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g-Glutamyl transferase: A novel prognostic marker for cardiovascular disease
Journal of Critical Care 29 (2014) 167–168
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
g-Glutamyl transferase: A novel prognostic marker for cardiovascular disease Gamma-glutamyl transferase (GGT), considered to be a marker of excessive alcohol consumption or liver disorders, is an enzyme present in the cell membranes of many tissues. It acts as a mediator in the transmembrane transfer of glutathione, a major component of intracellular antioxidant-protective mechanisms [1]. GGT activity has also been shown to increase in response to oxidative stress [2]. In vitro studies suggest that GGT accelerates the production of reactive oxygen species and glutathione-dependent low density lipoprotein (LDL) oxidation in the presence of iron ions [3,4]. Serum GGT activity may participate in the pathogenesis of coronary artery disease (CAD) and its complications. Previous epidemiological studies suggest that higher serum GGT is associated with the development of CAD risk factors, including high blood pressure, diabetes, dyslipidemia [5,6], and metabolic syndrome. Serum GGT levels are also positively related to novel cardiovascular risk factors such as C-reactive protein and fibrinogen [7] and are inversely related to antioxidant levels [8]. In a large study of normalrange GGT levels and long-term follow-up of British men, Wannamethee et al showed that GGT levels were related with all-cause mortality, especially in the highest quartile GGT level group (patients who died from CAD) [9]. Additionally, in an epidemiological investigation in a cohort of 163,944 Austrian adults, Ruttmann et al demonstrated that GGT was independently associated with cardiovascular mortality [10]. Lee et al, in the Framingham Heart Study with 20 years of follow-up, reported that an increase in serum GGT predicts the onset of metabolic syndrome, incident cardiovascular disease, and death, suggesting that GGT is a marker of metabolic and cardiovascular risk [11]. And also, in a systematic review and meta-analysis, Liu et al reported that the GGT level is independently associated with the development of hypertension [12]. In recent years, several studies have been published on the relationship between CAD and serum GGT activity [13,14]. Serum GGT levels are an independent prognostic factor for coronary artery calcification, coronary complexity, and adverse cardiac events in patients with CAD [13,15]. Several possible mechanisms have been proposed for the role of serum GGT in increasing cardiovascular risk. The most widely accepted mechanism is oxidative stress, followed by hepatic insulin resistance and subclinical inflammation. Both increased oxidative stress and systemic inflammation play an important roles in atherosclerosis, lipoprotein infiltration and modification [16,17]. Other important mechanism is the activity of GGT which has been detected in the atheromatous plaques of the coronary and carotid arteries [18]. Oxidized LDL may contribute to the binding of GGT with LDL, leading to the formation of LDL/GGT complexes within the plaque which are a potential source for the development of atherosclerotic lesions. The presence of GGT within the coronary plaque may represent a pathological basis for its direct involvement in atherogenesis and CAD progression. 0883-9441/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
Recently published studies have shown the prognostic value of GGT levels in patients with acute coronary syndrome (ACS) or STsegment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Dogan et al [19] reported that increased GGT levels can be associated with significant stenosis and major adverse cardiac events (MACE) in patients with non–STEMI ACS. Also, Emiroglu et al [20] showed that serum GGT levels were higher in patients with acute coronary syndrome when compared with the healthy subjects. Additionally, they found a significant difference between the control group and the unstable angina group versus the STEMI group and the NSTEMI group. Apek et al [21] reported that serum GGT activity was associated with inhospital MACE in 425 patients with STEMI who had undergone primary PCI. Another study with 337 patients by Lazzeri et al [22] showed that GGT values were independent predictors of early mortality and glucose dysmetabolism. In a 1-year follow-up study, Ozcan et al found that high GGT levels at hospital admission were associated with the no-reflow phenomenon and increased long-term mortality in patients with STEMI undergoing primary PCI [23]. Finally, Gul et al showed that the GGT level in patients with STEMI undergoing primary PCI was associated with an increased risk for inhospital cardiovascular mortality, but in the long-term (mean followup time was 29 months) analysis, no significant differences in mortality were found between the 2 groups [24]. In summary, the GGT level is widely available to clinicians as a novel biochemical parameter and a powerful prognostic factor for inhospital adverse cardiovascular outcomes. Ozgur Akgul, MD Huseyin Uyarel, MD, Prof. Clinic of Cardiology İstanbul Mehmet Akif Ersoy Thoracic Cardiovascular Surgery Education and Research Hospital İstanbul, Turkey
http://dx.doi.org/10.1016/j.jcrc.2013.10.024
References [1] Turgut O, Tandogan I. Gamma-glutamyltransferase to determine cardiovascular risk: shifting the paradigm forward. J Atheroscler Thromb 2011;18:177–81. [2] Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16:534–54. [3] Drozdz R, Parmentier C, Hachad H, et al. g-Glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system. Free Radic Biol Med 1998;25:786–92. [4] Paolicchi A, Minotti G, Tonarelli P, et al. gamma-Glutamyl transpeptidasedependent iron reduction and LDL oxidation-a potential mechanism in atherosclerosis. J Investig Med 1999;47:151–60. [5] Lee DH, Ha MH, Kim JR, et al. gamma-Glutamyltransferase, alcohol, and blood pressure. A four year follow-up study. Ann Epidemiol 2002;12:90–6.
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Letters/Editorials / Journal of Critical Care 29 (2014) 167–168
[6] Kim DJ, Noh JH, Cho NH, et al. Serum gammaglutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors. Diabet Med 2005;22:1134–40. [7] Lee DH, Jacobs Jr DR, Gross M, et al. gamma-Glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem 2003;49:1358–66. [8] Lee DH, Gross MD, Jacobs Jr DR. Cardiovascular Risk Development in Young Adults (CARDIA) Study. Association of serum carotenoids and tocopherols with gammaglutamyltransferase: the Cardiovascular Risk Development in Young Adults (CARDIA) study. Clin Chem 2004;50:582–8. [9] Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995;142:699–708. [10] Ruttmann E, Brant LJ, Concin H, et al. Vorarlberg Health Monitoring and Promotion Program Study Group. Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation 2005;112:2130–7. [11] Lee DS, Evans JC, Robins SJ, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007;27:127–33. [12] Liu Cun-Fei, Gu Yu-Ting, Wang Hai-Ya, et al. gamma-Glutamyltransferase level and risk of hypertension: a systematic review and meta-analysis. PLoS ONE 2012;7(11):e48878. http://dx.doi.org/10.1371/journal.pone.0048878. [13] Emdin M, Passino C, Michelassi C, et al. Prognostic value of serum gammaglutamyl transferase activity after myocardial infarction. Eur Heart J 2001;22: 1802–7. [14] Ulus T, Yildirir A, Sade LE, et al. Serum gammaglutamyl transferase activity: new high-risk criteria in acute coronary syndrome patients? Coron Artery Dis 2008;19: 489–95.
[15] Atar AI, Yilmaz OC, Akin K, et al. Association between gamma-glutamyltransferase and coronary artery calcification. Int J Cardiol 2012. http://dx.doi.org/10.1016/j.ijcard.2012.03.157 [in press]. [16] Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. [17] Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Enlg J Med 2005;352:1685–95. [18] Paolicchi A, Emdin M, Ghliozeni E, et al. Images in cardiovascular medicine. Human atherosclerotic plaques contain gamma-glutamyl transpeptidase enzyme activity. Circulation 2004;109:1440–1. [19] Dogan A, Icli A, Aksoy F, et al. Gamma-glutamyltransferase in acute coronary syndrome patients without ST elevation and its association with stenotic lesion and cardiac events. Coron Artery Dis 2012;23:39–44. [20] Emiroglu MY, Esen OB, Bulut M, et al. Gamma glutamyltransferase levels and its association with high sensitive C reactive protein in patients with acute coronary syndromes. N Am J Med Sci 2010;2:306–10. [21] Akpek M, Elcik D, Kalay N, et al. The prognostic value of serum gamma glutamyl transferase activity on admission in patients with STEMI undergoing primary PCI. Angiology 2012;63:579–85. [22] Lazzeri C, Valente S, Tarquini R, et al. The prognostic role of gammaglutamyltransferase activity in non-diabetic ST-elevation myocardial infarction. Intern Emerg Med 2011;6:213–9. [23] Ozcan F, Karakas MF, Ozlu MF, et al. Effect of serum gamma-glutamyl transferase levels on myocardial perfusion and long-term prognosis after primary angioplasty in patients with acute ST-elevation myocardial infarction. J Investig Med 2012 Dec;60(8):1186–93 [http://dx.doi.org/10.231/JIM.0b013e31826d9043]. [24] Gul M, Uyarel H, Ergelen M, et al. The relationship between γ-glutamyl transferase levels and the clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis 2013 Jun;24(4):272–8. http://dx.doi.org/10.1097/MCA.0b013e328360d131.
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
g-Glutamyl transferase: A novel prognostic marker for cardiovascular disease Gamma-glutamyl transferase (GGT), considered to be a marker of excessive alcohol consumption or liver disorders, is an enzyme present in the cell membranes of many tissues. It acts as a mediator in the transmembrane transfer of glutathione, a major component of intracellular antioxidant-protective mechanisms [1]. GGT activity has also been shown to increase in response to oxidative stress [2]. In vitro studies suggest that GGT accelerates the production of reactive oxygen species and glutathione-dependent low density lipoprotein (LDL) oxidation in the presence of iron ions [3,4]. Serum GGT activity may participate in the pathogenesis of coronary artery disease (CAD) and its complications. Previous epidemiological studies suggest that higher serum GGT is associated with the development of CAD risk factors, including high blood pressure, diabetes, dyslipidemia [5,6], and metabolic syndrome. Serum GGT levels are also positively related to novel cardiovascular risk factors such as C-reactive protein and fibrinogen [7] and are inversely related to antioxidant levels [8]. In a large study of normalrange GGT levels and long-term follow-up of British men, Wannamethee et al showed that GGT levels were related with all-cause mortality, especially in the highest quartile GGT level group (patients who died from CAD) [9]. Additionally, in an epidemiological investigation in a cohort of 163,944 Austrian adults, Ruttmann et al demonstrated that GGT was independently associated with cardiovascular mortality [10]. Lee et al, in the Framingham Heart Study with 20 years of follow-up, reported that an increase in serum GGT predicts the onset of metabolic syndrome, incident cardiovascular disease, and death, suggesting that GGT is a marker of metabolic and cardiovascular risk [11]. And also, in a systematic review and meta-analysis, Liu et al reported that the GGT level is independently associated with the development of hypertension [12]. In recent years, several studies have been published on the relationship between CAD and serum GGT activity [13,14]. Serum GGT levels are an independent prognostic factor for coronary artery calcification, coronary complexity, and adverse cardiac events in patients with CAD [13,15]. Several possible mechanisms have been proposed for the role of serum GGT in increasing cardiovascular risk. The most widely accepted mechanism is oxidative stress, followed by hepatic insulin resistance and subclinical inflammation. Both increased oxidative stress and systemic inflammation play an important roles in atherosclerosis, lipoprotein infiltration and modification [16,17]. Other important mechanism is the activity of GGT which has been detected in the atheromatous plaques of the coronary and carotid arteries [18]. Oxidized LDL may contribute to the binding of GGT with LDL, leading to the formation of LDL/GGT complexes within the plaque which are a potential source for the development of atherosclerotic lesions. The presence of GGT within the coronary plaque may represent a pathological basis for its direct involvement in atherogenesis and CAD progression. 0883-9441/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
Recently published studies have shown the prognostic value of GGT levels in patients with acute coronary syndrome (ACS) or STsegment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Dogan et al [19] reported that increased GGT levels can be associated with significant stenosis and major adverse cardiac events (MACE) in patients with non–STEMI ACS. Also, Emiroglu et al [20] showed that serum GGT levels were higher in patients with acute coronary syndrome when compared with the healthy subjects. Additionally, they found a significant difference between the control group and the unstable angina group versus the STEMI group and the NSTEMI group. Apek et al [21] reported that serum GGT activity was associated with inhospital MACE in 425 patients with STEMI who had undergone primary PCI. Another study with 337 patients by Lazzeri et al [22] showed that GGT values were independent predictors of early mortality and glucose dysmetabolism. In a 1-year follow-up study, Ozcan et al found that high GGT levels at hospital admission were associated with the no-reflow phenomenon and increased long-term mortality in patients with STEMI undergoing primary PCI [23]. Finally, Gul et al showed that the GGT level in patients with STEMI undergoing primary PCI was associated with an increased risk for inhospital cardiovascular mortality, but in the long-term (mean followup time was 29 months) analysis, no significant differences in mortality were found between the 2 groups [24]. In summary, the GGT level is widely available to clinicians as a novel biochemical parameter and a powerful prognostic factor for inhospital adverse cardiovascular outcomes. Ozgur Akgul, MD Huseyin Uyarel, MD, Prof. Clinic of Cardiology İstanbul Mehmet Akif Ersoy Thoracic Cardiovascular Surgery Education and Research Hospital İstanbul, Turkey
http://dx.doi.org/10.1016/j.jcrc.2013.10.024
References [1] Turgut O, Tandogan I. Gamma-glutamyltransferase to determine cardiovascular risk: shifting the paradigm forward. J Atheroscler Thromb 2011;18:177–81. [2] Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 2000;16:534–54. [3] Drozdz R, Parmentier C, Hachad H, et al. g-Glutamyltransferase dependent generation of reactive oxygen species from a glutathione/transferrin system. Free Radic Biol Med 1998;25:786–92. [4] Paolicchi A, Minotti G, Tonarelli P, et al. gamma-Glutamyl transpeptidasedependent iron reduction and LDL oxidation-a potential mechanism in atherosclerosis. J Investig Med 1999;47:151–60. [5] Lee DH, Ha MH, Kim JR, et al. gamma-Glutamyltransferase, alcohol, and blood pressure. A four year follow-up study. Ann Epidemiol 2002;12:90–6.
168
Letters/Editorials / Journal of Critical Care 29 (2014) 167–168
[6] Kim DJ, Noh JH, Cho NH, et al. Serum gammaglutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors. Diabet Med 2005;22:1134–40. [7] Lee DH, Jacobs Jr DR, Gross M, et al. gamma-Glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem 2003;49:1358–66. [8] Lee DH, Gross MD, Jacobs Jr DR. Cardiovascular Risk Development in Young Adults (CARDIA) Study. Association of serum carotenoids and tocopherols with gammaglutamyltransferase: the Cardiovascular Risk Development in Young Adults (CARDIA) study. Clin Chem 2004;50:582–8. [9] Wannamethee G, Ebrahim S, Shaper AG. Gamma-glutamyltransferase: determinants and association with mortality from ischemic heart disease and all causes. Am J Epidemiol 1995;142:699–708. [10] Ruttmann E, Brant LJ, Concin H, et al. Vorarlberg Health Monitoring and Promotion Program Study Group. Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation 2005;112:2130–7. [11] Lee DS, Evans JC, Robins SJ, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007;27:127–33. [12] Liu Cun-Fei, Gu Yu-Ting, Wang Hai-Ya, et al. gamma-Glutamyltransferase level and risk of hypertension: a systematic review and meta-analysis. PLoS ONE 2012;7(11):e48878. http://dx.doi.org/10.1371/journal.pone.0048878. [13] Emdin M, Passino C, Michelassi C, et al. Prognostic value of serum gammaglutamyl transferase activity after myocardial infarction. Eur Heart J 2001;22: 1802–7. [14] Ulus T, Yildirir A, Sade LE, et al. Serum gammaglutamyl transferase activity: new high-risk criteria in acute coronary syndrome patients? Coron Artery Dis 2008;19: 489–95.
[15] Atar AI, Yilmaz OC, Akin K, et al. Association between gamma-glutamyltransferase and coronary artery calcification. Int J Cardiol 2012. http://dx.doi.org/10.1016/j.ijcard.2012.03.157 [in press]. [16] Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. [17] Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Enlg J Med 2005;352:1685–95. [18] Paolicchi A, Emdin M, Ghliozeni E, et al. Images in cardiovascular medicine. Human atherosclerotic plaques contain gamma-glutamyl transpeptidase enzyme activity. Circulation 2004;109:1440–1. [19] Dogan A, Icli A, Aksoy F, et al. Gamma-glutamyltransferase in acute coronary syndrome patients without ST elevation and its association with stenotic lesion and cardiac events. Coron Artery Dis 2012;23:39–44. [20] Emiroglu MY, Esen OB, Bulut M, et al. Gamma glutamyltransferase levels and its association with high sensitive C reactive protein in patients with acute coronary syndromes. N Am J Med Sci 2010;2:306–10. [21] Akpek M, Elcik D, Kalay N, et al. The prognostic value of serum gamma glutamyl transferase activity on admission in patients with STEMI undergoing primary PCI. Angiology 2012;63:579–85. [22] Lazzeri C, Valente S, Tarquini R, et al. The prognostic role of gammaglutamyltransferase activity in non-diabetic ST-elevation myocardial infarction. Intern Emerg Med 2011;6:213–9. [23] Ozcan F, Karakas MF, Ozlu MF, et al. Effect of serum gamma-glutamyl transferase levels on myocardial perfusion and long-term prognosis after primary angioplasty in patients with acute ST-elevation myocardial infarction. J Investig Med 2012 Dec;60(8):1186–93 [http://dx.doi.org/10.231/JIM.0b013e31826d9043]. [24] Gul M, Uyarel H, Ergelen M, et al. The relationship between γ-glutamyl transferase levels and the clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis 2013 Jun;24(4):272–8. http://dx.doi.org/10.1097/MCA.0b013e328360d131.