[en] The beneficial effects of supplemental oxygen in patients with acute myocardial infarction are still uncertain: what are the effects of ischaemia-reperfusion injury during hyperoxia and normoxia in mature rats with and without cardiovascular risk factors? What is the main finding and its importance? Despite elevated baseline oxidative stress in rodents with cardiovascular risk factors, hyperoxic reperfusion limited myocardial necrosis and anti/pro-oxidant imbalance in spontaneously hypertensive and Zucker rats. In contrast, this effect was exacerbated in healthy Wistar rats. These results suggest that oxygen supplementation may not be harmful in patients with acute myocardial injury.
ABSTRACT: Recent studies on O2 supplementation in acute coronary syndrome patients are equivocal. We tested the hypothesis that oxidative stress is increased in rodents with cardiovascular risk factors and enhances ischaemia-reperfusion injury in the presence of hyperoxia. A total of 43 Wistar rats (WR), 30 spontaneously hypertensive rats (SHR) and 33 obese Zucker rats (ZR) were randomized in a sham procedure (one-third) or underwent a left anterior descending ligation of the coronary artery for 60 min (two-thirds). This was followed by 3 h of reperfusion while animals were randomized either in a hyperoxic (HR) or a normoxic reperfusion (NR) group. Myocardial infarction size and oxidative stress biomarkers (myeloperoxidase (MPO), malondialdehyde and total free thiols) were assessed in blood samples. Baseline troponin T was higher in SHR and ZR than in WR (both P < 0.001). Baseline total MPO was elevated in ZR in comparison to SHR and WR (both P < 0.001). SHR had lower thiol concentration compared to WR and ZR (P < 0.000001). HR was associated with a lower troponin T rise in SHR and ZR than in NR (both P < 0.001), while the reverse occurred in WR (P < 0.001). In SHR, HR limited total MPO increase as compared to NR (P = 0.0056) and the opposite effect was observed with total MPO in WR (P = 0.013). NR was associated with a drastic reduction of total thiols as compared to HR both in SHR and in ZR (both P < 0.001). Despite a heightened baseline oxidative stress level, HR limited myocardial necrosis and anti/pro-oxidant imbalance in SHR and ZR whereas this effect was exacerbated in healthy WR.
Research Center/Unit :
CORD - Centre de l'Oxygène, Recherche et Développement - ULiège
Erasme University Hospital KBS - Koning Boudewijnstichting
Funding text :
A.A. is a Research Fellow of the ‘Fond Erasme’ (Erasme Hospital, Brussels, Belgium) and of the Department of Cardiology (Erasme Hospital, Université Libre de Bruxelles, Belgium). Editorial assistance, in the form of language editing and correction, was provided by XpertScientific Editing and Consulting. This work was financially supported by ‘Fonds Erasme’ (Belgium), the ‘Docteur et Madame René Tagnon’ fund from the King Baudouin Foundation (Belgium), the ‘Fonds pour la Chirurgie Cardiaque’ (Belgium) and ‘Fond d'encouragement pour la recherche’ (Université Libre de Bruxelles, Brussels, Belgium).A.A. is a Research Fellow of the ‘Fond Erasme’ (Erasme Hospital, Brussels, Belgium) and of the Department of Cardiology (Erasme Hospital, Université Libre de Bruxelles, Belgium). Editorial assistance, in the form of language editing and correction, was provided by XpertScientific Editing and Consulting. This work was financially supported by ‘Fonds Erasme’ (Belgium), the ‘Docteur et Madame René Tagnon’ fund from the King Baudouin Foundation (Belgium), the ‘Fonds pour la Chirurgie Cardiaque’ (Belgium) and ‘Fond d'encouragement pour la recherche’ (Université Libre de Bruxelles, Brussels, Belgium).
Abete, P., Napoli, C., Santoro, G., Ferrara, N., Tritto, I., Chiariello, M., Rengo, F., & Ambrosio, G. (1999). Age-related decrease in cardiac tolerance to oxidative stress. Journal of Molecular and Cellular Cardiology, 31(1), 227–236.
Aeschbacher, S., Schoen, T., Bossard, M., van der Lely, S., Glättli, K., Todd, J., Estis, J., Risch, M., Mueller, C., Risch, L., & Conen, D. (2015). Relationship between high-sensitivity cardiac troponin I and blood pressure among young and healthy adults. American Journal of Hypertension, 28(6), 789–796.
Altman, D. G., Machin, D., Bryant, T. N., & Gardner, M. J. (2000). Statistics with confidence: Confidence intervals and statistical guidelines (2nd ed., pp. 79–84). London, BMJ Books.
Balaban, R. S., Nemoto, S., & Finkel, T. (2005). Mitochondria, oxidants, and aging. Cell, 120(4), 483–495.
Baldus, S., Heeschen, C., Meinertz, T., Zeiher, A. M., Eiserich, J. P., Münzel, T., Simoons, M. L., & Hamm, C. W.; CAPTURE Investigators (2003). Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation, 108(12), 1440–1445.
Bhalodia, Y. S., Sheth, N. R., Vaghasiya, J. D., & Jivani, N. P. (2010). Hyperlipidemia enhanced oxidative stress and inflammatory response evoked by renal ischemia/reperfusion injury. International Journal of Pharmacology, 6, 25–30.
Borato, D. C., Parabocz, G. C., Ribas, J. T., Netto, H. P., Erdmann, F. C., Wiecheteck, L. D., Manente, F. A., de Almeida Mello, L. R., Belló, C., dos Santos, F. A., Borba, L. M., & Vellosa, J. C. (2016). Biomarkers in obesity: Serum myeloperoxidase and traditional cardiac risk parameters. Experimental and Clinical Endocrinology & Diabetes, 124(1), 49–54.
Bugger, H., & Abel, E. D. (2009). Rodent models of diabetic cardiomyopathy. Disease Models & Mechanisms, 2(9–10), 454–466.
Bulluck, H., & Hausenloy, D. J. (2016). Letter by Bulluck and Hausenloy regarding article, “Air versus oxygen in ST-segment-elevation myocardial infarction. Circulation, 133(3), e28.
Burgeiro, A., Cerqueira, M. G., Varela-Rodríguez, B. M., Nunes, S., Neto, P., Pereira, F. C., Reis, F., & Carvalho, E. (2017). Glucose and lipid dysmetabolism in a rat model of prediabetes induced by a high-sucrose diet. Nutrients, 9(6), 638.
Conti, M., Morand, P. C., Levillain, P., & Lemonnier, A. (1991). Improved fluorometric determination of malonaldehyde. Clinical Chemistry, 37(7), 1273–1275.
Davidson, S. M., Ferdinandy, P., Andreadou, I., Bøtker, H. E., Heusch, G., Ibáñez, B., Ovize, M., Schulz, R., Yellon, D. M., Hausenloy, D. J., & Garcia-Dorado, D.; CARDIOPROTECTION COST Action (CA16225) (2019). Multitarget strategies to reduce myocardial ischemia/reperfusion injury: JACC review topic of the week. Journal of the American College of Cardiology, 73(1), 89–99.
Dobrian, A. D., Davies, M. J., Schriver, S. D., Lauterio, T. J., & Prewitt, R. L. (2001). Oxidative stress in a rat model of obesity-induced hypertension. Hypertension, 37(2 Pt 2), 554–560.
Doggrell, S. A., & Brown, L. (1998). Rat models of hypertension, cardiac hypertrophy and failure. Cardiovascular Research, 39(1), 89–105.
Ebrahim, Z., Yellon, D. M., & Baxter, G. F. (2007). Ischemic preconditioning is lost in aging hypertensive rat heart: Independent effects of aging and longstanding hypertension. Experimental Gerontology, 42(8), 807–814.
Eleftheriades, M., Pervanidou, P., Vafaei, H., Vaggos, G., Dontas, I., Skenderi, K., Sebire, N. J., & Nicolaides, K. (2014). Metabolic profiles of adult Wistar rats in relation to prenatal and postnatal nutritional manipulation: The role of birthweight. Hormones, 13(2), 268–279.
Esterbauer, H., & Cheeseman, K. H. (1990). Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hydroxynonenal. Methods in Enzymology, 186, 407–421.
Ferdinandy, P., Schulz, R., & Baxter, G. F. (2007). Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacological Reviews, 59(4), 418–458.
Friedman, J., Peleg, E., Kagan, T., Shnizer, S., & Rosenthal, T. (2003). Oxidative stress in hypertensive, diabetic, and diabetic hypertensive rats. American Journal of Hypertension, 16(12), 1049–1052.
Goyal, R., Singhai, M., & Faizy, A. F. (2011). Glutathione peroxidase activity in obese and nonobese diabetic patients and role of hyperglycemia in oxidative stress. Journal of Mid-Life Health, 2(2), 72–76.
Granger, D. N., & Kvietys, P. R. (2015). Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biology, 6, 524–551.
Grey, C., Jackson, R., Schmidt, M., Ezzati, M., Asaria, P., Exeter, D. J., & Kerr, A. J. (2017). One in four major ischaemic heart disease events are fatal and 60% are pre-hospital deaths: A national data-linkage study (ANZACS-QI 8). European Heart Journal, 38(3), 172–180.
Harrison, D. G., & Gongora, M. C. (2009). Oxidative stress and hypertension. The Medical Clinics of North America, 93(3), 621–635.
Hausenloy, D. J., & Yellon, D. M. (2013). Myocardial ischemia-reperfusion injury: A neglected therapeutic target. Journal of Clinical Investigation, 123(1), 92–100.
Hofmann, R., James, S. K., Jernberg, T., Lindahl, B., Erlinge, D., Witt, N., Arefalk, G., Frick, M., Alfredsson, J., Nilsson, L., Ravn-Fischer, A., Omerovic, E., Kellerth, T., Sparv, D., Ekelund, U., Linder, R., Ekström, M., Lauermann, J., Haaga, U., … DETO2X–SWEDEHEART Investigators (2017). Oxygen therapy in suspected acute myocardial infarction. New England Journal of Medicine, 377(13), 1240–1249.
Hosseini, L., Vafaee, M. S., & Badalzadeh, R. (2020). Melatonin and nicotinamide mononucleotide attenuate myocardial ischemia/reperfusion injury via modulation of mitochondrial function and hemodynamic parameters in aged rats. Journal of Cardiovascular Pharmacology and Therapeutics, 25(3), 240–250.
Ibanez, B., James, S., Agewall, S., Antunes, M. J., Bucciarelli-Ducci, C., Bueno, H., Caforio, A. L. P., Crea, F., Goudevenos, J. A., Halvorsen, S., Hindricks, G., Kastrati, A., Lenzen, M. J., Prescott, E., Roffi, M., Valgimigli, M., Varenhorst, C., Vranckx, P. & Widimský, P.; ESC Scientific Document Group (2018). 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal, 39(2), 119–177.
Iqbal, J., & Fox, K. (2010). Epidemiology. Epidemiological trends in acute coronary syndromes: Understanding the past to predict and improve the future. Archives of Medical Science, Special Issues, 14-14. https://www.termedia.pl/Epidemiology-Epidemiological-trends-in-acute-coronary-syndromes-understanding-the-past-to-predict-and-improve-the-future,52,14056,0,1.html
Ishihara, M., Inoue, I., Kawagoe, T., Shimatani, Y., Kurisu, S., Nishioka, K., Kouno, Y., Umemura, T., Nakamura, S., & Sato, H. (2001). Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction. Journal of the American College of Cardiology, 38(4), 1007–1011.
James, S. K., & Spertus, J. A. (2013). Evidence-based treatments for STEMI: Are we doing enough? Lancet, 382(9892), 576–579.
Kalogeris, T., Bao, Y., & Korthuis, R. J. (2014). Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning. Redox Biology, 2, 702–714.
Karami, S., Ahmadi, R., & Siavashi, M. (2014). Serum triglyceride, cholesterol and fasting blood sugar in male rats exposed to oil paint vapor. International Conference on Earth, Environment and Life sciences, 6–7. https://doi.org/10.15242/IICBE.C1214105
Kelly, R. F., Hursey, T. L., Parrillo, J. E., & Schaer, G. L. (1995). Effect of 100% oxygen administration on infarct size and left ventricular function in a canine model of myocardial infarction and reperfusion. American Heart Journal, 130(5), 957–965.
Kristiansen, S. B., Løfgren, B., Støttrup, N. B., Khatir, D., Nielsen-Kudsk, J. E., Nielsen, T. T., Bøtker, H. E., & Flyvbjerg, A. (2004). Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia, 47(10), 1716–1721.
Lellouche, F. (2018). Oxygen for myocardial infarction: Not an open bar! JACC. Cardiovascular Interventions, 11(16), 1598–1600.
Liu, M., Zhang, P., Chen, M., Zhang, W., Yu, L., Yang, X. C., & Fan, Q. (2012). Aging might increase myocardial ischemia /reperfusion-induced apoptosis in humans and rats. Age, 34(3), 621–632.
Loria, V., Dato, I., Graziani, F., & Biasucci, L. M. (2008). Myeloperoxidase: A new biomarker of inflammation in ischemic heart disease and acute coronary syndromes. Mediators of Inflammation, 2008, 135625.
Lucas, D. T., & Szweda, L. I. (1998). Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction. Proceedings of the National Academy of Sciences, USA, 95(2), 510–514.
Mariero, L. H., Rutkovskiy, A., Stensløkken, K. O., & Vaage, J. (2012). Hyperoxia during early reperfusion does not increase ischemia/reperfusion injury. European Journal of Cardio-Thoracic Surgery, 41(1), 149–153.
Marseglia, L., Manti, S., D'Angelo, G., Nicotera, A., Parisi, E., Di Rosa, G., Gitto, E., & Arrigo, T. (2014). Oxidative stress in obesity: A critical component in human diseases. International Journal of Molecular Sciences, 16(1), 378–400.
Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., Ferranti, S., Després, J. P., Fullerton, H. J., Howard, V. J., Huffman, M. D., Judd, S. E., Kissela, B. M., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Liu, S., Mackey, R. H., Matchar, D. B., … American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2015). Heart disease and stroke statistics–2015 update: A report from the American Heart Association. Circulation, 131(4), e29–e322.
Ndumele, C. E., Coresh, J., Lazo, M., Hoogeveen, R. C., Blumenthal, R. S., Folsom, A. R., Selvin, E., Ballantyne, C. M., & Nambi, V. (2014). Obesity, subclinical myocardial injury, and incident heart failure. JACC. Heart Failure, 2(6), 600–607.
O'Gara, P. T., Kushner, F. G., Ascheim, D. D., Casey, D. E. Jr, Chung, M. K., de Lemos, J. A., Ettinger, S. M., Fang, J. C., Fesmire, F. M., Franklin, B. A., Granger, C. B., Krumholz, H. M., Linderbaum, J. A., Morrow, D. A., Kristin Newby, L., Ornato, J. P., Ou, N., Radford, M. J., Tamis-Holland, J. E., … Society for Cardiovascular Angiography and Interventions (2013). 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions. Catheterization and Cardiovascular Interventions, 82(1), E1–E27.
Pedro-Botet, J., Covas, M. I., Martín, S., & Rubiés-Prat, J. (2000). Decreased endogenous antioxidant enzymatic status in essential hypertension. Journal of Human Hypertension, 14(6), 343–345.
Penna, C., Mancardi, D., Rastaldo, R., & Pagliaro, P. (2009). Cardioprotection: A radical view free radicals in pre and postconditioning. Biochimica et Biophysica Acta, 1787(7), 781–793.
Pourkhalili, K., Hajizadeh, S., Akbari, Z., Dehaj, M. E., Akbarzadeh, S., & Alizadeh, A. (2012). Hyperoxic preconditioning fails to confer additional protection against ischemia-reperfusion injury in acute diabetic rat heart. EXCLI Journal, 11, 263–273.
Przyklenk, K., Maynard, M., Greiner, D. L., & Whittaker, P. (2011). Cardioprotection with postconditioning: Loss of efficacy in murine models of type-2 and type-1 diabetes. Antioxidants & Redox Signaling, 14(5), 781–790.
Riddles, P. W., Blakeley, R. L., & Zerner, B. (1979). Ellman's reagent: 5,5′-dithiobis(2-nitrobenzoic acid)—A reexamination. Analytical Biochemistry, 94(1), 75–81.
Rosamond, W., Flegal, K., Furie, K., Go, A., Greenlund, K., Haase, N., Hailpern, S. M., Ho, M., Howard, V., Kissela, B., Kittner, S., Lloyd-Jones, D., McDermott, M., Meigs, J., Moy, C., Nichol, G., O'Donnell, C., Roger, V., Sorlie, P., … American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2008). Heart disease and stroke statistics–2008 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 117(4), e25–e146.
Roth, G. A., Forouzanfar, M. H., Moran, A. E., Barber, R., Nguyen, G., Feigin, V. L., Naghavi, M., Mensah, G. A., & Murray, C. (2015). Demographic and epidemiologic drivers of global cardiovascular mortality. New England Journal of Medicine, 372, 1333–1341.
Samsamshariat, S. A., Samsamshariat, Z. A., & Movahed, M. R. (2005). A novel method for safe and accurate left anterior descending coronary artery ligation for research in rats. Cardiovascular Revascularization Medicine: Including Molecular Interventions, 6(3), 121–123.
Sankhla, M., Sharma, T. K., Mathur, K., Rathor, J. S., Butolia, V., Gadhok, A. K., Vardey, S. K., Sinha, M., & Kaushik, G. G. (2012). Relationship of oxidative stress with obesity and its role in obesity induced metabolic syndrome. Clinical Laboratory, 58(5-6), 385–392.
Shnier, C. B., Cason, B. A., Horton, A. F., & Hickey, R. F. (1991). Hyperoxemic reperfusion does not increase myocardial infarct size. American Journal of Physiology, 260(4 Pt 2), H1307–H1312.
Stewart, R. (2019). NZOTACS – The New Zealand Oxygen Therapy in Acute Coronary Syndromes Trial. ESC Congress. https://esc365.escardio.org/Congress/ESC-CONGRESS-2019/Hot-Line-Session-2/202167-nzotacs-the-new-zealand-oxygen-therapy-in-acute-coronary-syndromes-trial#slide
Stub, D., Smith, K., Bernard, S., Bray, J. E., Stephenson, M., Cameron, P., Meredith, I. & Kaye, D. M.; AVOID Study (2012). A randomized controlled trial of oxygen therapy in acute myocardial infarction Air Verses Oxygen In myocarDial infarction study (AVOID study). American Heart Journal, 163(3), 339–345.e1.
Takeuchi, T., Ishii, Y., Kikuchi, K., & Hasebe, N. (2011). Ischemic preconditioning effect of prodromal angina is attenuated in acute myocardial infarction patients with hypertensive left ventricular hypertrophy. Circulation Journal, 75(5), 1192–1199.
Wang, D., Hu, X., Lee, S. H., Chen, F., Jiang, K., Tu, Z., Liu, Z., Du, J., Wang, L., Yin, C., Liao, Y., Shang, H., Martin, K. A., Herzog, R. I., Young, L. H., Qian, L., Hwa, J., & Xiang, Y. (2018). Diabetes exacerbates myocardial ischemia/reperfusion injury by down-regulation of microRNA and up-regulation of O-GlcNAcylation. JACC. Basic to Translational Science, 3(3), 350–362.
Xia, Z., Li, H., & Irwin, M. G. (2016). Myocardial ischaemia reperfusion injury: The challenge of translating ischaemic and anaesthetic protection from animal models to humans. British Journal of Anaesthesia, 117(Suppl 2), ii44–ii62.
Yellon, D. M., & Hausenloy, D. J. (2007). Myocardial reperfusion injury. New England Journal of Medicine, 357(11), 1121–1135.
Yoshida, T., Maulik, N., Engelman, R. M., Ho, Y. S., Magnenat, J. L., Rousou, J. A., Flack, J. E. 3rd, Deaton, D., & Das, D. K. (1997). Glutathione peroxidase knockout mice are susceptible to myocardial ischemia reperfusion injury. Circulation, 96(9 Suppl), II-216-20.
Yusuf, S., Joseph, P., Rangarajan, S., Islam, S., Mente, A., Hystad, P., Brauer, M., Kutty, V. R., Gupta, R., Wielgosz, A., AlHabib, K. F., Dans, A., Lopez-Jaramillo, P., Avezum, A., Lanas, F., Oguz, A., Kruger, I. M., Diaz, R., Yusoff, K., … Dagenais, G. (2019). Modifiable risk factors, cardiovascular disease, and mortality in 155 722 individuals from 21-high-income, middle-income, and low-income countries (PURE): A prospective cohort study. Lancet, 395, 795–808.