Canadian Journal of Cardiology 30 (2014) 3e5
Editorial
Vitamin C and Percutaneous Coronary Intervention: Some Answers, More Questions Catherine Gebhard, MD,a and Jean-Claude Tardif, MDa,b a b
Montreal Heart Institute, Montreal, Que bec, Canada
Department of Medicine, Universite de Montre al, Montreal, Que bec, Canada
See article by Wang et al., pages 96-101 of this issue. Cardiovascular diseases are the leading cause of death worldwide, and the majority of them are caused by atherosclerosis. Major therapeutic advances have been made during the past 2 decades; however, the risk of atherothrombotic complications remains high, causing millions of deaths worldwide each year.1 Based on the model that an imbalance between oxidative stress and antioxidant defense mechanisms may play a pivotal role in the progression of atherosclerosis and its complications, substantial interest has focused on the potential benefits of antioxidant vitamins in cardiovascular primary and secondary prevention. However, although experimental and observational studies have shown associations between the dietary and supplemental intake of the antioxidant vitamin C and lower risk of coronary heart disease,2 most randomized controlled clinical trials have revealed a lack of beneficial effects of vitamin C in cardiovascular prevention and no support for its routine use.3 One possible reason for the failure of these trials may be that a very heterogeneous group of patients was studied, and it could be argued that antioxidant therapy should be most effective in selected patients with angiographically proven atherosclerosis and an objective biochemical assessment of increased oxidative stress. Thus, recent research has aimed at identifying clinical scenarios in which a decreased antioxidant defense system enhances the vulnerability of myocardial tissue to oxidative challenges. Indeed, it became evident that increased oxidative stress may be one of the mechanisms accounting for impaired myocardial reperfusion after percutaneous coronary intervention (PCI).4 As a result of impaired coronary reperfusion, periprocedural myocardial injury occurs in about 30% of PCI procedures and appears to be associated with worse long-term outcomes.5 Although a number of strategies have been devised to ameliorate reperfusion injury, its incidence has not substantially decreased over the past 2 decades and Received for publication October 29, 2013. Accepted October 31, 2013. Corresponding author: Dr Jean-Claude Tardif, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada. Tel.: þ1-514376-3330 3612; fax: þ1-514-593-2521. E-mail: [email protected] See page 5 for disclosure information.
mechanisms are incompletely understood. Recent research indicates that vitamin C may have a role in counteracting myocardial reperfusion damage caused by PCI6; however, its clinical implications remain to be established. In this issue of the Canadian Journal of Cardiology, Wang et al. report that an intravenous infusion of vitamin C reduced periprocedural myocardial injury, possibly by inhibition of oxidative stress, in 532 patients with de novo lesions undergoing elective PCI.7 In this prospective placebo-controlled study, myocardial injury, as defined by creatine kinase-MB and troponin I release, was found to be significantly reduced in patients who had received 3 g of vitamin C 6 hours before PCI. Preprocedural vitamin C infusion was an independent negative predictor of postprocedure myocardial injury, whereas serum values of 8-hydroxy-2-deoxyguanosine, a product of hydroxyl radicaledeoxyribonucleic acid interaction, were reduced after vitamin C administration (P < 0.001 vs control group). Although the trial was not double-blinded, the fact that the end points were biomarkers of myocardial injury alleviates, at least in part, the concerns related to this suboptimal study design. This study confirms previous data from Basili et al. showing that impaired microcirculatory reperfusion improves with vitamin C infusion in patients undergoing elective PCI, as assessed by Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade.6 However, Wang et al. correctly point out that the role of reduced oxidative stress in vitamin Ceinduced improvement in myocardial injury cannot be established from their study. Thus, to date it remains unknown whether vitamin C exerts direct cardioprotective effects or whether reduced myocardial injury was coincident with oxidative stress reduction. Indeed, although PCI has been clearly associated with an increase in oxidative stress, data on the association between markers of oxidative stress and post-PCI myocardial injury are sparse and mixed.4,6,8,9 One explanation for this could be that quantitative measurements of reactive oxygen or nitrogen species are difficult to perform in vivo, because oxidative stress is not a continuous uniform process. Thus, what might be the mechanism by which vitamin C reduces periprocedural myocardial injury? A large number of
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.10.018
4
clinical trials have demonstrated that vitamin C acts as a first line of antioxidant defense in plasma, thereby inhibiting lowdensity lipoprotein oxidation and thus potentially reducing atherogenesis.10 There is also increasing evidence suggesting a pivotal role of vitamin C in maintaining normal endothelial function and inhibiting platelet aggregation, and thus microembolization, by increasing nitric oxide (NO) bioavailability through either reduced peroxynitrite production or enhanced NO synthase activity.11 Furthermore, it has recently been demonstrated that vitamin C reduces stress-induced cardiac damage by downregulating catecholamines and tumour necrosis factor-a.12 However, to date, assessment of the efficacy of antioxidant therapy is hampered by the lack of available methodology to quantify reactive oxygen species and NO in the vessel wall in vivo. Thus, antioxidant therapy is mostly judged on the basis of clinical or surrogate end points such as assessment of endothelial function or lipid peroxidation products in plasma. Coronary endothelial dysfunction caused by reduced availability of NO has been proposed to contribute to reperfusion injury; thus, one could speculate that vitamin C exerts its beneficial effects by interfering with the NO pathway. Considering the fact that vitamin C has a short half-life, the reduction of myocardial injury observed by Wang et al. could be the consequence of a short-term effect of vitamin C on NO and arterial dilatation. Nevertheless, the observed beneficial effects of vitamin C after PCI are encouraging and provide a scientific rationale to further test the clinical efficacy and underlying mechanisms of vitamin C infusion in this setting. Previous studies indicate that the scavenger activity of vitamin C requires high serum concentrations to prevent oxidative damage, which cannot be achieved by oral administration because of saturation of transporters.13 Consistent with this view, previous attempts to reduce free radical production with oral vitamin C after primary PCI have failed. Wang et al. demonstrated that vitamin C infusion blunted the increase of 8-hydroxy-2-deoxyguanosine in a subset of 30 patients of the current study, thereby further adding to the evidence that high doses of intravenous vitamin C are necessary to reduce oxidative stress markers. However, the authors did not provide data on pharmacokinetics; therefore, the optimal dose, timing of administration, and duration of vitamin C infusion before PCI were not identified. Nevertheless, previous data indicate that plasma concentrations of vitamin C of at least 10 mmol/L are needed to overcome competition with NO for superoxide.14 Importantly, plasma levels up to 60 mmol/L have not resulted in adverse events, except in specific clinical conditions such as renal disease.15 The study by Wang et al. supports the hypothesis that antioxidant therapy must be given before PCI to achieve a significant reduction in reperfusion injury. Oxidants may indeed rapidly activate signalling cascades and gene expression that, once initiated, no longer require the presence of reactive oxygen species. As discussed earlier, the half-life of parenteral vitamin C is short, and one can only speculate whether continued vitamin C administration would have produced an even larger effect. Thus, the temporal and spatial characteristics of oxidant production pose great challenges in regard to delivering effective therapy, and factors such as dosage, route, and timing of administration seem to play a crucial role in determining the efficacy of vitamin C treatment. It is of note
Canadian Journal of Cardiology Volume 30 2014
that previously published experimental and clinical data vary widely in their protocols, a fact that might in part explain the lack of effect on cardiovascular outcomes seen with vitamin C treatment in previous studies. The question of whether a drug combination would be more effective than vitamin C alone in preventing myocardial injury after PCI has not been resolved. Indeed, studies showing the failure of several antioxidants to protect against reperfusion injury in experimental or clinical settings led to the hypothesis that in many cases, a single antioxidant may not be sufficient to exert a potent therapeutic effect.16 Indeed, antioxidant combinations have shown promising results in an experimental model of myocardial reperfusion injury.17 Interestingly, there is solid evidence showing that statins effectively limit the production of oxidants.18 Accordingly, randomized clinical trials have demonstrated that pretreatment with statins significantly reduced periprocedural myocardial injury.19 In the present study, > 99% of patients were receiving statin therapy; thus, it cannot be excluded that this treatment combination may have had a positive impact on end points. Indeed, differences in standard-of-care regimens may also explain why some single-antioxidant therapies in previous studies have failed to influence cardiovascular outcomes. However, there is evidence suggesting that antioxidant vitamins may affect the metabolism of cholesterollowering drugs20; thus further research is warranted to test whether single or combined antioxidants will be effective on top of standard of care including intensive statin use, before recommendations can be confidently made. In summary, although the study by Wang et al. is encouraging, a number of questions remain unanswered. Larger clinical trials will be required to test whether or not antioxidant approaches will improve long-term outcomes and be effective in addition to standard of care including intensive statin use. The current study could not address this crucial issue because of its small size and short follow-up duration. Treatment duration and dosage should also be investigated in more detail. Plasma vitamin C levels and possibly NO bioactivity need to be monitored to identify those patients who may benefit the most from antioxidant therapy and to confirm that the treatment had the intended effects. A variety of risk factors cause inflammation and oxidative stress; thus, combination therapy that may simultaneously address multiple mechanisms underlying endothelial dysfunction and reperfusion injury may provide additional benefits over monotherapy or currently recommended treatment regimens, or both. Although this study raises as many questions as it answers, research on oxidative stress, antioxidants, and myocardial injury promises to be active in the coming years at basic and clinical levels. Acknowledgements J-C.T. holds the Canada Research Chair in translational and personalized medicine and the Universite de Montreal endowed research chair in atherosclerosis. Funding Sources This work was supported by the Swiss National Science Foundation (SNSF), the Swiss Foundation for Grants in
Gebhard and Tardif Vitamin C and PCI
Biology and Medicine (SFGBM), and the Novartis Jubilee Foundation, Switzerland (CG). Disclosures The authors have no conflicts of interest to disclose. References 1. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226-35. 2. Shihabi A, Li WG, Miller FJ Jr, et al. Antioxidant therapy for atherosclerotic vascular disease: the promise and the pitfalls. Am J Physiol Heart Circ Physiol 2002;282:H797-802. 3. Ye Y, Li J, Yuan Z. Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS One 2013;8:e56803. 4. Iuliano L, Pratico D, Greco C, et al. Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA. J Am Coll Cardiol 2001;37:76-80. 5. Babu GG, Walker JM, Yellon DM, et al. Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for cardioprotection. Eur Heart J 2011;32:23-31. 6. Basili S, Tanzilli G, Mangieri E, et al. Intravenous ascorbic acid infusion improves myocardial perfusion grade during elective percutaneous coronary intervention: relationship with oxidative stress markers. JACC Cardiovasc Interv 2010;3:221-9.
5
10. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A 1989;86:6377-81. 11. d’Uscio LV, Milstien S, Richardson D, et al. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 2003;92:88-95. 12. Kim H, Bae S, Kim Y, et al. Vitamin C prevents stress-induced damage on the heart caused by the death of cardiomyocytes, through downregulation of the excessive production of catecholamine, TNF-alpha, and ROS production in Gulo(-/-) mice. Free Radic Biol Med 2013;65C: 573-83. 13. Sherman DL, Keaney JF Jr, Biegelsen ES, et al. Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension. Hypertension 2000;35: 936-41. 14. Jackson TS, Xu A, Vita JA, et al. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 1998;83:916-22. 15. Padayatty SJ, Sun AY, Chen Q, et al. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 2010;5:e11414. 16. Bellows SD, Hale SL, Simkhovich BZ, et al. Do antioxidant vitamins reduce infarct size following acute myocardial ischemia/reperfusion? Cardiovasc Drugs Ther 1995;9:117-23. 17. Gao F, Yao CL, Gao E, et al. Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion injury. J Pharmacol Exp Ther 2002;301:543-50.
7. Wang ZJ, Hu WK MD, Liu YY, et al. The effect of intravenous vitamin c infusion on periprocedural myocardial injury for patients undergoing elective percutaneous coronary intervention. Can J Cardiol 2014;30: 96-101.
18. Hermida N, Balligand JL. Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal 2013. [Epub ahead of print]
8. Berg K, Wiseth R, Bjerve K, et al. Oxidative stress and myocardial damage during elective percutaneous coronary interventions and coronary angiography. A comparison of blood-borne isoprostane and troponin release. Free Radic Res 2004;38:517-25.
19. Pasceri V, Patti G, Nusca A, et al. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2004;110:674-8.
9. Guan W, Osanai T, Kamada T, et al. Effect of allopurinol pretreatment on free radical generation after primary coronary angioplasty for acute myocardial infarction. J Cardiovasc Pharmacol 2003;41:699-705.
20. Tousoulis D, Antoniades C, Stefanadis C. Statins and antioxidant vitamins: should co-administration be avoided? J Am Coll Cardiol 2006;47: 1237. author reply 1237-8.
Editorial
Vitamin C and Percutaneous Coronary Intervention: Some Answers, More Questions Catherine Gebhard, MD,a and Jean-Claude Tardif, MDa,b a b
Montreal Heart Institute, Montreal, Que bec, Canada
Department of Medicine, Universite de Montre al, Montreal, Que bec, Canada
See article by Wang et al., pages 96-101 of this issue. Cardiovascular diseases are the leading cause of death worldwide, and the majority of them are caused by atherosclerosis. Major therapeutic advances have been made during the past 2 decades; however, the risk of atherothrombotic complications remains high, causing millions of deaths worldwide each year.1 Based on the model that an imbalance between oxidative stress and antioxidant defense mechanisms may play a pivotal role in the progression of atherosclerosis and its complications, substantial interest has focused on the potential benefits of antioxidant vitamins in cardiovascular primary and secondary prevention. However, although experimental and observational studies have shown associations between the dietary and supplemental intake of the antioxidant vitamin C and lower risk of coronary heart disease,2 most randomized controlled clinical trials have revealed a lack of beneficial effects of vitamin C in cardiovascular prevention and no support for its routine use.3 One possible reason for the failure of these trials may be that a very heterogeneous group of patients was studied, and it could be argued that antioxidant therapy should be most effective in selected patients with angiographically proven atherosclerosis and an objective biochemical assessment of increased oxidative stress. Thus, recent research has aimed at identifying clinical scenarios in which a decreased antioxidant defense system enhances the vulnerability of myocardial tissue to oxidative challenges. Indeed, it became evident that increased oxidative stress may be one of the mechanisms accounting for impaired myocardial reperfusion after percutaneous coronary intervention (PCI).4 As a result of impaired coronary reperfusion, periprocedural myocardial injury occurs in about 30% of PCI procedures and appears to be associated with worse long-term outcomes.5 Although a number of strategies have been devised to ameliorate reperfusion injury, its incidence has not substantially decreased over the past 2 decades and Received for publication October 29, 2013. Accepted October 31, 2013. Corresponding author: Dr Jean-Claude Tardif, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada. Tel.: þ1-514376-3330 3612; fax: þ1-514-593-2521. E-mail: [email protected] See page 5 for disclosure information.
mechanisms are incompletely understood. Recent research indicates that vitamin C may have a role in counteracting myocardial reperfusion damage caused by PCI6; however, its clinical implications remain to be established. In this issue of the Canadian Journal of Cardiology, Wang et al. report that an intravenous infusion of vitamin C reduced periprocedural myocardial injury, possibly by inhibition of oxidative stress, in 532 patients with de novo lesions undergoing elective PCI.7 In this prospective placebo-controlled study, myocardial injury, as defined by creatine kinase-MB and troponin I release, was found to be significantly reduced in patients who had received 3 g of vitamin C 6 hours before PCI. Preprocedural vitamin C infusion was an independent negative predictor of postprocedure myocardial injury, whereas serum values of 8-hydroxy-2-deoxyguanosine, a product of hydroxyl radicaledeoxyribonucleic acid interaction, were reduced after vitamin C administration (P < 0.001 vs control group). Although the trial was not double-blinded, the fact that the end points were biomarkers of myocardial injury alleviates, at least in part, the concerns related to this suboptimal study design. This study confirms previous data from Basili et al. showing that impaired microcirculatory reperfusion improves with vitamin C infusion in patients undergoing elective PCI, as assessed by Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade.6 However, Wang et al. correctly point out that the role of reduced oxidative stress in vitamin Ceinduced improvement in myocardial injury cannot be established from their study. Thus, to date it remains unknown whether vitamin C exerts direct cardioprotective effects or whether reduced myocardial injury was coincident with oxidative stress reduction. Indeed, although PCI has been clearly associated with an increase in oxidative stress, data on the association between markers of oxidative stress and post-PCI myocardial injury are sparse and mixed.4,6,8,9 One explanation for this could be that quantitative measurements of reactive oxygen or nitrogen species are difficult to perform in vivo, because oxidative stress is not a continuous uniform process. Thus, what might be the mechanism by which vitamin C reduces periprocedural myocardial injury? A large number of
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.10.018
4
clinical trials have demonstrated that vitamin C acts as a first line of antioxidant defense in plasma, thereby inhibiting lowdensity lipoprotein oxidation and thus potentially reducing atherogenesis.10 There is also increasing evidence suggesting a pivotal role of vitamin C in maintaining normal endothelial function and inhibiting platelet aggregation, and thus microembolization, by increasing nitric oxide (NO) bioavailability through either reduced peroxynitrite production or enhanced NO synthase activity.11 Furthermore, it has recently been demonstrated that vitamin C reduces stress-induced cardiac damage by downregulating catecholamines and tumour necrosis factor-a.12 However, to date, assessment of the efficacy of antioxidant therapy is hampered by the lack of available methodology to quantify reactive oxygen species and NO in the vessel wall in vivo. Thus, antioxidant therapy is mostly judged on the basis of clinical or surrogate end points such as assessment of endothelial function or lipid peroxidation products in plasma. Coronary endothelial dysfunction caused by reduced availability of NO has been proposed to contribute to reperfusion injury; thus, one could speculate that vitamin C exerts its beneficial effects by interfering with the NO pathway. Considering the fact that vitamin C has a short half-life, the reduction of myocardial injury observed by Wang et al. could be the consequence of a short-term effect of vitamin C on NO and arterial dilatation. Nevertheless, the observed beneficial effects of vitamin C after PCI are encouraging and provide a scientific rationale to further test the clinical efficacy and underlying mechanisms of vitamin C infusion in this setting. Previous studies indicate that the scavenger activity of vitamin C requires high serum concentrations to prevent oxidative damage, which cannot be achieved by oral administration because of saturation of transporters.13 Consistent with this view, previous attempts to reduce free radical production with oral vitamin C after primary PCI have failed. Wang et al. demonstrated that vitamin C infusion blunted the increase of 8-hydroxy-2-deoxyguanosine in a subset of 30 patients of the current study, thereby further adding to the evidence that high doses of intravenous vitamin C are necessary to reduce oxidative stress markers. However, the authors did not provide data on pharmacokinetics; therefore, the optimal dose, timing of administration, and duration of vitamin C infusion before PCI were not identified. Nevertheless, previous data indicate that plasma concentrations of vitamin C of at least 10 mmol/L are needed to overcome competition with NO for superoxide.14 Importantly, plasma levels up to 60 mmol/L have not resulted in adverse events, except in specific clinical conditions such as renal disease.15 The study by Wang et al. supports the hypothesis that antioxidant therapy must be given before PCI to achieve a significant reduction in reperfusion injury. Oxidants may indeed rapidly activate signalling cascades and gene expression that, once initiated, no longer require the presence of reactive oxygen species. As discussed earlier, the half-life of parenteral vitamin C is short, and one can only speculate whether continued vitamin C administration would have produced an even larger effect. Thus, the temporal and spatial characteristics of oxidant production pose great challenges in regard to delivering effective therapy, and factors such as dosage, route, and timing of administration seem to play a crucial role in determining the efficacy of vitamin C treatment. It is of note
Canadian Journal of Cardiology Volume 30 2014
that previously published experimental and clinical data vary widely in their protocols, a fact that might in part explain the lack of effect on cardiovascular outcomes seen with vitamin C treatment in previous studies. The question of whether a drug combination would be more effective than vitamin C alone in preventing myocardial injury after PCI has not been resolved. Indeed, studies showing the failure of several antioxidants to protect against reperfusion injury in experimental or clinical settings led to the hypothesis that in many cases, a single antioxidant may not be sufficient to exert a potent therapeutic effect.16 Indeed, antioxidant combinations have shown promising results in an experimental model of myocardial reperfusion injury.17 Interestingly, there is solid evidence showing that statins effectively limit the production of oxidants.18 Accordingly, randomized clinical trials have demonstrated that pretreatment with statins significantly reduced periprocedural myocardial injury.19 In the present study, > 99% of patients were receiving statin therapy; thus, it cannot be excluded that this treatment combination may have had a positive impact on end points. Indeed, differences in standard-of-care regimens may also explain why some single-antioxidant therapies in previous studies have failed to influence cardiovascular outcomes. However, there is evidence suggesting that antioxidant vitamins may affect the metabolism of cholesterollowering drugs20; thus further research is warranted to test whether single or combined antioxidants will be effective on top of standard of care including intensive statin use, before recommendations can be confidently made. In summary, although the study by Wang et al. is encouraging, a number of questions remain unanswered. Larger clinical trials will be required to test whether or not antioxidant approaches will improve long-term outcomes and be effective in addition to standard of care including intensive statin use. The current study could not address this crucial issue because of its small size and short follow-up duration. Treatment duration and dosage should also be investigated in more detail. Plasma vitamin C levels and possibly NO bioactivity need to be monitored to identify those patients who may benefit the most from antioxidant therapy and to confirm that the treatment had the intended effects. A variety of risk factors cause inflammation and oxidative stress; thus, combination therapy that may simultaneously address multiple mechanisms underlying endothelial dysfunction and reperfusion injury may provide additional benefits over monotherapy or currently recommended treatment regimens, or both. Although this study raises as many questions as it answers, research on oxidative stress, antioxidants, and myocardial injury promises to be active in the coming years at basic and clinical levels. Acknowledgements J-C.T. holds the Canada Research Chair in translational and personalized medicine and the Universite de Montreal endowed research chair in atherosclerosis. Funding Sources This work was supported by the Swiss National Science Foundation (SNSF), the Swiss Foundation for Grants in
Gebhard and Tardif Vitamin C and PCI
Biology and Medicine (SFGBM), and the Novartis Jubilee Foundation, Switzerland (CG). Disclosures The authors have no conflicts of interest to disclose. References 1. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226-35. 2. Shihabi A, Li WG, Miller FJ Jr, et al. Antioxidant therapy for atherosclerotic vascular disease: the promise and the pitfalls. Am J Physiol Heart Circ Physiol 2002;282:H797-802. 3. Ye Y, Li J, Yuan Z. Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS One 2013;8:e56803. 4. Iuliano L, Pratico D, Greco C, et al. Angioplasty increases coronary sinus F2-isoprostane formation: evidence for in vivo oxidative stress during PTCA. J Am Coll Cardiol 2001;37:76-80. 5. Babu GG, Walker JM, Yellon DM, et al. Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for cardioprotection. Eur Heart J 2011;32:23-31. 6. Basili S, Tanzilli G, Mangieri E, et al. Intravenous ascorbic acid infusion improves myocardial perfusion grade during elective percutaneous coronary intervention: relationship with oxidative stress markers. JACC Cardiovasc Interv 2010;3:221-9.
5
10. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A 1989;86:6377-81. 11. d’Uscio LV, Milstien S, Richardson D, et al. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res 2003;92:88-95. 12. Kim H, Bae S, Kim Y, et al. Vitamin C prevents stress-induced damage on the heart caused by the death of cardiomyocytes, through downregulation of the excessive production of catecholamine, TNF-alpha, and ROS production in Gulo(-/-) mice. Free Radic Biol Med 2013;65C: 573-83. 13. Sherman DL, Keaney JF Jr, Biegelsen ES, et al. Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension. Hypertension 2000;35: 936-41. 14. Jackson TS, Xu A, Vita JA, et al. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 1998;83:916-22. 15. Padayatty SJ, Sun AY, Chen Q, et al. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 2010;5:e11414. 16. Bellows SD, Hale SL, Simkhovich BZ, et al. Do antioxidant vitamins reduce infarct size following acute myocardial ischemia/reperfusion? Cardiovasc Drugs Ther 1995;9:117-23. 17. Gao F, Yao CL, Gao E, et al. Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion injury. J Pharmacol Exp Ther 2002;301:543-50.
7. Wang ZJ, Hu WK MD, Liu YY, et al. The effect of intravenous vitamin c infusion on periprocedural myocardial injury for patients undergoing elective percutaneous coronary intervention. Can J Cardiol 2014;30: 96-101.
18. Hermida N, Balligand JL. Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: the role of statins. Antioxid Redox Signal 2013. [Epub ahead of print]
8. Berg K, Wiseth R, Bjerve K, et al. Oxidative stress and myocardial damage during elective percutaneous coronary interventions and coronary angiography. A comparison of blood-borne isoprostane and troponin release. Free Radic Res 2004;38:517-25.
19. Pasceri V, Patti G, Nusca A, et al. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2004;110:674-8.
9. Guan W, Osanai T, Kamada T, et al. Effect of allopurinol pretreatment on free radical generation after primary coronary angioplasty for acute myocardial infarction. J Cardiovasc Pharmacol 2003;41:699-705.
20. Tousoulis D, Antoniades C, Stefanadis C. Statins and antioxidant vitamins: should co-administration be avoided? J Am Coll Cardiol 2006;47: 1237. author reply 1237-8.
