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© 2015 Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon.
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Just Accepted by Scandinavian Cardiovascular Journal
Association of Thiol / Disulphide Ratio with Syntax score in Patients with NSTEMI Harun Kundi , Özcan Erel , Ahmet Balun , Hülya Çiçekçioğlu , Mustafa Cetin , Emrullah Kızıltunç , Salim Neşelioğlu , Canan Topçuoğlu & Ender Örnek
Doi: 10.3109/14017431.2015.1013153
Abstract
Objective: The aim of this study was to investigate the relation between native thiol/ disulphide ratio (TDR) and severity of coronary atherosclerosis as assessed by the Syntax score (SXscore) in patients with non-ST elevation myocardial infarction (NSTEMI) who underwent coronary angiography. Material and Methods: A total of 290 patients with NSTEMI who under-went coronary angiography, were included in the study between Janu-ary and August 2014. Baseline coronary angiography determined the SXscore. The patients were divided into two groups: one with low SXs-cores (< 23) and the other with high SXscores (≥ 23). Results: TDR was signifi cantly lower in patients with high SXscores (p < 0.001). In-hospital mortality was higher in the group with low TDR and high SXscores. The cut-off value of TDR on admission that predicted a high SXscore in the groups combined was 14, with a sensitivity of 73% and a specifi city of 68%. Conclusion: TDR can be determined by an easy, inexpensive, auto-mated or optionally manual spectrophotometric assay, and correlates inversely with SXscore in patients with NSTEMI.
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Original Article
Association of Thiol / Disulphide Ratio with Syntax score in
Patients with NSTEMI
Harun Kundi2, Özcan Erel1, Ahmet Balun2, Hülya Çiçekçioğlu2, Mustafa Cetin2, Emrullah
Kızıltunç2, Salim Neşelioğlu1, Canan Topçuoğlu2 & Ender Örnek2
1Yıldırım Beyazıt University, Biochemistry Department, Ankara, Turkey and 2Ankara
Numune Education and Research Hospital, Cardiology Department, Ankara, Turkey
Corresponding Author: Harun Kundi, MD, Ankara Numune Education and Research Hospital, Cardiology Department, Ankara, Turkey. Phone: +90 532 352 9393. Fax: +90 532 352 9393. E-mail: harunkundi@hotmail.com)
Short title: Association of TDR with SXscore
Abstract
Objective: The aim of this study was to investigate the relation between
native thiol/ disulphide ratio (TDR) and severity of coronary atherosclerosis as
assessed by the Syntax score (SXscore) in patients with non-ST elevation
myocardial infarction (NSTEMI) who underwent coronary angiography.
Material and Methods: A total of 290 patients with NSTEMI who
underwent coronary angiography, were included in the study between January
and August 2014. Baseline coronary angiography determined the SXscore. The
patients were divided into two groups: one with low SXscores (< 23) and the
other with high SXscores (≥ 23).
Results: TDR was significantly lower in patients with high SXscores (p
<0.001). In-hospital mortality was higher in the group with low TDR and high
SXscores. The cut-off value of TDR on admission that predicted a high SXscore
in the groups combined was 14, with a sensitivity of 73% and a specificity of
68%.
Conclusion: TDR can be determined by an easy, inexpensive, automated
or optionally manual spectrophotometric assay, and correlates inversely with
SXscore in patients with NSTEMI.
Keywords: non ST elevation myocardial infarction, oxidative stress, syntax score, thiol to disulphide ratio
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INTRODUCTION
Thiols, or as they are better known, mercaptans contain a sulfhydryl group (-
SH) [1]. The plasma thiol pool is largely formed by albumin and protein
thiols, with smaller contributions from low-molecular-weight thiols such as
cysteinylglycine, cysteine (Cys), homocysteine, glutathione, and γ-
glutamylcysteine [2]. Thiols can undergo oxidation reaction via oxidants and
form disulphide bonds [3]. Oxidation of Cys residues can lead to reversible
formation of mixed disulphides between low-molecular-mass thiols and
protein thiol groups when oxidative stress increases. Formed disulphide
bonds can again be reduced to thiol groups, therefore thiol- disulphide
homeostasis is maintained [4].
Thiol/ disulphide ratio (TDR) has been shown to play critical roles in
detoxification, antioxidant protection, signal transduction, regulation of
enzymatic activity, apoptosis, and cellular signaling mechanisms [5, 6]. TDR
has been increasingly investigated in many disorders, and a growing body of
evidence shows that an abnormal thiol- disulphide homeostasis state is
involved in the pathogenesis of a variety of disorders including
cardiovascular diseases [7].
Previous studies have shown that oxidative stress markers increase after
myocardial infarction (MI) [8, 9] and acute coronary syndromes, and a strong
correlation has been shown between oxidative stress and coronary artery
disease (CAD) [10-12].
Syntax score (SXscore) evaluates the angiographic severity of coronary
lesions [13], and can predict early and late mortality and morbidity
irrespective of disease severity in different clinical conditions, including non-
ST elevation myocardial infarction (NSTEMI) [14-20].
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To the best of our knowledge, this study is the first report on the correlation
between native thiol / disulphide ratio (TDR) and SXscores in NSTEMI
patients, with analysis of the correlations of TDR with angiographic and
clinical risk scores.
MATERIAL AND METHODS
Patients admitted to our clinic with NSTEMI, who underwent coronary
angiography between January and August 2014, were included in the study.
The diagnosis of NSTEMI was based on increased troponin levels and the
presence of at least one of the following; ischemic symptoms, ischemic ECG
changes other than acute ST segment elevations, or new wall motion
abnormalities/new loss of viable myocardium assessed by cardiac imaging
modalities [29]. Patients with troponin elevation due to other than acute
coronary events, like acute heart failure, pulmonary embolism, active
infection or sepsis, chronic kidney disease, stroke, arrhythmias or aortic
dissection, were excluded from the study. Patients with chronic inflammatory
diseases, hematologic disorders, liver disease, previous stroke, rheumatologic
diseases, malignancy, previous MI, and ST elevation myocardial infarction
(STEMI) were excluded too.
Transthoracic echocardiography was performed within 72 hours after
admission of the patients to hospital. Left ventricular ejection fraction
(LVEF) was calculated using Simpson’s method.
Blood samples from the patients after a fasting period of 12 hours were
collected into plain tubes, and serum was separated after centrifugation at
1500 g for 10 minutes and stored at
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-800C until analysis. Blood samples from calcium- EDTA tubes were
analyzed in an auto-analyzer. Complete blood count and differentials were
determined from the peripheral venous blood samples obtained at admission.
TDR was determined as described previously [30]. Briefly, reducible
disulphide bonds were first reduced to form free functional thiol groups.
Unused reductant sodium borohydride was consumed and removed with
formaldehyde, and all thiol groups including reduced and native ones were
detected after reaction with DTNB [5, 5’-dithiobis-(2-nitrobenzoic) acid].
Half of the difference between total and native thiols provided the dynamic
disulphide amount (-S-S). After the determination of native thiol (-SH) and
disulphide (-S-S) amount, native TDR (-SH/-S-S-) was calculated.
Two independent and experienced interventional cardiologists unaware of the
clinical data of the patients calculated SXscores. There were no discrepancies
between the interventional cardiologists that assessed the SX score. Each
lesion ≥ 1.5 mm in diameter and had ≥ 50% stenosis was scored using
version 2.1 of the on-line (www.syntaxscore.com). An SXscore ≥23 was
regarded as severe coronary artery disease, by definition. After this, the
patients were divided into two groups: the ones with low SXscores (< 23)
and the ones with high SXscores (≥ 23).
SPSS 22.0 statistical software (SPSS Inc. Chicago, IL) was used to analyze
data. Kolmogorov-Smirnov test was used to analyze the distribution pattern.
Continuous data were presented as median and interquartile range (IQR), or
mean ± standard deviation (SD). The Spearman correlation coefficient was
calculated to analyze the association between two continuous variables. The
effects of different variables on SXscore were determined with univariate
analysis. Variables with unadjusted p values < 0.2 in logistic regression
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analysis were identified as potential risk factors and included in the full
model. We eliminated potential risk factors using likelihood ratio tests with
reduced model, using stepwise multivariate logistic regression analysis. A p
value < 0.05 was considered statistically significant. The receiver operating
characteristics (ROC) curve was used to show the sensitivity and specificity
of TDR, and optimal cut-off value for predicting SXscore.
At the time of diagnosis, and before coronary angiography, all patients were
given 300 mg acetyl salicylic acid po, the ones < 75 years of age were
administered 300 mg clopidogrel po, and the ones ≥ 75 years of age were
given 75 mg clopidogrel po, and 5,000 U heparin iv.
The standard Judkins technique and 6F catheters (Massachusetts, Expo;
Boston Scientific Corporation) were used to perform baseline angiography
through the femoral artery, and Siemens Axiom Sensis XP device was used.
Ankara Numune Education and Research Hospital’s local ethics committee
approved the study protocol, and all patients provided their written informed
consents.
RESULTS
Baseline clinical characteristics of the study patients and univariate analysis
results (p-values) are presented in Table 1. There were 290 patients in the
study group, and 96 of them (33%) had high SXscores. Gender, age, smoking
status, rate of diabetes mellitus, levels of total cholesterol, low density
lipoprotein, high density lipoprotein, creatinine, total bilirubin, hemoglobin,
mean platelet volume, as well as counts of white blood cells, neutrophils, and
platelets were similar in low- and high- SXscore groups.
Univariate analysis showed that TDR, peak Troponin I level, LVEF, free
thiol and disulphide levels were significantly correlated with SXscore in
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NSTEMI patients. Twenty- six patients died during hospitalization. In-
hospital mortality rate was higher in patients with higher SXscores. When
those four variables were incorporated in a multivariate analysis, the
independent predictors of high SXscore were native TDR (95% confidence
interval 6.949 to 13.741, p <0.001), and LVEF (95% confidence interval 4.14
to 12.7, p = 0.001). Those variables were significantly lower in the high
SXscore group (Table 2). In-hospital mortality was higher in high SXscore
group. Patients with high SXscores had lower TDR compared to the ones
with low SXscores (Figure 1). As shown in Figure 2, there was a negative
correlation between TDR and SXscore in patients with NSTEMI (n =290, r =
-0.445, p < 0.001)
Lastly, receiver-operating characteristic curve (ROC) analysis was performed
to determine the cut-off value of TDR to predict a high SXscore. The cut-off
value of TDR on admission to predict a high SXscore in all population was
14, with a sensitivity of 73% and a specificity of 68% (area under the curve
0.80, p <0.001; Figure 3).
The patients were divided into two groups based on TDR cut-off value of 14.
Patients with a TDR ≥ 14 were younger than the patients with TDR <14 (p
=0.043). In addition, peak Troponin I and SXscores were smaller, but LVEF
was higher in the high TDR group. Finally, in- hospital mortality was higher
in patients with a TDR < 14 compared to the ones with a TDR ≥ 14 (17% vs
4%, p <0.001; Table 3).
DISCUSSION
To the best of our knowledge, the present study is the first investigation on
the correlation between thiol- disulphide homeostasis and Syntax risk scores
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in NSTEMI patients. Our results indicated that TDR was significantly
correlated with clinical risk factors and angiographic risk scores.
The SXscore, an anatomic scoring system based on coronary angiography
that quantifies lesion severity, also predicts poor cardiovascular outcomes
including mortality in NSTEMI patients [21, 22]. Palmerini et al. [21]
reported that SXscore was an independent predictor of 1-year death rate, MI,
cardiac death and target vessel revascularization in patients with NSTEMI.
Scherff et al. [22] found that the SXscore anticipated short-term adverse
clinical events in elderly who had MI and underwent primary percutaneous
coronary intervention (PCI). In another study, high SXscore was found to be
an independent factor for stent thrombosis in patients with STEMI, and a
predictor of late mortality [23]. Magro et al. [23] demonstrated a relation
between SXscore and the development of no reflow in patients that were
treated with primary PCI for STEMI.
In a recent study, Yadav et al. [24] showed a strong link between the severity
and complexity of CAD as assessed by the SXscore, and the occurrence of
stent thrombosis at 30-day and 1-year follow-up in patients with NSTEMI
who underwent PCI. The present study confirms that SXscore predicts in-
hospital mortality rate in patients with NSTEMI. A SXscore ≥ 23 was
associated with higher in-hospital mortality rate. Our findings demonstrates
that TDR is correlated with age, peak Troponin levels and LVEF. All these
findings suggest that admission to hospital TDR can be beneficial for clinical
and angiographic risk assessment in NSTEMI patients.
It has been shown that oxidative stress indices increase after MI [8, 9].
NSTEMI alters biomarker levels including oxidative stress indices. The
relationship between oxidative stress and CAD has attracted clinical interest
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for a long time, and it has been shown that both excessive oxidative stress
and inadequate defense can induce early onset of severe CAD [25]. Increased
oxidative stress markers act synergistically with the standard risk factors of
CAD [26, 27]. Oxidative stress starts as result of an impaired balance
between antioxidant defense and reactive oxygen species. The onset of
atherosclerotic disease increases oxidative stress [10–12].
TDR has critical roles in detoxification, antioxidant protection, signal
transduction, transcription factors and regulation of enzymatic activity,
apoptosis, and cellular signaling mechanisms [5, 6]. It has been reported that
an abnormal thiol- disulphide homeostasis state is involved in the
pathogenesis of a variety of diseases including cardiovascular diseases [7]
and diabetes [28]. Recently, Erel and Neselioglu showed that plasma
disulphide levels were higher in patients with degenerative diseases such as,
diabetes, obesity, pneumonia and in case of smoking, and were lower in
patients with proliferative diseases such as multiple myeloma, urinary
bladder cancer, colon cancer and renal cancer [30].
We hypothesized that TDR might correlate to SXscores since previous
studies support a close relation between TDR and anti-oxidative processes,
and found a significant correlation. The role of anti-oxidation in the
pathophysiology of coronary atherosclerosis also supports our hypothesis.
Our study has several limitations. First, coronary angiography was assessed
visually, and only major lesions of coronary arteries can be detected in this
way. The second limitation is the inclusion of a relatively small number of
patients, all admitted to a single center. Finally, TDR was not compared with
other oxidative stress indices, including lipid hydroperoxide, total antioxidant
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status, total oxidant status, oxidative stress index, paraoxonase and
arylesterase.
Conclusion
TDR was significantly lower in NSTEMI patients with high SXscores.
Therefore, we believe that measuring TDR NSTEMI patients on their
admission to hospital could beneficial for clinical and angiographic risk
assessment. Plasma TDR can be determined by the method used in our study
since it is an easy, inexpensive, automated and optionally manual
spectrophotometric assay.
Acknowledgments:
None
Funding:
This research received no grant from any funding agency in the public,
commercial or not-for-profit sectors.
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Table Legends Table 1. Baseline clinical and biochemical characteristics of the study population, and univariate analyses.
NSTEMI
Total
(n=290) (100%)
Syntax Score ≥ 23
(n=96, 33%)
Syntax Score < 23
(n=194, 67%) p
Male
n(%) 222 (76.6) 72 (75) 150 (77.3) 0.762
Gender Female
n(%) 68 (23.4) 24 (25) 44 (22.7) 0.715
Age
Mean ± SD 61 ± 13 59 ± 14 62 ± 13 0.217
DM
n(%) 72 (24.8) 26 (27) 46 (23.7) 0.283
Smoking
n(%) 152 (52.4) 50 (52.08) 102 (52.5) 0.745
Free thiol
(µmol/L) 228 ± 76 200 ± 78 242 ± 71 0.004*
Disulphide
(µmol/L) 13.9 ± 6.5 14.1 ± 7.4 12.3 ± 5.4 0.065*
Thiol/ disulphide
ratio
Median (IQR)
15.4 (10.9-20.4) 10.6 (5.9-15.8) 18.1 (13.3-23.9) <0.001*
WBC count
Mean ± SD
(x109/L)
11.2 ± 4.02 11.5 ± 4.47 11.1 ± 3.76 0.654
Hemoglobin
Median (IQR)
(g/L)
141 (126-155) 140 (121-152) 142 (130-160) 0.716
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Neutrophil count
Mean ± SD
( x109/L)
8.4 ± 3.8 8.4 ± 4.3 8.4 ± 3.5 0.830
Lymphocyte
count
Median (IQR) (
x109/L)
1.3 (1.0 - 1.6) 1.5 (1.1-2.4) 1.7 (1.0-2.4) 0.886
Platelet count
Median (IQR)
( x109/L)
220 (190-257) 220 (181-255) 221 (193-258) 0.271
MPV
Median (IQR)
(fL)
10.6 (9.7-11.4) 10.5 (9.7-11) 10.6 (9.7-11.5) 0.851
Total cholesterol
Mean ± SD
(µmol/L)
4.99 ± 1.13 4.97 ± 1.11 4.99 ± 1.13 0.953
LDL
Mean ± SD
(µmol/L)
3.15 ± 1.01 3.13 ± 0.90 3.15 ± 1.06 0.894
HDL
Mean ± SD
(µmol/L)
1.06 ± 0.36 1.03 ± 0.28 1.06 ± 0.38 0.596
Peak Troponin I
Median (IQR)
(µg/L)
25 (5-51) 34 (4-50) 24 (6-47) 0.595
Creatinine
Mean ± SD
(µmol/L)
79.5 ± 6.2 85.7 ± 6.2 94.5 ± 7.9 0.322
Total Bilirubin 9.5 ± 5.1 9.4 ± 5.1 9.5 ± 5.1 0.573
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Mean ± SD
(µmol/L)
LVEF (%)
Mean ± SD 48 ± 11 42 ± 12 51 ± 9 <0.001*
In hospital
mortality
n(%)
26 (8.9) 18 (18.7) 8 (4.1) <0.001*
NSTEMI: non-ST elevation myocardial infarction, DM: diabetes mellitus, HDL: high density
lipoprotein, IQR: interquartile range, LDL: low density lipoprotein, LVEF: left ventricular ejection
fraction, MPV: mean platelet volume, SD: standard deviation, TG: triglyceride, WBC: white blood
cell.
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Table 2. Multivariate logistic regression analysis showing independent
predictors of high Syntax scores.
95% Confidence Interval P value Β
Lower Upper
Thiol/ disulphide ratio <0.001* -0.455 6.949 13.741
Free thiol (µmol/L) 0.053 -0.153 13.860 70.111
Disulphide (µmol/L) 0.076 0.122 10.856 45.036
LVEF (%) 0.001* -0.250 4.143 12.731
LVEF: Left Ventricular Ejection Fraction
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Table 3. Clinical characteristics of the study population according to thiol/ disulphide ratios
NSTEMI
Total
(n=290)
(100%)
Thiol/ disulphide
ratio
≥ 14
(n=170) (58.6%)
Thiol/ disulphide
ratio
< 14
(n=120) (42.4%)
P value
Female
n(%) 68 (23.4) 40 (23.5) 28 (23.3) 0.952
Age
Mean ± SD 61 ± 13 59 ± 13 63 ± 14 0.043*
DM
n(%) 72 (24.8) 43 (25.2) 29 (24.1) 0.879
WBC count
Mean ± SD
(x109/L)
11.2 ± 4 11.0 ± 3.7 10.8 ± 3.7 0.743
Neutrophil count
Mean ± SD
(x109/L)
8.4 ± 3.8 8.2 ± 3.7 8.5 ± 3.3 0.645
Platelet count
Median (IQR)
( x109/L)
220 (190-257) 226 (194-254) 218 (199-251) 0.851
HDL
Mean ± SD
(µmol/L)
1.06 ± 0.36 1.08 ± 0.31 1.06 ± 0.46 0.849
Peak Troponin I
Median (IQR)
(µg/L)
25 (5-51) 18 (8-50) 23 (9-50) 0.045*
LVEF (%)
Mean ± SD 48 ± 11 49 ± 10 45 ± 10 0.009*
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In hospital
mortality
n(%)
26 (8.9) 6 (3.5) 20 (16.6) <0.001*
Syntax score 18 ± 8 14 ± 6 22 ± 7 <0.001*
NSTEMI: non-ST elevation myocardial infarction, DM: diabetes mellitus, HDL: high density
lipoprotein, IQR: interquartile range SD: standard deviation, WBC: white blood cell.
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Figure Legends
Figure 1. Comparison of thiol / disulphide ratio in high and low Syntax score
groups. Logarithmic scale on y-axis.
SXscore: Syntax score.
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Figure 2. Correlation of thiol / disulphide ratio and Syntax scores.
SXscore: Syntax score.
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Figure 3. Receiver-operating characteristic (ROC) analysis of thiol /
disulphide ratios in patients with high Syntax scores.
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