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From cardiac mitochondrial dysfunction to clinical arrhythmias
International Journal of Cardiology 184 (2015) 597–599
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
From cardiac mitochondrial dysfunction to clinical arrhythmias☆ David Montaigne a,b,c,d,e,⁎, Xavier Maréchal a,b,c,d, Dominique Lacroix f, Bart Staels a,b,c,d a
Université Lille 2, F-59000 Lille, France Inserm, U1011, F-59000 Lille, France c EGID, F-59000 Lille, France d Institut Pasteur de Lille, F-59019 Lille, France e Service d'Explorations Fonctionnelles CardioVasculaires, University Hospital of Lille, France f Clinique de Cardiologie, Service de Rythmologie, University Hospital of Lille, France b
a r t i c l e
i n f o
Article history: Received 16 January 2015 Accepted 1 March 2015 Available online 3 March 2015 Keywords: Mitochondria Arrhythmia Electrophysiology
Bench studies identified cardiac mitochondria as new key players in the control of cardiac electrical function. After briefly exposing relevant basic principles of mitochondrial physiology, we detail mechanisms and recent translational data linking cardiac arrhythmias and mitochondrial dysfunction.
1. Mitochondrial physiology Mitochondria are subcellular organelles playing important roles in most cellular biological processes [1]. Among the most critical functions are: (i) providing the cell with a constant and adaptive amount of energy through the synthesis of adenosine triphosphate (ATP) via oxidative phosphorylation by the respiratory chain complexes; (ii) dealing with cellular reactive oxygen species (ROS), by-products of mitochondrial respiration which can activate cell death signaling pathways; and (iii) participating in calcium homeostasis through a cross-talk between sarcoplasmic reticulum and mitochondria calcium crosstalk, energized mitochondria being able to accumulate calcium. The heart is one of the organs with the highest rates of energy conversion in the body, being critically dependent on mitochondrial oxidative phosphorylation as a major source of ATP [1]. Mitochondrial oxidative phosphorylation which takes place along the inner mitochondrial membrane, is to the oxidation of reduced forms of nicotinamide ☆ No disclosure to declare. ⁎ Corresponding author at: University Lille 2, place de Verdun, Lille Cedex 59045 France. E-mail address: [email protected] (D. Montaigne).
http://dx.doi.org/10.1016/j.ijcard.2015.03.012 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH), produced during fatty acid beta-oxidation and by the citric acid cycle, by oxygen allowing the synthesis of adenosine tri-phosphate (ATP) (Fig. 1). The oxidative process is catalyzed by the 4 respiratory chain complexes (complexes I, II, III and IV) with oxygen as final electron acceptor at complex IV. Along the consecutive oxido-reduction reactions, part of the high redox energy of the electrons from NADH and FADH is turned into an electrochemical gradient of protons across the mitochondrial inner membrane, protons being pumped from the matrix to the inter-membrane space by complexes I, III and IV. As such mitochondrial respiration creates a mitochondrial membrane potential (ΔΨm) which is the driving force by which mitochondria participate in cardiomyocyte calcium homeostasis: cytosolic calcium cations are driven by mitochondria into its matrix which is negatively charged. The proton gradient allows the ATP synthase (F1–F0 ATPase) to synthesize energy-enriched ATP from ADP, a process called phosphorylation. In physiology, oxidation and phosphorylation are coupled. Reactive oxygen species (ROS) are highly reactive compounds which become harmful when produced in large amounts. Minute amounts of ROS are by-products of normal mitochondrial respiration and are involved in physiologic signaling pathways in cardiomyocyte. Yet, produced in large amounts during mitochondrial dysfunction, ROS activate cardiomyocyte cell death signaling pathways. Thus, mitochondria are key players in cardiomyocyte bioenergetics preventing any mismatch between ATP production and utilization. Thus, it is not surprising that mitochondrial dysfunction can contribute to the development of arrhythmia. 2. Mechanisms linking mitochondrial dysfunction and arrhythmia Inherited and acquired mitochondrial disorders are responsible for cardiac function impairment, and can thus indirectly lead to arrhythmias complicating myocardial remodeling in an unspecific manner. However, the direct involvement of mitochondria in cardiac electrical function has recently emerged from in vitro studies showing that modulation of mitochondrial respiration, membrane potential, and ion channels alter action potential genesis and myocardial conduction properties [2,3]. Almost half of cardiomyocyte ATP is consumed for ion channel homeostasis, i.e. sarcolemmal and sarcoplasmic reticulum pumps and transporters, which is mandatory for proper electrical activity. In
598
D. Montaigne et al. / International Journal of Cardiology 184 (2015) 597–599
Fig. 1. Mitochondrial oxidative phosphorylation. Details in text. β: fatty acid beta-oxidation; κ: citric acid cycle.
conditions of mitochondrial dysfunction or increased metabolic stress such as myocardial ischemia, the resulting loss in mitochondrial membrane potential diminishes ATP synthesis, thus disrupting electrical stability by reducing the energy supply to these channels and transporters (Fig. 2). Moreover, a drop of the ATP/ADP ratio results in the opening of the sarcolemmal KATP channels, which slows electrical propagation by creating current sinks in the myocardium and shortens refractory periods, both promoting arrhythmias [4–6]. ROS are by-products of mitochondrial respiration and mitochondria harbor major cellular anti-ROS systems (e.g. manganese superoxide dismutase, glutathione peroxidase, glutathione). Mitochondria are thus master regulators of redox status and signaling in cardiomyocyte. Mitochondrial dysfunction leads to increased ROS production which has been shown to directly alter cardiomyocyte excitability and cellto-cell coupling (Fig. 2) [7–9]. The latter is mainly regulated by connexins (Cx) which normally translocate between the sarcolemma and the cytosol, and are regulated by de/re-phosphorylation by protein
phosphatase1 (PP1)/PKA [10]. During ischemia, myocardial conduction velocity is slowed due to reduced Cx phosphorylation resulting in the translocation of Cx to the cytosol [11]. During reperfusion, Cx translocate back to the sarcolemmal gap junctions to recover conduction velocity in a PP1-dependent manner [10]. Interestingly, PP1 activity is affected by high levels of ROS [10,12]. Therefore, by increasing ROS production, mitochondrial dysfunction may maintain PP1 activity, preserve Cx de-phosphorylation, and reduce recovery in normal conduction velocity. Regarding cardiomyocyte excitability, arrhythmias following ROS exposure have been observed in reperfused ischemic rat myocardium [13] or in the failing pig heart [14]. These arrhythmias are ascribed to a severe impairment in calcium homeostasis [15]. In this context, the sarcolemmal sodium–calcium exchanger (NCX) plays a pivotal role in the generation of transient inward currents involved in delayed after-depolarization secondary to spontaneous calcium release from the sarcoplasmic reticulum [16]. Moreover, long-term ROS exposure promotes cardiomyocyte hypertrophy, apoptosis and interstitial
Fig. 2. Mechanisms linking mitochondrial dysfunction and arrhythmias. Mitochondrial dysfunction results in the shortening of the action potential as a result of the opening of the sarcolemmal KATP channel, due to a low ATP/ADP ratio and an inhibition of the calcium (ICa++) and sodium (INa+) depolarising current by redox modifications of their related sarcolemmal channels. Weak INa+ current and ROS-induced connexin (Cx) modifications lead to poor cell-to-cell coupling and decreased conduction velocities in myocardium. Both increased NADH/ NAD ratio and ROS production associated with mitochondrial dysfunction modify the ryanodine receptor (RyR2) and sarcoplasmic calcium ATPase (SERCA), respectively leading to sarcoplasmic calcium leaking, and incomplete removal of calcium from the cytosol during diastole. In the absence of proper respiratory chain complex function, the mitochondrial membrane potential is low and mitochondria are unable to participate in cardiomyocyte calcium homeostasis. The resulting elevated diastolic calcium concentration in the cytosol activates the sarcolemmal Na–Ca exchanger (NCX), which is responsible for delayed after-depolarizations (DADs). Shortened action potential, low conduction velocities and DAD render the myocardium displaying mitochondrial dysfunction more prone to arrhythmias.
D. Montaigne et al. / International Journal of Cardiology 184 (2015) 597–599
fibrosis by activating redox-sensitive transcription factors and inducing transcription of pro-inflammatory cytokines and chemokine genes [17]. Therefore, ROS may be arrhythmogenic by creating chronic damages together with initiating paroxysmal arrhythmias. 3. Insights from translational studies in patients Our group has recently demonstrated that pre-operative mitochondrial dysfunction of the atrial myocardium is associated with increased incidence of atrial fibrillation after cardiac surgery, identifying the mitochondrium as a potential player in clinically relevant arrhythmias [18]. Moreover, in a small size study, remote ischemic preconditioning has been reported to preserve atrial mitochondrial function during cardiac surgery and decrease post-operative atrial fibrillation incidence in patients [19]. These promising translational data warrant further investigation to explore mitochondria as potential therapeutic targets in clinical arrhythmias particularly in diabetic patients which display cardiac mitochondrial dysfunction [20]. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] R.S. Balaban, Perspectives on: SGP symposium on mitochondrial physiology and medicine: metabolic homeostasis of the heart, J. Gen. Physiol. 139 (2012) 407–414. [2] D.A. Brown, B. O'Rourke, Cardiac mitochondria and arrhythmias, Cardiovasc. Res. 88 (2010) 241–249. [3] E.M. Jeong, M. Liu, M. Sturdy, et al., Metabolic stress, reactive oxygen species, and arrhythmia, J. Mol. Cell. Cardiol. 52 (2012) 454–463. [4] B. O'Rourke, B.M. Ramza, E. Marban, Oscillations of membrane current and excitability driven by metabolic oscillations in heart cells, Science 265 (1994) 962–966. [5] L. Zhou, S. Solhjoo, B. Millare, et al., Effects of regional mitochondrial depolarization on electrical propagation: implications for arrhythmogenesis, Circ. Arrhythm. Electrophysiol. 7 (2014) 143–151. [6] R.M. Smith, R. Visweswaran, I. Talkachova, J.K. Wothe, E.G. Tolkacheva, Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart, Am. J. Physiol. Heart Circ. Physiol. 305 (2013) H9–H18.
599
[7] A.A. Sovari, C.A. Rutledge, E.M. Jeong, et al., Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death, Circ. Arrhythm. Electrophysiol. 6 (3) (2013) 623–631. [8] A.V. Zima, J. Kockskämper, R. Mejia-Alvarez, L.A. Blatter, Pyruvate modulates cardiac sarcoplasmic reticulum Ca2 + release in rats via mitochondria-dependent and -independent mechanisms, J. Physiol. 550 (2003) 765–783. [9] M. Liu, H. Liu, S.C. Dudley Jr., Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel, Circ. Res. 107 (2010) 967–974. [10] M. Jeyaraman, S. Tanguy, R.R. Fandrich, A. Lukas, E. Kardami, Ischaemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by okadaic acid and calyculin A but not fostriecin, Mol. Cell. Biochem. 242 (2003) 129–134. [11] M.A. Beardslee, D.L. Lerner, P.N. Tadros, J.G. Laing, E.C. Beyer, K.A. Yamada, A.G. Kleber, R.B. Schuessler, J.E. Saffitz, Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischaemia, Circ. Res. 87 (2000) 656–662. [12] J.S. Fetrow, N. Siew, J. Skolnick, Structure-based functional motif identifies a potential disulfide oxidoreductase active site in the serine/threonine protein phosphatase-1 subfamily, FASEB J. 13 (1999) 1866–1874. [13] T. Ravingerova, J. Slezak, N. Tribulova, A. Dzurba, B. Uhrik, A. Ziegelhoffer, Free oxygen radicals contribute to high incidence of reperfusion-induced arrhythmias in isolated rat heart, Life Sci. 65 (1999) 1927–1930. [14] F. Brigadeau, P. Gelé, C. Marquié, B. Soudan, D. Lacroix, Ventricular arrhythmias following exposure of failing hearts to oxydative stress in vitro, J. Cardiovasc. Electrophysiol. 16 (2005) 629–636. [15] W.D. Gao, Y. Liu, E. Marban, Selective effects of oxygen free radicals on excitation– contraction coupling in ventricular muscle: implications for the mechanism of stunned myocardium, Circulation 94 (1996) 2597–2604. [16] J. Fauconnier, S. Roberge, N. Saint, A. Lacampagne, Type 2 ryanodine receptor: a novel therapeutic target in myocardial ischemia/reperfusion, Pharmacol. Ther. 138 (3) (2013 Jun) 323–332. [17] H.M. Lander, An essential role for free radicals and derived species in signal transduction, FASEB J. 11 (1997) 118–124. [18] D. Montaigne, X. Marechal, P. Lefebvre, et al., Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops, J. Am. Coll. Cardiol. 62 (2013) 1466–1473. [19] K.H. Slagsvold, O. Rognmo, M. Høydal, U. Wisløff, A. Wahba, Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery, Circ. Res. 114 (2014) 851–859. [20] D. Montaigne, X. Marechal, A. Coisne, et al., Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients, Circulation 130 (2014) 554–564.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
From cardiac mitochondrial dysfunction to clinical arrhythmias☆ David Montaigne a,b,c,d,e,⁎, Xavier Maréchal a,b,c,d, Dominique Lacroix f, Bart Staels a,b,c,d a
Université Lille 2, F-59000 Lille, France Inserm, U1011, F-59000 Lille, France c EGID, F-59000 Lille, France d Institut Pasteur de Lille, F-59019 Lille, France e Service d'Explorations Fonctionnelles CardioVasculaires, University Hospital of Lille, France f Clinique de Cardiologie, Service de Rythmologie, University Hospital of Lille, France b
a r t i c l e
i n f o
Article history: Received 16 January 2015 Accepted 1 March 2015 Available online 3 March 2015 Keywords: Mitochondria Arrhythmia Electrophysiology
Bench studies identified cardiac mitochondria as new key players in the control of cardiac electrical function. After briefly exposing relevant basic principles of mitochondrial physiology, we detail mechanisms and recent translational data linking cardiac arrhythmias and mitochondrial dysfunction.
1. Mitochondrial physiology Mitochondria are subcellular organelles playing important roles in most cellular biological processes [1]. Among the most critical functions are: (i) providing the cell with a constant and adaptive amount of energy through the synthesis of adenosine triphosphate (ATP) via oxidative phosphorylation by the respiratory chain complexes; (ii) dealing with cellular reactive oxygen species (ROS), by-products of mitochondrial respiration which can activate cell death signaling pathways; and (iii) participating in calcium homeostasis through a cross-talk between sarcoplasmic reticulum and mitochondria calcium crosstalk, energized mitochondria being able to accumulate calcium. The heart is one of the organs with the highest rates of energy conversion in the body, being critically dependent on mitochondrial oxidative phosphorylation as a major source of ATP [1]. Mitochondrial oxidative phosphorylation which takes place along the inner mitochondrial membrane, is to the oxidation of reduced forms of nicotinamide ☆ No disclosure to declare. ⁎ Corresponding author at: University Lille 2, place de Verdun, Lille Cedex 59045 France. E-mail address: [email protected] (D. Montaigne).
http://dx.doi.org/10.1016/j.ijcard.2015.03.012 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH), produced during fatty acid beta-oxidation and by the citric acid cycle, by oxygen allowing the synthesis of adenosine tri-phosphate (ATP) (Fig. 1). The oxidative process is catalyzed by the 4 respiratory chain complexes (complexes I, II, III and IV) with oxygen as final electron acceptor at complex IV. Along the consecutive oxido-reduction reactions, part of the high redox energy of the electrons from NADH and FADH is turned into an electrochemical gradient of protons across the mitochondrial inner membrane, protons being pumped from the matrix to the inter-membrane space by complexes I, III and IV. As such mitochondrial respiration creates a mitochondrial membrane potential (ΔΨm) which is the driving force by which mitochondria participate in cardiomyocyte calcium homeostasis: cytosolic calcium cations are driven by mitochondria into its matrix which is negatively charged. The proton gradient allows the ATP synthase (F1–F0 ATPase) to synthesize energy-enriched ATP from ADP, a process called phosphorylation. In physiology, oxidation and phosphorylation are coupled. Reactive oxygen species (ROS) are highly reactive compounds which become harmful when produced in large amounts. Minute amounts of ROS are by-products of normal mitochondrial respiration and are involved in physiologic signaling pathways in cardiomyocyte. Yet, produced in large amounts during mitochondrial dysfunction, ROS activate cardiomyocyte cell death signaling pathways. Thus, mitochondria are key players in cardiomyocyte bioenergetics preventing any mismatch between ATP production and utilization. Thus, it is not surprising that mitochondrial dysfunction can contribute to the development of arrhythmia. 2. Mechanisms linking mitochondrial dysfunction and arrhythmia Inherited and acquired mitochondrial disorders are responsible for cardiac function impairment, and can thus indirectly lead to arrhythmias complicating myocardial remodeling in an unspecific manner. However, the direct involvement of mitochondria in cardiac electrical function has recently emerged from in vitro studies showing that modulation of mitochondrial respiration, membrane potential, and ion channels alter action potential genesis and myocardial conduction properties [2,3]. Almost half of cardiomyocyte ATP is consumed for ion channel homeostasis, i.e. sarcolemmal and sarcoplasmic reticulum pumps and transporters, which is mandatory for proper electrical activity. In
598
D. Montaigne et al. / International Journal of Cardiology 184 (2015) 597–599
Fig. 1. Mitochondrial oxidative phosphorylation. Details in text. β: fatty acid beta-oxidation; κ: citric acid cycle.
conditions of mitochondrial dysfunction or increased metabolic stress such as myocardial ischemia, the resulting loss in mitochondrial membrane potential diminishes ATP synthesis, thus disrupting electrical stability by reducing the energy supply to these channels and transporters (Fig. 2). Moreover, a drop of the ATP/ADP ratio results in the opening of the sarcolemmal KATP channels, which slows electrical propagation by creating current sinks in the myocardium and shortens refractory periods, both promoting arrhythmias [4–6]. ROS are by-products of mitochondrial respiration and mitochondria harbor major cellular anti-ROS systems (e.g. manganese superoxide dismutase, glutathione peroxidase, glutathione). Mitochondria are thus master regulators of redox status and signaling in cardiomyocyte. Mitochondrial dysfunction leads to increased ROS production which has been shown to directly alter cardiomyocyte excitability and cellto-cell coupling (Fig. 2) [7–9]. The latter is mainly regulated by connexins (Cx) which normally translocate between the sarcolemma and the cytosol, and are regulated by de/re-phosphorylation by protein
phosphatase1 (PP1)/PKA [10]. During ischemia, myocardial conduction velocity is slowed due to reduced Cx phosphorylation resulting in the translocation of Cx to the cytosol [11]. During reperfusion, Cx translocate back to the sarcolemmal gap junctions to recover conduction velocity in a PP1-dependent manner [10]. Interestingly, PP1 activity is affected by high levels of ROS [10,12]. Therefore, by increasing ROS production, mitochondrial dysfunction may maintain PP1 activity, preserve Cx de-phosphorylation, and reduce recovery in normal conduction velocity. Regarding cardiomyocyte excitability, arrhythmias following ROS exposure have been observed in reperfused ischemic rat myocardium [13] or in the failing pig heart [14]. These arrhythmias are ascribed to a severe impairment in calcium homeostasis [15]. In this context, the sarcolemmal sodium–calcium exchanger (NCX) plays a pivotal role in the generation of transient inward currents involved in delayed after-depolarization secondary to spontaneous calcium release from the sarcoplasmic reticulum [16]. Moreover, long-term ROS exposure promotes cardiomyocyte hypertrophy, apoptosis and interstitial
Fig. 2. Mechanisms linking mitochondrial dysfunction and arrhythmias. Mitochondrial dysfunction results in the shortening of the action potential as a result of the opening of the sarcolemmal KATP channel, due to a low ATP/ADP ratio and an inhibition of the calcium (ICa++) and sodium (INa+) depolarising current by redox modifications of their related sarcolemmal channels. Weak INa+ current and ROS-induced connexin (Cx) modifications lead to poor cell-to-cell coupling and decreased conduction velocities in myocardium. Both increased NADH/ NAD ratio and ROS production associated with mitochondrial dysfunction modify the ryanodine receptor (RyR2) and sarcoplasmic calcium ATPase (SERCA), respectively leading to sarcoplasmic calcium leaking, and incomplete removal of calcium from the cytosol during diastole. In the absence of proper respiratory chain complex function, the mitochondrial membrane potential is low and mitochondria are unable to participate in cardiomyocyte calcium homeostasis. The resulting elevated diastolic calcium concentration in the cytosol activates the sarcolemmal Na–Ca exchanger (NCX), which is responsible for delayed after-depolarizations (DADs). Shortened action potential, low conduction velocities and DAD render the myocardium displaying mitochondrial dysfunction more prone to arrhythmias.
D. Montaigne et al. / International Journal of Cardiology 184 (2015) 597–599
fibrosis by activating redox-sensitive transcription factors and inducing transcription of pro-inflammatory cytokines and chemokine genes [17]. Therefore, ROS may be arrhythmogenic by creating chronic damages together with initiating paroxysmal arrhythmias. 3. Insights from translational studies in patients Our group has recently demonstrated that pre-operative mitochondrial dysfunction of the atrial myocardium is associated with increased incidence of atrial fibrillation after cardiac surgery, identifying the mitochondrium as a potential player in clinically relevant arrhythmias [18]. Moreover, in a small size study, remote ischemic preconditioning has been reported to preserve atrial mitochondrial function during cardiac surgery and decrease post-operative atrial fibrillation incidence in patients [19]. These promising translational data warrant further investigation to explore mitochondria as potential therapeutic targets in clinical arrhythmias particularly in diabetic patients which display cardiac mitochondrial dysfunction [20]. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] R.S. Balaban, Perspectives on: SGP symposium on mitochondrial physiology and medicine: metabolic homeostasis of the heart, J. Gen. Physiol. 139 (2012) 407–414. [2] D.A. Brown, B. O'Rourke, Cardiac mitochondria and arrhythmias, Cardiovasc. Res. 88 (2010) 241–249. [3] E.M. Jeong, M. Liu, M. Sturdy, et al., Metabolic stress, reactive oxygen species, and arrhythmia, J. Mol. Cell. Cardiol. 52 (2012) 454–463. [4] B. O'Rourke, B.M. Ramza, E. Marban, Oscillations of membrane current and excitability driven by metabolic oscillations in heart cells, Science 265 (1994) 962–966. [5] L. Zhou, S. Solhjoo, B. Millare, et al., Effects of regional mitochondrial depolarization on electrical propagation: implications for arrhythmogenesis, Circ. Arrhythm. Electrophysiol. 7 (2014) 143–151. [6] R.M. Smith, R. Visweswaran, I. Talkachova, J.K. Wothe, E.G. Tolkacheva, Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart, Am. J. Physiol. Heart Circ. Physiol. 305 (2013) H9–H18.
599
[7] A.A. Sovari, C.A. Rutledge, E.M. Jeong, et al., Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death, Circ. Arrhythm. Electrophysiol. 6 (3) (2013) 623–631. [8] A.V. Zima, J. Kockskämper, R. Mejia-Alvarez, L.A. Blatter, Pyruvate modulates cardiac sarcoplasmic reticulum Ca2 + release in rats via mitochondria-dependent and -independent mechanisms, J. Physiol. 550 (2003) 765–783. [9] M. Liu, H. Liu, S.C. Dudley Jr., Reactive oxygen species originating from mitochondria regulate the cardiac sodium channel, Circ. Res. 107 (2010) 967–974. [10] M. Jeyaraman, S. Tanguy, R.R. Fandrich, A. Lukas, E. Kardami, Ischaemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by okadaic acid and calyculin A but not fostriecin, Mol. Cell. Biochem. 242 (2003) 129–134. [11] M.A. Beardslee, D.L. Lerner, P.N. Tadros, J.G. Laing, E.C. Beyer, K.A. Yamada, A.G. Kleber, R.B. Schuessler, J.E. Saffitz, Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischaemia, Circ. Res. 87 (2000) 656–662. [12] J.S. Fetrow, N. Siew, J. Skolnick, Structure-based functional motif identifies a potential disulfide oxidoreductase active site in the serine/threonine protein phosphatase-1 subfamily, FASEB J. 13 (1999) 1866–1874. [13] T. Ravingerova, J. Slezak, N. Tribulova, A. Dzurba, B. Uhrik, A. Ziegelhoffer, Free oxygen radicals contribute to high incidence of reperfusion-induced arrhythmias in isolated rat heart, Life Sci. 65 (1999) 1927–1930. [14] F. Brigadeau, P. Gelé, C. Marquié, B. Soudan, D. Lacroix, Ventricular arrhythmias following exposure of failing hearts to oxydative stress in vitro, J. Cardiovasc. Electrophysiol. 16 (2005) 629–636. [15] W.D. Gao, Y. Liu, E. Marban, Selective effects of oxygen free radicals on excitation– contraction coupling in ventricular muscle: implications for the mechanism of stunned myocardium, Circulation 94 (1996) 2597–2604. [16] J. Fauconnier, S. Roberge, N. Saint, A. Lacampagne, Type 2 ryanodine receptor: a novel therapeutic target in myocardial ischemia/reperfusion, Pharmacol. Ther. 138 (3) (2013 Jun) 323–332. [17] H.M. Lander, An essential role for free radicals and derived species in signal transduction, FASEB J. 11 (1997) 118–124. [18] D. Montaigne, X. Marechal, P. Lefebvre, et al., Mitochondrial dysfunction as an arrhythmogenic substrate: a translational proof-of-concept study in patients with metabolic syndrome in whom post-operative atrial fibrillation develops, J. Am. Coll. Cardiol. 62 (2013) 1466–1473. [19] K.H. Slagsvold, O. Rognmo, M. Høydal, U. Wisløff, A. Wahba, Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery, Circ. Res. 114 (2014) 851–859. [20] D. Montaigne, X. Marechal, A. Coisne, et al., Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients, Circulation 130 (2014) 554–564.