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Biomarker-based Prognostication of Adverse Cardiac Remodeling after STEMI: the Role of Single Nucleotide Polymorphism T786C in Endothelial NO-synthase gene

Olga V. Petyunina, Mykola P. Kopytsya, Alexander E. Berezin

Olga V. Petyunina (OVP), MD, PhD, Senior researcher of department of prevention and treatment of emergency conditions, Government Institution “L.T.Malaya Therapy National Institute NAMSU”, 2A Liubovi Maloy av., 61039, Kharkiv, Ukraine
Mykola P. Kopytsya (MPK), MD, PhD, Professor, Chief of Department of prevention and treatment of emergency conditions, Government Institution “L.T.Malaya Therapy National Institute NAMSU”, 2A Liubovi Maloy av., 61039, Kharkiv, Ukraine

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Alexander E. Berezin (AEB), Professor, MD, PhD, Senior Consultant of Therapeutic Unit, Internal Medicine Department, State Medical University of Zaporozhye, 26, Mayakovsky av., Zaporozhye, UA-69035, Ukraine.
Email: aeberezin@gmail.com; dr_berezin@mail.ru
Telephone: +966-12-2266666, ext. 25797
Fax: +380612894585

Received: December 14, 2018
Revised: January 11, 2019
Accepted: January 14 2019
Published online: February 2, 2019

ABSTRACT

BACKGROUND: Endothelial NO-synthase (eNOS) is constitutive enzyme, which expresses in mature endothelial cells and promotes direct vascular dilatation. Single nucleotide polymorphism (SNP) of T786C in eNOS gene may influence on adverse cardiac remodeling after ST-elevation myocardial infarction (STEMI). Purpose of the study was to investigate possible associations between SNP Т786С in eNOS gene and adverse cardiac remodeling after STEMI.

METHODS: 177 acute STEMI patients treated with percutaneous coronary intervention and thrombolysis that were admitted to intensive care unit of GI “L.T.Malaya TNI NAMSU” were enrolled in the study. Anthropometry, cardiovascular risk assay, coronary angiography, echocardiography and biomarkers’ measure were performed at baseline. The DNA extraction was performed with a commercial kit using real-time polymerase chain reaction PCR.

RESULTS: There were correlations between 786СС polymorphism in eNOs gene and adverse cardiac remodeling (r = 0.48; p =0.001), LDL cholesterol (r = 0.32; p =0.012), type 2 diabetes mellitus (r = 0.30; p =0.042), diastolic BP (r = -0.26; p =0.048), unstable angina prior to STEMI (r = 0.25; p =0.047) and total quantity of complicated STEMI (r = 0.23; p =0.042). Additionally, there were not significant relations between 786СС polymorphism in eNOs gene and multiple coronary vessel injury, STEMI localization, levels of circulating biomarkers of myocardial injury, and amount of damaged coronary arteries. Using univariate and multivariate regressive logistic analysis we found that 786СС genotype of eNOS was independent predictor for late adverse LV remodeling (β-coefficient =1.57342; odds ration = 4.8231; 95% confidence interval = 1.5349-15.1552; p =0.0071).

CONCLUSION: The polymorphism 786СС in eNOs gene was found as an independent predictor for late adverse cardiac remodeling after STEMI.

Key words: STEMI; Single nucleotide polymorphism Т786С; Endothelial NO-synthase gene; Adverse cardiac remodeling

© 2019 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Petyunina OV, Kopytsya MP, Berezin AE. Biomarker-based Prognostication of Adverse Cardiac Remodeling after STEMI: the Role of Single Nucleotide Polymorphism T786C in Endothelial NO-synthase gene. Journal of Cardiology and Therapy 2019; 6(1): 768-774 Available from: URL: http://www.ghrnet.org/index.php/jct/article/view/2497

INTRODUCTION

Nitric oxide (NO) is well established factor that directly promotes vascular dilatation, regulates vascular smooth muscle cell proliferation and migration, endothelial permeability and has indirect antithrombotic effects[1]. NO is synthesized in vascular endothelium from its precursor L-arginine with endothelial NO synthase (eNOs)[2]. Endothelium-derived NOs appears to be a constitutive enzyme, expression of which is depended on appropriate eNOs gene[3]. Previous preclinical and clinical studies have been shown that genetic deletion of promoter region of eNOs gene – single nucleotide polymorphisms (SNP) T786C - frequently associated with lowered NO production[4]. SNP T786C in eNOs gene corresponded to lipid infiltration of vascular wall, apoptosis of mature and progenitor endothelial cells, oxidative stress-induced microvascular inflammation, mononuclear infiltration, proliferation of vascular smooth muscle cells (VSMCs), accumulation of extracellular matrix components, and platelet aggregation on the surface of endothelium[5-7]. Collectively, impaired eNO bioavailability was found as main trigger for endothelial dysfunction, accelerating atherosclerosis, and thrombosis[8]. Additionally, deficiency of eNO through activating oxidant-sensitive pro-inflammatory cellular transcription factors, such as nuclear factor κB (NFκB) and FOXO-3, attenuate oxidative stress, and mitochondrial dysfunction that are considered as a main factor contributing in apoptosis and necrosis[9]. Indeed, altered suppressive effect due to eNO deficiency influenced on proliferation of VSMCs, declined production of vascular endothelial growth factor-A and accumulation of inflammatory / immune cells, which exacerbate dysfunctional endothelium, persistence cell injury and modulate vessel stenosis and intravascular thrombus[10]. On the other hand, restored eNOs activity and improved NO production was able to inhibited cardiac myocyte apoptosis and promoted cardiac function after STEMI[11]. Because all these factors play a pivotal role in pathogenesis of adverse cardiac remodeling after successful opening of coronary artery with percutaneous coronary intervention (PCI) due to ST-elevation myocardial infarction (STEMI)[12], and SNP N786C in eNOs gene, a G to T substitution at nucleotide 894 in exon 7 of eNOS, was found to be associated with STEMI[13], we have been hypothesized that this polymorphism could be a predictor of adverse cardiac remodeling. Previous studies have shown that T-786C Glu298Asp polymorphism in eNOs gene has yielded conflicting associations with cardiovascular and renal diseases in numerous general populations[14-16], but adverse cardiac remodeling was not being investigated in this conclusion. The aim of the study was to investigate possible associations between SNP Т786С in eNOS gene and adverse cardiac remodeling after STEMI.

METHODS

Patients’ population

A total of 268 patients with confirmed acute STEMI were analyzed for participation in the study. From entire population of STEMI (n = 268) according to inclusion and non-inclusion criteria it was enrolled 177 individuals that were admitted to intensive care unit of GI “L.T.Malaya TNI NAMSU” with acute STEMI during 2-12 hours of symptoms onset in a given period between August 2016 and July 2018. STEMI was diagnosed according to ECS Guidelines (2017)[5]. Inclusion criteria were: confirmed STEMI, age > 18 years old, and lack of contraindication to PCI. Non-inclusion criteria were previous myocardial infarction, established chronic heart failure, known malignancy, severe comorbidities (anemia, chronic obstructive lung disease, bronchial asthma, liver cirrhosis, chronic kidney disease, valvular heart disease, bleeding), inability to understand of written informed consent. Primary PCI with bare-metal stent (COMMANDER, “Alvimedica”, Turkey) implantation was performed in 133 patients and 44 patients were previously treated with primary thrombolysis (tenecteplase, alteplase) before admission with followed PCI during 6-12 hours after initial STEMI confirmation. Thrombolysis was done with tenecteplase (Metalise, Boehringer Ingelheim Pharma, Germany), depending on patients weight and was not more then 50 mg iv bolus. Alteplase (Actilyse, Boehringer Ingelheim Pharma, Germany) 100mg infused intravenous during 2 hours. All investigated patients received adjuvant treatment due to current ESC recommendations[17].

Ethical declaration

All procedures performed in the study involving human participants were in accordance with the ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and approved by the local ethics committee (Protocol №8, 29.08.2016). Inform consent was obtained from each patient.

Adverse LV remodeling determination

The study patients were followed through the outpatient clinic of our institution at 6-month observation. Adverse cardiac remodeling was defined as increased LVEDV (>10% from baseline)[18].

Coronary angiography

Conventional coronary angiography was performed immediately after admission of the patients to the hospital using Digital X-Ray system “Integris Allura” (Philips Healthcare, Best, The Netherlands) and managed by radial or femoral vascular access. Coronary arteries were visualized with two-to-three orthogonal projections per conventional protocol. In this study the contrast “Ultravist-370” (Baier Pharma GmbH, Germany) and automatic contrast injector were used. The contrast amount used in coronary angiography in each injection was 8 - 10 mL at 4 mL/s for the left coronary artery and 6 mL at 3 mL/s for the right coronary artery (radiation exposure 20 to 35 mGycm). The number of views obtained was decided by the operator depending on coronary anatomy. The coronary arteries were divided into segments according to the American Heart Association classification[19].

Determination of STEMI prognosis

TIMI score was used to validate prognostic capacity after STEMI[20].

Determination of risk factors and comorbidities

Hypercholesterolemia (HCE) was diagnosed if total cholesterol (TC) level was above 5.2 mmol/L, and/or low density lipoprotein cholesterol (LDL) level was above 3.0 mmol/L, and/or level of triglycerides (ТG) was above 1.7 mmol/L according to with European Cardiology Society dyslipidemia guideline (2016)[21]. Hypertension was diagnosed if systolic blood pressure (SBP) was >140 mm Hg, and/or diastolic blood pressure (DBP) >90 mm Hg according to European guideline on diagnostics and treatment of arterial hypertension (2018)[22]. Type 2 diabetes mellitus determined according to new ADA statement (2017)[23]. Premature MI was verified if it appeared to be diagnosed in patients 55 years and younger.

Echo and Doppler examination

Echo-CG performed on “Aplio 500” (TUS-A500) TOSHIBA MEDICAL SYSTEMS CORPORATION with usage of 3.5 MHz phase probe at discharge and at 6-month observation period. Left ventricular end diastolic volume (LV EDV), left ventricular end systolic volume (LV ESV), left ventricular ejection fraction (LVEF) measuring were done according to Simpson’s method per contemporary recommendation[24]. Left ventricular myocardial mass (LVMM) was calculated in automatic manner per protocol of echocardiograms evaluation[24].

Blood samples

Blood samples were drawn immediately before PCI and at 6 month of investigation. Blood samples were centrifuged, serum was isolated within 30 min of sample acquisition and after then they were freezed with -700C and stored in plastic tubes until being shipped to the laboratory of immune-chemical and molecular-genetic researches of GI “L.T.Malaya TNI NAMSU”.

Troponin I (Tn I) level measuring performed with chemo luminescent immunoassay (Humalyser 2000, Mannheim, Germany). The TnI level average was 0.5-50 ng/mL.

Total cholesterol (TC), low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides (TG) were measured direct enzymatic method (Roche P800 analyzer, Basel, Switzerland). The intra-assay and inter-assay coefficients of variation were < 5%.

Fasting glucose level was measured by a double-antibody sandwich immunoassay (Elecsys 1010 analyzer, F. Hoffmann-La Roche Diagnostics, Mannheim, Germany). The intra-assay and inter-assay coefficients of variation were < 5%.

Total creatine kinase (CK) and CK MB-fraction (CK-MB) were analyzed using immunoinhibition method on quantitative immunoassay analyzer Humalyser 2000 (HUMAN GmbH, Germany) according to the manufacturers’ recommendations.

N-terminal fragment of brain natriuretic peptide (NT-proBNP) was measured by commercially available standard kit (R&D Systems GmbH, Wiesbaden-Nordenstadt, Germany). The NT-proBNP level average was 10-12000 pg/mL.

SNP T786C (rs2070744) in eNOS gene determination

The DNA extraction was performed according to the protocol for a commercial set «DNA-Sorb-B» (AmplySens, Russia). The assessment of allelic states of SNP studied was performed using real-time polymerase chain reaction (PCR). For real-time PCR a commercial kit qPCR mix “SNP-Screen», catalogue number NP-554-100 (Syntol, Russia) was used. PCR was performed on CFX96 thermocycler (BioRad, USA) using an allelic discrimination test. PCR conditions: 95°C – 3’, 40 cycles of 95°C – 15’’, 65°C – 40’’.

Statistics

Statistical analyses were performed using SPSS for Windows v.23 (USA). Continuous variables are presented as mean ± standard deviation (SD) when normally distributed, or median and interquartile range (IQR) if otherwise. Categorical variables are presented as frequencies (n) and percentages (%). Mann-Whitney and Wald-Wolfowitz criteria were used for intergroup differences and quantitative values. The qualitative variables are expressed as percentages, and were analyzed by the χ2 and exact Fisher tests. The genotypic data were checked for Mendelian pedigree. Allele frequencies were estimated, and all polymorphisms were tested for Hardy–Weinberg Equilibrium. We preformed univariate and multiple variate log-regression analysis to determine the factors that could predict late adverse cardiac remodeling at 6 month and combined end point. We calculated beta coefficient, standard errors (SE), odds ratio (OR), 95% confidence interval (CI) for each factor. Factor, for which P values were calculated as >0.5 were not included in the multiple variate log-regression analysis. All differences were considered statistically significant with 2-tailed p < 0.05.

RESULTS

Table 1 is reported characteristic of the STEMI patients included in the study. It turned out that T and C alleles were presented about 60% and 40% of entire cohort patients. Sorting of STEMI patients according to genotypes of Т786С eNOs gene appeared to be shown following, such as ТТ genotype was found in 73 patients (42%), ТС genotypes was identified in 64 patients (36%) and CC genotypes was determined in 40 patients (22%) respectively. All STEMI patients were completely matched each other to age, sex, hypertension, stable CAD prior to STEMI, hypercholesterolemia, and obesity. Consequently, T2DM, smoking unstable angina prior to STEMI, premature MI and previously reported MI were determined frequently in patients with 786СС genotype than in other individuals. Therefore, all cohorts were comparable in serum concentrations of troponin T, CK-MB, NT-proBNP, total cholesterol and high-density lipoprotein cholesterol. Additionally, serum levels of low-density lipoprotein cholesterol in patients with CC-genotype were significantly higher to those who had other genotypes of eNOs gene.

Table 2 is presented STEMI risk according to TIMI score, STEMI localization and number of damaged coronary arteries in patients included in the study depending on major / minor alleles. There were not significant differences between three cohorts in TIMI risk, STEMI localization, number of damaged coronary arteries, and complication of MI, while damages in left anterior descending artery were found frequently in patients with CC genotype of eNOs gene. On contrary, left main damage was determined frequently in individuals with TT genotypes than in those who had TC genotype, but there was not sufficient difference between rate of left main damage between patients with CC genotype and TC / TT genotypes. Additionally, there were not significant different between patients’ cohorts in complications of MI apart from adverse LV remodeling at 6 month. In fact, total amount of STEMI patients with adverse LV remodeling was identified in 46 individuals. eNOs gene polymorphism was dispensed as following: 19.2% - TT genotype, 26.6% - TC genotype and 37.5% - CC genotype (p = 0.033). Hemodynamics in STEMI patients enrolled in the study is reported in Table 3. Apart from HR and LV end-diastolic volume other hemodynamic performances did not distinguished between patients’ cohorts.

Table 1 Characteristics of STEMI patients included in the study depending on major / minor alleles.
Entire population n=177TT genotype (n=73)TC genotype (n=64)CC genotype (n=40)P value
123
Age, years (SD)61.73 ± 9.4459.00 ± 10.1059.27 ± 9.9258.53 ± 8.29NS
Male, n (%)139 (78.5%)57 (78.1%)50 (78.1%)32 (80.0%)NS
Female, n (%)38 (21.5%)16 (21.9%)14 (21.9 %)8 (20.0%) 
Hypertension, n (%)146 (82.5%)60 (82.2 %)55 (85.9 %)31 (77.5 %)NS
T2DM, n (%)44 (24.9%)15 (20.5 %)13 (20.3 %)16 (40.0 %)

PTT-CC =0.027;

PTC-CC =0.029

Smoking, n (%)84 (47.5%)29 (39.7 %)31 (48.4 %)24 (60.0 %)PTT-CC =0.039

Stable CAD prior to STEMI,

n (%)

107 (60.5%)42 (57.5%)39 (60.9 %)26 (65.0 %)NS
HCE, n (%)105 (59.3%)45 (61.6 %)37 (57.8 %)23 (57.5 %)NS
BMI > 30 кг/м2, n (%)69 (39.0%)29 (39.7 %)26 (40.6 %)14 (35.0 %)NS

Unstable angina prior to

STEMI, n (%)

67 (37.9%)21 (28.8 %)24 (37.5 %)22 (55.0 %)

PTT-CC =0.011;

PTC-CC =0.080

Previous MI, n (%)31 (17.5%)11 (15.1 %)7 (10.9 %)13 (32.5 %)PTT-TC =0.084
Premature MI, n (%)74 (41.8%)29 (39.7 %) 21 (32.8 %)24 (60.0%)

PTT-CC =0.039;

PTC-CC =0.007

Peak TnI, ng/mL 17.7 [6.34-77.2]17.97 [9.73-60.5]17.7 [3.87-129.0]25.05 [3.99-180.0]NS
Peak CK-MB,U/L103.3 [44.9-28.95]108.90 [74.30-328.40]112.90 [55.00-196.90]43.85 [30.20-158.50]PTT-CC =0.064
NT-proBNP, pg/mL246 [107 - 405]247 [118 - 388]253 [121 - 375]241 [105 - 344]NS
Total cholesterol, mmol / L4.82 [3.95-5.63]4.83 [3.91-5.79]4.62 [3.95-5.50]4.89 [3.79-5.58]NS
HDL-cholesterol, mmol / L1,12 [0.92-1.28]1.12 [0.92-1.28]1.13 [0.94-1.31]1.05 [0.90-1.28]NS
LDL cholesterol, mmol / L3,00 2.03-3.63]2.64 [1.87-3.46]2,79 [2.04-3.56]3.36 [2.46-4.13]PTT-CC =0.048
BMI: body mass index; CAD: coronary artery disease; T2DM: type 2 diabetes mellitus; HCE: hypercholesterolemia; MI: myocardial infarction; LDL: low-density lipoprotein; HDL: high-density lipoprotein; Tn: cardiac troponin; NT-proBNP: N-terminal fragment of pro-brain natriuretic peptide; CK-MB: creatinkinase MB fraction.

Table 2 STEMI localization and number of damaged coronary arteries in patients included in the study depending on major / minor alleles.
Entire population n=177TT genotype (n=73)TC genotype (n=64) CC genotype (n=40)P value
123
STEMI risk scoring
TIMI risk score, point (IQR)6 [4-7]6 [5-7]6 [4-7]7 [5-8]0.62
STEMI Localization     
Anterior LV wall, n (%)97 (54.8%)44 (60.3 %)33 (51.6 %)20(50.0 %)NS
Posterior LV wall, n (%)70 (39.5%)29 (39.7 %)31 (48.4 %)20 (50.0 %) 
Amount of coronary vessels injured
One artery, n (%)53 (29.9%)24 (32.9 %)18 (33.3 %)11 (33.3 %)NS
Two and more arteries, n (%)103 (58.2%)45 (61.6 %)36 (66.6 %)22 (66.6 %)NS
Left anterior descending, n (%)47 (26.6%)25 (34.2%)9 (14.1%)13 (32.5%)

PTT-TC = 0.009;

PTT-CC = 0.048

Right coronary artery, n (%)41 (23.2%)22 (30.1%)12 (18.8%)7 (17.5%)NS
Circumflex coronary artery, n (%)20 (11.3%)9 (12.3%)6 (9.4%)5 (12.5%)NS
Left main, n (%)12 (6.8%)7(9.6%)2 (3.1%)3 (7.5%)

PTT-TC = 0.035;

PTT-CC = 0.05

Complications of STEMI
Total quantity of complicated STEMI, n (%)69 (38.9%)30 (41.1 %)22 (34.4 %)17 (42.5 %)

p1-2 = 0.419;

p1-3 = 0.885;

p2-3 = 0.405

II-III Killip class of HF, n (%)28 (15.8%)16 (21.9 %)8 (12.5 %)4 (10.0 %)

p1-2 = 0.148;

p1-3 = 0.090;

p2-3 = 0.698

IV Killip class of HF, n (%)10 (0.6%)5 (6.8 %)1 (1.6 %)4 (10 %)PTC-CC = 0.071
Cardiac arrest, n (%)3 (1.7%)1 (1.4 %)02 (5.0 %)NS
Acute 2-3 grade av-block, n (%)5 (2.8%)2 (2.7 %)1 (1.6 %)2 (5.0 %)NS
Recurrent angina1 (0.6%)1 (1.4 %)00NS
Adverse remodeling at 6 month, n (%)46 (26.0%)14 (19.2%)17 (26.6%)15 (37.5%) PTT-CC = 0.033
AV: atrium-ventricular; HF: heart failure; MI: myocardial infarction; IQR: interquartile range.

Table 3 Hemodynamics in STEMI patients enrolled in the study.
ParametersTT genotype (n=73)TC genotype (n=64)CC genotype (n=40)P value
HR, per min80.81 ± 16,6874.17 ± 14.8477.00 ± 16.64 PTT-CC = 0.012
SBP, mmHg138.48 ± 27.13136.70 ± 29.00139.00 ± 27.52NS
DBP, mmHg82.14 ± 13.1880.92 ± 12.7280.00 ± 13.88NS
LV EDV, ml137.60 ± 33.36131.91 ± 45.47149.72 ± 44.63NS
LV ESV, ml65.08 ± 23.3460.98 ± 31.2777.32 ± 36.96PTC-CC =0,065
LA, cm4.14 ± 0.604.09 ± 0.444.22 ± 0.43NS
LV EF, %51.25 ± 8.2354.59 ± 8.9650.84 ± 11.96NS
Е/А, unit 1.00 ± 0.531.03 ± 0.461.16 ± 0.52NS
LV MM, g266.39 ± 70.88249.63 ± 74.72268.98 ± 93.31NS
DBP: diastolic blood pressure; HR: heat rate; LA: left atrium; LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; LVEF: left ventricular ejection fraction; LVMM: left ventricular myocardial mass; SBP: systolic blood pressure.

There were correlations between 786СС polymorphism in eNOs gene and adverse LF remodeling (r = 0.48; p = 0.001), LDL cholesterol (r = 0.32; p = 0.012), T2DM (r = 0.30; p = 0.042), DBP (r = -0.26; p = 0.048), unstable angina prior to STEMI (r = 0.25; p =0.047) and total quantity of complicated STEMI (r = 0.23; p = 0.042). Additionally, there were not significant relations between 786СС polymorphism in eNOs gene and multiple coronary vessel injury, STEMI localization, levels of circulating biomarkers of myocardial injury, and amount of damaged coronary arteries.

Using univariate and multivariate regressive logistic analysis (Table 4) we found that 786СС genotype of eNOs gene was independent predictor for late adverse LV remodeling (β-coefficient = 1.57342; odds ration = 4.8231; 95% confidence interval = 1.5349 - 15.1552; p = 0.0071).

Table 4 The factors contributing late adverse LV remodeling at 6-month after STEMI: The results of univariate and multivariate logistic regression analysis.
DataDepending variable: late adverse LV remodeling
Univariate regressive logistic analysis Multivariate regressive logistic analysis
β-coefficientOR 95% CI pβ-coefficientOR 95% CI p
786СС genotype of eNOS1.583664.8728 1.4093-16.84810.01231.573424.8231 1.5349-15.15520.0071
Smoking 0.512641.66970.3756 -7.42220.5006----
T2DM0.350650.70420.2961 -1.67480.4276----
Previous MI prior to STEMI0.149080.86150.0713 -4.33380.8565----
Stable CAD prior to STEMI0.439681.55220.3988 -6.04190.526----
Unstable CAD prior to STEMI0.782642.31771.0611 -4.15220.04620.715511.23170.9815 -4.17720.1622
Multiple coronary vessel injury0.223590.79960.1766 -1.26220.337----
LDL cholesterol0.72551.42710.9388 -3.2290.663----
OR: odds ratio; T2DM: type 2 diabetes mellitus; CAD: coronary artery disease; LDL: low-density lipoprotein; LV: left ventricular.

DISCUSSION

The results of the study have revealed first that the 786СС genotype of eNOs gene was able to independently predict a late adverse cardiac remodeling in STEMI after primary or facilitate PCI. Consequently, we yielded unexpectedly result because other risk factors of poor clinical outcomes, such as T2DM, left main damage, did not corresponded to adverse cardiac remodeling at 6 month after successful PCI. Recent clinical studies have shown a pivotal role of DNA variants in the eNOS gene in vascular nitric oxide production and consequently vascular tone modulating[25-27]. Yet, SNP in promoter region of eNOs gene was strongly associated with a risk of cardiovascular and renal disease in several populations[28,29]. Moreover, meta-analysis provided by Kong XZ et al (2017)[30] is reported that 786СС polymorphism in eNOs gene corresponded well with increased risk of primary MI. Therefore, negative impact of the 786СС polymorphism in eNOs gene on a risk of death after MI was determined in manyfore populations[31-34]. However, previous clinical studies were tackled SNP in eNOs gene with endogenous NO production and vascular endothelial growth factor (VEGF), which is reported as key regulator of angiogenesis, coagulation and tissue reparation[35,36]. We have hypothesized that 786СС polymorphism in eNOs gene suppressing endogenous production of NO and VEGF may worse myocardial perfusion and impair LV function due to persistent ischemia leading to late adverse cardiac remodeling. Although complete opening of large MI-relating artery is discussed as main factor contributing to improve survival in STEMI patients, metabolic regulation of effective myocardial perfusion through small collateral branches could be sufficient trigger to prevent post-MI remodeling and improving survival rate. Indeed, adverse cardiac remodeling strongly associated with short-term as well as long-term mortality regardless of initial TIMI status of STEMI patients after PCI[37]. In this context, the 786СС polymorphism in eNOs gene could be a cause for restricted effect of endogenous ischemia-induced metabolites (oxidized lipids, free radicals, active molecules of cell adhesion) that regulate vascular tone and prevent small coronary artery thrombosis[38]. Taken together, altered production of NO and VEGF in patients with 786СС polymorphism in eNOs gene may potentially contribute to adverse cardiac remodeling that requires to be validated in future investigations. Finally, it can suggest that there is linkage between several polymorphisms affecting not just eNOs gene, but other genes corresponding to VEGF, collagen, matrix metalloproteinases, apoptotic-related and heat-shock proteins, which are involved into post-MI cardiac remodeling and play a protective role from ischemia preventing necrosis. Hens, our results clearly indicate that the 786СС polymorphism in eNOs gene has turn out to be core element of the molecular mechanisms underlying cardiac remodeling that pre-specified a factor for poor clinical outcomes in STEMI patients. We suggest that the risk stratification in the STEMI population based on 786СС polymorphism in eNOs gene identification could be useful for aggressive medical care after PCI and probably pre-treatment procedure implementation.

In conclusion, polymorphism 786СС in eNOs gene was found as an independent predictor for late adverse cardiac remodeling after STEMI.

ACKNOWLEDGEMENTS

There are no previous presentations of the information reported in the article. We thank Nataliia Tytarenko and Igor Polivenok for performing ultrasound examination and cardiac interventions respectively. Additionally, we thank, Galina Bugrimenko for her excellent technical assistance. Permission to acknowledge has been obtained.

AUTHOR CONTRIBUTION

Conception and design: Olga V. Petyunina; writing of the article Olga V Petyunina, Mykola P. Kopytsya, Alexander E. Berezin; critical revision of the article for intellectual content Alexander E Berezin.

FOUNDING

The study is a fragment of the research project: “To study the biochemical, genetic mechanisms of reperfusion damage of the myocardium and to assess the cardioprotective effect of antiplatelet therapy in acute myocardial infarction”, State Registration No. 0117U003028 / Ukraine

REFERENCES

1. F rstermann U. Nitric oxide and oxidative stress in vascular disease. Pflugers Arch. 2010; 459(6): 923-39. [PMID: 20306272]; [DOI: 10.1007/s00424-010-0808-2]

2. Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol. 2006; 47(8 Suppl): C7-12

3. Navarro-López F. Genes and coronary heart disease Rev Esp Cardiol. 2002; 55(4): 413-31. [PMID: 11975906]

4. Ciftci C, Melil S, Cebi Y, Ersoz M, Cagatay P, M Kilicgedik, Susleyici B Duman. Association of endothelial nitric oxide synthase promoter region (T-786C) gene polymorphism with acute coronary syndrome and coronary heart disease. Lipids in Health and Disease. 2008; 7: 5 [PMID: 18298848]; [PMCID: PMC2267783]; [DOI: 10.1186/1476-511X-7-5]

5. Li H, Horke S, Forstermann U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis. 2014; 237(1): 208-19

6. Schalkwijk CG, van Dam B, Stehouwer CD, van Hinsbergh VW. Mevastatin increases eNO synthase expression and inhibits lipid peroxidation in human endothelial cells. Clin Hemorheol Microcirc. 2007; 37(1-2): 179-84. [PMID: 17641407]

7. Xiang-Zhen Kong, Zheng-Yi Zhang, Lian-Hua Wei, Rui Li, Jing Yu. The Endothelial Nitric Oxide Synthase Gene T-786C Polymorphism Increases Myocardial Infarction Risk: A Meta-Analysis. Med Sci Monit. 2017; 23: 759-766. [PMID: 28188309]; [PMCID: PMC5317294]

8. Chen JY, Ye ZX, Wang XF, Chang J, Yang MW, Zhong HH, Hong FF, Yang SL. Nitric oxide bioavailability dysfunction involves in atherosclerosis. Biomed Pharmacother. 2018; 97: 423-428. [PMID: 29091892]; [DOI: 10.1016/j.biopha.2017.10.122]

9. Harris MB, Blackstone MA, Ju H, Venema VJ, Venema RC. Heat-induced increases in endothelial NO synthase expression and activity and endothelial NO release. Am J Physiol Heart Circ Physiol. 2003; 285(1): H333-40. [PMID: 12663266]; [DOI: 10.1152/ajpheart.00726.2002]

10. Berezin AE. Predicitive role of circulating vascular endothelial growth factor-1 in patients with cardiovascular diseases. J Dis Markers. 2014; 1(3): id1013

11. Chen Z, Qi Y, Gao C. Cardiac myocyte-protective effect of microRNA-22 during ischemia and reperfusion through disrupting the caveolin-3/eNOS signaling. Int J Clin Exp Pathol. 2015; 8(5): 4614-26. [PMID: 26191152]; [PMCID: PMC4503024]

12. Heltianu C, Costache G, Gafencu A, Diaconu M, Bodeanu M, Cristea C, Azibi K, Poenaru L, Simionescu M. Relationship of eNOS gene variants to diseases that have in common an endothelial cell dysfunction. J Cell Mol Med. 2005; 9(1): 135-42. [PMID: 15784171]

13. Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Ogawa H, Kugiyama K, Nakamura S, Ito T, Mizuno Y, Harada E, Yasue H, Miyamoto Y, Saito Y, Nakao K. T(-786)—> C mutation in the 5’-flanking region of the endothelial nitric oxide synthase gene is associated with myocardial infarction, especially without coronary organic stenosis. Am J Cardiol. 2000; 86: 628-634. [PMID: 10980213]

14. Niu W, Qi Y. An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension. PLoS One. 2011; 6(9): e24266. [PMID: 21912683]; [PMCID: PMC3166328]; [DOI: 10.1371/journal.pone.0024266]

15. Jo I, Moon J, Yoon S, Kim H-T, Kim E, Park H-Y, Shin C, Min J, Jin YM, Cha SH, Jo SA. Interaction between -786TC polymorphism in the endothelial nitric oxide synthase gene and smoking for myocardial infarction in Korean population. Clin Chim Acta. 2006; 365: 86-92. [PMID: 16157324]; [DOI: 10.1016/j.cca.2005.07.029]

16. Kim IJ, Bae J, Lim SW, Cha DH, Cho HJ, Kim S, Yang DH, Hwang SG, Oh D, Kim NK. Influence of endothelial nitric oxide synthase gene polymorphisms (-786T>C, 4a4b, 894G>T) in Korean patients with coronary artery disease. Thromb Res. 2007; 119: 579-585. [DOI: 10.1016/j.thromres.2006.06.005]; [PMID: 16842840]

17. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P.; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018; 39(2): 119-177. [PMID: 28886621]; [DOI: 10.1093/eurheartj/ehx393]

18. Lupón J, Gaggin HK, de Antonio M, Domingo M, Galán A. Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score. International Journal of Cardiology. 2015; 184: 337-343. [PMID: 25734941]; [DOI: 10.1016/j.ijcard.2015.02.019]

19. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS, McGoon DC, Murphy ML, Roe BB. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation. 1975; 51: 5-40. [PMID: 1116248]

20. Morrow DA, Antman EM, Charlesworth A, Cairns R, Murphy SA, de Lemos JA, Giugliano RP, McCabe CH, Braunwald E. TIMI Risk Score for ST-Elevation Myocardial Infarction: A Convenient, Bedside, Clinical Score for Risk Assessment at Presentation. An Intravenous nPA for Treatment of Infarcting Myocardium Early II Trial Substudy. Circulation. 2000; 102: 2031-2037. [PMID: 11044416]

21. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner , Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016; 253: 281-344. [PMID: 27594540]; [DOI: 10.1016/j.atherosclerosis.2016.08.018]

22. Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018; 39 (33): 3021-3104. [PMID: 30165516]; [DOI: 10.1093/eurheartj/ehy339]

23. Standards of medical care in diabetes -2017: summary of revisions. Diabetes Care 2017; 40: S4-5. [PMID: 27979887]; [DOI: 10.2337/dc17-S003]

24. Galderisi M, Henein MY, D’hooge J, Sicari R, Badano LP, Zamorano JL, Roelandt JR; European Association of Echocardiography. Recommendations of the European Association of Echocardiography: how to use echo-Doppler in clinical trials: different modalities for different purposes. Eur J Echocardiogr. 2011; 12(5): 339-53. [PMID: 21555455]; [DOI: 10.1093/ejechocard/jer051

25. Wang XL, Wang J. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab. 2000; 70: 241-51. [PMID: 10993711]

26. Hingorani AD. Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep. 2003; 5: 19-25. [PMID: 12530931]

27. Tsukada T, Yokoyama K, Arai T, et al. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun. 1998; 245: 190-3. [PMID: 9535806]

28. Hoffmann IS, Tavares-Mordwinkin R, Castejon AM, Alfieri AB, Cubeddu LX. Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics. J Hum Hypertens. 2005; 19: 233-40. [PMID: 15565175]

29. Casas JP, Cavalleri GL, Bautista LE, Smeeth L, Humphries SE, Hingorani AD. Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease: a HuGE review. Am J Epidemiol. 2006; 164: 921-35. [PMID: 17018701]

30. Kong XZ, Zhang ZY, Wei L-H, Li R, Yu J. The Endothelial Nitric Oxide Synthase Gene T-786C Polymorphism Increases Myocardial Infarction Risk: A Meta-Analysis Med Sci Monit 2017; 23: 759-766. [PMID: 28188309]; [PMCID: PMC5317294]

31. Xu ZX, Li GQ. Association between endothelial nitric oxide synthase gene786T/C polymorphism and myocardial infarction in Xinjiang Uygur and Han population. Journal of Chinese Practical Diagnosis and Therapy 2013; 27: 753-55

32. Zigra AM, Rallidis LS, Anastasiou G, Merkouri E, Gialeraki A. eNOS gene variants and the risk of premature myocardial infarction. Dis Markers. 2013; 34(6): 431-6. [PMID: 23594558]; [PMCID: PMC3809742]; [DOI: 10.3233/DMA-130987]

33. Arun Kumar AS, Umamaheswaran G, Padmapriya R, Balachandar J, Adithan C. Endothelial nitric oxide synthase gene polymorphisms and the risk of acute myocardial infarction in a South Indian population. Mol Biol Rep. 2013 Feb; 40(2): 1275-81. [PMID: 23108994]; [DOI: 10.1007/s11033-012-2170-2]

34. da Costa Escobar Piccoli J, Manfredini V, Hamester FI, Bandinelli JB, Turkienicz IM, Chies JA, Peres A, Bodanese LC, Bogo MR. Interaction between endothelial nitric oxide synthase gene polymorphisms (-786T>C, 894G>T and intron 4 a/b) and cardiovascular risk factors in acute coronary syndromes. Arch Med Res. 2012; 43(3): 205-11. [PMID: 22475779]; [DOI: 10.1016/j.arcmed.2012.03.011]

35. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacological Rewiews. 2004; 56(4): 549-580. [PMID: 15602010]; [DOI: 10.1124/pr.56.4.3]

36. Devaux Y, Vausort M, Azuaje F, Vaillant M, Lair ML, Gayat E, Lassus J, Ng LL, Kelly D, Wagner DR, Squire IB. Low levels of vascular endothelial growth factor B predicts left ventricular remodeling after acute myocardial infarction. J Card Fail. 2012; 18(4): P.330-337. [DOI: 10.1016/j.cardfail.2012.01.010]

37. Shimokawahara H, Jougasaki M, Setoguchi M, Ichiki T, Sonoda M, Nuruki N, Nakashima H, Murohara T, Tsubouchi H. Relationship between vascular endothelial growth factor and left ventricular dimension in patients with acute myocardial infarction. J Cardiol. 2014; 64(5): 360-365. [PMID: 24698007]; [DOI: 10.1016/j.jjcc.2014.02.017]

38. Doshi AA, Ziolo MT, Wang H, Burke E, Lesinski A, Binkley P. A promoter polymorphism of the endothelial nitric oxide synthase gene is associated with reduced mRNA and protein expression in failing human myocardium. J Card Fail. 2010; 16(4): 314-9. [PMID: 20350698]; [PMCID: PMC2848179]; [DOI: 10.1016/j.cardfail.2009.12.013]

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