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Small conductance Ca-activated K channel: Small but powerful proarrhythmogenic?
EDITORIAL COMMENTARY
Small conductance Ca-activated K channel: Small but powerful proarrhythmogenic? Stefan Wagner, MD, Lars S. Maier, MD, FESC, FAHA From the Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum fu¨r Herzkreislaufforschung, Georg-AugustUniversit¨at G¨ottingen, Germany.
Atrial fibrillation (AF) is the most important arrhythmia worldwide.1 Although not directly dangerous per se as compared to ventricular tachycardias, it is life-threatening because of the formation of intra-atrial thrombi and their embolization into different organs, for example, the brain. In addition, AF can cause supraventricular tachycardia, which is of special relevance for patients with impaired left ventricular function (eg, in heart failure). Its occurrence can be a critical step toward decompensation resulting in hospitalization, which often is followed by difficult antiarrhythmic therapy and problematic anticoagulation. AF can be maintained by 2 mechanisms: (1) very rapid focal ectopic activity (ie, from the pulmonary veins) and/or (2) various forms of reentry.2 The former is due to triggered activity because of early or delayed afterdepolarizations (EADs or DADs, respectively). EADs occur on action potential (AP) prolongation due to increased depolarizing currents or reduced repolarizing currents. Increased activity of sarcolemmal Na channels3 may be involved. DADs occur as a consequence of cellular Ca overload and spontaneous diastolic Ca release from the sarcoplasmic reticulum through the sarcoplasmic reticulum Ca release channel (RyR2). In chronic AF, diastolic activity of RyR2 has been shown to be increased possibly via increased phosphorylation.4 The second mechanism involved in persistent AF is reentry. If the distance an impulse travels within 1 refractory period (ie, the wavelength of impulse propagation) is small, reentry is favored. The wavelength, which is proportional to Dr. Wagner and Dr. Maier are funded by Deutsche Forschungsgemeinschaft (DFG) through an International Research Training Group GRK 1816 RP3. Dr Maier is funded by DFG grants MA 1982/4-2, TPA03 SFB 1002, the DZHK (Deutsches Zentrum fu¨r Herz-Kreislauf-Forschung [German Centre for Cardiovascular Research]), and the Fondation Leducq “Alliance for CaMKII Signaling in Heart” as well as “Redox and Nitrosative Regulation of Cardiac Remodeling.” Address reprint requests and correspondence: Prof. Dr. med. Lars S. Maier, Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum fu¨r Herzkreislaufforschung, Georg-August-Universit¨at G¨ottingen, Robert-Koch-Str 40, 37075 G¨ottingen, Germany. E-mail address: [email protected].
1547-5271/$-see front matter B 2013 Heart Rhythm Society. All rights reserved.
refractory period and conduction velocity, becomes smaller with shorter AP duration. The shorter AP providing the basis for the arrhythmogenic substrate is a common feature of electrical remodeling during persistent AF.2 AP shortening can be due to both reduced inward currents (eg, L-type Ca current [ICa]) and/or increased outward currents, particularly IK1 and acteylcholine-regulated K currents. In addition, several genetic variations of sarcolemmal ion channels were reported to be associated with AF, including Ca channels, Na channels, and K channels.5 Interestingly, common variants in the KCNN3 gene encoding for a small conductance Ca-activated K (SK) channel have recently been shown to be associated with lone AF.6 SK channels (SK1-SK3) are voltage insensitive and are activated by intracellular Ca (Kd 600–700 nM). One channel is made of 4 subunits, and each subunit consists of 6 transmembrane domains (similar to voltage-gated K channels). The cytoplasmatic C-terminal region has a calmodulin-binding domain, which accounts for the Ca sensitivity of the channel. This is interesting since during pathophysiological conditions such as AF and/or heart failure, intracellular Ca levels seem to be elevated, thereby possibly activating calmodulin and hence SK channels. Thus, even calmodulin-dependent kinase II that is also activated by Ca and calmodulin7 may be involved in the regulation of these channels similar to Na channels,8 but this is just a hypothesis so far. Although of small conductance ( 10 pS), SK channels have been shown to contribute to the late phase of cardiac repolarization. It was suggested that enhanced trafficking of SK2 channels to the membrane may contribute to AP shortening and electrical remodeling in AF.9 Moreover, it was shown that selective SK channel inhibitors suppressed AF in guinea pig, rat, and rabbit hearts by prolonging atrial effective refractory.10 This picture, however, was challenged by recent evidence showing that genetic ablation of SK2 significantly increases AF susceptibility in mice.11 Although species differences may account for the discrepancy, the story may be far more complex. Indeed, consistent with the role of SK channels in late phase repolarization, Li et al showed that the genetic http://dx.doi.org/10.1016/j.hrthm.2013.02.002
900 ablation of SK2 results in the expected prolongation of AP duration. However, this did not translate into reduced AF susceptibility. In contrast, SK2 null mice showed an increased propensity for EADs.11 Increased EADs can trigger very rapid focal ectopic activity. The role of increased K currents for AP prolongation and triggered activity is supported by other studies in human atrial myocytes. Olson et al12 showed that a nonsense mutation in KCN5A, which encodes for Kv1.5, can lead to AP prolongation, EADs, and AF.12 Moreover, a single nucleotide polymorphism in the KCNE1 gene encoding for the b-subunit (minK) of the delayed rectifier current IKs has been shown to be associated with AF.13 Expression of this mutant in heterologous expression systems resulted in reduced IKs.14 Thus, both reduced but also increased activity of K currents has been associated with AF. In this issue of HeartRhythm, Hsueh et al15 extend our knowledge on SK channels by pharmacologically investigating inhibitors in healthy isolated dog left atria using optical mapping and report that these promote arrhythmias. Specifically, they investigate apamin as well as UCL-1684 and find increased overall AP duration but maybe more importantly AP duration heterogeneity as well as the occurrence of electrical alternans and wave breaks. In addition to the previously suggested increased EADs, the inhibition of SK channels may also be proarrhythmic because spatial differences in SK current expression and regulation are equalized by global SK current inhibition. This could lead to altered dispersion of repolarization, which can result in reentry. Indeed, Hsueh et al show that SK channel expression is not equally distributed with less expression at the apex but higher expression at the base of the left atrial appendage. This unequal expression correlates with the effect of SK channel inhibition on APD prolongation, being more pronounced in the regions of greater SK channel expression. Although the current study provides novel information about the proarrhythmic effects of blocking SK channels in healthy dog atria, it is unclear whether the current results extrapolate to proarrhythmia in disease states such as AF, for example, in a dog model of AF. From our perspective, to resolve the discrepancies between the different studies and to understand whether blocking SK channels is beneficial or not, studies in an animal model for AF are needed as well as functional experiments in human atrial tissue. What we found interesting in the current study is that the inhibitory effects of apamin and UCL-1684 are most obvious at very long and very short pacing cycle lengths. The latter situation is typical during AF. Thus, short pacing cycle lengths that lead to intracellular Ca accumulation may activate SK channels. Hence, SK channels may considerably contribute to cardiac repolarization especially at higher heart rates.
Heart Rhythm, Vol 10, No 6, June 2013 Questions to be answered are as follows: Is the AP heterogeneity also found in pulmonary veins? How much are noncardiac cells involved in the effects of apamin and UCL-1684? There is preliminary evidence for increased SK expression and current through SK channels (ISK) in cells from pulmonary veins compared to left atrial myocytes.16 Nevertheless, these findings challenge current strategies of AF treatment. Targeting the reduced wavelength of impulse propagation by increasing AP duration (ie, by increasing ICa and reducing IK1 or ISK) may be of limited efficacy since this is archived at the expense of increased triggered activity and altered spatial heterogeneity in repolarization. Moreover, these strategies are not limited to the atrial myocardium; the same effects might occur in the ventricular myocardium substantially increasing the propensity for severe ventricular arrhythmias.
References 1. Chen LY, Shen WK. Epidemiology of atrial fibrillation: a current perspective. Heart Rhythm 2007;4:S1–S6. 2. Nattel S, Dobrev D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur Heart J 2012;33:1870–1877. 3. Sossalla S, Kallmeyer B, Wagner S, et al. Altered Naþ currents in atrial fibrillation: effects of ranolazine on arrhythmias and contractility in human atrial myocardium. J Am Coll Cardiol 2010;55:2330–2342. 4. Neef S, Dybkova N, Sossalla S, et al. CaMKII-dependent diastolic SR Ca2þ leak and elevated diastolic Ca2þ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res 2010;106:1134–1144. 5. Wakili R, Voigt N, K¨aa¨ b S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest 2011;121:2955–2968. 6. Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010;42:240–244. 7. Rokita AG, Anderson ME. New therapeutic targets in cardiology: arrhythmias and Ca2þ/calmodulin-dependent kinase II (CaMKII). Circulation 2012;126:2125–2139. 8. Maier LS. CaMKII regulation of voltage-gated Naþ channels and cell excitability. Heart Rhythm 2011;8:474–477. 9. Ozgen N, Dun W, Sosunov EA, et al. Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc Res 2007;75:758–769. 10. Diness JG, Sorensen US, Nissen JD, et al. Inhibition of small-conductance Ca2þactivated Kþ channels terminates and protects against atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:380–390. 11. Li N, Timofeyev V, Tuteja D, et al. Ablation of a Ca2þ-activated Kþ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol 2009;587:1087–1100. 12. Olson TM, Alekseev AE, Liu XK, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 2006;15:2185–2191. 13. Lai LP, Su MJ, Yeh HM, et al. Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J 2002;144:485–490. 14. Ehrlich JR, Zicha S, Coutu P, Hebert TE, Nattel S. Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res 2005;67:520–528. 15. Hsueh C-H, Chang P-C, Hsieh Y-C, Reher T, Chen PS, Lin SF. Pro-arrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium. Heart Rhythm. 2013;10:891–898. 16. Qi XY, Naud P, Brundel B, Harada M, Nattel S. Potential role of Ca2þ-dependent Kþ channels in atrial fibrillation [abstract]. Circulation 2011;124:A10620.
Small conductance Ca-activated K channel: Small but powerful proarrhythmogenic? Stefan Wagner, MD, Lars S. Maier, MD, FESC, FAHA From the Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum fu¨r Herzkreislaufforschung, Georg-AugustUniversit¨at G¨ottingen, Germany.
Atrial fibrillation (AF) is the most important arrhythmia worldwide.1 Although not directly dangerous per se as compared to ventricular tachycardias, it is life-threatening because of the formation of intra-atrial thrombi and their embolization into different organs, for example, the brain. In addition, AF can cause supraventricular tachycardia, which is of special relevance for patients with impaired left ventricular function (eg, in heart failure). Its occurrence can be a critical step toward decompensation resulting in hospitalization, which often is followed by difficult antiarrhythmic therapy and problematic anticoagulation. AF can be maintained by 2 mechanisms: (1) very rapid focal ectopic activity (ie, from the pulmonary veins) and/or (2) various forms of reentry.2 The former is due to triggered activity because of early or delayed afterdepolarizations (EADs or DADs, respectively). EADs occur on action potential (AP) prolongation due to increased depolarizing currents or reduced repolarizing currents. Increased activity of sarcolemmal Na channels3 may be involved. DADs occur as a consequence of cellular Ca overload and spontaneous diastolic Ca release from the sarcoplasmic reticulum through the sarcoplasmic reticulum Ca release channel (RyR2). In chronic AF, diastolic activity of RyR2 has been shown to be increased possibly via increased phosphorylation.4 The second mechanism involved in persistent AF is reentry. If the distance an impulse travels within 1 refractory period (ie, the wavelength of impulse propagation) is small, reentry is favored. The wavelength, which is proportional to Dr. Wagner and Dr. Maier are funded by Deutsche Forschungsgemeinschaft (DFG) through an International Research Training Group GRK 1816 RP3. Dr Maier is funded by DFG grants MA 1982/4-2, TPA03 SFB 1002, the DZHK (Deutsches Zentrum fu¨r Herz-Kreislauf-Forschung [German Centre for Cardiovascular Research]), and the Fondation Leducq “Alliance for CaMKII Signaling in Heart” as well as “Redox and Nitrosative Regulation of Cardiac Remodeling.” Address reprint requests and correspondence: Prof. Dr. med. Lars S. Maier, Abt. Kardiologie und Pneumologie/Herzzentrum, Deutsches Zentrum fu¨r Herzkreislaufforschung, Georg-August-Universit¨at G¨ottingen, Robert-Koch-Str 40, 37075 G¨ottingen, Germany. E-mail address: [email protected].
1547-5271/$-see front matter B 2013 Heart Rhythm Society. All rights reserved.
refractory period and conduction velocity, becomes smaller with shorter AP duration. The shorter AP providing the basis for the arrhythmogenic substrate is a common feature of electrical remodeling during persistent AF.2 AP shortening can be due to both reduced inward currents (eg, L-type Ca current [ICa]) and/or increased outward currents, particularly IK1 and acteylcholine-regulated K currents. In addition, several genetic variations of sarcolemmal ion channels were reported to be associated with AF, including Ca channels, Na channels, and K channels.5 Interestingly, common variants in the KCNN3 gene encoding for a small conductance Ca-activated K (SK) channel have recently been shown to be associated with lone AF.6 SK channels (SK1-SK3) are voltage insensitive and are activated by intracellular Ca (Kd 600–700 nM). One channel is made of 4 subunits, and each subunit consists of 6 transmembrane domains (similar to voltage-gated K channels). The cytoplasmatic C-terminal region has a calmodulin-binding domain, which accounts for the Ca sensitivity of the channel. This is interesting since during pathophysiological conditions such as AF and/or heart failure, intracellular Ca levels seem to be elevated, thereby possibly activating calmodulin and hence SK channels. Thus, even calmodulin-dependent kinase II that is also activated by Ca and calmodulin7 may be involved in the regulation of these channels similar to Na channels,8 but this is just a hypothesis so far. Although of small conductance ( 10 pS), SK channels have been shown to contribute to the late phase of cardiac repolarization. It was suggested that enhanced trafficking of SK2 channels to the membrane may contribute to AP shortening and electrical remodeling in AF.9 Moreover, it was shown that selective SK channel inhibitors suppressed AF in guinea pig, rat, and rabbit hearts by prolonging atrial effective refractory.10 This picture, however, was challenged by recent evidence showing that genetic ablation of SK2 significantly increases AF susceptibility in mice.11 Although species differences may account for the discrepancy, the story may be far more complex. Indeed, consistent with the role of SK channels in late phase repolarization, Li et al showed that the genetic http://dx.doi.org/10.1016/j.hrthm.2013.02.002
900 ablation of SK2 results in the expected prolongation of AP duration. However, this did not translate into reduced AF susceptibility. In contrast, SK2 null mice showed an increased propensity for EADs.11 Increased EADs can trigger very rapid focal ectopic activity. The role of increased K currents for AP prolongation and triggered activity is supported by other studies in human atrial myocytes. Olson et al12 showed that a nonsense mutation in KCN5A, which encodes for Kv1.5, can lead to AP prolongation, EADs, and AF.12 Moreover, a single nucleotide polymorphism in the KCNE1 gene encoding for the b-subunit (minK) of the delayed rectifier current IKs has been shown to be associated with AF.13 Expression of this mutant in heterologous expression systems resulted in reduced IKs.14 Thus, both reduced but also increased activity of K currents has been associated with AF. In this issue of HeartRhythm, Hsueh et al15 extend our knowledge on SK channels by pharmacologically investigating inhibitors in healthy isolated dog left atria using optical mapping and report that these promote arrhythmias. Specifically, they investigate apamin as well as UCL-1684 and find increased overall AP duration but maybe more importantly AP duration heterogeneity as well as the occurrence of electrical alternans and wave breaks. In addition to the previously suggested increased EADs, the inhibition of SK channels may also be proarrhythmic because spatial differences in SK current expression and regulation are equalized by global SK current inhibition. This could lead to altered dispersion of repolarization, which can result in reentry. Indeed, Hsueh et al show that SK channel expression is not equally distributed with less expression at the apex but higher expression at the base of the left atrial appendage. This unequal expression correlates with the effect of SK channel inhibition on APD prolongation, being more pronounced in the regions of greater SK channel expression. Although the current study provides novel information about the proarrhythmic effects of blocking SK channels in healthy dog atria, it is unclear whether the current results extrapolate to proarrhythmia in disease states such as AF, for example, in a dog model of AF. From our perspective, to resolve the discrepancies between the different studies and to understand whether blocking SK channels is beneficial or not, studies in an animal model for AF are needed as well as functional experiments in human atrial tissue. What we found interesting in the current study is that the inhibitory effects of apamin and UCL-1684 are most obvious at very long and very short pacing cycle lengths. The latter situation is typical during AF. Thus, short pacing cycle lengths that lead to intracellular Ca accumulation may activate SK channels. Hence, SK channels may considerably contribute to cardiac repolarization especially at higher heart rates.
Heart Rhythm, Vol 10, No 6, June 2013 Questions to be answered are as follows: Is the AP heterogeneity also found in pulmonary veins? How much are noncardiac cells involved in the effects of apamin and UCL-1684? There is preliminary evidence for increased SK expression and current through SK channels (ISK) in cells from pulmonary veins compared to left atrial myocytes.16 Nevertheless, these findings challenge current strategies of AF treatment. Targeting the reduced wavelength of impulse propagation by increasing AP duration (ie, by increasing ICa and reducing IK1 or ISK) may be of limited efficacy since this is archived at the expense of increased triggered activity and altered spatial heterogeneity in repolarization. Moreover, these strategies are not limited to the atrial myocardium; the same effects might occur in the ventricular myocardium substantially increasing the propensity for severe ventricular arrhythmias.
References 1. Chen LY, Shen WK. Epidemiology of atrial fibrillation: a current perspective. Heart Rhythm 2007;4:S1–S6. 2. Nattel S, Dobrev D. The multidimensional role of calcium in atrial fibrillation pathophysiology: mechanistic insights and therapeutic opportunities. Eur Heart J 2012;33:1870–1877. 3. Sossalla S, Kallmeyer B, Wagner S, et al. Altered Naþ currents in atrial fibrillation: effects of ranolazine on arrhythmias and contractility in human atrial myocardium. J Am Coll Cardiol 2010;55:2330–2342. 4. Neef S, Dybkova N, Sossalla S, et al. CaMKII-dependent diastolic SR Ca2þ leak and elevated diastolic Ca2þ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res 2010;106:1134–1144. 5. Wakili R, Voigt N, K¨aa¨ b S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest 2011;121:2955–2968. 6. Ellinor PT, Lunetta KL, Glazer NL, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet 2010;42:240–244. 7. Rokita AG, Anderson ME. New therapeutic targets in cardiology: arrhythmias and Ca2þ/calmodulin-dependent kinase II (CaMKII). Circulation 2012;126:2125–2139. 8. Maier LS. CaMKII regulation of voltage-gated Naþ channels and cell excitability. Heart Rhythm 2011;8:474–477. 9. Ozgen N, Dun W, Sosunov EA, et al. Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc Res 2007;75:758–769. 10. Diness JG, Sorensen US, Nissen JD, et al. Inhibition of small-conductance Ca2þactivated Kþ channels terminates and protects against atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:380–390. 11. Li N, Timofeyev V, Tuteja D, et al. Ablation of a Ca2þ-activated Kþ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol 2009;587:1087–1100. 12. Olson TM, Alekseev AE, Liu XK, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 2006;15:2185–2191. 13. Lai LP, Su MJ, Yeh HM, et al. Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J 2002;144:485–490. 14. Ehrlich JR, Zicha S, Coutu P, Hebert TE, Nattel S. Atrial fibrillation-associated minK38G/S polymorphism modulates delayed rectifier current and membrane localization. Cardiovasc Res 2005;67:520–528. 15. Hsueh C-H, Chang P-C, Hsieh Y-C, Reher T, Chen PS, Lin SF. Pro-arrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium. Heart Rhythm. 2013;10:891–898. 16. Qi XY, Naud P, Brundel B, Harada M, Nattel S. Potential role of Ca2þ-dependent Kþ channels in atrial fibrillation [abstract]. Circulation 2011;124:A10620.