==== Front Medicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30024510MD-D-17-0702710.1097/MD.0000000000011393113933400Research ArticleObservational StudySerum gamma-glutamyl transferase is a predictor of mortality in patients with acute myocardial infarction Kim Jae Gyung MDaChang Kiyuk MD, PhDb∗Choo Eun Ho MDaLee Jong-Min MD, PhDaSeung Ki-Bae MD, PhDbPatanè. Salvatore a Cardiovascular Center and Cardiology Division, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Uijeongbub Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.∗ Correspondence: Kiyuk Chang, Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul 06591, Republic of Korea (e-mail: kiyuk@catholic.ac.kr).7 2018 20 7 2018 97 29 e1139312 11 2017 12 6 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract Gamma-glutamyl transferase (GGT) is involved in the pathogenesis of atherosclerosis and has been associated with adverse cardiovascular outcomes in patients with ischemic heart disease. However, the association between GGT and long-term mortality has not been studied in patients with acute myocardial infarction (AMI). A total of 2239 AMI patients for whom serum GGT values were available and who underwent percutaneous coronary intervention (PCI) were enrolled in the COREA-AMI (CardiOvascular Risk and idEntificAtion of potential high-risk population in Korean patients with AMI) registry. Patients with acute liver injury were excluded. Patients were classified into 2 groups according to normal (n = 1983) or elevated (n = 256) levels of serum GGT. The primary clinical outcome was all-cause mortality. The secondary outcome was cardiac death and recurrent non-fatal myocardial infarction (MI). The median follow-up period was 3.7 years, and both groups had similar characteristics. Patients with elevated GGT had significantly higher all-cause mortality compared to patients with normal GGT (21.9% vs. 14.4%, P = .001). The multivariate Cox proportional hazards model showed that elevated serum GGT level was independently correlated with mortality (hazard ratio 2.12[1.44–3.11]; P < .001). Although elevated serum GGT was independently associated with long-term mortality after 30 days after PCI, there was no association within 30 days after PCI. Elevated GGT was also associated with death of cardiac causes with statistical significance. In the subgroup analysis, stronger associations were observed in the young and female patients and in patients who had ST-segment elevation MI and preserved left ventricular ejection fraction at the first echocardiography after the indexed PCI. Elevated serum GGT is an independent predictor of long-term mortality in AMI patients. Keywords gamma-glutamyl transferaselong-term mortalitymyocardial infarctionOPEN-ACCESSTRUE ==== Body 1 Introduction The enzyme gamma-glutamyl transferase (GGT) is present in the serum and on the surface of various cell membranes. GGT is considered a marker of liver or biliary tract diseases and alcohol consumption. However, GGT has recently been identified as a novel indicator of the development and prognosis of cardiovascular diseases. Although the exact mechanism has not been elucidated, the abundance of GGT in atheroma and its function in blood vessels may play a role. GGT catalyzes the first step in the extracellular degradation of glutathione. During the process of GGT-mediated glutathione degradation, low-density lipoprotein (LDL) is oxidized and accumulates in the arterial wall; this process is involved in the pathogenesis of atherosclerosis.[1] Moreover, degradation of the antioxidant glutathione results in formation of peroxide free radicals and, consequently, oxidative stress. Thus, the combination of abundant oxidized LDL and GGT in atherosclerotic plaques causes oxidative stress in the endothelium, which can affect plaque evolution and rupture.[2] Furthermore, many studies have reported an association between serum GGT levels and various established cardiovascular disease risk factors, such as hypertension, diabetes, metabolic syndrome, and coronary artery disease (CAD).[3–6] In addition, increased GGT levels in established CAD patients have been associated with an increase in secondary events, including myocardial infarction (MI), stroke, and cardiovascular death.[7,8] However, studies of the association between serum GGT levels and long-term clinical outcomes in patients with acute MI (AMI) have included only a few patients with ST-segment elevation MI (STEMI) and yielded inconsistent results.[9,10] Therefore, we investigated whether higher serum GGT levels can predict short-term and long-term mortality in patients with AMI. 2 Methods This study used data from the CardiOvascular Risk and idEntificAtion of potential high-risk population in Korean patients with AMI (COREA-AMI) registry, which was designed to evaluate real-world outcomes in “all-comers” with AMI. The COREA-AMI, a large, observational registry included clinical, angiographic, short-term and long-term outcome data for AMI patients who underwent percutaneous coronary intervention (PCI) at 9 major cardiac centers in Korea between January 2004 and December 2009.[11] Initially, our study sample included a total of 4748 patients. Among these, 2281 patients who had serum GGT values were available were enrolled. To avoid the confounding effects of unknown underlying active liver disease on the prognosis, patients who had a serum alanine aminotransferase (ALT) level >3 times the upper limit of normal (ULN) and the ALT greater than the level of aspartate aminotransferase (AST) were excluded (n = 28).[12] To avoid unreasonable deviation of GGT level, the data were trimmed with exclusion of extreme values. The value of 5 patients (who were excluded because of lower than measurable range) was recorded near to zero; these cases were deleted for the possibility of data collection errors. We screened the accessible electrical medical records of the patients from the highest GGT level. The number of patients with GGT level over 2× ULN), 3× ULN, and 5× ULN were 47 (2.1%), 14 (0.6%), and 9 (0.4%), respectively. We excluded the only 9 patients of over 5× ULN because 3 of them had obvious hepatobiliary problems; one died from GB cancer, another had recurrent cholangitis, and the other had pancreatic disease. We could not find clear reason of GGT elevation among the others. Finally, a total 2239 of patients were included in this analysis (Fig. 1). Figure 1 Study flow chart. Inclusion and exclusion criteria of study population. ALT = alanine aminotransferase, AMI = acute myocardial infarction, AST = aspartate aminotransferase, GGT = gamma-glutamyl transferase. AMI was diagnosed based on characteristic clinical symptoms, serial changes on electrocardiograms (ECGs) consistent with infarction, and increased cardiac enzyme values. The diagnosis was confirmed by coronary angiography in all patients. We excluded patients who were not indicated for PCI based on coronary angiography to strengthen the homogeneity of the study population. All patients received standard medical treatment during PCI and hospitalization. The study protocol was approved by the institutional review board at each participating center and is in accordance with the Declaration of Helsinki. All patients provided written informed consent at the time of admission to enrollment in the registry and the use of their clinical data in future retrospective analyses. We recorded demographic data, cardiovascular risk factors, and laboratory data for all patients. Cardiovascular risk factors included smoking status, previously diagnosed diabetes mellitus, hypertension, chronic kidney disease, and history of familial CAD. Data on other risk factors were reported by the patients themselves or extracted from medical records. Blood samples were drawn within 24 hours of the initial visit and used for a standard battery of hematological and biochemical tests. Serum GGT levels were measured using the enzymatic colorimetric test at 37°C, and l-g-glutamyl-3-carboxy-4-nitroanilide was used as the substrate at each cardiac center under identical conditions.[10] Patients were categorized into 2 groups based on elevated or normal serum GGT levels compared to the upper limit of the clinical reference range. The normal reference range was 9 to 85 U/L for males and 5 to 55 U/L for females.[13] All procedures were performed according to current standard guidelines. The specific drug-eluting stent used in the procedures was chosen by the operator. The operator assessed the type of lesion according to American College of Cardiology/American Heart Association guidelines. After the procedure, aspirin was prescribed indefinitely, and clopidogrel was prescribed for at least 6 months. Immediate post-procedural and in-hospital events were recorded. Patient follow-up was conducted during office visits or through telephone interviews at 1, 6, and 12 months and annually thereafter. Echocardiography was performed within 3 days of the PCI, and a quantitative assessment of the left ventricular systolic function was performed using the modified biplane Simpson method to calculate the left ventricular ejection fraction (LVEF). The primary objective of this study was to evaluate the association between GGT level and all-cause mortality during clinical follow-up post intervention. The secondary objectives were to evaluate the association between high GGT levels and cardiac death and recurrent non-fatal MI. Cardiac death was defined as death from CAD, heart failure, or arrhythmia, and death was attributed to cardiac events unless non-cardiac death could be clearly identified.[14] Recurrent MI was defined as the presence of recurrent symptoms and new ECG changes that considered to be MI or cardiac markers that were at least twice the normal limit. Medical records were thoroughly reviewed by an independent research nurse. Telephone interviews were conducted to collect data on the occurrence of adverse events following PCI. Clinical outcomes of interest were confirmed by source documents and centrally adjudicated by a local events committee at the Cardiovascular Center of Seoul St. Mary's Hospital and an independent group of clinicians who were unaware of patient status. To verify the accuracy of mortality data, we matched our data to official national data collected by the National Statistical Office from death certificates, which previous studies have shown to be reliable.[11] We classified patients into two groups according to normal or high GGT levels and used these 2 categories in the subsequent analyses. Differences between groups of continuous variables were evaluated using an independent t-test or the Mann-Whitney U test. Differences in discrete variables were analyzed using a chi-square or Fisher's exact test and expressed as counts and percentages. Landmark analyses were performed to evaluate the impact of high serum GGT on short-term and long-term mortality. The landmark method of survival analysis uses a fixed time after PCI. In this study, the cut-off for early mortality was the 30th day after PCI. We constructed Kaplan-Meier curves to the end points for patients with normal GGT or high GGT, and differences between the groups were assessed by the log-rank test. Cox proportional hazard models were applied to calculate estimated hazard ratios (HRs) for each end-point. We selected covariates that differed significantly between the groups at baseline and that previous studies have related to GGT level or cardiovascular outcomes after PCI. [15,16] The HRs were adjusted for important covariates that had significant effects (p < 0.05) on clinical outcomes in the univariate analysis. All analyses were two-tailed, and clinical significance was defined as p < 0.05. The same process was used for subgroup analyses to evaluate differences according to age, gender, STEMI or Non ST-segment elevation MI (NSTEMI), body mass index (BMI), high or low levels of LDL cholesterol (LDL-C), high or low levels of high-density lipoprotein (HDL) cholesterol (HDL-C), hypertriglyceridemia (triglyceride >150), glycated hemoglobin(HbA1c), and LVEF ≥50% at the first echocardiography after the indexed PCI. To analyze the association between GGT levels and the mortality in our study group of AMI patients, we computed receiver-operating characteristic (ROC) curves, tested for equality of the areas under the curves (AUCs), and calculated 95% confidence intervals (CIs) for GGT. Statistical analyses were performed using the statistical package SPSS V.20.0 (SPSS Inc., Chicago, IL) and MedCalc V.12.7 (MedCalc Software, Mariakerke, Belgium). 3 Results Patient GGT levels were non-normally distributed, and a high GGT level, defined as above the normal range, was observed in 256 patients (11.4%). The median GGT level was 31 ( interquartile range [IQR] 20–55; mean 46 ± 44.6) U/L in males and 21 (IQR 13–34; mean 29.3 ± 26.4) U/L in females, and the percentages of male and female patients with high GGT levels were 11.3% and 11.7%, respectively. The baseline characteristics of the GGT groups are summarized in Table 1. At baseline, patients in the high serum GGT group had more conventional cardiovascular risk factors compared to the normal serum GGT group. Patients in the high GGT group were younger than those in the normal serum GGT group (mean age of 59.7 ± 13.6 vs. 62.5 ± 12.6 years, respectively). Compared with the normal GGT group, more patients in the high GGT group were obese (BMI ≥25 kg/m2; 36.7% vs. 43.1%, P = .048). High-sensitive C-reactive protein (hsCRP), uric acid, and serum triglyceride were positively associated with high serum GGT levels, and the difference of them was also significant. No reflow phenomenon after PCI was also more frequently observed in high GGT group (7.8% vs. 4.2%, P = .009). Biomarkers associated with liver disease, including AST, ALT, and alkaline phosphatase (ALP), were higher in the high GGT group. No other differences were observed between the two groups. Table 1 Baseline characteristics of normal GGT group and high GGT group. A total of 341 deaths (15.2%) were recorded during a median follow-up time of 3.7 years (IQR: 2.4–5.0 years). The number of cardiac death and noncardiac death of high GGT versus normal GGT group was 31 (12.1%) vs. 153 (7.7%) and 19 (7.4%) vs.123 (6.2%), respectively. The proportion of unrevealed cause of death was 2.3% (n = 6) vs. 0.9% (n = 18). All-cause mortality during the entire follow-up period was significantly higher in the high GGT group than the normal GGT group (21.9% vs. 14.4%, P = .001 by the log-rank test). Early mortality at day 30 following PCI (5.9% vs. 3.2%, P = .03) and late mortality from day 30 to the end of follow-up (17.1% vs. 11.5%, P = .013) were also higher in the high GGT group than the normal GGT group. The Kaplan-Meier curves for all-cause mortality are presented in Figure 2. Compared with the normal GGT group, the high GGT group had an age and sex adjusted HR for death of 1.97 (P < .0001, Model 1). Additional adjustment for differences at baseline (Model 2: BMI ≥25 kg/m2, ALT, AST, ALP, uric acid, hsCRP, hypertriglyceridemia (triglyceride >150), and presence of no-reflow phenomenon after PCI) and other cardiovascular risk factors (Model 3: hypertension, diabetes, chronic kidney disease, current smoking, high LDL-C (LDL ≥100 mg/dL), Killip class ≥ II at admission and final TIMI flow 150 mg/dL), high LDL cholesterol (LDL ≥100 mg/dL), Killip class ≥II at admssion, presence of no-reflow phenomenon during PCI, and TIMI flow 150 mg/dL), high low-density lipoprotein (LDL) cholesterol (LDL ≥100 mg/dL), Killip class ≥ II at admssion, presence of no-reflow phenomenon during percutaneous coronary intervention (PCI) and thrombolysis in myocardial infarction flow 30 kg/m2) is commonly considered as a predictor of worse outcomes, and the mortality of overt obese (BMI >30 kg/m2; n = 97, 11.3%) group tended to be higher than that of overweight (BMI of 25–30 kg/m2; n = 731, 9.7%) group in our AMI patients, but it was not statistically significant (HR = 1.21, Log rank, P = .557). Third, our study population is unique in that we included both STEMI and NSTEMI patients and all patients underwent PCI with drug eluting stent. Previous studies have included either STEMI patients or non-ST segment elevation-ACS patients. According to current guidelines on long-term management following ACS, the treatment strategy depends primarily on whether the clinical outcome is MI.[28–30] Therefore, the overall outcome following AMI is also crucial. The all-cause mortality rates in our study population and in the high GGT level group were slightly higher and much higher, respectively, than those in the HORIZONS AMI trial in patients with STEMI (approximately 6%–7%).[31] When the early mortality rate was assessed, it was similar to the result that obtained using the long-term outcome. This result suggests that the initial GGT level might reflect not only the acute phase of inflammation, but also the chronic systemic metabolic status of an individual, which can affect the long-term outcome. 5 Limitations This study has several limitations. First, this was an observational study and may be subject to bias and confounding. Specifically, information on alcohol consumption, which can influence the level of GGT, was not included in this study and 52% of patients did not have a GGT serum level recorded. Moreover, the exclusion of liver disease in patients was not confirmed by imaging or serology for viral hepatitis.[27,32] Isolated GGT elevation has not been significantly associated with adverse outcomes in liver disease; therefore, the relevance of GGT elevation in MI should not to be attenuated. Second, there were a limited number of adverse events, and we were unable to specify the various subtypes of adverse cardiovascular events. Third, although many possible hypotheses of the mechanisms of GGT have existed, no clear evidence was proven. Even there is no report on the time course of GGT in the setting of AMI like AST, LDH, or CPK. Recently, various subtypes of GGTs with specific functions have been studied.[33,34] These studies might be a key to understand the mechanism of the association between GGT and cardiovascular disease. In addition, a large prospective study with serial GGT values and associated variables will contribute to a detailed understanding of the pathogenesis of cardiovascular disease. 6 Conclusion In summary, an elevated GGT level is an independent predictor of adverse long-term prognosis and increase of cardiac mortality in patients with AMI. Stronger associations were observed in the young and female patients and in patients who had STEMI and initially preserved LVEF after the indexed PCI. Author contributions Conceptualization: Eun Ho Choo, Kiyuk Chang. Data curation: Eun Ho Choo, Kiyuk Chang, Ki-Bae Seung. Formal analysis: Jae Gyung Kim, Eun Ho Choo, Kiyuk Chang. Investigation: Jae Gyung Kim, Kiyuk Chang, Ki-Bae Seung. Methodology: Jae Gyung Kim, Eun Ho Choo. Project administration: Jae Gyung Kim, Kiyuk Chang. Resources: Kiyuk Chang, Ki-Bae Seung. Software: Jae Gyung Kim. Supervision: Jong-Min Lee, Kiyuk Chang. Visualization: Jae Gyung Kim. Writing – original draft: Jae Gyung Kim. Writing – review & editing: Jae Gyung Kim, Kiyuk Chang. Abbreviations: 2xULN = two-times of upper limit of normal, ALP = alkaline phosphatase, ALT = alanine aminotransferase, AMI = acute myocardial infarction, AST = aspartate aminotransferase, AUC = areas under the curve, BMI = body mass index, CAD = coronary artery disease, CI = confidence interval, ECG = electrocardiogram, GGT = gamma-glutamyl transferase, HbAc1 = glycated hemoglobin, HDL-C = High-density lipoprotein cholesterol, HR = hazard ratio, hsCRP = high-sensitivity C-reactive protein, IQR = interquartile range, LDL-C = low-density lipoprotein cholesterol, LVEF = left ventricular ejection fraction, MI = myocardial infarction, NSTEMI = Non ST-segment elevation myocardial infarction, PCI = percutaneous coronary intervention, ROC = receiver-operating characteristic, STEMI = ST-segment elevation myocardial infarction, TIMI = thrombolysis in myocardial infarction. The authors claim no relationships with industry. 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