- Email: [email protected]
Editorial commentary: This sodium current may be late, but it is important
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
This sodium current may be late, but it is important Wayne R. Giles, PhDa,b,n, and Edward E. Carmeliet, MD, PhDc a
Faculty of Kinesiology, University of Calgary, Calgary, Canada Faculty of Medicine, University of Calgary, Calgary, Canada c Faculty of Medicine, K.U.L., Leuven, Belgium b
In this issue of Trends in Cardiovascular Medicine, Makielski [1] provides a timely, succinct, and well-illustrated review on the established and emerging roles of the late Naþ current in Clinical Cardiac Electrophysiology. This manuscript is likely to serve as an important resource/reference for basic scientists and clinical fellows, as well as tertiary care physicians. Characteristics of the late Naþ current, INaL, are briefly summarized with the assistance of the related review articles by Belardinelli and his colleagues [2,3] and others [4] From this background it is known that the INaL (i) arises from Naþ influx through the conventional heart Naþ channel α subunit, Nav1.5, (ii) consists of a small very slowly inactivating component of the much larger rapid transient or peak Naþ current that is responsible for action potential depolarization, intercellular conduction, and the absolute refractory period, and (iii) is a drug target of increasing importance. Its pharmacological (anti-arrhythmic) is due to the fact that this Naþ conductance is significantly enhanced or up-regulated in a large (and growing) number of genetic or acquired settings/ conditions that initiate, enhance, or sustain arrhythmogenic activity in both ventricular substrates and in the atria [5]. Makielski [1] draws attention to the slow reactivation of INaL as a potentially important principle in rationalizing its role in health and disease; and in attempting to further understand when, and how, INaL can provide the equivalent of an electrophysiological “trigger” for ventricular and/or supra-ventricular rhythm disturbances. We agree with this emphasis. In fact, a number of the early descriptions of the “persistent or window” Naþ current in Purkinje tissue recognized that (i) the inactivation of the peak vs. the late component of INa in mammalian hearts were separate and
distinct processes [6–8] and (ii) that these reactivation mechanisms contributed importantly to the corresponding fast and slow phase of electrical restitution of the ventricles. This reactivation concept is important when restitution is measured in terms of either recovery of the conduction velocity or action potential duration or APD [9]. Subsequent experimental and theoretical work has provided important insights into the changes that arise from the slow recovery of INaL, coupled with the strong dependence of its reactivation kinetics on the diastolic membrane potential. It is also important that late INa flows during the plateau of the action potential [10]. The plateau of the mammalian cardiac action potential is a phase/time period during which the myocyte or syncytium exhibits very high input resistance. Accordingly, the associated net currents that are critical for initiating action potential repolarization and providing the “repolarization reserve” in atria and ventricles are very small, both under baseline conditions and in pathophysiological settings [11]. Activation or enhancement of the late Na+ current can significantly change this net current “set point”. A second point of emphasis in this Makielski review [1] is that the Naþ influx that corresponds to the small (10–50 pA/ myocyte) but long-lasting late Naþ current may significantly increase intracellular Naþ, [Naþ]i in the myocyte/ventricular myocardium. The Makielski group has addressed this possibility previously [12] based in part on the published findings of others [13,14]. Nevertheless, direct evidence for this important concept/change remains quite limited. We note that (i) in the globally ischemic myocardium [Naþ]i levels can be elevated substantially [15,16] and (ii) during maintained ventricular tachycardia or persistent atrial fibrillation [Naþ]i may
The authors have indicated there are no conflicts of interest. n Corresponding author at: Faculty of Kinesiology, University of Calgary, Calgary, Canada. Tel.: þ1 403 220 4280. E-mail address: [email protected] (W.R. Giles). http://dx.doi.org/10.1016/j.tcm.2015.06.003 1050-1738/& 2016 Elsevier Inc. All rights reserved.
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increase [9,10]. It is plausible that the Naþ influx due to the late INa flows into a small or restricted intracellular space/ volume of distribution within each “affected” myocyte. As documented previously [17] in analyses of [Naþ]i in this “fuzzy space” even a very small but maintained Naþ influx can indeed increase [Naþ]i. This change may alter other essential cellular physiology transport processes and result in time- and frequency-dependent changes in the action potential when analyzed in terms of either the onset or recovery time-course [18]. Such an increase in [Naþ]i would also be expected to disrupt pH homeostasis in the myocyte and alter associated intercellular communication [19]. Changes of this kind can also reduce the effectiveness of, and perhaps even reverse, Naþ/Ca2þ exchanger current [20]. As Makielski [1] notes, an extensive body of recent literature links enhanced late Naþ current to associated increases in intracellular Ca2þ and activation of calmodulin-dependent kinases that then further augments late INa by an established site-specific phosphorylation of defined residues of the Nav1.5 α subunit [21–23]. There is substantial precedent for this type of calmodulin-mediated signaling being both isoform specific and spatially constrained due to the essential signaling molecules (the signalosome components) being physically positioned by scaffolding proteins and related components of the extracellular matrix [24]. In this review [1] attention is drawn to the fact that agents that block late INa often are associated with a significant coronary vasodilation. In fact, the most fully characterized and tested late INa blocker, ranolazine, was originally developed as a coronary circulation vasodilator [25]. At that time, it was hypothesized that the vasorelaxation of the coronary circulation arose from an inhibition of one or more of the AMP kinases (the so-called energetic switches) isoforms that are expressed in heart tissue. Although this predominantly biochemical mechanism for the action of ranolazine is now known to be incorrect, it is interesting that inhibition of AMP kinases in atrium in fact does result in an augmented late Naþ current that is ranolazine-sensitive [26]. The Belardinelli group and others5 have advanced a plausible alternative working hypothesis for the well-known effects of ranolazine on the coronary circulation: late INa is expressed/manifested in a heterogeneous fashion across the transmural aspect of the left ventricle [27]. This raises the possibility that the timecourse of the contraction changes when ranolazine is applied are such that (on average) the coronary arteries and microcirculation are compressed for a reduced time during each systole and thus LV perfusion is augmented by ranolazine. This seems plausible. However, there are reports that the endothelial cells of the coronary vasocirculation express Naþ channels [28] and that TTX-sensitive Naþ current can be identified in endothelial cell preparations that have been maintained in conventional 2-D culture [29]. Interestingly ranolazine has a considerable inhibitory effect on the sensitivity of endothelial cells to changes in shear forces [30,31]. The principle that inhibition of late Naþ current can lead to electrophysiological stabilization of the mammalian heart in a variety of important contexts continues to be pursued with promising clinical results. In addition, supportive, consistent multidisciplinary data from animal models has been complemented with mathematical modeling [32] that illustrates anti-
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arrhythmic efficacy. A number of new agents have now been developed and are being tested extensively in attempts to achieve improved selectivity as judged by preferential, perhaps selective actions on Naþ channel isoforms, and/or on the peak vs. late component of INa [33]. As an example, the free radical (primarily hydrogen peroxide) challenge that is associated with sterile inflammation of the myocardium includes strong activation of the late Naþ current [34]. In principle, the proarrhythmic phenotype of this substrate could be addressed with ranolazine-like compounds. It will be necessary however, to have detailed knowledge of the pharmacokinetics and volume of distribution of these compounds, with emphasis on whether or not they cross the blood–brain barrier since a “persistent Naþ background” current is an essential component of the mammalian CNS respiratory oscillator/pacemaker [35]. Finally, even when the late Naþ current in the heart is the drug target it is important to recall that a number of different isoforms of both cardiac and nerve Naþ channel α subunits and their related β subunit complement are expressed in the various cell types that comprise both the atrial and the ventricular myocardium [36,37]. The primary material that the Makielski review provides will be very useful in rationalizing and taking advantage of future opportunities and challenges associated with selective modulation of late Naþ current in the mammalian heart.
Acknowledgments Financial support from the Canadian Institutes for Health Research and an Alberta Innovates Health Solutions Scientist Award (WRG) is gratefully acknowledged.
re fe r en ces
[1]
[2]
[3]
[4]
[5]
[6]
[7] [8]
[9]
Makielski JC. Late sodium current: a mechanism for angina, heart failure, and arrhythmia. Trends Cardiovasc Med 2015;26:115–22. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac ‘late sodium current’. Pharmacol Ther 2008;119:326–39. Shryock JC, Song Y, Rajamani S, Antzelevitch C, Belardinelli L. The arrhythmogenic consequences of increasing late INa in the cardiomyocyte. Cardiovasc Res 2013;99:600–11. Sossalla S, Maier LS. Role of ranolazine in angina, heart failure, arrhythmias and diabetes. Pharmacol Ther 2012;133: 311–23. Belardinelli L, Giles WR, Rajamani S, Karagueuzian HS, Shryock JC. Cardiac late Naþ current: proarrhythmic effects, roles in long QT syndromes and pathological relationship to CaMKII and oxidative stress. Heart Rhythm 2015;12:440–8. Liu YM, De Felice LJ, Mazzanti M. Naþ channels that remain open throughout the cardiac action potential plateau. Biophys J 1992;63:654–62. Carmeliet E. Slow inactivation of the sodium current in rabbit cardiac Purkinje fibres. Pflügers Archiv 1987;408:18–26. Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady state TTX-sensitive (window) sodium current in cardiac Purkinje fibres. Pflügers Archiv 1979;379:137–42. Attwell D, Cohen I, Eisner DA. The effects of heart rate on the action potential of guinea-pig and human ventricular muscle. J Physiol 1981;313:439–61.
TR
[10]
[11] [12]
[13]
[14]
[15] [16]
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
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Carmeliet E. Action potential duration, rate of stimulation, and intracellular sodium. J Cardiovasc Electrophysiol 2006;17:S2–7. Carmeliet E. Electrical alternans: membrane-limited and subcellular components. J Cardiovasc Electrophysiol 2006;17:94–6. Makielski JC, Farley AL. Naþ current in human ventricle: implications for sodium loading and homeostasis. J Cardiovasc Electrophysiol 2006;1:S15–20. Bosteels S, Carmeliet E. Estimation of intracellular Na concentration and transmembrane Na flux in cardiac Purkinje fibres. Pflugers Archiv 1972;336:35–47. Verdonck F, Volders PG, Vos MA, Sipido KR. Increased Naþ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells. Cardiovasc Res 2003;57:1035–43. Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev 1999;79:917–1017. Van Emous JG, Nederhoff GJ, Ruigrok TJC, Van Echteld CJ. The role of the Naþ channel in the accumulation of intracellular Naþ during myocardial ischemia: consequences for postischemic recovery. J Mol Cell Cardiol 1997;29:85–96. Carmeliet E. A fuzzy subsarcolemmal space for intracellular Naþ in cardiac cells? Cardiovasc Res 1992;26:433–42. Horvath B, Banyasz T, Zhong J, Hegyi B, Kistamas K, Nanasi PP, et al. Dynamics of the late Naþ current during cardiac action potential and its contribution to afterdepolarizations. J Mol Cell Cardiol 2013;64:59–68. Swietach P, Spitzer KW, Vaughan-Jones RD. Naþ ions as spatial intracellular messengers for co-ordinating Ca2þ signals during pH heterogeneity in cardiomyocytes. Cardiovasc Res 2015;105(2):171–81. Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodiumcalcium overload. Heart 2006;92(Suppl. 4):iv1–5. Ben-Johny M, Yang PS, Niu J, Yang W, Joshi-Mukherjee R, Yue DT. Conservation of Ca2þ/calmodulin regulation across Na and Ca2þ channels. Cell 2014;157:1657–70. Ma H, Groth RD, Cohen SM, Emery JF, Li B, Hoedt E, et al. yCaMKII shuttles Ca2þ/CaM to the nucleus to trigger CREB phosphorylation and gene expression. Cell 2014;159:281–94. Xie LH, Chen F, Karagueuzian HS, Weiss JN. Oxidative stress-induced afterdepolarizations and calmodulin kinase II signaling. Circ Res 2009;104:79–86. Abriel H. Cardiac sodium channel Nav1.5 and interacting proteins: physiology and pathophysiology. J Mol Cell Cardiol 2010;48:2–11. Morrow DA, Scirica BM, Chaitman BR, McGuire DK, Murphy SA, Karwatowska-Prokopczuk E, et al. Evaluation of the glycometabolic effects of ranolazine in patients with and
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[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
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without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation 2009;119:2032–9. Bazzazi H, Clark RB, Giles WR. Mathematical simulations of the effects of altered AMP kinase activity on INa and the action potential in rat ventricle. J Cardiovasc Electrophysiol 2006;17:S162–8. Ashamalla SM, Navarro D, Ward CA. Gradient of sodium current across the left ventricular wall of adult rat hearts. J Physiol 2001;536:439–43. Walsh KB, Wolf MB, Fan J. Voltage-gated sodium channels in cardiac microvascular endothelial cells. Am J Physiol 1998;274:H506–12. Andrikopoulos P, Fraser SP, Patterson L, Ahmad Z, Burcu H, Ottaviani D, et al. Angiogenic functions of voltage-gated Naþ channels in human endothelial cells. J Biol Chem 2011;286:16846–60. Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009;61:16–26. Strege P, Beyder A, Bernard C, Crespo-Diaz R, Behfar A, Terzic A, et al. Ranolazine inhibits shear sensitivity of endogenous Naþ current and spontaneous action potentials in HL-1 cells. Channels 2012;6:457–62. Yang PC, Song Y, Giles WR, Horvath B, Chen-Izu Y, Belardinelli L, et al. A computational modeling approach combined with cellular electrophysiology data provides insights into the therapeutic benefit of targeting the late Nþ current. J Physiol 2015;593:1429–42. Bonatti R, Garcia Silva AF, Pereira Batatinha JA, Sobrado LF, Machado AD, Varone BB, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemiainduced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm 2014;11:1827–35. Ward CA, Bazzazi H, Clark RB, Nygren A, Giles WR. Actions of emigrated neutrophils on Naþ and Kþ currents in rat ventricular myocytes. Prog Biophys Mol Biol 2006;90:249–69. Montandon G, Horner RL. State-dependent contribution of the hyperpolarization-activated Naþ/Kþ and persistent Naþ currents to respiratory rhythmogenesis in vivo. J Neurosci 2013;33:8716–28. Calhoun JD, Isom LL. The role of non-pore-forming β subunits in physiology and pathophysiology of voltagegated sodium channels. Handb Exp Pharmacol 2014;221: 51–89. Biet M, Barajas-Martinez H, Ton AT, Delabre JF, Morin N, Dumaine R. About half of the late sodium current in cardiac myocytes from dog ventricle is due to non-cardiac-type Naþ channels. J Mol Cell Cardiol 2012;53:593–8.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
This sodium current may be late, but it is important Wayne R. Giles, PhDa,b,n, and Edward E. Carmeliet, MD, PhDc a
Faculty of Kinesiology, University of Calgary, Calgary, Canada Faculty of Medicine, University of Calgary, Calgary, Canada c Faculty of Medicine, K.U.L., Leuven, Belgium b
In this issue of Trends in Cardiovascular Medicine, Makielski [1] provides a timely, succinct, and well-illustrated review on the established and emerging roles of the late Naþ current in Clinical Cardiac Electrophysiology. This manuscript is likely to serve as an important resource/reference for basic scientists and clinical fellows, as well as tertiary care physicians. Characteristics of the late Naþ current, INaL, are briefly summarized with the assistance of the related review articles by Belardinelli and his colleagues [2,3] and others [4] From this background it is known that the INaL (i) arises from Naþ influx through the conventional heart Naþ channel α subunit, Nav1.5, (ii) consists of a small very slowly inactivating component of the much larger rapid transient or peak Naþ current that is responsible for action potential depolarization, intercellular conduction, and the absolute refractory period, and (iii) is a drug target of increasing importance. Its pharmacological (anti-arrhythmic) is due to the fact that this Naþ conductance is significantly enhanced or up-regulated in a large (and growing) number of genetic or acquired settings/ conditions that initiate, enhance, or sustain arrhythmogenic activity in both ventricular substrates and in the atria [5]. Makielski [1] draws attention to the slow reactivation of INaL as a potentially important principle in rationalizing its role in health and disease; and in attempting to further understand when, and how, INaL can provide the equivalent of an electrophysiological “trigger” for ventricular and/or supra-ventricular rhythm disturbances. We agree with this emphasis. In fact, a number of the early descriptions of the “persistent or window” Naþ current in Purkinje tissue recognized that (i) the inactivation of the peak vs. the late component of INa in mammalian hearts were separate and
distinct processes [6–8] and (ii) that these reactivation mechanisms contributed importantly to the corresponding fast and slow phase of electrical restitution of the ventricles. This reactivation concept is important when restitution is measured in terms of either recovery of the conduction velocity or action potential duration or APD [9]. Subsequent experimental and theoretical work has provided important insights into the changes that arise from the slow recovery of INaL, coupled with the strong dependence of its reactivation kinetics on the diastolic membrane potential. It is also important that late INa flows during the plateau of the action potential [10]. The plateau of the mammalian cardiac action potential is a phase/time period during which the myocyte or syncytium exhibits very high input resistance. Accordingly, the associated net currents that are critical for initiating action potential repolarization and providing the “repolarization reserve” in atria and ventricles are very small, both under baseline conditions and in pathophysiological settings [11]. Activation or enhancement of the late Na+ current can significantly change this net current “set point”. A second point of emphasis in this Makielski review [1] is that the Naþ influx that corresponds to the small (10–50 pA/ myocyte) but long-lasting late Naþ current may significantly increase intracellular Naþ, [Naþ]i in the myocyte/ventricular myocardium. The Makielski group has addressed this possibility previously [12] based in part on the published findings of others [13,14]. Nevertheless, direct evidence for this important concept/change remains quite limited. We note that (i) in the globally ischemic myocardium [Naþ]i levels can be elevated substantially [15,16] and (ii) during maintained ventricular tachycardia or persistent atrial fibrillation [Naþ]i may
The authors have indicated there are no conflicts of interest. n Corresponding author at: Faculty of Kinesiology, University of Calgary, Calgary, Canada. Tel.: þ1 403 220 4280. E-mail address: [email protected] (W.R. Giles). http://dx.doi.org/10.1016/j.tcm.2015.06.003 1050-1738/& 2016 Elsevier Inc. All rights reserved.
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increase [9,10]. It is plausible that the Naþ influx due to the late INa flows into a small or restricted intracellular space/ volume of distribution within each “affected” myocyte. As documented previously [17] in analyses of [Naþ]i in this “fuzzy space” even a very small but maintained Naþ influx can indeed increase [Naþ]i. This change may alter other essential cellular physiology transport processes and result in time- and frequency-dependent changes in the action potential when analyzed in terms of either the onset or recovery time-course [18]. Such an increase in [Naþ]i would also be expected to disrupt pH homeostasis in the myocyte and alter associated intercellular communication [19]. Changes of this kind can also reduce the effectiveness of, and perhaps even reverse, Naþ/Ca2þ exchanger current [20]. As Makielski [1] notes, an extensive body of recent literature links enhanced late Naþ current to associated increases in intracellular Ca2þ and activation of calmodulin-dependent kinases that then further augments late INa by an established site-specific phosphorylation of defined residues of the Nav1.5 α subunit [21–23]. There is substantial precedent for this type of calmodulin-mediated signaling being both isoform specific and spatially constrained due to the essential signaling molecules (the signalosome components) being physically positioned by scaffolding proteins and related components of the extracellular matrix [24]. In this review [1] attention is drawn to the fact that agents that block late INa often are associated with a significant coronary vasodilation. In fact, the most fully characterized and tested late INa blocker, ranolazine, was originally developed as a coronary circulation vasodilator [25]. At that time, it was hypothesized that the vasorelaxation of the coronary circulation arose from an inhibition of one or more of the AMP kinases (the so-called energetic switches) isoforms that are expressed in heart tissue. Although this predominantly biochemical mechanism for the action of ranolazine is now known to be incorrect, it is interesting that inhibition of AMP kinases in atrium in fact does result in an augmented late Naþ current that is ranolazine-sensitive [26]. The Belardinelli group and others5 have advanced a plausible alternative working hypothesis for the well-known effects of ranolazine on the coronary circulation: late INa is expressed/manifested in a heterogeneous fashion across the transmural aspect of the left ventricle [27]. This raises the possibility that the timecourse of the contraction changes when ranolazine is applied are such that (on average) the coronary arteries and microcirculation are compressed for a reduced time during each systole and thus LV perfusion is augmented by ranolazine. This seems plausible. However, there are reports that the endothelial cells of the coronary vasocirculation express Naþ channels [28] and that TTX-sensitive Naþ current can be identified in endothelial cell preparations that have been maintained in conventional 2-D culture [29]. Interestingly ranolazine has a considerable inhibitory effect on the sensitivity of endothelial cells to changes in shear forces [30,31]. The principle that inhibition of late Naþ current can lead to electrophysiological stabilization of the mammalian heart in a variety of important contexts continues to be pursued with promising clinical results. In addition, supportive, consistent multidisciplinary data from animal models has been complemented with mathematical modeling [32] that illustrates anti-
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26 (2016) 123–125
arrhythmic efficacy. A number of new agents have now been developed and are being tested extensively in attempts to achieve improved selectivity as judged by preferential, perhaps selective actions on Naþ channel isoforms, and/or on the peak vs. late component of INa [33]. As an example, the free radical (primarily hydrogen peroxide) challenge that is associated with sterile inflammation of the myocardium includes strong activation of the late Naþ current [34]. In principle, the proarrhythmic phenotype of this substrate could be addressed with ranolazine-like compounds. It will be necessary however, to have detailed knowledge of the pharmacokinetics and volume of distribution of these compounds, with emphasis on whether or not they cross the blood–brain barrier since a “persistent Naþ background” current is an essential component of the mammalian CNS respiratory oscillator/pacemaker [35]. Finally, even when the late Naþ current in the heart is the drug target it is important to recall that a number of different isoforms of both cardiac and nerve Naþ channel α subunits and their related β subunit complement are expressed in the various cell types that comprise both the atrial and the ventricular myocardium [36,37]. The primary material that the Makielski review provides will be very useful in rationalizing and taking advantage of future opportunities and challenges associated with selective modulation of late Naþ current in the mammalian heart.
Acknowledgments Financial support from the Canadian Institutes for Health Research and an Alberta Innovates Health Solutions Scientist Award (WRG) is gratefully acknowledged.
re fe r en ces
[1]
[2]
[3]
[4]
[5]
[6]
[7] [8]
[9]
Makielski JC. Late sodium current: a mechanism for angina, heart failure, and arrhythmia. Trends Cardiovasc Med 2015;26:115–22. Zaza A, Belardinelli L, Shryock JC. Pathophysiology and pharmacology of the cardiac ‘late sodium current’. Pharmacol Ther 2008;119:326–39. Shryock JC, Song Y, Rajamani S, Antzelevitch C, Belardinelli L. The arrhythmogenic consequences of increasing late INa in the cardiomyocyte. Cardiovasc Res 2013;99:600–11. Sossalla S, Maier LS. Role of ranolazine in angina, heart failure, arrhythmias and diabetes. Pharmacol Ther 2012;133: 311–23. Belardinelli L, Giles WR, Rajamani S, Karagueuzian HS, Shryock JC. Cardiac late Naþ current: proarrhythmic effects, roles in long QT syndromes and pathological relationship to CaMKII and oxidative stress. Heart Rhythm 2015;12:440–8. Liu YM, De Felice LJ, Mazzanti M. Naþ channels that remain open throughout the cardiac action potential plateau. Biophys J 1992;63:654–62. Carmeliet E. Slow inactivation of the sodium current in rabbit cardiac Purkinje fibres. Pflügers Archiv 1987;408:18–26. Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C. The steady state TTX-sensitive (window) sodium current in cardiac Purkinje fibres. Pflügers Archiv 1979;379:137–42. Attwell D, Cohen I, Eisner DA. The effects of heart rate on the action potential of guinea-pig and human ventricular muscle. J Physiol 1981;313:439–61.
TR
[10]
[11] [12]
[13]
[14]
[15] [16]
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
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Carmeliet E. Action potential duration, rate of stimulation, and intracellular sodium. J Cardiovasc Electrophysiol 2006;17:S2–7. Carmeliet E. Electrical alternans: membrane-limited and subcellular components. J Cardiovasc Electrophysiol 2006;17:94–6. Makielski JC, Farley AL. Naþ current in human ventricle: implications for sodium loading and homeostasis. J Cardiovasc Electrophysiol 2006;1:S15–20. Bosteels S, Carmeliet E. Estimation of intracellular Na concentration and transmembrane Na flux in cardiac Purkinje fibres. Pflugers Archiv 1972;336:35–47. Verdonck F, Volders PG, Vos MA, Sipido KR. Increased Naþ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells. Cardiovasc Res 2003;57:1035–43. Carmeliet E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev 1999;79:917–1017. Van Emous JG, Nederhoff GJ, Ruigrok TJC, Van Echteld CJ. The role of the Naþ channel in the accumulation of intracellular Naþ during myocardial ischemia: consequences for postischemic recovery. J Mol Cell Cardiol 1997;29:85–96. Carmeliet E. A fuzzy subsarcolemmal space for intracellular Naþ in cardiac cells? Cardiovasc Res 1992;26:433–42. Horvath B, Banyasz T, Zhong J, Hegyi B, Kistamas K, Nanasi PP, et al. Dynamics of the late Naþ current during cardiac action potential and its contribution to afterdepolarizations. J Mol Cell Cardiol 2013;64:59–68. Swietach P, Spitzer KW, Vaughan-Jones RD. Naþ ions as spatial intracellular messengers for co-ordinating Ca2þ signals during pH heterogeneity in cardiomyocytes. Cardiovasc Res 2015;105(2):171–81. Noble D, Noble PJ. Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodiumcalcium overload. Heart 2006;92(Suppl. 4):iv1–5. Ben-Johny M, Yang PS, Niu J, Yang W, Joshi-Mukherjee R, Yue DT. Conservation of Ca2þ/calmodulin regulation across Na and Ca2þ channels. Cell 2014;157:1657–70. Ma H, Groth RD, Cohen SM, Emery JF, Li B, Hoedt E, et al. yCaMKII shuttles Ca2þ/CaM to the nucleus to trigger CREB phosphorylation and gene expression. Cell 2014;159:281–94. Xie LH, Chen F, Karagueuzian HS, Weiss JN. Oxidative stress-induced afterdepolarizations and calmodulin kinase II signaling. Circ Res 2009;104:79–86. Abriel H. Cardiac sodium channel Nav1.5 and interacting proteins: physiology and pathophysiology. J Mol Cell Cardiol 2010;48:2–11. Morrow DA, Scirica BM, Chaitman BR, McGuire DK, Murphy SA, Karwatowska-Prokopczuk E, et al. Evaluation of the glycometabolic effects of ranolazine in patients with and
M
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[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
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