Editorial Mitochondrial Protective Agents for Ischemia/Reperfusion Injury Robert A. Kloner, MD, PhD
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schemia of organs, including that of the heart, kidney, and brain, account for major morbidity and mortality in the United States. When an organ is ischemic, the logical approach is to relieve the ischemia by re-establishing blood flow as is accomplished by percutaneous interventions, such as angioplasty and placing a stent in an occluded coronary artery or occluded renal artery. However, even after establishing patency of the large obstructed blood vessel, a degree of organ damage may persist because of reperfusion injury.1 In the heart, this may manifest as reperfusion arrhythmias, stunned myocardium (postischemic left ventricular dysfunction), and no reflow or microvascular obstruction. Whether reperfusion actually kills myocardial cells remains debatable. In the kidneys, reperfusion injury may manifest as microvascular damage, loss of glomerular filtration, and damage because of reactive oxygen species that includes loss of cortical structure. It has been postulated that abrupt reperfusion results in reactive oxygen species production by the mitochondria, opening of the mitochondrial permeability transition pore, an influx of calcium into the mitochondria, release of cytochrome C, and peroxidation of cardiolipin in the inner mitochondrial membrane.2 Certainly, angioplasty/stenting for renal artery stenosis alone for the treatment of hypertension has been disappointing in its effect on major adverse clinical outcomes.3 Most patients need to remain on medical therapies, and there is limited evidence of preservation of renal function. One potential explanation is that reperfusion injury has contributed to the disappointing outcomes.
promise in preclinical studies, most did not work in the clinical trials. There are less data on adjunctive therapies for renal ischemia/reperfusion. There is still an unmet need to develop better treatments for reperfusion injury. In the heart, for example, the presence of no reflow or microvascular obstruction after percutaneous coronary intervention of a proximally occluded coronary artery is associated with worse left ventricular remodeling, including left ventricular dilatation, congestive heart failure, and death.5 One potential therapy for STEMI is drugs that target the mitochondria. Cyclosporine A is an agent that is known to keep the mitochondrial permeability transition pore closed and in experimental studies and in some initial clinical trials appeared to mimic ischemic postconditioning and reduced myocardial infarct size. However, in larger clinical trials, its effect was neutral.6 Szeto and Schiller developed a series of small peptides that targeted the inner mitochondrial membrane and protected the mitochondria in situations of cellular stress.7 It is thought that these peptides interact with cardiolipin, a phospholipid on the inner mitochondrial membrane that maximizes membrane shape to improve the functioning of the electron transport chain and also minimizes the production of mitochondrialderived reactive oxygen species. In several experimental studies, some of these peptides, including elamipretide (formerly called Bendavia or MTP-131), when given at or near reperfusion reduced experimental myocardial infarct size in ischemia/ reperfusion models in guinea pigs, rabbits, sheep,8 and rat. In in vitro studies, elamipretide was shown to reduce production of reactive oxygen species of isolated cardiomyocytes exposed to hypoxia and then reoxygenation. However, in our laboratory, the drug did not significantly reduce myocardial infarct size in a rabbit model (although there was a nonsignificant trend with a 11% reduction), and our results, therefore, differed from several other independent laboratories that tested it.8 However, we did note that for any given ischemic area at risk, the extent of no reflow was smaller in rabbits treated with elamipretide. These results paralleled those of Eirin et al’s9 observations in the swine model of renal atherosclerotic stenosis and reperfusion, in which the drug improved postischemic renal blood flow. Recently, we reported the results of another of these peptides, SBT-20. In our experimental rat model of myocardial infarct size, it significantly reduced myocardial infarct size by ≈20%, which is a similar observation compared with a study that Szeto previously published in the rat model with this agent.10 The EMBRACE STEMI study was a sizable multicenter study investigating the use of elamipretide as an adjunct therapy to percutaneous coronary intervention for STEMI. The drug was to be given to patients before reperfusion because it was noted in preclinical models that if the drug was only given after reperfusion had already commenced, it
See Article by Saad et al Numerous therapies have been tested in preclinical models to try to reduce ischemia/reperfusion injury.4 In the setting of clinical ST-elevation–myocardial infarction (STEMI), various adjunctive agents have been tried along with reperfusion to further reduce myocardial infarct size and limit ischemia/ reperfusion injury. Although many of these therapies showed The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Research Institute, Huntington Medical Research Institutes, Pasadena, CA; and Cardiovascular Division, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA. Correspondence to Robert A. Kloner, MD, PhD, Cardiovascular Division, Department of Medicine, Keck School of Medicine of University of Southern California, 10 Pico, Pasadena, Los Angeles, CA 91105. E-mail [email protected] (Circ Cardiovasc Interv. 2017;10:e005805. DOI: 10.1161/CIRCINTERVENTIONS.117.005805.) © 2017 American Heart Association, Inc. Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.117.005805
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had no beneficial effects on either infarct size or no reflow. The end points of this clinical trial included myocardial infarct size as assessed by biomarkers of necrosis, as well as myocardial infarct size assessed at day 4 by MRI. The findings from this study were negative, in that there was no reduction of myocardial infarct size assessed by either technique.11 However, there was a surprising finding that might have contributed to the negative results. Usually, when STEMI studies are performed, most patients demonstrate occluded proximal coronary arteries when they first present in the catheterization laboratory. In clinical myocardial infarction trials, only a relatively small percentage of patients demonstrate open arteries at the time of catheterization laboratory presentation because of presumed spontaneous thrombolysis. In the EMBRACE STEMI study, a large percentage (39%) presented with open infarctrelated arteries in the laboratory. However, studies showed that for elamipretide to be effective, the drug needed to be on board before reperfusion. Giving the drug after reperfusion had already occurred negated any potential beneficial effect. This is one of several potential reasons for the negative results of the EMBRACE STEMI study. Why a high percentage of EMBRACE STEMI patients demonstrated patent infarctrelated arteries is unknown. It is possible that current wider use of antiplatelet agents and statins might have contributed. It is unlikely that there will be further clinical studies examining the effects of this agent for the purpose of trying to reduce STEMI size; however, as discussed below, there are many other potential clinical applications under investigation with elamipretide, and when used after an STEMI, it may have a role in preventing adverse postmyocardial left ventricular remodeling. Although elamipretide did not reduce evidence of ischemia/ reperfusion injury in the clinical setting of reperfused STEMI, the present study by Saad et al,2 in this issue of Circulation: Cardiovascular Interventions, demonstrates that the drug shows promise in reducing ischemia/reperfusion injury in another vital organ, the kidney. This group of researchers from the Mayo Clinic previously used an atherosclerotic swine model of renal artery stenosis and observed that administration of elamipretide before and during angioplasty reduced ischemia/reperfusion-induced oxidative stress and apoptosis of the kidneys. Elamipretide improved renal function and microvascular perfusion. The present study describes the first use of this drug in a limited number of patients undergoing percutaneous transluminal renal angioplasty and stenting to assess its effect on estimated glomerular filtration rate, extent of renal parenchymal hypoxia determined by blood oxygen level–dependent MRI imaging, renal blood flow by contrast-enhanced multidetector computed tomography, and blood pressure. For 3 months, estimated glomerular filtration rate increased more in the elamipretide group than in the placebo group. Blood pressure fell more in the treated group. Fractional hypoxia as assessed by blood oxygen level–dependent imaging was less at 24 hours in the kidneys of elamipretidetreated patients than placebo patients although these equalized by 3 months. Stenotic kidney renal blood flow rose at 3 months in the elamipretide group but not in the placebo group; this was largely related to an increase in cortical perfusion. The authors concluded that elamipretide given during renal artery percutaneous angioplasty/stenting attenuated postprocedural hypoxia, increased single-kidney blood flow, and improved kidney
function in this pilot trial and that targeted mitochondrial protection shows promise. There are some limitations to this study that the authors correctly discuss, including relatively small numbers of patients (n=14); both revascularization and contrast injection were done as part of the same procedure and both could have contributed to tissue hypoxia; concern that contrast retention could have affected the second blood oxygen level–dependent image; and other limitations. Still, this is an important article because it is one of the first showing a clinical benefit of the mitochondrial targeted peptide elamipretide in patients experiencing ischemia and reperfusion of a vital organ. The results pave the way for future larger studies assessing the outcome of these novel mitochondrial protective drugs. An especially intriguing observation was that after 3 months, there was a substantial drop in systolic blood pressure from ≈155 mm Hg at baseline to ≈130 mm Hg in the elamipretide groups, but no significant drop in the placebo group. Angioplasty/stenting for renal artery stenosis is a therapy that has been questioned because most patients who have received the procedure still need to remain on medication, and renal function is not always improved. However, if elamipretide is on board, there could be a resurgence of this approach for treating resistant hypertension. The authors are to be congratulated for first performing preclinical studies that showed benefit of the drug and then extending this to the clinical realm and finding similar results. Sometimes our preclinical efforts do translate in a positive manner and pay off. Of course, this study is small and will need to be repeated with larger numbers of patients and a more diverse group of patients. Finally, although elamipretide did not show a reduction of myocardial infarction size in the EMBRACE STEMI trial, there are other cardiac applications under study. Our group showed that when the drug was administered chronically after experimental myocardial infarction, it reduced infarct expansion and adverse left ventricular remodeling and improved post-myocardial infarction left ventricular dysfunction.12 Elamipretide also reduced the extent of apoptosis at the border zone of these infarcts. Sabbah’s13 group at Henry Ford Hospital showed that this drug was effective in a canine heart failure model induced by microembolization. Elamipretide improved cardiac ATP synthesis and mitochondrial function in this model, improved left ventricular ejection fraction, and improved biomarkers of heart failure. This same research group observed benefits on left ventricular function when the drug was administered either acutely or chronically. In addition, elamipretide preserved mitochondrial ultrastructure and the functioning of the electron transport chain. Clinical trials of the drug in patients with heart failure are underway. Other investigators have shown that the drug is effective in angiotensin-induced cardiomyopathy, in which it improved diastolic dysfunction and reduced adverse left ventricular remodeling.14 The drug is also being studied in patients with mitochondrial myopathies, rare genetic defects of mitochondrial function characterized by muscle weakness, exercise intolerance, and a host of other medical problems. Karra et al15,16 studied 36 patients with documented genetically confirmed primary mitochondrial disease. The patients received placebo or escalating intravenous doses of elamipretide daily for 5 days. Elamipretide improved 6-minute walk tests in a dose-dependent fashion. At
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the highest dose (0.25 mg/kg per hour for 2 hours), the drug increased the 6-minute walk test by 65 versus 20 m for placebo (P=0.053).15 Additional preliminary data were recently presented by Karaa et al17 showing that a 4-week treatment improved 6-minute walk times by a distance of 20 m and appeared to be most beneficial in those patients with the worse baseline limitations. In addition, elamipretide improved various fatigue scores reported by the patients compared with placebo. The drug also was tested in elderly patients to determine whether it will improve their muscle strength. In a preliminary study by Roshanravan et al,16,18 39 elderly subjects received a single intravenous dose of elamipretide at 0.25 mg/kg per hour for 2 hours. Elamipretide increased ATP synthesis to a similar level to 6 months of exercise training. In addition, patients receiving elamipretide showed a trend toward improved hand strength testing compared with placebo.18 In summary, Saad et al2 are to be congratulated for providing some of the first evidence in patients that mitochondrialtargeted peptide reduced elements of ischemia/reperfusion injury in the kidneys of patients undergoing renal artery angioplasty and stenting. Elamipretide reduced continued kidney hypoxia after intervention, improved renal blood flow, preserved kidney function, and importantly reduced systolic blood pressure. This same drug or related drugs shows promise for a host of medical problems that are not limited to renal ischemia and reperfusion but extend to other organs and other disease states involving the impaired mitochondria.
Disclosures Dr Kloner’s laboratory has received funding in the past for preclinical studies from Stealth Biotherapeutics, Newton, MA.
References 1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–1135. doi: 10.1056/NEJMra071667. 2. Saad A, Herrnannm SMS, Eirin A, Ferguson CM, Glockner JF, Bjarnason H, McKusick MA, Misra S, Lerman LO, Textor SC. Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis. Circ Cardiovasc Interv. 2017;10:e005487. doi: 10.1161/CIRCINTERVENTIONS.117.005487. 3. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, Prince MR, Lewis EF, Tuttle KR, Shapiro JI, Rundback JH, Massaro JM, D’Agostino RB, Sr, Dworkin LD; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370:13–22. doi: 10.1056/NEJMoa1310753. 4. Kloner RA. Current state of clinical translation of cardioprotective agents for acute myocardial infarction. Circ Res. 2013;113:451–463. doi: 10.1161/CIRCRESAHA.112.300627. 5. Kloner RA. No-reflow phenomenon: maintaining vascular integrity. J Cardiovasc Pharmacol Ther. 2011;16:244–250. doi: 10.1177/ 1074248411405990. 6. Cung TT, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, Bonnefoy-Cudraz E, Guérin P, Elbaz M, Delarche N, Coste P, Vanzetto G, Metge M, Aupetit JF, Jouve B, Motreff P, Tron C, Labeque JN, Steg PG, Cottin Y, Range G, Clerc J, Claeys MJ, Coussement P, Prunier F,
Moulin F, Roth O, Belle L, Dubois P, Barragan P, Gilard M, Piot C, Colin P, De Poli F, Morice MC, Ider O, Dubois-Randé JL, Unterseeh T, Le Breton H, Béard T, Blanchard D, Grollier G, Malquarti V, Staat P, Sudre A, Elmer E, Hansson MJ, Bergerot C, Boussaha I, Jossan C, Derumeaux G, Mewton N, Ovize M. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med. 2015;373:1021–1031. doi: 10.1056/ NEJMoa1505489. 7. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171:2029–2050. doi: 10.1111/bph.12461. 8. Kloner RA, Hale SL, Dai W, Gorman RC, Shuto T, Koomalsingh KJ, Gorman JH, 3rd, Sloan RC, Frasier CR, Watson CA, Bostian PA, Kypson AP, Brown DA. Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide. J Am Heart Assoc. 2012;1:e001644. doi: 10.1161/JAHA.112.001644. 9. Eirin A, Li Z, Zhang X, Krier JD, Woollard JR, Zhu XY, Tang H, Herrmann SM, Lerman A, Textor SC, Lerman LO. A mitochondrial permeability transition pore inhibitor improves renal outcomes after revascularization in experimental atherosclerotic renal artery stenosis. Hypertension. 2012;60:1242–1249. doi: 10.1161/HYPERTENSIONAHA.112.199919. 10. Dai W, Cheung E, Alleman RJ, Perry JB, Allen ME, Brown DA, Kloner RA. Cardioprotective effects of mitochondria-targeted peptide SBT-20 in two different models of rat ischemia/reperfusion. Cardiovasc Drugs Ther. 2016;30:559–566. doi: 10.1007/s10557-016-6695-9. 11. Gibson CM, Giugliano RP, Kloner RA, Bode C, Tendera M, Jánosi A, Merkely B, Godlewski J, Halaby R, Korjian S, Daaboul Y, Chakrabarti AK, Spielman K, Neal BJ, Weaver WD. EMBRACE STEMI study: a phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. Eur Heart J. 2016;37:1296–1303. doi: 10.1093/eurheartj/ehv597. 12. Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondriarelated gene expression in rats. J Cardiovasc Pharmacol. 2014;64:543– 553. doi: 10.1097/FJC.0000000000000155. 13. Sabbah HN, Gupta RC, Kohli S, Wang M, Hachem S, Zhang K. Chronic therapy with elamipretide (MTP-131), a novel mitochondria-targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ Heart Fail. 2016;9:e002206. doi: 10.1161/ CIRCHEARTFAILURE.115.002206. 14. Dai DF, Chen T, Szeto H, Nieves-Cintrón M, Kutyavin V, Santana LF, Rabinovitch PS. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol. 2011;58:73–82. doi: 10.1016/j.jacc.2010.12.044. 15. Karra A, Cihen BH, Goldstein A, Vockley J, Haas R. MMPOWER: the effect of treatment with elamipretide in patients with genetically confirmed primary mitochondrial disease. J Cachexia Sarcopenia Muscle. 2017;8:170–171. 16. Abstracts of the 9th International Conference on cachexia, sarcopenia, and muscle wasting. Berlin, Germany, December 10–11, 2016;(part 2; abstract 1–61):170–171. 17. Karaa A, Haas R, Goldstein A, Vockley G, and Cohen BH. Effects of elamipretide in adults with primary mitochondrial myopathy: a phase 2 double-blind, randomized, placebo-controlled crossover trial. Presented at 2017 UMDF Mitochondrial Medicine Meeting, Washington, DC, June 28–July 1, 2017. Oral Presentation. 18. Roshanravan B, Liu Z, Ali AS, Amory JK, Robertson HL, Goss C, Shankland EG, Marcinek DM, Conley KE. Elamipretide improves skeletal muscle function in elderly subjects: results from a randomized, doubleblind, placebo-controlled, single IV dose study. J Cachexia Sarcopenia Muscle. 2017;8:171. KEY WORDS: Editorials ◼ heart failure ◼ percutaneous coronary intervention ◼ renal artery obstruction ◼ ST elevation myocardial infarction
Mitochondrial Protective Agents for Ischemia/Reperfusion Injury Robert A. Kloner Downloaded from http://circinterventions.ahajournals.org/ by guest on October 3, 2017
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schemia of organs, including that of the heart, kidney, and brain, account for major morbidity and mortality in the United States. When an organ is ischemic, the logical approach is to relieve the ischemia by re-establishing blood flow as is accomplished by percutaneous interventions, such as angioplasty and placing a stent in an occluded coronary artery or occluded renal artery. However, even after establishing patency of the large obstructed blood vessel, a degree of organ damage may persist because of reperfusion injury.1 In the heart, this may manifest as reperfusion arrhythmias, stunned myocardium (postischemic left ventricular dysfunction), and no reflow or microvascular obstruction. Whether reperfusion actually kills myocardial cells remains debatable. In the kidneys, reperfusion injury may manifest as microvascular damage, loss of glomerular filtration, and damage because of reactive oxygen species that includes loss of cortical structure. It has been postulated that abrupt reperfusion results in reactive oxygen species production by the mitochondria, opening of the mitochondrial permeability transition pore, an influx of calcium into the mitochondria, release of cytochrome C, and peroxidation of cardiolipin in the inner mitochondrial membrane.2 Certainly, angioplasty/stenting for renal artery stenosis alone for the treatment of hypertension has been disappointing in its effect on major adverse clinical outcomes.3 Most patients need to remain on medical therapies, and there is limited evidence of preservation of renal function. One potential explanation is that reperfusion injury has contributed to the disappointing outcomes.
promise in preclinical studies, most did not work in the clinical trials. There are less data on adjunctive therapies for renal ischemia/reperfusion. There is still an unmet need to develop better treatments for reperfusion injury. In the heart, for example, the presence of no reflow or microvascular obstruction after percutaneous coronary intervention of a proximally occluded coronary artery is associated with worse left ventricular remodeling, including left ventricular dilatation, congestive heart failure, and death.5 One potential therapy for STEMI is drugs that target the mitochondria. Cyclosporine A is an agent that is known to keep the mitochondrial permeability transition pore closed and in experimental studies and in some initial clinical trials appeared to mimic ischemic postconditioning and reduced myocardial infarct size. However, in larger clinical trials, its effect was neutral.6 Szeto and Schiller developed a series of small peptides that targeted the inner mitochondrial membrane and protected the mitochondria in situations of cellular stress.7 It is thought that these peptides interact with cardiolipin, a phospholipid on the inner mitochondrial membrane that maximizes membrane shape to improve the functioning of the electron transport chain and also minimizes the production of mitochondrialderived reactive oxygen species. In several experimental studies, some of these peptides, including elamipretide (formerly called Bendavia or MTP-131), when given at or near reperfusion reduced experimental myocardial infarct size in ischemia/ reperfusion models in guinea pigs, rabbits, sheep,8 and rat. In in vitro studies, elamipretide was shown to reduce production of reactive oxygen species of isolated cardiomyocytes exposed to hypoxia and then reoxygenation. However, in our laboratory, the drug did not significantly reduce myocardial infarct size in a rabbit model (although there was a nonsignificant trend with a 11% reduction), and our results, therefore, differed from several other independent laboratories that tested it.8 However, we did note that for any given ischemic area at risk, the extent of no reflow was smaller in rabbits treated with elamipretide. These results paralleled those of Eirin et al’s9 observations in the swine model of renal atherosclerotic stenosis and reperfusion, in which the drug improved postischemic renal blood flow. Recently, we reported the results of another of these peptides, SBT-20. In our experimental rat model of myocardial infarct size, it significantly reduced myocardial infarct size by ≈20%, which is a similar observation compared with a study that Szeto previously published in the rat model with this agent.10 The EMBRACE STEMI study was a sizable multicenter study investigating the use of elamipretide as an adjunct therapy to percutaneous coronary intervention for STEMI. The drug was to be given to patients before reperfusion because it was noted in preclinical models that if the drug was only given after reperfusion had already commenced, it
See Article by Saad et al Numerous therapies have been tested in preclinical models to try to reduce ischemia/reperfusion injury.4 In the setting of clinical ST-elevation–myocardial infarction (STEMI), various adjunctive agents have been tried along with reperfusion to further reduce myocardial infarct size and limit ischemia/ reperfusion injury. Although many of these therapies showed The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Research Institute, Huntington Medical Research Institutes, Pasadena, CA; and Cardiovascular Division, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA. Correspondence to Robert A. Kloner, MD, PhD, Cardiovascular Division, Department of Medicine, Keck School of Medicine of University of Southern California, 10 Pico, Pasadena, Los Angeles, CA 91105. E-mail [email protected] (Circ Cardiovasc Interv. 2017;10:e005805. DOI: 10.1161/CIRCINTERVENTIONS.117.005805.) © 2017 American Heart Association, Inc. Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.117.005805
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had no beneficial effects on either infarct size or no reflow. The end points of this clinical trial included myocardial infarct size as assessed by biomarkers of necrosis, as well as myocardial infarct size assessed at day 4 by MRI. The findings from this study were negative, in that there was no reduction of myocardial infarct size assessed by either technique.11 However, there was a surprising finding that might have contributed to the negative results. Usually, when STEMI studies are performed, most patients demonstrate occluded proximal coronary arteries when they first present in the catheterization laboratory. In clinical myocardial infarction trials, only a relatively small percentage of patients demonstrate open arteries at the time of catheterization laboratory presentation because of presumed spontaneous thrombolysis. In the EMBRACE STEMI study, a large percentage (39%) presented with open infarctrelated arteries in the laboratory. However, studies showed that for elamipretide to be effective, the drug needed to be on board before reperfusion. Giving the drug after reperfusion had already occurred negated any potential beneficial effect. This is one of several potential reasons for the negative results of the EMBRACE STEMI study. Why a high percentage of EMBRACE STEMI patients demonstrated patent infarctrelated arteries is unknown. It is possible that current wider use of antiplatelet agents and statins might have contributed. It is unlikely that there will be further clinical studies examining the effects of this agent for the purpose of trying to reduce STEMI size; however, as discussed below, there are many other potential clinical applications under investigation with elamipretide, and when used after an STEMI, it may have a role in preventing adverse postmyocardial left ventricular remodeling. Although elamipretide did not reduce evidence of ischemia/ reperfusion injury in the clinical setting of reperfused STEMI, the present study by Saad et al,2 in this issue of Circulation: Cardiovascular Interventions, demonstrates that the drug shows promise in reducing ischemia/reperfusion injury in another vital organ, the kidney. This group of researchers from the Mayo Clinic previously used an atherosclerotic swine model of renal artery stenosis and observed that administration of elamipretide before and during angioplasty reduced ischemia/reperfusion-induced oxidative stress and apoptosis of the kidneys. Elamipretide improved renal function and microvascular perfusion. The present study describes the first use of this drug in a limited number of patients undergoing percutaneous transluminal renal angioplasty and stenting to assess its effect on estimated glomerular filtration rate, extent of renal parenchymal hypoxia determined by blood oxygen level–dependent MRI imaging, renal blood flow by contrast-enhanced multidetector computed tomography, and blood pressure. For 3 months, estimated glomerular filtration rate increased more in the elamipretide group than in the placebo group. Blood pressure fell more in the treated group. Fractional hypoxia as assessed by blood oxygen level–dependent imaging was less at 24 hours in the kidneys of elamipretidetreated patients than placebo patients although these equalized by 3 months. Stenotic kidney renal blood flow rose at 3 months in the elamipretide group but not in the placebo group; this was largely related to an increase in cortical perfusion. The authors concluded that elamipretide given during renal artery percutaneous angioplasty/stenting attenuated postprocedural hypoxia, increased single-kidney blood flow, and improved kidney
function in this pilot trial and that targeted mitochondrial protection shows promise. There are some limitations to this study that the authors correctly discuss, including relatively small numbers of patients (n=14); both revascularization and contrast injection were done as part of the same procedure and both could have contributed to tissue hypoxia; concern that contrast retention could have affected the second blood oxygen level–dependent image; and other limitations. Still, this is an important article because it is one of the first showing a clinical benefit of the mitochondrial targeted peptide elamipretide in patients experiencing ischemia and reperfusion of a vital organ. The results pave the way for future larger studies assessing the outcome of these novel mitochondrial protective drugs. An especially intriguing observation was that after 3 months, there was a substantial drop in systolic blood pressure from ≈155 mm Hg at baseline to ≈130 mm Hg in the elamipretide groups, but no significant drop in the placebo group. Angioplasty/stenting for renal artery stenosis is a therapy that has been questioned because most patients who have received the procedure still need to remain on medication, and renal function is not always improved. However, if elamipretide is on board, there could be a resurgence of this approach for treating resistant hypertension. The authors are to be congratulated for first performing preclinical studies that showed benefit of the drug and then extending this to the clinical realm and finding similar results. Sometimes our preclinical efforts do translate in a positive manner and pay off. Of course, this study is small and will need to be repeated with larger numbers of patients and a more diverse group of patients. Finally, although elamipretide did not show a reduction of myocardial infarction size in the EMBRACE STEMI trial, there are other cardiac applications under study. Our group showed that when the drug was administered chronically after experimental myocardial infarction, it reduced infarct expansion and adverse left ventricular remodeling and improved post-myocardial infarction left ventricular dysfunction.12 Elamipretide also reduced the extent of apoptosis at the border zone of these infarcts. Sabbah’s13 group at Henry Ford Hospital showed that this drug was effective in a canine heart failure model induced by microembolization. Elamipretide improved cardiac ATP synthesis and mitochondrial function in this model, improved left ventricular ejection fraction, and improved biomarkers of heart failure. This same research group observed benefits on left ventricular function when the drug was administered either acutely or chronically. In addition, elamipretide preserved mitochondrial ultrastructure and the functioning of the electron transport chain. Clinical trials of the drug in patients with heart failure are underway. Other investigators have shown that the drug is effective in angiotensin-induced cardiomyopathy, in which it improved diastolic dysfunction and reduced adverse left ventricular remodeling.14 The drug is also being studied in patients with mitochondrial myopathies, rare genetic defects of mitochondrial function characterized by muscle weakness, exercise intolerance, and a host of other medical problems. Karra et al15,16 studied 36 patients with documented genetically confirmed primary mitochondrial disease. The patients received placebo or escalating intravenous doses of elamipretide daily for 5 days. Elamipretide improved 6-minute walk tests in a dose-dependent fashion. At
3 Kloner Mitochondrial Protective Agents
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the highest dose (0.25 mg/kg per hour for 2 hours), the drug increased the 6-minute walk test by 65 versus 20 m for placebo (P=0.053).15 Additional preliminary data were recently presented by Karaa et al17 showing that a 4-week treatment improved 6-minute walk times by a distance of 20 m and appeared to be most beneficial in those patients with the worse baseline limitations. In addition, elamipretide improved various fatigue scores reported by the patients compared with placebo. The drug also was tested in elderly patients to determine whether it will improve their muscle strength. In a preliminary study by Roshanravan et al,16,18 39 elderly subjects received a single intravenous dose of elamipretide at 0.25 mg/kg per hour for 2 hours. Elamipretide increased ATP synthesis to a similar level to 6 months of exercise training. In addition, patients receiving elamipretide showed a trend toward improved hand strength testing compared with placebo.18 In summary, Saad et al2 are to be congratulated for providing some of the first evidence in patients that mitochondrialtargeted peptide reduced elements of ischemia/reperfusion injury in the kidneys of patients undergoing renal artery angioplasty and stenting. Elamipretide reduced continued kidney hypoxia after intervention, improved renal blood flow, preserved kidney function, and importantly reduced systolic blood pressure. This same drug or related drugs shows promise for a host of medical problems that are not limited to renal ischemia and reperfusion but extend to other organs and other disease states involving the impaired mitochondria.
Disclosures Dr Kloner’s laboratory has received funding in the past for preclinical studies from Stealth Biotherapeutics, Newton, MA.
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Mitochondrial Protective Agents for Ischemia/Reperfusion Injury Robert A. Kloner Downloaded from http://circinterventions.ahajournals.org/ by guest on October 3, 2017
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