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J Gen Physiol
2019 Feb 04;1512:214-230. doi: 10.1085/jgp.201812192.
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Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations.
Furutani K
,
Tsumoto K
,
Chen IS
,
Handa K
,
Yamakawa Y
,
Sack JT
,
Kurachi Y
.
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Drug-induced block of the cardiac rapid delayed rectifying potassium current (IKr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of IKr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing IKr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.
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Figure 1. Cardiac APs induce hERG facilitation with nifekalant. (A and B) Representative cell currents from hERG channels in Xenopus oocytes evoked by a test pulse from holding potential of –90 to –50 mV before and after AP stimulation (1 Hz, 20×, AP waveform is the same as Fig. 2 H) and a step pulse (+60 mV for 4 s) in the presence of 30 µM nifekalant at room temperature. (C) AP–facilitation relation. The fraction of facilitation induced by repeating APs is normalized to the fraction induced by the +60 mV conditioning step pulse. Experimental data are means ± SEM (n = 8–15). The curve fit indicates exponential increase in the facilitation fraction by AP stimulation (facilitation = 1.02 − 0.70 ⋅ exp[−(#APs)/τ), τ = 5.45 ± 0.02]. (D) Requirement of nifekalant in the induction of facilitation. Effects of AP stimulation (1 Hz, 20×, AP waveform) on the increase in the hERG current were tested in the absence and presence of 30 µM nifekalant in the Xenopus oocytes (n = 7).
Figure 2. Experimental and simulated macroscopic hERG/IKr currents as modified by nifekalant. (A–C) The macroscopic hERG/IKr currents in response to voltage-clamp pulses from −80 to +60 mV in 10-mV increments from a holding potential of −80 mV at room temperature; representative traces (A), the relationship between membrane voltage and the steady-state current amplitude and membrane voltage (B), and the tail current amplitude (activation curve; C). Experimental data are means ± SEM (n = 11). (D–G) Simulated effects of nifekalant on hERG/IKr currents at room temperature condition. The model assumes two populations of channels, with or without facilitation effect by nifekalant (100 nM). The V1/2 of activation for the facilitated fraction of channel was approximately −31 mV, almost 26 mV negative to that of control channel (see also Materials and methods). (D and E) The macroscopic hERG/IKr currents in response to voltage-clamp pulses from −80 to −30 mV (D) or +30 mV (E) at room temperature. (F and G) The relationship between the tail current amplitude and membrane voltage before (F) and after (G) the induction of facilitation effect. Experimental data are means ± SEM (n = 5). (H) The macroscopic hERG/IKr currents in response to cardiac AP at 37°C. In D–H, black, red, and green solid lines indicate with control, block with facilitation, and conventional block (block without facilitation), respectively. Under the condition in the block with facilitation, IKr comprises two fractions of IKr (see also main text), i.e., facilitated and unfacilitated fractions of IKr. In G right panel, orange and cyan dashed lines represent the facilitated and unfacilitated fractions of IKr, respectively. Experimental data are means ± SEM (n = 6–11).
Figure 3. Effect of IKr facilitation on cardiac AP. (A–D) Simulated APs in an endocardial ventricular myocyte (A), IKr (B), activation state values for unfacilitated (xr1) and facilitated (xr2) fractions of IKr (C), and IK1 during APs with 100 nM nifekalant (D). Through A to D, black, green, and magenta solid lines indicate with control, block with facilitation, and conventional block (block without facilitation), respectively. In B and C, orange and cyan dashed lines represent the facilitated and unfacilitated fractions of IKr, respectively. Roman numerals above A indicate the phases of the AP in the case of with facilitation.
Figure 4. Frequency-dependent effect of nifekalant on APD in non–heart failure model. Increases in simulated APD90 from the control condition in normal, non–heart failure model with 100 nM nifekalant (40% IKr block) at each stimulation frequency. Effects of IKr block and facilitation on the APs in normal, non–heart failure model at various simulation frequencies with 100 nM nifekalant.
Figure 5. Frequency-dependent effect of nifekalant on APD in heart failure model. (A and C) Increases in simulated APD90 from the control condition in heart failure model with 100 nM nifekalant (40% IKr block; A) and 50% IKr block (C) at each stimulation frequency. (B and D) Effects of IKr block and facilitation on the APs in heart failure model at various simulation frequencies with 100 nM nifekalant (40% IKr block; B) and 50% IKr block (D). The small “hook” at the beginning of the AP of 2 Hz is the repolarization phase of the previous one.
Figure 6. The effect of IKr facilitation on the APD prolongation and EAD development by IKr block. (A–C) The steady-state AP trains with 40% (A), 50% (B), and 55% (C) IKr block in heart failure model with and without facilitation. (D) Effect of IKr block and facilitation on the APD and the development of EADs in heart failure model. Green and magenta lines indicate APD90 of AP (without EAD) for block with facilitation or block without facilitation, respectively. Asterisk, dagger, and double dagger indicate the conditions in A–C, respectively. Sections and pipes indicate the upper limits of IKr block where APs were normally terminated. When EAD was observed, it was classified as either alternated EAD or periodic EAD. In the bottom panel of D, red and deep purple dots indicate APD90 of AP with EAD for block without facilitation, while light and deep green dots indicate APD90 of AP with EAD for block with facilitation. Horizontal bars above the dots indicate alternated EAD, AL, or periodic EAD, EAD; see also main text.
Figure 7. The preventive effects of IKr facilitation on EAD development in several ventricular AP models. Simulated AP responses in the modified ORd human ventricular myocyte AP models, the modified TNNP human ventricular myocyte AP models, and the modified FRd guinea pig ventricular myocyte AP models of ENDO, MID, and EPI cells. APs in ORd and TNNP models were stimulated at 0.5 Hz, while APs in FRd model were stimulated at 1 Hz. In each panel, the intensity of IKr block is indicated as % Block. Magenta lines indicate AP responses in the IKr block without facilitation, while green lines indicate AP responses in the IKr block with facilitation at the same degree of IKr block as the overlaid magenta line (as an exception, in FRd model of EPI cell, EAD was not observed even by complete IKr block).
Figure 8. Ionic mechanism of EAD development by IKr block and the influence of IKr facilitation. (A–E) Simulated APs and the changes in the membrane potential (Vm; A and B), L-type Ca2+ channels current, ICaL (C), the net ionic current, Inet (D), and IKr (E) during APs with 55% IKr block in heart failure model. Each simulation of block (left) and facilitation (right) was started from the same initial values. In each panel of B–E, three curves are overlaid. Thin dashed line, thick dashed line, and solid line indicate 6th, 29th, and 31st AP responses after the 55% IKr block, respectively, and these APs are marked with squares in A. In C, an arrowhead indicates the time point of the reactivation of L-type Ca2+ channels, and asterisks indicate the time point of the inward-outward balance of Inet in 31st AP response in the case without facilitation (magenta solid line; see also main text). In E, the increase in the IKr current in the case with facilitation is highlighted by two horizontal dashed lines and an arrow.
Figure 9. The antiarrhythmic effect of IKr facilitation. Simulation of block and facilitation effect on the reexcitation by the second stimulation (S2) in the ORd model of nonfailing ENDO cell with the prolonged APD90 by 500 ms. AP responses to the S2 stimuli applied at the time indicated.
Figure 10. Effect of IKr facilitation on the safety window of nifekalant. The changes in the membrane potential (Vm; upper) and IKr (lower) in the presence of various concentrations of nifekalant in normal, non–heart failure model. The therapeutic dose is set as the concentration that prolongs APD90 by 500 ms and effectively suppresses the ectopic excitation as shown in Fig. 9. 2.74× indicates 2.74 times higher drug concentration compared with its therapeutic dose (1×). Green and magenta lines indicate IKr block with and without facilitation, respectively. Roman numerals at the bottom indicate the phases of the AP with facilitation.
Figure 11. Rabbit cardiac myocyteAPs are more stable in nifekalant than dofetilide. AP responses in the isolated rabbit ventricular myocytes were stimulated by minimal current injection at 0.5 Hz in whole-cell current clamp mode at 37°C. (A and B) After recording of the control responses (black lines), cells were treated with either 1 µM dofetilide (pink lines) or 10 µM nifekalant (green line). (A) Representative AP responses without (left) or with (right) EAD in 1 µM dofetilide. Of 19 cells treated with 1 µM dofetilide, five cells showed EAD responses (26%). 14 cells showed the prolongation of APD in 1 µM dofetilide but did not show EAD responses. (B) Representative AP responses in 10 µM nifekalant. All cells treated with 10 µM nifekalant showed prolongation of APD upon 1 µM dofetilide but did not show EAD responses. (C and D) Prolongation of APD and beat-to-beat instability by 1 µM dofetilide and 10 µM nifekalant. Only the data from the cells showing AP responses without EAD were included in this analysis (14 cells of 1 µM dofetilide-treated group; 19 cells of 10 µM nifekalant-treated group). 30 consecutive APs responses in control and under the treatment of either 1 µM dofetilide or 10 µM nifekalant were recorded, and APD90 of the i+1th action potential (APD90i+1) was plotted against APD90 of the one action potential before (ith; APD90i). APD90s were prolonged by treatment with 1 µM dofetilide (C) or 10 µM nifekalant (D) compared with control. 1 µM dofetilide prolonged APD90 longer (P = 4.26 × 10−13, Student’s t test) than 10 µM nifekalant. The control APD90s were identical between dofetilide- and nifekalant-treated cells (P = 0.58).
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999, Pubmed,
Xenbase
Abbott,
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia.
1999,
Pubmed
,
Xenbase
Aiba,
Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil.
2005,
Pubmed
Asai,
A versatile platform for multilevel modeling of physiological systems: template/instance framework for large-scale modeling and simulation.
2013,
Pubmed
Bayer,
Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling.
2010,
Pubmed
Brendorp,
Effect of dofetilide on QT dispersion and the prognostic implications of changes in QT dispersion for patients with congestive heart failure.
2002,
Pubmed
Carmeliet,
Use-dependent block and use-dependent unblock of the delayed rectifier K+ current by almokalant in rabbit ventricular myocytes.
1993,
Pubmed
Cheng,
Differential effects of MS-551 and E-4031 on action potentials and the delayed rectifier K+ current in rabbit ventricular myocytes.
1996,
Pubmed
Choi,
Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QT syndrome.
2002,
Pubmed
Clancy,
K+ channel structure-activity relationships and mechanisms of drug-induced QT prolongation.
2003,
Pubmed
De Ponti,
Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus.
2001,
Pubmed
Drew,
Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation.
2010,
Pubmed
Drouin,
Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells.
1995,
Pubmed
Elshrif,
Representing variability and transmural differences in a model of human heart failure.
2015,
Pubmed
Faber,
Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study.
2000,
Pubmed
Food and Drug Administration, HHS,
International Conference on Harmonisation; guidance on S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals; availability. Notice.
2005,
Pubmed
Furutani,
A mechanism underlying compound-induced voltage shift in the current activation of hERG by antiarrhythmic agents.
2011,
Pubmed
,
Xenbase
Gessner,
The amiodarone derivative KB130015 activates hERG1 potassium channels via a novel mechanism.
2010,
Pubmed
,
Xenbase
Gintant,
Evolution of strategies to improve preclinical cardiac safety testing.
2016,
Pubmed
Guo,
Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes.
2011,
Pubmed
Hafner,
Electrophysiological characterization of the class III activity of sotalol and its enantiomers. New interpretation of use-dependent effects.
1988,
Pubmed
Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed
Hondeghem,
Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence.
1990,
Pubmed
Hosaka,
Mutational analysis of block and facilitation of HERG current by a class III anti-arrhythmic agent, nifekalant.
2007,
Pubmed
,
Xenbase
Igawa,
Anti-arrhythmic efficacy of nifekalant hydrochloride, a pure class III anti-arrhythmic agent, in patients with healed myocardial infarction and inducible sustained ventricular tachycardia.
2002,
Pubmed
Jaiswal,
Dofetilide induced torsade de pointes: mechanism, risk factors and management strategies.
2014,
Pubmed
Jiang,
Use-dependent 'agonist' effect of azimilide on the HERG channel.
1999,
Pubmed
,
Xenbase
Jost,
Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle.
2005,
Pubmed
Jurkiewicz,
Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide.
1993,
Pubmed
Konarzewska,
Repolarizing K+ currents in nonfailing human hearts. Similarities between right septal subendocardial and left subepicardial ventricular myocytes.
1995,
Pubmed
Kramer,
MICE models: superior to the HERG model in predicting Torsade de Pointes.
2013,
Pubmed
Maruyama,
Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome.
2011,
Pubmed
Mirams,
Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.
2011,
Pubmed
Nakaya,
Effects of MS-551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes.
1993,
Pubmed
Nalos,
Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.
2012,
Pubmed
Nattel,
Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation.
2007,
Pubmed
Näbauer,
Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle.
1996,
Pubmed
O'Hara,
Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation.
2011,
Pubmed
Okada,
Assessment of reverse use-dependent blocking actions of class III antiarrhythmic drugs by 24-hour Holter electrocardiography.
1996,
Pubmed
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Roden,
Acquired long QT syndromes and the risk of proarrhythmia.
2000,
Pubmed
Roden,
Cellular basis of drug-induced torsades de pointes.
2008,
Pubmed
Sager,
Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium.
2014,
Pubmed
Sanguinetti,
Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
1990,
Pubmed
Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed
Sanguinetti,
A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.
1995,
Pubmed
,
Xenbase
Sato,
Meta-analysis of the efficacies of amiodarone and nifekalant in shock-resistant ventricular fibrillation and pulseless ventricular tachycardia.
2017,
Pubmed
Sato,
Irregularly appearing early afterdepolarizations in cardiac myocytes: random fluctuations or dynamical chaos?
2010,
Pubmed
Satoh,
Electropharmacological and proarrhythmic effects of a class III antiarrhythmic drug nifekalant hydrochloride assessed using the in vivo canine models.
2004,
Pubmed
Studenik,
Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome.
2001,
Pubmed
Sugiyama,
Sensitive and reliable proarrhythmia in vivo animal models for predicting drug-induced torsades de pointes in patients with remodelled hearts.
2008,
Pubmed
Surawicz,
Electrophysiologic substrate of torsade de pointes: dispersion of repolarization or early afterdepolarizations?
1989,
Pubmed
Szabó,
Asymmetrical distribution of ion channels in canine and human left-ventricular wall: epicardium versus midmyocardium.
2005,
Pubmed
Takenaka,
Initial experience with nifekalant hydrochloride (MS-551), a novel class III antiarrhythmic agent, in patients with acute extensive infarction and severe ventricular dysfunction.
2001,
Pubmed
Tamargo,
Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide.
2015,
Pubmed
Tande,
Rate-dependent class III antiarrhythmic action, negative chronotropy, and positive inotropy of a novel Ik blocking drug, UK-68,798: potent in guinea pig but no effect in rat myocardium.
1990,
Pubmed
Thomsen,
Electrophysiological safety of sertindole in dogs with normal and remodeled hearts.
2003,
Pubmed
Torp-Pedersen,
Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group.
1999,
Pubmed
Toyama,
Vesnarinone prolongs action potential duration without reverse frequency dependence in rabbit ventricular muscle by blocking the delayed rectifier K+ current.
1997,
Pubmed
Trudeau,
HERG, a human inward rectifier in the voltage-gated potassium channel family.
1995,
Pubmed
Tsumoto,
Hysteretic Dynamics of Multi-Stable Early Afterdepolarisations with Repolarisation Reserve Attenuation: A Potential Dynamical Mechanism for Cardiac Arrhythmias.
2017,
Pubmed
Vandersickel,
A study of early afterdepolarizations in a model for human ventricular tissue.
2014,
Pubmed
Vaughan Williams,
Classifying antiarrhythmic actions: by facts or speculation.
1992,
Pubmed
Weiss,
Early afterdepolarizations and cardiac arrhythmias.
2010,
Pubmed
Wood,
Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.
2018,
Pubmed
Xie,
Oxidative-stress-induced afterdepolarizations and calmodulin kinase II signaling.
2009,
Pubmed
Xu,
Left ventricular hypertrophy decreases slowly but not rapidly activating delayed rectifier potassium currents of epicardial and endocardial myocytes in rabbits.
2001,
Pubmed
Yamakawa,
Pharmacophore modeling for hERG channel facilitation.
2012,
Pubmed
,
Xenbase
Zeng,
Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization.
1995,
Pubmed
Zeng,
Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence.
1995,
Pubmed
Zhao,
Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: predominant by Ca waves or Ca currents?
2012,
Pubmed
Zhou,
Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature.
1998,
Pubmed
ten Tusscher,
A model for human ventricular tissue.
2004,
Pubmed
ten Tusscher,
Alternans and spiral breakup in a human ventricular tissue model.
2006,
Pubmed
