European Heart Journal Advance Access published September 1, 2014
EDITORIAL
European Heart Journal doi:10.1093/eurheartj/ehu380
Mitochondrial care in acute myocardial infarction Hans Erik Bøtker* Department of Cardiology, Aarhus University Hospital Skejby, Brendstrupgaardsvej 100, DK-8200, Aarhus N, Denmark Received 8 August 2014; revised 19 August 2014; accepted 20 August 2014
This editorial refers to “Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: the MITOCARE study results” doi:10.1093/eurheartj/ehu331
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +45-7845-2026, Fax: +45-7845-2052, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from by guest on December 5, 2014
Rapid restoration of blood flow has the greatest impact on reducing infarct size and improving patient prognosis in patients with ST-elevation myocardial infarction (MI). However, reperfusion itself can exacerbate myocardial damage on top of the initial ischaemic damage.1 Lethal reperfusion injury develops when sudden restoration of blood flow causes necrosis of myocytes that—albeit injured by the preceding ischaemia—were potentially salvageable at the time of reperfusion. In animal models, reperfusion injury may account for up to 50% of the final infarct size.1 Reperfusion injury is modifiable. Pre-infarct angina and repetitive episodes of ischaemia before ST-elevation MI reduce final infarct size, and are thought to be innate forms of pre-conditioning that reduce reperfusion injury.2 Hence, reperfusion injury is a target for improving outcomes in patients with acute MI undergoing optimal revascularization. Pre-conditioning by mechanical intervention, with repeated cycles of brief ischaemia and reperfusion before extended ischaemia, cannot be applied in acute MI due to its unpredictable nature. Repeated cycles of re-occlusion and reperfusion of the coronary artery within the first minute of reflow (postconditioning) and repeated cycles of brief ischaemia and reperfusion in a distant organ (remote conditioning), typically the upper arm, can protect from lethal reperfusion injury and reduce infarct size by 30–70% according to experimental animal studies. Although the initial promising results with post-conditioning, which ultimately confirmed a specific intervention against reperfusion injury,3 have not been quite consistent in more recent studies,4,5 the intervention by remote conditioning has been translated into the clinical setting in proof-of-concept studies,6,7 and also demonstrated improvement in clinical outcome.8 The demonstration of cardioprotective effects by various forms of ischaemic conditioning therapies have encouraged the pursuit of underlying mechanisms and drugs that recapitulate mechanical conditioning by specifically addressing signal transduction pathways. Mechanical conditioning activates several protective mechanisms in the target organ, including three parallel signalling cascades: the
nitric oxide-dependent G-protein coupled receptor-eNOS-protein kinase G pathway, the reperfusion-injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) signalling pathway (Figure 1).9 The pathways interact and converge on the mitochondria to modify membrane integrity by inhibiting the opening of the membrane permeability transition pore (MPTP). The MPTP is closed during myocardial ischaemia but opens during reperfusion,10 causing mitochondrial swelling, loss of function and, potentially, cellular necrosis. Cyclosporine A prevents MPTP opening, provided that it is ‘on board’ at start of reperfusion. In the clinical setting, cyclosporine has been shown to reduce infarct size in patients undergoing primary PCI.11 Other pharmacological approaches for preventing or modifying the MPTP opening, e.g. by volatile anaesthetics or metformin,12 have shown cardioprotective capacity in experimental studies, but remain to be tested systematically in clinical trials. In this light, the MITOCARE study—a proof-of-concept study investigating the cardioprotective effect of TRO40303, a new mitochondrial-targeted drug, as an adjunct to primary percutaneous coronary intervention in patients with acute ST-elevation MI—is appropriate and timely. However, the study demonstrated no protection from TRO40303 as measured by biomarker release over 3 days, cardiac magnetic resonance (CMR)-assessed myocardial salvage index, CMR-assessed infarct size or left ventricular ejection fraction. The strength of the study is its multicentre design, inclusion of patients with totally occluded culprit vessels and large area-at-risk, use of CMR in a subgroup of patients and independent measurement of left ventricular function as secondary endpoints. The active study group started out on slightly more negative premises with respect to age, baseline biomarkers and unsuccessful revascularization. Endpoint limitations include lack of individual area-at-risk assessment using biomarkers and potential interference with the area-at-risk determination from T2-weighted oedema with CMR by any cardioprotective intervention. The study is challenged by the excellent outcomes from modern, standard therapy of ST-elevation MI and the power is borderline. The translation of the cardioprotective efficacy of TRO40303 from healthy animals to humans may be attenuated by conditions that are also known to attenuate protection by mechanical conditioning, such as age and co-morbidities—in particular
Page 2 of 3
Editorial
Figure 1: Simplified schematic presentation of the cytosol pathways that converge to prevent opening of the mitochondrial permeability tran-
hypercholesterolemia, diabetes, obesity and hypertension—which are common among patients suffering from acute MI.13 Medications may also attenuate the efficacy of cardioprotective treatment.13 Even so, the results imply the absence of cardioprotection. The drug may be challenged by some safety concerns, although the study was not powered for safety analysis. Extrapolation from animal studies using 2.5 mg/kg and 0.3, 1.0, 3.0 and 10 mg/kg body weight14,15 has indicated that infarct size reduction may be achievable with a bolus injection of 6 mg TRO40303 per kg body weight. Reductions were modest and associated with variations in area-at-risk, such that interpretation may have been ambiguous.14,15 Simultaneous circulating TRO40303 concentrations after equivalent doses also appeared somewhat lower in the experimental model than in humans in a Phase 1 study using a formulation different from that used in animals, to evaluate safety.15 In the MITOCARE study, circulating concentrations of TRO40303 were not measured at the time of reperfusion. Also, importantly, mitochondrial-targeted drugs act differently from each other and our understanding of their mechanisms is still immature. While the properties of the MPTP are reasonably well defined, the identity of the molecules that assemble to form the MPTP remains uncertain (Figure 1). Cyclosporine A targets matrix cyclophilin D (CyD), where Ca2+ overload triggers opening of the MPTP. TRO40303 binds to the translocator protein 18 kDa (TSPO) in the outer membrane.14 The inhibitory effects of
TRO40303 seem to be mediated primarily through reduction of Reactive oxygen species (ROS) production, whereas cyclosporine A inhibits MPTP opening, mainly by displacement of CyD. Cyclosporine A inhibition of MPTP opening appears to coincide with its effects on ROS production and calcium overload, while the effects of TRO40303 occur slightly earlier, potentially creating a mismatch in mechanisms that may need to be simultaneous to elicit cardioprotection. Unlike cyclosporine A, TRO40303 has no effect on the calcium retention capacity of isolated mitochondria, even though it still seems to reduce reactive oxygen species production and subsequent calcium overload in an in vivo model.14 Finally, mechanical cardioprotection, e.g. by remote conditioning, induces a range of systemic effects including multi-organ protection, anti-inflammatory properties, reduced platelet activation, and increased exercise performance, perhaps indicating that this inherent protection system in mammalian species is a fundamental and complex part of the biological response to stress that may yet prove too complex to be fully recapitulated by a single pharmacological intervention. Despite the disappointing results of the MITOCARE study, reduction in reperfusion injury remains a major target in improving outcomes after successful revascularization in patients with MI. The mechanisms underlying reperfusion injury and the increasing insight into the mechanisms behind the cardioprotective effects of ischaemic conditioning have not only demonstrated that reperfusion injury is a
Downloaded from by guest on December 5, 2014
sition pore (MPTP) in cardioprotection. eNOS/PGK: the nitric oxide dependent G-protein coupled receptor-eNOS-protein kinase G pathway; the reperfusion-injury salvage kinase pathway (RISK) based on protein kinase B; PI3K-Akt and glycogen synthase kinase 3 b and the survivor activating factor enhancement (SAFE) signaling pathway involving the JAK-STAT system and TNF-alpha receptors. Proteins implicated in MPTP formation include the matrix cyclophilin D (CyD), the inner membrane adenine nucleotide translocase (ANT) and the outer membrane voltage-dependent anion channel (VDAC). Additional proteins such as the translocator protein 18 kDa (TSPO), located in the outer mitochondrial membrane, interact with proteins implicated in MPTP formation. Under pathophysiological conditions, such as high Ca2+ concentration and increased oxidative stress, the complex forms an open pore between the inner and outer membranes that ultimately results in mitochondrial swelling, mitochondrial Ca2+ efflux and the release of apoptogenic proteins. Cyclosporine-A targets matrix CyD, where Ca2+ overload triggers MPTP opening. TRO40303 binds to TSPO in the outer membrane. Abbreviations: eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated kinase; GFR: growth factor receptor (insulin-like growth factor-1 and fibroblast growth factor-2); GPCR: G-protein-coupled receptor; GSK3-ß: glycogen synthase kinase 3ß ; IMM: inner mitochondrial membrane; OMM: outer mitochondrial membrane; PKC: protein kinase C; TNF-R: tumor necrosis factor receptor.
Page 3 of 3
Editorial
true, modifiable clinical entity, but have also revealed targets for pharmacological intervention that potentially may generate effects similar to local and remote ischaemic conditioning. Intervening in ‘upstream’ events of the signalling cascade of conditioning by akt-activation with GLP-1 analogues and ‘downstream‘ events, such as inhibiting MPTP opening with cyclosporine A, seem promising, while TRO40303—despite similar but not identical action—by may either not have been given in a proper dose or add to a list of inadequate pharmacological strategies.
Funding
6.
7.
8.
The author received funding from The Novo Nordic Foundation, Fondation Leducq (06CVD), The Danish Research Council for Strategic Research (11-115818) and The Danish Research Council (11-108354)
Declaration of interest Shareholder CellAegis Inc. Note: the opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
10. 11.
12.
13.
14.
15.
Downloaded from by guest on December 5, 2014
1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357(11): 1121– 1135. 2. Terkelsen CJ, Kaltoft AK, Norgaard BL, Bottcher M, Lassen JF, Clausen K, Nielsen SS, Thuesen L, Nielsen TT, Botker HE, Andersen HR. ST changes before and during primary percutaneous coronary intervention predict final infarct size in patients with ST elevation myocardial infarction. J Electrocardiol 2009;42(1):64 –72. 3. Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R, Working Group of Cellular Biology of Heart of European Society of C. Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2010;87(3):406 – 423. 4. Freixa X, Bellera N, Ortiz-Perez JT, Jimenez M, Pare C, Bosch X, De Caralt TM, Betriu A, Masotti M. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J 2012; 33(1):103 – 112. 5. Limalanathan S, Andersen GO, Klow NE, Abdelnoor M, Hoffmann P, Eritsland J. Effect of ischaemic postconditioning on infarct size in patients with ST-elevation
9.
myocardial infarction treated by primary PCI results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) randomized trial. J Am Heart Assoc 2014;3(2):e000679. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 2010;375(9716):727 –734. Rentoukas I, Giannopoulos G, Kaoukis A, Kossyvakis C, Raisakis K, Driva M, Panagopoulou V, Tsarouchas K, Vavetsi S, Pyrgakis V, Deftereos S. Cardioprotective role of remote ischaemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc Interv 2010;3(1):49– 55. Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Botker HE, Investigators C. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 2014;35(3):168 –175. Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 2008;118(19):1915 –1919. Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 1995;307(Pt 1):93 –98. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359(5):473 –481. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM. Metformin protects the ischaemic heart by the Aktmediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol 2008;103(3):274–284. Hausenloy DJ, Erik Botker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JP, Yellon DM, Ovize M. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2013;98(1):7 –27. Schaller S, Paradis S, Ngoh GA, Assaly R, Buisson B, Drouot C, Ostuni MA, Lacapere JJ, Bassissi F, Bordet T, Berdeaux A, Jones SP, Morin D, Pruss RM. TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition. J Pharmacol Exp Ther 2010;333(3):696–706. Le Lamer S, Paradis S, Rahmouni H, Chaimbault C, Michaud M, Culcasi M, Afxantidis J, Latreille M, Berna P, Berdeaux A, Pietri S, Morin D, Donazzolo Y, Abitbol JL, Pruss RM, Schaller S. Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial. J Transl Med 2014;12:38.
EDITORIAL
European Heart Journal doi:10.1093/eurheartj/ehu380
Mitochondrial care in acute myocardial infarction Hans Erik Bøtker* Department of Cardiology, Aarhus University Hospital Skejby, Brendstrupgaardsvej 100, DK-8200, Aarhus N, Denmark Received 8 August 2014; revised 19 August 2014; accepted 20 August 2014
This editorial refers to “Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: the MITOCARE study results” doi:10.1093/eurheartj/ehu331
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +45-7845-2026, Fax: +45-7845-2052, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from by guest on December 5, 2014
Rapid restoration of blood flow has the greatest impact on reducing infarct size and improving patient prognosis in patients with ST-elevation myocardial infarction (MI). However, reperfusion itself can exacerbate myocardial damage on top of the initial ischaemic damage.1 Lethal reperfusion injury develops when sudden restoration of blood flow causes necrosis of myocytes that—albeit injured by the preceding ischaemia—were potentially salvageable at the time of reperfusion. In animal models, reperfusion injury may account for up to 50% of the final infarct size.1 Reperfusion injury is modifiable. Pre-infarct angina and repetitive episodes of ischaemia before ST-elevation MI reduce final infarct size, and are thought to be innate forms of pre-conditioning that reduce reperfusion injury.2 Hence, reperfusion injury is a target for improving outcomes in patients with acute MI undergoing optimal revascularization. Pre-conditioning by mechanical intervention, with repeated cycles of brief ischaemia and reperfusion before extended ischaemia, cannot be applied in acute MI due to its unpredictable nature. Repeated cycles of re-occlusion and reperfusion of the coronary artery within the first minute of reflow (postconditioning) and repeated cycles of brief ischaemia and reperfusion in a distant organ (remote conditioning), typically the upper arm, can protect from lethal reperfusion injury and reduce infarct size by 30–70% according to experimental animal studies. Although the initial promising results with post-conditioning, which ultimately confirmed a specific intervention against reperfusion injury,3 have not been quite consistent in more recent studies,4,5 the intervention by remote conditioning has been translated into the clinical setting in proof-of-concept studies,6,7 and also demonstrated improvement in clinical outcome.8 The demonstration of cardioprotective effects by various forms of ischaemic conditioning therapies have encouraged the pursuit of underlying mechanisms and drugs that recapitulate mechanical conditioning by specifically addressing signal transduction pathways. Mechanical conditioning activates several protective mechanisms in the target organ, including three parallel signalling cascades: the
nitric oxide-dependent G-protein coupled receptor-eNOS-protein kinase G pathway, the reperfusion-injury salvage kinase (RISK) pathway and the survivor activating factor enhancement (SAFE) signalling pathway (Figure 1).9 The pathways interact and converge on the mitochondria to modify membrane integrity by inhibiting the opening of the membrane permeability transition pore (MPTP). The MPTP is closed during myocardial ischaemia but opens during reperfusion,10 causing mitochondrial swelling, loss of function and, potentially, cellular necrosis. Cyclosporine A prevents MPTP opening, provided that it is ‘on board’ at start of reperfusion. In the clinical setting, cyclosporine has been shown to reduce infarct size in patients undergoing primary PCI.11 Other pharmacological approaches for preventing or modifying the MPTP opening, e.g. by volatile anaesthetics or metformin,12 have shown cardioprotective capacity in experimental studies, but remain to be tested systematically in clinical trials. In this light, the MITOCARE study—a proof-of-concept study investigating the cardioprotective effect of TRO40303, a new mitochondrial-targeted drug, as an adjunct to primary percutaneous coronary intervention in patients with acute ST-elevation MI—is appropriate and timely. However, the study demonstrated no protection from TRO40303 as measured by biomarker release over 3 days, cardiac magnetic resonance (CMR)-assessed myocardial salvage index, CMR-assessed infarct size or left ventricular ejection fraction. The strength of the study is its multicentre design, inclusion of patients with totally occluded culprit vessels and large area-at-risk, use of CMR in a subgroup of patients and independent measurement of left ventricular function as secondary endpoints. The active study group started out on slightly more negative premises with respect to age, baseline biomarkers and unsuccessful revascularization. Endpoint limitations include lack of individual area-at-risk assessment using biomarkers and potential interference with the area-at-risk determination from T2-weighted oedema with CMR by any cardioprotective intervention. The study is challenged by the excellent outcomes from modern, standard therapy of ST-elevation MI and the power is borderline. The translation of the cardioprotective efficacy of TRO40303 from healthy animals to humans may be attenuated by conditions that are also known to attenuate protection by mechanical conditioning, such as age and co-morbidities—in particular
Page 2 of 3
Editorial
Figure 1: Simplified schematic presentation of the cytosol pathways that converge to prevent opening of the mitochondrial permeability tran-
hypercholesterolemia, diabetes, obesity and hypertension—which are common among patients suffering from acute MI.13 Medications may also attenuate the efficacy of cardioprotective treatment.13 Even so, the results imply the absence of cardioprotection. The drug may be challenged by some safety concerns, although the study was not powered for safety analysis. Extrapolation from animal studies using 2.5 mg/kg and 0.3, 1.0, 3.0 and 10 mg/kg body weight14,15 has indicated that infarct size reduction may be achievable with a bolus injection of 6 mg TRO40303 per kg body weight. Reductions were modest and associated with variations in area-at-risk, such that interpretation may have been ambiguous.14,15 Simultaneous circulating TRO40303 concentrations after equivalent doses also appeared somewhat lower in the experimental model than in humans in a Phase 1 study using a formulation different from that used in animals, to evaluate safety.15 In the MITOCARE study, circulating concentrations of TRO40303 were not measured at the time of reperfusion. Also, importantly, mitochondrial-targeted drugs act differently from each other and our understanding of their mechanisms is still immature. While the properties of the MPTP are reasonably well defined, the identity of the molecules that assemble to form the MPTP remains uncertain (Figure 1). Cyclosporine A targets matrix cyclophilin D (CyD), where Ca2+ overload triggers opening of the MPTP. TRO40303 binds to the translocator protein 18 kDa (TSPO) in the outer membrane.14 The inhibitory effects of
TRO40303 seem to be mediated primarily through reduction of Reactive oxygen species (ROS) production, whereas cyclosporine A inhibits MPTP opening, mainly by displacement of CyD. Cyclosporine A inhibition of MPTP opening appears to coincide with its effects on ROS production and calcium overload, while the effects of TRO40303 occur slightly earlier, potentially creating a mismatch in mechanisms that may need to be simultaneous to elicit cardioprotection. Unlike cyclosporine A, TRO40303 has no effect on the calcium retention capacity of isolated mitochondria, even though it still seems to reduce reactive oxygen species production and subsequent calcium overload in an in vivo model.14 Finally, mechanical cardioprotection, e.g. by remote conditioning, induces a range of systemic effects including multi-organ protection, anti-inflammatory properties, reduced platelet activation, and increased exercise performance, perhaps indicating that this inherent protection system in mammalian species is a fundamental and complex part of the biological response to stress that may yet prove too complex to be fully recapitulated by a single pharmacological intervention. Despite the disappointing results of the MITOCARE study, reduction in reperfusion injury remains a major target in improving outcomes after successful revascularization in patients with MI. The mechanisms underlying reperfusion injury and the increasing insight into the mechanisms behind the cardioprotective effects of ischaemic conditioning have not only demonstrated that reperfusion injury is a
Downloaded from by guest on December 5, 2014
sition pore (MPTP) in cardioprotection. eNOS/PGK: the nitric oxide dependent G-protein coupled receptor-eNOS-protein kinase G pathway; the reperfusion-injury salvage kinase pathway (RISK) based on protein kinase B; PI3K-Akt and glycogen synthase kinase 3 b and the survivor activating factor enhancement (SAFE) signaling pathway involving the JAK-STAT system and TNF-alpha receptors. Proteins implicated in MPTP formation include the matrix cyclophilin D (CyD), the inner membrane adenine nucleotide translocase (ANT) and the outer membrane voltage-dependent anion channel (VDAC). Additional proteins such as the translocator protein 18 kDa (TSPO), located in the outer mitochondrial membrane, interact with proteins implicated in MPTP formation. Under pathophysiological conditions, such as high Ca2+ concentration and increased oxidative stress, the complex forms an open pore between the inner and outer membranes that ultimately results in mitochondrial swelling, mitochondrial Ca2+ efflux and the release of apoptogenic proteins. Cyclosporine-A targets matrix CyD, where Ca2+ overload triggers MPTP opening. TRO40303 binds to TSPO in the outer membrane. Abbreviations: eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated kinase; GFR: growth factor receptor (insulin-like growth factor-1 and fibroblast growth factor-2); GPCR: G-protein-coupled receptor; GSK3-ß: glycogen synthase kinase 3ß ; IMM: inner mitochondrial membrane; OMM: outer mitochondrial membrane; PKC: protein kinase C; TNF-R: tumor necrosis factor receptor.
Page 3 of 3
Editorial
true, modifiable clinical entity, but have also revealed targets for pharmacological intervention that potentially may generate effects similar to local and remote ischaemic conditioning. Intervening in ‘upstream’ events of the signalling cascade of conditioning by akt-activation with GLP-1 analogues and ‘downstream‘ events, such as inhibiting MPTP opening with cyclosporine A, seem promising, while TRO40303—despite similar but not identical action—by may either not have been given in a proper dose or add to a list of inadequate pharmacological strategies.
Funding
6.
7.
8.
The author received funding from The Novo Nordic Foundation, Fondation Leducq (06CVD), The Danish Research Council for Strategic Research (11-115818) and The Danish Research Council (11-108354)
Declaration of interest Shareholder CellAegis Inc. Note: the opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
10. 11.
12.
13.
14.
15.
Downloaded from by guest on December 5, 2014
1. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007;357(11): 1121– 1135. 2. Terkelsen CJ, Kaltoft AK, Norgaard BL, Bottcher M, Lassen JF, Clausen K, Nielsen SS, Thuesen L, Nielsen TT, Botker HE, Andersen HR. ST changes before and during primary percutaneous coronary intervention predict final infarct size in patients with ST elevation myocardial infarction. J Electrocardiol 2009;42(1):64 –72. 3. Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R, Working Group of Cellular Biology of Heart of European Society of C. Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2010;87(3):406 – 423. 4. Freixa X, Bellera N, Ortiz-Perez JT, Jimenez M, Pare C, Bosch X, De Caralt TM, Betriu A, Masotti M. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J 2012; 33(1):103 – 112. 5. Limalanathan S, Andersen GO, Klow NE, Abdelnoor M, Hoffmann P, Eritsland J. Effect of ischaemic postconditioning on infarct size in patients with ST-elevation
9.
myocardial infarction treated by primary PCI results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) randomized trial. J Am Heart Assoc 2014;3(2):e000679. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 2010;375(9716):727 –734. Rentoukas I, Giannopoulos G, Kaoukis A, Kossyvakis C, Raisakis K, Driva M, Panagopoulou V, Tsarouchas K, Vavetsi S, Pyrgakis V, Deftereos S. Cardioprotective role of remote ischaemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc Interv 2010;3(1):49– 55. Sloth AD, Schmidt MR, Munk K, Kharbanda RK, Redington AN, Schmidt M, Pedersen L, Sorensen HT, Botker HE, Investigators C. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 2014;35(3):168 –175. Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 2008;118(19):1915 –1919. Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 1995;307(Pt 1):93 –98. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359(5):473 –481. Bhamra GS, Hausenloy DJ, Davidson SM, Carr RD, Paiva M, Wynne AM, Mocanu MM, Yellon DM. Metformin protects the ischaemic heart by the Aktmediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol 2008;103(3):274–284. Hausenloy DJ, Erik Botker H, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, Lecour S, van Laake LW, Madonna R, Ruiz-Meana M, Schulz R, Sluijter JP, Yellon DM, Ovize M. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2013;98(1):7 –27. Schaller S, Paradis S, Ngoh GA, Assaly R, Buisson B, Drouot C, Ostuni MA, Lacapere JJ, Bassissi F, Bordet T, Berdeaux A, Jones SP, Morin D, Pruss RM. TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition. J Pharmacol Exp Ther 2010;333(3):696–706. Le Lamer S, Paradis S, Rahmouni H, Chaimbault C, Michaud M, Culcasi M, Afxantidis J, Latreille M, Berna P, Berdeaux A, Pietri S, Morin D, Donazzolo Y, Abitbol JL, Pruss RM, Schaller S. Translation of TRO40303 from myocardial infarction models to demonstration of safety and tolerance in a randomized Phase I trial. J Transl Med 2014;12:38.
