- Email: [email protected]
The doubtful association between blood lipid changes and progression of coronary calcification
224
Letters to the Editor
Contrary to HORIZONS AMI, our early clinical results suggest that the routine use of bivalirudin when combined with prasugrel is not associated with an excess of acute stent thrombosis. It is important to highlight that none of our patients treated with bivalirudin (Group A) received additional heparin. In contrast to unfractionated heparin, bivalirudin exerts additional antiplatelet effects [10] during angioplasty. Effective thrombin and platelet inhibition is essential for the prevention of acute stent thrombosis. It is likely that the excess of early stent thrombosis seen in HORIZONS-AMI were caused by delayed and heterogeneous platelet inhibition arising from the use of oral clopidogrel and cessation of bivalirudin (a rapidly reversible thrombin inhibitor) immediately after completion of the procedure as suggested by the trial protocol [11]. Our protocol allowed for extension of the bivalirudin infusion beyond the end of the procedure. The extended infusion of bivalirudin potentially conferred some protection against acute stent thrombosis through prolongation of the antithrombin and anti-platelet effects of the drug. It has been suggested elsewhere that prolongation of the bivalirudin infusion for 4 h postprocedure [12], the routine use of a high loading dose of clopidogrel [11], or routine use of low dose unfractionated heparin may also minimise the risk of early stent thrombosis. Further studies, including an on-going pharmacodynamic assessment of this protocol are required to optimise platelet inhibition in the interventional treatment of STEMI. References [1] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010;31:2501–55.
[2] Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–30. [3] Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation 2011;123:1745–56. [4] Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007;116:2923–32. [5] Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for STelevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723–31. [6] Angiolillo DJ, Badimon JJ, Saucedo JF, et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011;32:838–46. [7] Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409–20. [8] Ludman PF. British Cardiovascular Intervention Society Registry for audit and quality assessment of percutaneous coronary interventions in the United Kingdom. British Cardiovascular Intervention Society. Heart 2011 Aug;97 (16):1293–7. [9] Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51. [10] Sibbing D, Busch G, Braun S, et al. Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention. Eur Heart J 2008;29:1504–9. [11] Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009;54:1438–46. [12] Moser LR, Nemerovski CW, Good KL. Use of prolonged bivalirudin infusions following percutaneous coronary intervention. Cardiovasc Drugs Ther 2011 Jun;25(3):267–76.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.09.059
The doubtful association between blood lipid changes and progression of coronary calcification Alexander Tenenbaum a,b,⁎, Enrique Z. Fisman a,b, Joseph Shemesh a,b, Michael Motro a,b a b
Cardiac Rehabilitation Institute, the Chaim Sheba Medical Center, Tel-Hashomer, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
a r t i c l e
i n f o
Article history: Received 5 September 2011 Accepted 17 September 2011 Available online 11 October 2011 Keywords: Coronary calcification Cholesterol Computerized tomography Lipid lowering therapy
We greatly appreciated the interesting and stimulating discussion letter by Ravnskov [1] commenting on our recent study which concluded that both cholesterol changes over time and presence of ⁎ Corresponding author at: Cardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel-Hashomer, 52621 Israel. Tel.: + 972 3 5302361; fax: +972 3 5305905. E-mail address: [email protected] (A. Tenenbaum).
lipid lowering therapy do not seem to have any measurable effect on the rate of progression of coronary calcification when assessed by computerized tomography (CT) [2]. We believe that the process of calcification may spread out in a different manner than the overall development of atherosclerosis. It is interesting to point out a total failure of statins and/or ezetimibe based lipid lowering therapy to stop the progression of calcific aortic stenosis [3–5] despite their clear clinical benefits in reducing atherosclerotic vascular events. With regard to the important aspect of the causation of atherosclerosis by plasma lipoproteins and of exposure–response effects of lipid lowering therapy, we did not investigate this specific aspect because this expansive topic was not the focus of our study. Particularly, we did not investigate “soft” plaques composition and volume in relation to lipid level and lipid lowering therapy. However, several studies have demonstrated a beneficial effect of statins [6,7], fibrates [8] and niacin [9] in this issue. Therefore, our study does not support the thesis that abnormal plasma lipoproteins level is not related to atherosclerosis. We consider that abnormal plasma lipoproteins level represents an essential therapeutic target for
Letters to the Editor
atherosclerotic cardiovascular disease prevention. However, serial CT scanning, that tracks the progression of calcification as a “surrogate marker” for atherosclerosis appears to be an unsuitable tool for evaluation of anti-atherosclerotic therapy.
[5]
[6]
References [7] [1] Ravnskov U. The doubtful association between blood lipid changes and progression of atherosclerosis. Int J Cardiol 2011;153(1):95. [2] Tenenbaum A, Shemesh J, Koren-Morag N, et al. Long-term changes in serum cholesterol level does not influence the progression of coronary calcification. Int J Cardiol 2011;150:130–4. [3] Cowell SJ, Newby DE, Prescott RJ, et al. Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–97. [4] Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. ASTRONOMER investigators. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic
[8]
[9]
225
stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306–14. Rossebø AB, Pedersen TR, Boman K, et al, SEAS investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56. Nissen SE, Nicholls SJ, Sipahi I, et al, ASTEROID investigators. Effect of very highintensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556–65. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29–38. Ayaori M, Momiyama Y, Fayad ZA, et al. Effect of bezafibrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia. Atherosclerosis 2008;196:425–33. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55:2721–6.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.09.058
Serum ferritin: A potential determinant of myocardial ischemic burden in the setting of ischemic conditions? Kenan Yalta a,⁎, Nasir Sivri a, Tulin Yalta b, Ertan Yetkin c a b c
Trakya Üniversity, Cardiology Department, Edirne, Turkey Trakya Üniversity, Pathology Department, Edirne, Turkey IMC Hospital, Cardiology Department, Mersin, Turkey
a r t i c l e
i n f o
Article history: Received 9 September 2011 Accepted 17 September 2011 Available online 13 October 2011 Keywords: Serum ferritin Cellular anti-ischemics Antioxidation
Ferritin (Fr) has been one of the most extensively investigated serum marker in the medical research arena possibly due to its relatively inexpensive and broadly applicable laboratory assays. Numerous studies have tried to unravel its potential role in a variety of cardiovascular pathologies including genesis of atherosclerosis and acute coronary syndromes (ACS). In their recently published article, Dominguez-Rodriguez et al. have demonstrated that lower serum Fr levels might denote poor prognosis in a group of non-ST segment elevation myocardial infarction (NSTEMI) patients within 30 days after the acute event [1]. Even though numerous studies investigating the association between serum Fr and cardiovascular diseases including ACSs have yielded conflicting results, we agree with the authors that serum Fr might potentially harbor anti-oxidant properties, and, hence lower serum Fr levels might account for major adverse cardiovascular events (MACE) in patients with ACSs [1] possibly due to enhanced plaque destabilization, etc. in these patients. However, as described below, regardless of its potential impact at the vascular level (effects on endothelial function, atherothrombosis, etc.) that still needs to be clarified, serum Fr may also play a fundamental role in the ⁎ Corresponding author. E-mail address: [email protected] (K. Yalta).
regulation of myocardial oxygen (O2) and energy metabolism at the cellular level, and hence might serve as a determinant of myocardial ischemic burden in the setting of ischemic conditions. Myocardial ischemia is well known to be associated primarily with an imbalance between myocardial O2 supply and demand. At the myocardial level, increased O2 demand (tachycardia etc.) and/or decreased O2 supply (anemia, coronary steal etc.) may serve as triggers of ischemic response in the ischemia-prone myocardium (with significant coronary arterial obstruction, left ventricular (LV) hypertrophy, etc.), or to a lesser extent, in the normal heart as well. In the recent years, cellular pathways regarding the regulation of myocardial O2 and energy metabolism (utilization and production) have gained particular importance as alternative or adjunctive targets for the management of myocardial ischemia. Based on this concept, a variety of agents, namely cellular anti-ischemics including trimetazidine (TMZ) (an inhibitor of free fatty acid (FFA) oxidation) has been used as complementary antiischemic options due to their potential beneficial effects on myocardial energy metabolism along with a consequent reduction in total myocardial ischemic burden as previously demonstrated in diabetic patients with coronary artery disease (CAD) [2]. Interestingly, allopurinol (xanthine oxidase inhibitor),an antioxidant agent primarily used in gout disease, was also demonstrated to be of therapeutic value in patients with stable angina pectoris (SAP) due to its cellular antiischemic effects along with its potential to improve endothelial function [3]. The potential increase in the amount of free molecular O2 readily available for the ischemic myocardium and enhanced production of high energy phosphates including adenosine triphosphate (ATP) (possibly due to the allopurinol-induced inhibition of oxidative process in the myocardial tissue) were suggested as potential mechanisms underlying cellular anti-ischemic effects of this agent [3]. Given the potentially complex and multi-aspect nature of the relation between cellular oxidation–reduction reactions and myocardial O2-energy metabolism, it seems likely that cellular anti-ischemic effects of antioxidation may
Letters to the Editor
Contrary to HORIZONS AMI, our early clinical results suggest that the routine use of bivalirudin when combined with prasugrel is not associated with an excess of acute stent thrombosis. It is important to highlight that none of our patients treated with bivalirudin (Group A) received additional heparin. In contrast to unfractionated heparin, bivalirudin exerts additional antiplatelet effects [10] during angioplasty. Effective thrombin and platelet inhibition is essential for the prevention of acute stent thrombosis. It is likely that the excess of early stent thrombosis seen in HORIZONS-AMI were caused by delayed and heterogeneous platelet inhibition arising from the use of oral clopidogrel and cessation of bivalirudin (a rapidly reversible thrombin inhibitor) immediately after completion of the procedure as suggested by the trial protocol [11]. Our protocol allowed for extension of the bivalirudin infusion beyond the end of the procedure. The extended infusion of bivalirudin potentially conferred some protection against acute stent thrombosis through prolongation of the antithrombin and anti-platelet effects of the drug. It has been suggested elsewhere that prolongation of the bivalirudin infusion for 4 h postprocedure [12], the routine use of a high loading dose of clopidogrel [11], or routine use of low dose unfractionated heparin may also minimise the risk of early stent thrombosis. Further studies, including an on-going pharmacodynamic assessment of this protocol are required to optimise platelet inhibition in the interventional treatment of STEMI. References [1] Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2010;31:2501–55.
[2] Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–30. [3] Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation 2011;123:1745–56. [4] Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007;116:2923–32. [5] Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for STelevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723–31. [6] Angiolillo DJ, Badimon JJ, Saucedo JF, et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011;32:838–46. [7] Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 2011;377:1409–20. [8] Ludman PF. British Cardiovascular Intervention Society Registry for audit and quality assessment of percutaneous coronary interventions in the United Kingdom. British Cardiovascular Intervention Society. Heart 2011 Aug;97 (16):1293–7. [9] Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–51. [10] Sibbing D, Busch G, Braun S, et al. Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention. Eur Heart J 2008;29:1504–9. [11] Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009;54:1438–46. [12] Moser LR, Nemerovski CW, Good KL. Use of prolonged bivalirudin infusions following percutaneous coronary intervention. Cardiovasc Drugs Ther 2011 Jun;25(3):267–76.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.09.059
The doubtful association between blood lipid changes and progression of coronary calcification Alexander Tenenbaum a,b,⁎, Enrique Z. Fisman a,b, Joseph Shemesh a,b, Michael Motro a,b a b
Cardiac Rehabilitation Institute, the Chaim Sheba Medical Center, Tel-Hashomer, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
a r t i c l e
i n f o
Article history: Received 5 September 2011 Accepted 17 September 2011 Available online 11 October 2011 Keywords: Coronary calcification Cholesterol Computerized tomography Lipid lowering therapy
We greatly appreciated the interesting and stimulating discussion letter by Ravnskov [1] commenting on our recent study which concluded that both cholesterol changes over time and presence of ⁎ Corresponding author at: Cardiac Rehabilitation Institute, Chaim Sheba Medical Center, Tel-Hashomer, 52621 Israel. Tel.: + 972 3 5302361; fax: +972 3 5305905. E-mail address: [email protected] (A. Tenenbaum).
lipid lowering therapy do not seem to have any measurable effect on the rate of progression of coronary calcification when assessed by computerized tomography (CT) [2]. We believe that the process of calcification may spread out in a different manner than the overall development of atherosclerosis. It is interesting to point out a total failure of statins and/or ezetimibe based lipid lowering therapy to stop the progression of calcific aortic stenosis [3–5] despite their clear clinical benefits in reducing atherosclerotic vascular events. With regard to the important aspect of the causation of atherosclerosis by plasma lipoproteins and of exposure–response effects of lipid lowering therapy, we did not investigate this specific aspect because this expansive topic was not the focus of our study. Particularly, we did not investigate “soft” plaques composition and volume in relation to lipid level and lipid lowering therapy. However, several studies have demonstrated a beneficial effect of statins [6,7], fibrates [8] and niacin [9] in this issue. Therefore, our study does not support the thesis that abnormal plasma lipoproteins level is not related to atherosclerosis. We consider that abnormal plasma lipoproteins level represents an essential therapeutic target for
Letters to the Editor
atherosclerotic cardiovascular disease prevention. However, serial CT scanning, that tracks the progression of calcification as a “surrogate marker” for atherosclerosis appears to be an unsuitable tool for evaluation of anti-atherosclerotic therapy.
[5]
[6]
References [7] [1] Ravnskov U. The doubtful association between blood lipid changes and progression of atherosclerosis. Int J Cardiol 2011;153(1):95. [2] Tenenbaum A, Shemesh J, Koren-Morag N, et al. Long-term changes in serum cholesterol level does not influence the progression of coronary calcification. Int J Cardiol 2011;150:130–4. [3] Cowell SJ, Newby DE, Prescott RJ, et al. Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) investigators. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389–97. [4] Chan KL, Teo K, Dumesnil JG, Ni A, Tam J. ASTRONOMER investigators. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic
[8]
[9]
225
stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010;121:306–14. Rossebø AB, Pedersen TR, Boman K, et al, SEAS investigators. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343–56. Nissen SE, Nicholls SJ, Sipahi I, et al, ASTEROID investigators. Effect of very highintensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556–65. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29–38. Ayaori M, Momiyama Y, Fayad ZA, et al. Effect of bezafibrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia. Atherosclerosis 2008;196:425–33. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55:2721–6.
0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.09.058
Serum ferritin: A potential determinant of myocardial ischemic burden in the setting of ischemic conditions? Kenan Yalta a,⁎, Nasir Sivri a, Tulin Yalta b, Ertan Yetkin c a b c
Trakya Üniversity, Cardiology Department, Edirne, Turkey Trakya Üniversity, Pathology Department, Edirne, Turkey IMC Hospital, Cardiology Department, Mersin, Turkey
a r t i c l e
i n f o
Article history: Received 9 September 2011 Accepted 17 September 2011 Available online 13 October 2011 Keywords: Serum ferritin Cellular anti-ischemics Antioxidation
Ferritin (Fr) has been one of the most extensively investigated serum marker in the medical research arena possibly due to its relatively inexpensive and broadly applicable laboratory assays. Numerous studies have tried to unravel its potential role in a variety of cardiovascular pathologies including genesis of atherosclerosis and acute coronary syndromes (ACS). In their recently published article, Dominguez-Rodriguez et al. have demonstrated that lower serum Fr levels might denote poor prognosis in a group of non-ST segment elevation myocardial infarction (NSTEMI) patients within 30 days after the acute event [1]. Even though numerous studies investigating the association between serum Fr and cardiovascular diseases including ACSs have yielded conflicting results, we agree with the authors that serum Fr might potentially harbor anti-oxidant properties, and, hence lower serum Fr levels might account for major adverse cardiovascular events (MACE) in patients with ACSs [1] possibly due to enhanced plaque destabilization, etc. in these patients. However, as described below, regardless of its potential impact at the vascular level (effects on endothelial function, atherothrombosis, etc.) that still needs to be clarified, serum Fr may also play a fundamental role in the ⁎ Corresponding author. E-mail address: [email protected] (K. Yalta).
regulation of myocardial oxygen (O2) and energy metabolism at the cellular level, and hence might serve as a determinant of myocardial ischemic burden in the setting of ischemic conditions. Myocardial ischemia is well known to be associated primarily with an imbalance between myocardial O2 supply and demand. At the myocardial level, increased O2 demand (tachycardia etc.) and/or decreased O2 supply (anemia, coronary steal etc.) may serve as triggers of ischemic response in the ischemia-prone myocardium (with significant coronary arterial obstruction, left ventricular (LV) hypertrophy, etc.), or to a lesser extent, in the normal heart as well. In the recent years, cellular pathways regarding the regulation of myocardial O2 and energy metabolism (utilization and production) have gained particular importance as alternative or adjunctive targets for the management of myocardial ischemia. Based on this concept, a variety of agents, namely cellular anti-ischemics including trimetazidine (TMZ) (an inhibitor of free fatty acid (FFA) oxidation) has been used as complementary antiischemic options due to their potential beneficial effects on myocardial energy metabolism along with a consequent reduction in total myocardial ischemic burden as previously demonstrated in diabetic patients with coronary artery disease (CAD) [2]. Interestingly, allopurinol (xanthine oxidase inhibitor),an antioxidant agent primarily used in gout disease, was also demonstrated to be of therapeutic value in patients with stable angina pectoris (SAP) due to its cellular antiischemic effects along with its potential to improve endothelial function [3]. The potential increase in the amount of free molecular O2 readily available for the ischemic myocardium and enhanced production of high energy phosphates including adenosine triphosphate (ATP) (possibly due to the allopurinol-induced inhibition of oxidative process in the myocardial tissue) were suggested as potential mechanisms underlying cellular anti-ischemic effects of this agent [3]. Given the potentially complex and multi-aspect nature of the relation between cellular oxidation–reduction reactions and myocardial O2-energy metabolism, it seems likely that cellular anti-ischemic effects of antioxidation may