Ischemia–reperfusion injury is still a big hurdle to overcome for treatment of acute myocardial infarction
2015; Elsevier BV; Volume: 67; Issue: 4 Linguagem: Inglês
10.1016/j.jjcc.2015.09.002
ISSN1876-4738
Autores Tópico(s)Mechanical Circulatory Support Devices
ResumoSince it has been elucidated that myocardial reperfusion can reduce myocardial infarct size following an acute coronary artery occlusion, nowadays, myocardial reperfusion therapy using primary percutaneous coronary intervention (PCI) is an established treatment for patients with acute ST-segment elevation myocardial infarction (STEMI). Although the primary PCI substantially increases the survival rate in STEMI patients, we still need more efforts to reduce mortality rates. The duration of myocardial ischemia is a critical determinant of infarct size, and thereby, minimizing the time from chest pain onset to primary PCI is the treatment priority. To reduce pre-hospital death, rapid transfer to the PCI center is essential. At the hospital, a treatment protocol that minimizes the door-to-PCI time is required. On the other hand, increased survival in STEMI caused by prevalence of primary PCI ironically leads to an increase in heart failure patients. Although primary PCI actually reduces infarct size, preserves left ventricular systolic function, and improves survival in the STEMI patients, it paradoxically comes at a price, as it can in itself induce myocardial injury and cardiomyocyte death, a phenomenon termed 'myocardial ischemia–reperfusion injury' [1Piper H.M. Garcia-Dorado D. Ovize M. A fresh look at reperfusion injury.Cardiovasc Res. 1998; 38: 291-300Crossref PubMed Scopus (461) Google Scholar, 2Yellon D.M. Hausenloy D.J. Myocardial reperfusion injury.N Engl J Med. 2007; 357: 1121-1135Crossref PubMed Scopus (2831) Google Scholar]. There are currently no effective therapies for preventing ischemia–reperfusion injury in reperfused-STEMI patients, making it an important residual target for cardioprotection. In this issue of the Journal of Cardiology, Kimura et al. [[3]Kimura K. Nakao K. Shibata Y. Sone T. Takayama T. Fukuzawa S. Nakama Y. Hirayama H. Matsumoto N. Kosuge M. Hiro T. Sakuma H. Ishihara M. Asakura M. Hamada C. et al.Randomized controlled trial of TY-51924, a novel hydrophilic NHE inhibitor, in acute myocardial infarction.J Cardiol. 2016; 67: 307-313Abstract Full Text Full Text PDF Scopus (11) Google Scholar] report an interesting study that evaluated cardioprotective effects of a novel Na+/H+ exchanger inhibitor, TY-51924 in STEMI patients undergoing primary PCI. They conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which 105 patients with first anterior STEMI undergoing primary PCI were randomly assigned to receive an intravenous infusion of either TY-51924 or placebo. Consequently, myocardial salvage index (MSI) determined by single photon emission computed tomography (SPECT) 3–5 days after primary PCI, as the primary efficacy endpoint, did not differ between the two groups of TY-51924 and placebo in overall patients (0.200 vs. 0.290, p = 0.56). The MSI 3 months after primary PCI was also comparable between the two groups (0.470 vs. 0.500, p = 0.76). However, on post hoc analysis of 52 patients with a large area at risk (≥38%) and no antegrade coronary flow (thrombolysis in myocardial infarction 0), the MSI at 3 months after primary PCI was significantly higher in the TY-51924 group, compared with the placebo group (0.450 vs. 0.320, p = 0.03). There was no significant difference between the two groups in the incidence of adverse events or side effects up to 7 days or up to 3 months. They conclude that TY-51924 is potentially cardioprotective in the presence of a large area at risk and no antegrade coronary flow in patients with STEMI undergoing primary PCI, and discuss that the cardioprotective effect of TY-51924 might be owing to its ability to inhibit myocardial ischemia–reperfusion injury. Pathophysiological mechanisms of the myocardial ischemia–reperfusion injury are complex. As a result of coronary artery occlusion, reduced myocardial oxygen supply switches cell metabolism to anaerobic respiration, resulting in decrease in intracellular pH, mainly due to lactate production. Decreased intracellular pH induces activation of the Na+/H+ exchanger, which extrudes H+ to result in intracellular Na+ overload. The intracellular Na+ overload activates the 2Na+/Ca2+ exchanger to function in reverse to extrude Na+ and leads to intracellular Ca2+ overload. Acidic conditions by decreased intracellular pH during ischemia prevent the opening of the mitochondrial permeability transition pore (MPTP) and cardiomyocyte hypercontracture at this time. Reperfusion leads to rapid correction of pH due to lactate leaching and reactivation of the Na+/H+ exchanger. As a result, the intracellular Na+ concentration again increases, leading to inhibition of retrograde Ca2+ transportation through the 2Na+/Ca2+ exchanger, or even its reversal, which accelerates intracellular Ca2+ accumulation. Consequently, the activation of a number of enzymes and contractile apparatus leads to cardiomyocyte hypercontracture in the early stage of reperfusion. Sudden reperfusion also induces oxidative stress due to the influx of oxygenated blood and inflammatory cell activation. Reactive oxygen species cause lipid peroxidation of the cell membrane and damage to various intracellular enzymes, and DNA. Moreover, the permeability to Ca2+ and intracellular Ca2+ overload still increases. An important component of the myocardial ischemia–reperfusion injury is also infiltration of inflammatory cells and endothelial cell swelling, rapid deterioration of endothelial function and microthrombosis, which lead to the "no-reflow" phenomenon. These mechanisms lead to the opening of MPTP. The MPTP opening causes deep and usually irreversible changes in mitochondrial bioenergetics and leads to the start of mechanisms causing necrosis and apoptosis of cardiomyocytes [4Hausenloy D.J. Yellon D.M. Myocardial ischemia–reperfusion injury: a neglected therapeutic target.J Clin Invest. 2013; 123: 92-100Crossref PubMed Scopus (1437) Google Scholar, 5Araszkiewicz A. Grygier M. Lesiak M. Grajek S. The impact of ischemia–reperfusion injury on the effectiveness of primary angioplasty in ST-segment elevation myocardial infarction.Postep Kardiol Inter. 2013; 3: 275-281Google Scholar]. There remains no effective therapeutic agent for preventing myocardial ischemia–reperfusion injury in patients with STEMI who are undergoing primary PCI. Unfortunately, therapies targeting the individual components of myocardial ischemia–reperfusion injury, including oxidative stress, calcium overload, pH correction, and, more recently, inflammation have produced disappointing results [6Ludman A.J. Yellon D.M. Hausenloy D.J. Cardiac preconditioning for ischaemia: lost in translation.Dis Model Mech. 2010; 3: 35-38Crossref PubMed Scopus (90) Google Scholar, 7Hausenloy D.J. Baxter G. Bell R. Botker H.E. Davidson S.M. Downey J. Heusch G. Kitakaze M. Lecour S. Mentzer R. Mocanu M.M. Ovise M. Schulz R. Shannon R. Walker M. et al.Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations.Basic Res Cardiol. 2010; 105: 677-686Crossref PubMed Scopus (214) Google Scholar]. However, novel emerging therapeutic strategies for preventing myocardial ischemia–reperfusion injury have emerged to show promise in small proof-of-concept clinical studies, and multicenter randomized clinical trials are currently underway. Several mechanical therapeutic interventions have been shown to be effective. Ischemic post-conditioning, represented as the interruption of myocardial reperfusion with several cycles of coronary artery re-occlusion and reflow, has been demonstrated to prevent myocardial ischemia–reperfusion injury and reduced infarct size. Other mechanical therapeutic interventions include therapeutic hyperoxemia and therapeutic hypothermia. The results of clinical studies in reperfused-STEMI patients using these invasive therapeutic interventions have shown to be somewhat promising. The phenomenon of remote ischemic conditioning allows the therapeutic intervention to be applied to an organ or tissue away from the heart, thereby facilitating its clinical application. Remote ischemic conditioning refers to the cardioprotective effect induced by non-invasively applying several cycles of brief non-lethal ischemia and reperfusion using a blood pressure cuff applied to the upper arm, which was demonstrated to increase myocardial salvage. Elucidation of the mechanistic pathways underlying mechanical therapeutic interventions has resulted in the identification of a number of new targets to prevent myocardial ischemia–reperfusion injury. These include pharmacologic modulators of the reperfusion injury salvage kinase prosurvival pathway, such as adenosine, atrial natriuretic peptide, atorvastatin, erythropoietin, glucagon-like peptide-1 analogue, and glucose–insulin–potassium therapy. Other agents are known to preserve mitochondrial function during acute myocardial ischemia–reperfusion injury, such as cyclosporin A, sodium nitrite, and an indirect MPTP inhibitor, TRO40303. However, the results of clinical studies investigating these agents have been mixed [4Hausenloy D.J. Yellon D.M. Myocardial ischemia–reperfusion injury: a neglected therapeutic target.J Clin Invest. 2013; 123: 92-100Crossref PubMed Scopus (1437) Google Scholar, 5Araszkiewicz A. Grygier M. Lesiak M. Grajek S. The impact of ischemia–reperfusion injury on the effectiveness of primary angioplasty in ST-segment elevation myocardial infarction.Postep Kardiol Inter. 2013; 3: 275-281Google Scholar]. As described above, the myocardial Na+/H+ exchanger represents a major mechanism for pH regulation during myocardial ischemia–reperfusion. Pharmacological development of Na+/H+ exchanger inhibitors such as cariporide or eniporide has been focused on their efficacy for cardiac therapeutics. These agents have now been extensively demonstrated to possess excellent cardioprotective properties. The salutary effects of Na+/H+ exchanger inhibitors have been demonstrated using a variety of experimental models as well as animal species suggesting that the role of the Na+/H+ exchanger in mediating injury is not species specific. In addition, the success of Na+/H+ exchanger inhibitors in experimental studies has led to clinical trials for the evaluation of these agents in high-risk patients with chronic coronary artery disease as well as in patients with acute myocardial infarction. Three large-scale clinical trials of Na+/H+ exchanger inhibitors including cariporide and eniporide have been reported. In the GUARDIAN trial, cariporide was given to patients with unstable angina/non-STEMI, or who were undergoing high-risk PCI or being subjected to high-risk coronary artery bypass grafting (CABG) [[8]Théroux P. Chaitman B.R. Danchin N. Erhardt L. Meinertz T. Schroeder J.S. Tognoni G. White H.D. Willerson J.T. Jessel A. Inhibition of the sodium–hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators.Circulation. 2000; 102: 3032-3038Crossref PubMed Scopus (366) Google Scholar]. But benefit was limited to CABG, in which cariporide was administered prior to ischemia. However, the EXPEDITION trial reported that a higher dose of cariporide administered before CABG had reduced the incidence of myocardial infarction events, but increased the incidence of cerebrovascular and neuronal events [[9]Mentzer Jr., R.M. Bartels C. Bolli R. Boyce S. Buckberg G.D. Chaitman B. HaverichA Knight J. Menasche P. Myers M.L. Nicolau J. Simoons M. Thulin L. Weisel R.D. Sodium–hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study.Ann Thorac Surg. 2008; 85: 1261-1270Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar]. In the ESCAMI trial, eniporide was administered just before reperfusion in patients with STEMI, but did not significantly reduce cardiac enzyme release at any doses [[10]Zeymer U. Suryapranata H. Monassier J.P. Opolski G. Davies J. Rasmanis G. Linssen G. Tebbe U. Schroder R. Tiemann R. Machnig T. Neuhaus K.L. The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the evaluation of the safety and cardio-protective effects of eniporide in acute myocardial infarction (ESCAMI) trial.JAm Coll Cardiol. 2001; 38: 1644-1650Abstract Full Text Full Text PDF PubMed Google Scholar]. One possible reason for its failure is under-titration to avoid the neuronal side effects [11Allen D.G. Xiao X.H. Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion.Cardiovasc Res. 2003; 57: 934-941Crossref PubMed Scopus (107) Google Scholar, 12Touret N. Tanneur V. Godart H. Seidler R. Taki N. Burger E. Dammgen J. Counillon L. Characterization of sabiporide, a new specific NHE-1 inhibitor exhibiting slow dissociation kinetics and cardioprotective effects.Eur J Pharmacol. 2003; 459: 151-158Crossref PubMed Scopus (42) Google Scholar]. Therefore, developing Na+/H+ exchanger inhibitors without side effects, particularly without central neurotoxicity appeared to be an important matter. TY-51924, a novel water-soluble Na+/H+ inhibitor, has been developed to overcome the problem of central neurotoxicity. After intravenous administration, TY-51924 penetrated to central nervous tissue at a low level in central nervous tissue and was rapidly eliminated from blood and tissues in animal experiments. In a canine ischemia–reperfusion model, TY-51924 administered intravenously before reperfusion reduced infarct size [[13]Sasamori J. Hasegawa T. Takaya A. Watanabe Y. Tanaka M. Ogino Y. Chiba T. Aihara K. The cardioprotective effects of novel Na+/H+ exchanger inhibitor TY-51924 on ischemia/reperfusion Injury.J Cardiovasc Pharmacol. 2014; 63: 351-359Crossref PubMed Scopus (7) Google Scholar]. TY-51924 was also well tolerated in Phase I trials and a small phase IIa pilot trial [[14]Takayama T. Kimura K. Fukuzawa S. Hirayama H. Sone T. Ueda Y. Uematsu M. Ishihara M. Nakao K. Matsumoto N. Kosuge M. Hiro T. Asakura M. Kaneko A. Yokoi T. et al.Evaluation of the safety and efficacy of TY-51924 in patients with ST elevated acute myocardial infarction – early phase II first in patient pilot study.J Cardiol. 2015; ([Epub ahead of print])https://doi.org/10.1016/j.jjcc.2015.04.004Abstract Full Text Full Text PDF Scopus (3) Google Scholar]. The study by Kimura et al. [[3]Kimura K. Nakao K. Shibata Y. Sone T. Takayama T. Fukuzawa S. Nakama Y. Hirayama H. Matsumoto N. Kosuge M. Hiro T. Sakuma H. Ishihara M. Asakura M. Hamada C. et al.Randomized controlled trial of TY-51924, a novel hydrophilic NHE inhibitor, in acute myocardial infarction.J Cardiol. 2016; 67: 307-313Abstract Full Text Full Text PDF Scopus (11) Google Scholar] is a late phase IIb trial, which first elucidated potential efficacy for cardioprotection without side effects such as central neurotoxicity. Since myocardial ischemia–reperfusion injury is still a big hurdle to overcome for treatment of STEMI, we should never forget further efforts to discover new cardioprotective drugs. Randomized controlled trial of TY-51924, a novel hydrophilic NHE inhibitor, in acute myocardial infarctionJournal of CardiologyVol. 67Issue 4PreviewIn patients with ST-elevation acute myocardial infarction (STEMI), reperfusion therapy limits infarct size, but can directly evoke myocardial reperfusion injury. Activation of the Na+/H+ exchanger (NHE) plays an important role in reperfusion injury. TY-51924, a novel NHE inhibitor, significantly reduced infarct size in animal studies and was well tolerated in early-phase clinical trials. This study aim was to evaluate the efficacy and safety of TY-51924 in patients with STEMI. Full-Text PDF Open Archive
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