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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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