Combination Therapy to Target Reperfusion Injury After ST-Segment–Elevation Myocardial Infarction

HomeCirculationVol. 136, No. 10Combination Therapy to Target Reperfusion Injury After ST-Segment–Elevation Myocardial Infarction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCombination Therapy to Target Reperfusion Injury After ST-Segment–Elevation Myocardial InfarctionA More Effective Approach to Cardioprotection Derek J. Hausenloy, MBChB, PhD and Derek M. Yellon, PhD, DSc Derek J. HausenloyDerek J. Hausenloy From Hatter Cardiovascular Institute, University College London, United Kingdom (D.J.H., D.M.Y.); Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom (D.J.H); National Heart Research Institute Singapore, National Heart Centre Singapore (D.J.H); Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (D.J.H); and Yong Loo Lin School of Medicine, National University Singapore (D.J.H). and Derek M. YellonDerek M. Yellon From Hatter Cardiovascular Institute, University College London, United Kingdom (D.J.H., D.M.Y.); Barts Heart Centre, St Bartholomew's Hospital, London, United Kingdom (D.J.H); National Heart Research Institute Singapore, National Heart Centre Singapore (D.J.H); Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (D.J.H); and Yong Loo Lin School of Medicine, National University Singapore (D.J.H). Originally published5 Sep 2017https://doi.org/10.1161/CIRCULATIONAHA.117.029859Circulation. 2017;136:904–906Article, see p 894Timely reperfusion therapy by primary percutaneous coronary intervention (PPCI) combined with effective secondary preventive therapy has contributed to a decline in mortality rates after ST-segment–elevation myocardial infarction (STEMI) over the last few years. However, the incidence and severity of heart failure after STEMI are rising. Therefore, novel cardioprotective therapies are required to reduce myocardial infarct (MI) size and preserve left ventricular (LV) systolic function to prevent heart failure and improve clinical outcomes after PPCI.1,2Over recent years, a large number of cardioprotective therapies, which have been demonstrated to be effective at reducing MI size in the laboratory setting, have been unable either to reduce MI size or to improve clinical outcomes after STEMI. The reasons for this are manifold and have been discussed extensively in the recent literature.1–3 In summary, the failure to translate cardioprotection for patient benefit has been attributed to several key factors: the inadequacy of the animal models used for testing novel cardioprotective therapies in the laboratory setting, a failure to demonstrate consistent and robust cardioprotection in experimental studies before proceeding to clinical studies, and poorly designed clinical cardioprotection studies.1–3Another major reason for the failure to translate cardioprotection may have been the adoption of a single-targeted monotherapy approach, a strategy that may be inadequate to address the multifaceted components of myocardial reperfusion injury, including endothelial dysfunction, microvascular obstruction, oxidative stress, calcium overload, mitochondrial dysfunction, and inflammation.2,4 To address this issue, an emerging concept in the cardioprotection field has been to adopt a multitargeted strategy using ≥2 therapies in combination to reduce MI size after STEMI.1,2,5–7 The adoption of combination therapy as a multitargeted cardioprotective strategy may be mediated as follows: (1) using ≥2 therapies to target different cardioprotective intracellular signaling pathways within the cardiomyocyte5,7; (2) using ≥2 therapies to target cardioprotection in different cell components within the heart such as endothelial cells, platelets, cardiomyocytes, and inflammatory cells; and (3) using 1 therapy with capabilities of reducing MI size through ≥2 cardioprotective targets such as inflammatory cells and cardiomyocytes.In this regard, the NACIAM study (NAC in Acute Myocardial Infarction) by Pasupathy et al8 in this issue of Circulation investigated the MI-limiting effects of combining 2 "old" cardioprotective therapies, N-acetylcysteine (NAC; an antioxidant) and nitroglycerin (a nitric oxide donor),9 in patients with STEMI treated by PPCI. In a multicenter study of 112 patients with STEMI, they found that the administration of a 48-hour intravenous infusion of NAC, initiated before PPCI, on a background of a low-dose 48-hour intravenous nitroglycerin infusion reduced acute MI size by >30% in a subset of 75 patients (quantified by late-gadolinium-enhancement cardiovascular magnetic resonance [CMR]). The MI-limiting effect of NAC was still present at 3 months after PPCI, with a 50% reduction in chronic MI size compared with placebo, suggesting a long-term cardioprotective effect with this therapeutic approach.The concept of combining nitroglycerin and NAC was first tested nearly 30 years ago in patients with unstable angina. It was shown to reduce the incidence of acute MI and was based on the premise that NAC may augment the antiplatelet and vasodilatory effects of nitroglycerin, although significant hypotension resulted from this combination.10 However, the combination had not been tested on MI size in patients with STEMI, and the combination of NAC and nitroglycerin did not cause symptomatic hypotension in the NACIAM trial.8Previous experience with antioxidant therapies to target myocardial reperfusion injury has been largely disappointing, with NAC failing to reduce MI size in experimental studies11 and trimetazidine having no beneficial effects after STEMI.12 The failure of antioxidant therapy as a cardioprotective strategy has been attributed to the inability to effectively scavenge reactive oxygen species, especially at the level of mitochondria. Therefore, the use of a relatively high dose of NAC (29 g over 48 hours) in the NACIAM trial may, in part, have overcome this limitation of antioxidant therapy.The authors are to be congratulated for demonstrating a cardioprotective effect with the antioxidant NAC in patients with STEMI on a background of low-dose nitroglycerin. However, there are several issues to be discussed concerning the trial design of the NACIAM trial. First is the lack of factorial design for testing the cardioprotective effects of NAC and nitroglycerin, separately and in combination. This would have allowed the authors to ascertain whether the combination of NAC and nitroglycerin is more effective at reducing MI size in patients with STEMI compared with either agent given alone. Given that it is not routine clinical practice to give low-dose intravenous nitroglycerin for 48 hours to reperfused patients with STEMI, it is not clear why this was adopted as background therapy for the NACIAM trial. The factorial design also would have provided additional information on whether intravenous nitroglycerin per se can limit MI size in the STEMI setting. Nitric oxide is a well-known mediator of cardioprotection, and nitric oxide donors have been shown to limit MI size in experimental animal models. However, the use of intracoronary nitrite13 and inhaled nitric oxide (NOMI trial [Effects of Nitric Oxide for Inhalation in Myocardial Infarction Size]; NCT01398384) as adjuvants to PPCI has failed to reduce MI size after STEMI, although this may relate to patient selection (post hoc subgroup analysis showed benefit in patients with STEMI presenting with an occluded coronary artery)13 and prior administration of sublingual nitrates (NOMI trial).Second, the wide range of timing of the initial CMR scan in the NACIAM trial of 3 to 7 days after PPCI may have affected detection of the edema-based area at risk, microvascular obstruction, and MI size, given that recent data have suggested that these CMR variables are dynamic in nature over the first week after PPCI.14 Under ideal circumstances, the initial CMR scan should be performed between 3 to 5 days after STEMI, when these variables are at their peak.15 However, it is appreciated that timing the initial CMR scan to particular days can be logistically challenging in the first few days after STEMI. Moreover, the use of different CMR vendors (Philip and Siemens) within the NACIAM trial may also have affected the quantification of the area at risk by T2-weighted CMR and MI size by CMR.Last, the authors demonstrated impressive reductions in MI size (30%–50%) with NAC treatment on the initial and follow-up CMR scans, yet there were no beneficial effects on post-MI LV remodeling with no change in either LV dimensions or ejection fraction at 3 months. The reason for the discrepancy is unclear, and further studies are required to investigate the impact of NAC treatment on parameters of post-MI LV remodeling and whether it can improve clinical outcomes after STEMI.In summary, the NACIAM study by Pasupathy et al8 marks a step in the right direction for the field of cardioprotection in that it highlights the therapeutic potential of combining 2 different cardioprotective therapies to reduce MI size after STEMI. However, further studies are required to elucidate the individual contributions of NAC and nitroglycerin to the cardioprotective effects observed in the NACIAM study and to investigate the effects of NAC on post-MI LV remodeling and clinical outcomes after PPCI.Sources of FundingDrs Hausenloy and Yellon are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Center. In addition, Dr Hausenloy is supported by the British Heart Foundation (FS/10/039/28270), Duke-National University Singapore Medical School, Singapore Ministry of Health's National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Center Grant scheme (NMRC/CGAug16C006), and Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-021).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Derek M. Yellon, DSc, The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, United Kingdom. E-mail [email protected]References1. 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Olivares-Silva F, Espitia-Corredor J, Letelier A, Vivar R, Parra-Flores P, Olmedo I, Montenegro J, Pardo-Jiménez V and Díaz-Araya G (2021) TGF-β1 decreases CHOP expression and prevents cardiac fibroblast apoptosis induced by endoplasmic reticulum stress, Toxicology in Vitro, 10.1016/j.tiv.2020.105041, 70, (105041), Online publication date: 1-Feb-2021. Cho Y and Kim W (2019) Perioperative Cardioprotection by Remote Ischemic Conditioning, International Journal of Molecular Sciences, 10.3390/ijms20194839, 20:19, (4839) Montone R, Stiermaier T, Niccoli G and Eitel I (2019) Response by Montone et al to Letter Regarding Article, "Optimized Treatment of ST-Elevation Myocardial Infarction", Circulation Research, 125:6, (e30-e30), Online publication date: 30-Aug-2019.Niccoli G, Montone R, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy D, Berry C, Stiermaier T, Camici P and Eitel I (2019) Optimized Treatment of ST-Elevation Myocardial Infarction, Circulation Research, 125:2, (245-258), Online publication date: 5-Jul-2019. Hou J, He H, Huang S, Qian M, Wang J, Tan X, Han G, Song Y, Xu Z and Liu Y (2019) A mitochondria-targeted nitric oxide donor triggered by superoxide radical to alleviate myocardial ischemia/reperfusion injury, Chemical Communications, 10.1039/C8CC07304J, 55:9, (1205-1208) Cokkinos D (2019) The Ishemia Reperfusion Injury Challenge Myocardial Preservation, 10.1007/978-3-319-98186-4_6, (87-103), . Davidson S and Yellon D (2018) Protection From Cardiac Ischemia-Reperfusion Injury by Epigenetic Regulation of NADPH Oxidase, Circulation, 138:24, (2837-2840), Online publication date: 11-Dec-2018. Ravingerova T, Murarikova M, Farkasova V, Griecsova L, Adameova A and Bernatova I (2018) REMOTE PRECONDITIONING ATTENUATES HIGHER SUSCEPTIBILITY TO ISCHEMIA/REPERFUSUION INJURY IN HYPERTENSIVE RAT HEARTS, BUT EFFICIENCY OF PROTECTIVE INTERVENTION IS LOWER, Pathophysiology, 10.1016/j.pathophys.2018.07.044, 25:3, (178), Online publication date: 1-Sep-2018. Morciano G, Preti D, Pedriali G, Aquila G, Missiroli S, Fantinati A, Caroccia N, Pacifico S, Bonora M, Talarico A, Morganti C, Rizzo P, Ferrari R, Wieckowski M, Campo G, Giorgi C, Trapella C and Pinton P (2018) Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F 1 /F O -Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction , Journal of Medicinal Chemistry, 10.1021/acs.jmedchem.8b00278, 61:16, (7131-7143), Online publication date: 23-Aug-2018. Do Carmo H, Arjun S, Petrucci O, Yellon D and Davidson S (2018) The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway, Cardiovascular Drugs and Therapy, 10.1007/s10557-018-6781-2, 32:2, (165-168), Online publication date: 1-Apr-2018. September 5, 2017Vol 136, Issue 10 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.117.029859PMID: 28874421 Originally publishedSeptember 5, 2017 KeywordsreperfusioncardioprotectionSTEMIEditorialsischemiaPDF download Advertisement