group I,
54 (96.4%) were non-dyslipidemic and 6 (10.7%) were
dyslipidemic; whereas all the twenty-five healthy controls
in group II (100%) were non-dyslipidemic. The
comparative study between the two groups shows no
significant difference (p > 0.05). Other risk factor shows no
significant difference where all of them shows (p> 0.05).
Table 1: Baseline characteristic of the study
population
Baseline
characteristic
Control
group
(N=25)
STEMI group
(N=56)
p-value
Age (years) 51±9 56±9 0.056
male gender 15 (60%) 41 (73.2%) 0.351
Smoking 3 (12%) 30 (53.6%) 0.008
DM 3 (12%) 24 (42.9%) 0.040
HTN 5 (20%) 24 (42.9%) 0.139
Dyslipidemia 0 (0.0%) 6 (10.7%) 0.331
Obesity 0 (0.0%) 5 (8.9%) 0.557
Past history of CAD 0 (0.0%) 4 (7.1%) 0.572
Family history of CAD 0 (0.0%) 1 (1.8%) 1.000
CKD 0 (0.0%) 1 (1.8%) 1.000
Heart block 0 (0.0%) 1 (1.8%) 1.000
Data are presented as mean ± SD; CAD=coronary artery
disease; CKD=chronic kidney disease; DM=diabetes
mellitus; HTN=hypertension; N=number
Figure 1: Prevalence of relevant risk factors and co-
morbidities among cases with STEMI and controls.
Comparison of cardiac markers in cases with STEMI
and control groups
As shown in (Table 2) (figure 2,3,4): Regarding CK-T, the
median range of CK-T level was 143.5 IU/L in patient
group and 66 IU/L in control group. The comparative study
between the two groups shows a significant difference (p
<0.05). In troponin T, the median range of CTnT level was
45.4pg/ml in patient group and 8.26pg/ml in control group.
The comparative study between the two groups shows a
significant difference (p < 0.05). Regarding copeptin, the
median range of copeptin level was 242.5pg/ml in patient
group and 75pg/ml in control group. The comparative
study between the two groups shows a significant
difference (p < 0.05).
Table 2: Comparison of cardiac markers in cases with
STEMI and control groups:
Control group
(N=25)
STEMI group
(N=56)
p-value
Total CK
(IU/ml)
66 (49.8 to 78.5) 143.5 (98 to 176) <0.001
hs-cTnT
(pg/ml)
8.26 (6.1 to 10.1) 45.4 (15.2 to 132) <0.001
Copeptin
(pg/ml)
75 (46.3 to 107.5)242.5 (137.5 to 975)<0.001
Data area median (interquartile rang e). Mann-Whitney
test.
Figure (2): Box plot showing the hs-cTnT in cases with
STEMI and controls. Box represents the range from the
first to third quartile (interquartile range). Line inside the
box represents the median (second quartile). Whiskers
represent the range between the minimum and maximum
values excluding outliers (rounded markers) and extreme
observations (asterisks).

4. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
Al-Kishk et al. 075
Figure 3: Box plot showing the total CK in cases Figure 4: Box plot showing the copeptin in cases with STEMI
with STEMI and controls. Box represents the range and controls. Box represents the range from the first to third
from the first to third quartile (interquartile range). quartile (interquartile range). Line inside the box represents the
Line inside the box represents the median (second median (second quartile). Whiskers represent the range
quartile). Whiskers represent the range between between the minimum and maximum values.
the minimum and maximum values.
Table (3): Receiver-operating characteristic (ROC) curve analysis for discrimination between cases with STEMI
and controls using serum total CK, hs-cTnT, or copeptin
Sample size 81 patients
Positive group (STEMI) 56(78.9%)
Negative group (Controls) 25(21.1%)
Disease prevalence 78.9%
Marker
Index Total CK hscTnT Copeptin
Area under the ROC curve (AUC) 0.929 0.885 0.910
95% CI 0.842 to0.976
0.787 to
0.948
0.818 to
0.965
z statistic 13.409 9.626 11.917
p-value <0.0001 <0.0001 <0.0001
Youden index J 0.808 0.688 0.724
Cut-off criterion >80 IU/ml
>12.9
(pg/ml)
>110
(pg/ml)
Sensitivity 87.5 82.14 85.71
95% CI 75.9 - 94.8 69.6 - 91.1 73.8 - 93.6
Specificity 73.33 86.67 86.67
95% CI 68.1 - 99.8 59.5 - 98.3 59.5 - 98.3
+LR 13.13 6.16 6.43
95% CI 2.0 - 87.4 1.7 - 22.5 1.8 - 23.5
-LR 0.13 0.21 0.16
95% CI 0.07 - 0.3 0.1 - 0.4 0.08 - 0.3
+PV 98 95.8 96
95% CI 89.4 - 99.9 85.7 - 99.5 86.3 - 99.5
-PV 66.7 56.5 61.9
95% CI 43.0 - 85.4 34.5 - 76.8 38.4 - 81.9
Delong method.

5. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
Int. J. Cardiol. Cardiovasc. Res. 076
Figure (5): Receiver-operating characteristic (ROC) curve
for discrimination between cases with STEMI and controls
using hs- cTnT.
At an area under the curve of 92.2% and cut off crition
value of 80 IU/L, CK-T has a sensitivity of 87.5%,
specificity 93 %, positive predictive value 98% and
negative predictive value 66.7 %.
Figure (6): Receiver-operating characteristic (ROC)
curve for discrimination between cases with STEMI and
controls using serum total CK.
At an area under the curve of 88.5% and cut off crition
value of >12.9pg/ml, hs-cTnT has a sensitivity of 82.14%
,specificity 86.67%, positive predictive value 95.8% and
negative predictive value 56.5%
Figure (7): Receiver-operating characteristic (ROC) curve
for discrimination between cases with STEMI and controls
using copeptin.
At an area under the curve of 91% and cut off crition value
of >110pg/ml, copeptin has a sensitivity of 85.71%,
specificity 86.67%, positive predictive value 96% and
negative predictive value 61.9%.
Table (4): Comparison of the receiver-operating
characteristic (ROC) curves for discrimination
between cases with STEMI and controls using serum
total CK, hscTnT, or copeptin
Marker AUC 95% CI
Total CK 0.929 0.842 to 0.976
hs-cTnT 0.885 0.787 to 0.948
Copeptin 0.91 0.818 to 0.965
Comparison ΔAUC 95% CI for ΔAUC Z
p-
value
Total CK versus
Hs-cTnT
0.044 -0.044 to 0.132 0.985 0.325
Total CK versus
Copeptin
0.019 -0.065 to 0.102 0.434 0.664
Hs-cTnT versus
Copeptin
0.02
6
-0.062 to 0.113 0.571 0.568
AUC= Area under the ROC curve; ΔAUC= difference
between AUCs. =Delong method.

6. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
Al-Kishk et al. 077
Figure (8): Comparison of the receiver-operating
characteristic (ROC) curves for discrimination between
cases with STEMI and controls using serum total CK, hs-
cTnT, or copeptin.
Table (5): Backward multivariable binary logistic
regression analysis for discrimination between
patients with STEMI and controls
Independent
variable
B SE Wald
p-
value
OR
95% CI for
OR
Total CK
(IU/ml)
0.06 0.02 7.52 0.006 1.06
1.02 to
1.10
Copeptin
(pg/ml)
0.03 0.01 5.22 0.022 1.03
1.005 to
1.064
Constant -8.66
Variables excluded from the model
hs-cTnT, Smoking, DM, Age, DBP
B=regression coefficient; SE=standard error; Wald=Wald
statistic; OR=odds ratio.
According to Backward multivariable binary logistic
regression analysis for discrimination between patients
with STEMI and controls there is significant in dependable
variable CK-T and copeptin p value <0.05.
Table (6): Correlation between cardiac markers and
other relevant quantitative variables
Total CKhs-cTnT Copeptin
Total CK
Correlation
coefficient
- 0.31 0.20
p-value - 0.009 0.093
hs-cTnT
Correlation
coefficient
0.31 - 0.47
p-value 0.009 - <0.0001
Copeptin
Correlation
coefficient
0.20 0.47 -
p-value 0.093 <0.0001 -
Age
Correlation
coefficient
0.15 0.01 -0.05
p-value 0.207 0.913 0.656
Duration of
chest pain
Correlation
coefficient
0.82 0.10 -0.13
p-value <0.0001 0.467 0.336
SBP
Correlation
coefficient
0.11 -0.01 0.07
p-value 0.383 0.926 0.550
DBP
Correlation
coefficient
0.11 -0.02 0.13
p-value 0.359 0.899 0.291
Spearman rank correlation; SBP= systolic blood pressure;
DBP= diastolic blood pressure
According to the previous table there is statistically
significant correlation between CK-T and hs-cTnT p value
<0.05and there is statistically significant correlation
between hs-cTnT and Copeptin p value <0.05. And there
is statistically significant correlation between CK-T and
SBP with p value <0.001.
DISCUSSION
Myocardial infarction (MI) can be recognized by clinical
features, including electrocardiographic (ECG) findings,
elevated values of biochemical markers (biomarkers) of
myocardial necrosis, and by imaging, or may be defined
by pathology. The development of ever more sensitive and
myocardial tissue-specific cardiac biomarkers and more
sensitive imaging techniques now allows for detection of
very small amounts of myocardial injury or necrosis
(Thygesen et al., 2012).
Copeptin is a strong marker for mortality and morbidity in
patients with heart failure after an acute MI. It is released
very early during the onset of an acute myocardial
infarction (AMI), raising the question of its potential value
in the diagnosis of AMI and particularly in ruling-out AMI.
Indeed, copeptin is released much earlier than Troponin
making the interpretation of their complementary kinetics
a useful tool to rule-out AMI (Maisel et al., 2013).
The aim of this work was to detect the diagnostic value of
Copeptin as a novel biomarker in early diagnosis of acute
myocardial infarction. We have enrolled 56 patients with
acute Myocardial Infarction-on (S.T.E.M.I.) and 15 healthy
controls who are admitted to the Cardiology and Clinical
Pathology Departments at national heart institute. The
principal finding of current study was that copeptin has a
sensitivity of 85.71%, specificity of 86.67%, positive
predictive value of 96% and negative predictive value of
61.9% with an accuracy of 86%. (cutoff value of 110 pg/ml)
while, cardiac troponin T has a sensitivity of 82.14 %,
specificity of 86.67 %, positive predictive value of 95.8%
and negative predictive value of 56.5% with an accuracy
of 85%. (Cutoff value of 12.9 pg/ml) but CK-T has a
sensitivity of 80%, specificity of 73%, positive predictive

7. Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction
Int. J. Cardiol. Cardiovasc. Res. 078
value of 98% and negative predictive value of 66.7 % with
an accuracy of 86%. (Cut off value of 80 IU/L).
Reichlin et al. (2009) evaluated the contribution of copeptin
to the management of 487 consecutive patients with chest
pain presenting to the ED. In those patients with the final
gold standard diagnosis of AMI (17%), copeptin
concentrations were already elevated 4 h after the onset
of symptoms, at a time when troponin T was still
undetectable in many patients. As copeptin concentrations
declined, and troponin concentrations increased, this
distinct kinetics resulted in an additive value of both
markers for the diagnosis of AMI.
Maisel et al. (2013) have shown that copeptin is released
very early during the onset of an acute myocardial
infarction (AMI), raising the question of its potential value
in the diagnosis of AMI and particularly in ruling-out AMI.
Indeed, copeptin is released much earlier than Troponin
making the interpretation of their complementary kinetics
a useful tool to rule-out AMI.
Reichlin et al. (2009) studied 487 consecutive patients
presenting to the emergency department with symptoms
suggestive of AMI, we measured levels of copeptin at
presentation, using a novel sandwich immune-
luminometric assay in a blinded fashion. The final
diagnosis was adjudicated by 2 independent cardiologists
using all available data. The adjudicated final diagnosis
was AMI in 81 patients (17%). Copeptin levels were
significantly higher in AMI patients compared with those in
patients having other diagnosis (median 20.8 pmol/l vs. 6.0
pmol/l, p 0.001).
Maisel et al. (2013) who studied how Copeptin could help
in the Early Detection of Patients with Acute Myocardial
Infarction This was a 16-site study in 1,967 patients with
chest pain presenting to an ED within 6 hours of pain
onset. Base line demographic characteristics and clinical
data were collected prospectively. AMIs not detected by
the initial cTnI alone were picked up with copeptin >14
pmol/l in 23 (72%) of 32 patients. Keller et al. (2010)
demonstrated that the combined measurement of copeptin
and troponin T in the first blood sample improved the c
index from 0.85 for troponin T alone to 0.94 for a
combination of copeptin and troponin T. The effect was
particularly prominent in patients presenting within 3 h
after symptom onset. In this group, the combination
increased the c index from 0.77 to 0.91.
Giannitsis et al. (2011) confirmed that the combination of
a negative troponin and negative copeptin value on
presentation allows the rule out of AMI with an NPV >99%.
It is important to remember that a large part of the NPV is
contributed by troponin. Thus, using an analytically
sensitive troponin assay, in combination with copeptin, will
likely lead to an even higher NPV than the less sensitive
troponin assay used here.
STUDY LIMITATIONS
1-the sample size was rather small.
2-the populations included was only admitted to a single
center.
3- We do not have data about short and long term
complication and it is correlation with copeptin levels.
CONCLUSION
Copeptin is a reliable diagnostic tool in patients with AMI
(STEMI) with sensitivity 85.7%, specificity 86.7%, PPV
96% and NPV 61.9%. Also there is significant correlation
between Hs-cTnT and copeptin levels.
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Accepted 17 September 2018
Citation: Al-Kishk ES, EL-Darky EAE, Ilian MAE, Tawfik
SF, El-Nakeeb AG (2018). Copeptin as a Novel Biomarker
in the Diagnosis of Acute Myocardial Infarction.
International Journal of Cardiology and Cardiovascular
Research, 4(2): 072-078.
Copyright: © 2018 Al-Kishk et al. This is an open-access
article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium,
provided the original author and source are cited.