doi: 10.1161/CIRCULATIONAHA.105.562777
(Circulation. 2005;112:1376-1378.)
© 2005 American Heart Association, Inc.
Editorial |
Protecting the Heart Against Arrhythmias: Potassium Current Physiology and Repolarization Reserve
From the Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Director, Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, 532 Medical Research Building I, Nashville, TN 37232. E-mail dan.roden{at}vanderbilt.edu
Key Words: Editorials • arrhythmia • ion channels • potassium • repolarization
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Introduction |
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 Top Introduction Separating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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Hodgkin and Huxley’s classic experiments in the squid giant axon were the first to define a role for potassium efflux as a mechanism to return the membrane potential of an excitable cell to resting values.1 They showed that depolarization was caused by a rapid influx of sodium into the squid giant axon, an event which then initiated movement of potassium from inside the axon to the exterior. The resulting repolarizing current, termed IK, was identified decades later as a major contributor to repolarization in heart cells.2 IK appeared to not only drive normal repolarization but also respond to adrenergic activation. By the 1970s it was apparent that ß-adrenergic stimulation markedly increases inward calcium current in myocytes3; this would prolong the QT interval on exercise were it not for a "balancing" effect of IK activation.4
See p 1384 and 1392
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Separating IK Into IKr and IKs in Heart |
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TopIntroductionSeparating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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In the late 1980s, there was some enthusiasm for the concept that arrhythmias could be suppressed by drugs that selectively delay repolarization (ie, without exerting other electrophysiological effects such as sodium channel block). A number of potent QT-prolonging agents were developed; in fact, 2—dofetilide and ibutilide—have reached clinical use. Studies of the molecular basis of such selective action potential prolongation led to the key discovery by Michael Sanguinetti, then at Merck, that "IK" in guinea pig myocytes actually represented 2 distinct currents: a small drug-sensitive current that activated rapidly (hence, termed IKr) and a large drug-resistant currrent that activated slowly, IKs.5 IKr block is now recognized as the overwhelmingly common mechanism whereby drugs produce QT prolongation. Work by many laboratories has defined key electrophysiological and pharmacological properties of IKr. Notably, the Sanguinetti laboratory has proposed a structural basis for the peculiar "promiscuity" of IKr to block not only by antiarrhythmics but also by a wide range of "noncardiovascular" agents such as antihistamines, antipsychotics, and antibiotics, many of which have been relabeled or withdrawn because of risks thought to be associated with QT interval prolongation.6–8
The physiological and pharmacological separation of IKr and IKs were followed in the mid-1990s by the cloning of the genes whose expression generates these currents, and the identification of mutations in those genes as the commonest causes for the congenital long QT syndrome.9–11 Expression of HERG (now also known as KCNH2) is sufficient to recapitulate most properties of IKr, although ancillary function-modifying subunits have been proposed.12,13 By contrast, recapitulation of IKs requires coexpression not only of the gene encoding the pore-forming subunit, KCNQ1 (formerly known as KvLQT1), but also an important function-modifying protein, termed KCNE1 (or minK),14,15 which was initially cloned from a rat kidney cDNA library.16
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IKr Block Causes Torsade de Pointes, But Not Always |
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TopIntroductionSeparating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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The vast majority of heart beats in patients with loss of function mutations in HERG are, in fact, normal and in many instances even accompanied by normal QT intervals. Similarly, although IKr block is now recognized as the major initiating mechanism in drug-induced torsade de pointes, not every patient receiving culprit drugs develops marked QT prolongation or the arrhythmia. This lack of a simple relationship between reduced IKr and a manifest clinical phenotype tells us that risk can be modulated by factor(s) beyond IKr alone. Variable drug metabolism can be invoked in some cases of drug-associated torsade de pointes17 but this is far from a universal explanation and does not explain variability in the congenital syndrome. To explain this variability in response to reduction or block of IKr, we proposed the concept of "repolarization reserve."18 We hypothesized that because multiple mechanisms were increasingly recognized as contributing to normal repolarization, loss of function in one of these (eg, reduced IKr) may not lead to clinical consequences unless other lesions were present. Examples of such lesions are subclinical mutations in ion channel or other genes or disordered electrogenesis increasingly recognized in acquired diseases such as heart failure or left ventricular hypertrophy. Two articles in this issue of Circulation provide evidence that IKs may be a major source of repolarization reserve that protects against torsade de points during IKr block.19,20
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At First Glance, IKs Does Not Seem Large in Human Ventricular Myocytes |
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TopIntroductionSeparating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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When long depolarizations are used to elicit outward current, IKs can be huge; however, an appreciation of the role of IKs under more physiological conditions, especially in larger mammals,21 has been slower to evolve. Although both IKr and IKs have previously been identified in voltage-clamped human heart cells,22,23 their relative contributions to repolarization have not been explored. The laboratory of András Varró used relatively specific IKr and IKs blockers as tools to probe this issue.19 Whereas IKr blockers routinely prolonged action potentials, especially at slow rates (no surprise), it was a surprise that none of the IKs blockers did much at any stimulation rate. In fact, direct measurement of the currents with depolarizations approximating the human action potential duration showed that IKr is much larger than IKs; with longer depolarizations (one way of simulating longer action potentials), IKs did get a bit bigger. One possible interpretation is that the current is not important, but this is difficult to reconcile with the fact that losing the current can be fatal because mutations in KCNQ1 are the single most common cause of the congenital long QT syndrome.24 Many explanations are possible: The specific cells studied may not have had much IKs (we know from work in canines that some cells exhibit less IKs than others), or IKs may have been damaged by the isolation procedure, or IKs is only important when action potentials get long, or, in fact, IKs is not important under basal conditions. The apparent paradox was partially resolved by additional experiments demonstrating that when IKr is blocked and the cells are exposed to adrenalin, IKs block prolonged action potentials. There are 2 reasonable conclusions. The first is that incorporating some basal sympathetic activity should be strongly considered in any study of action potential control. Indeed, in canine models, IKs block produces little discernible effect in the absence of catecholamines.25,26 The second conclusion is that IKs protects against action potential prolongation when IKr is blocked (ie, that it contributes to repolarization reserve).
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What Does KCNE1 Do to K+ Current to Make It IKs? |
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TopIntroductionSeparating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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The problem of predicting how a complex system with multiple interrelated elements (eg, action potential) responds to a change in the behavior of an individual component is a general one in systems biology. One approach is to evaluate the effects of pharmacological probes (eg, blockers of specific components), but often these are not available. The laboratory of Yoram Rudy27 has devoted considerable effort to an alternate approach: incorporation of physiological properties of individual components of the action potential, such as IKr, IKs, inward currents, and intracellular calcium control mechanisms, into a computational model of the action potential, thereby allowing the effects of alterations in individual components to be simulated over a wide range of "in silico" experimental conditions. An issue that motivated the study reported here by Silva and Rudy20 was the question of how currents generated by KCNQ1 alone and by KCNQ1 + KCNE1 (IKs) differ as a function of rate. Action potentials and QT intervals are shorter at fast rates, and a larger IKs is thought to be an important contributor, although the mechanism has been uncertain. In guinea pig myocytes, a depolarizing pulse activates IKs but with a delay, and with repolarization IKs undergoes deactivation, which is slow. These properties generated the conventional wisdom that IKs "accumulates" at fast rates because slow deactivation prevents the current from returning completely to baseline.28 Such accumulation could certainly account for shorter action potential duration and QT interval at fast rates, as is observed physiologically. A fly in this ointment is that IKs deactivation in other species such as the dog, is faster,21 so the accumulation hypothesis needs closer reexamination.
Silva and Rudy have explored new state models for KCNQ1 and for KCNQ1 + KCNE1 to address this issue. The simplest model to explain the behavior of an ion channel is one in which the channel can occupy 1 of 2 states, closed or open, with state transitions described by individual rate constants. The observation that IKs activation occurs with depolarization, but only after a delay, suggests that the channel may move through multiple closed states before opening during a depolarization.29 Silva and Rudy used physiological data obtained from multiple previous reports to construct a much more complex view of KCNQ1 behavior alone and in presence of KCNE1 to generate IKs. The simulations strongly suggest that IKs accumulation at rapid rates is not caused by slow deactivation but rather by preferential occupancy of the channel in "proximal" closed states, very near the open one, at fast rates. When the channel exists in these proximal closed states, IKs can open with a minimal delay after a depolarization and rapidly become rather large. A particularly intriguing observation is that KCNQ1 alone cannot prevent an arrhythmogenic, pause-dependent early afterdepolarization, whereas IKs, by activating during the plateau potential, can. In this way, repolarization reserve is generated by coexpression of KCNE1 with KCNQ1. "States" in models such as these represent either biophysical abstractions or, conceivably, individual conformations of the dynamic behaviors of these proteins. As Silva and Rudy are at pains to point out, although the results from the model are provocative, interesting, and physiologically rational, they are hypothesis-generating until additional physiological studies, which they even outline, address them.
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Approaches to the Study of Complex Biological Systems |
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TopIntroductionSeparating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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Taken together, the studies suggest that an important role of IKs in the human heart is to protect against pathological action potential prolongation (ie, to provide repolarization reserve). More generally, "repolarization reserve" is shorthand for the much broader concept that physiological systems often include considerable redundancies, and that these can protect against manifest disease phenotypes arising from a single lesion. This concept has wide applicability not only in cardiovascular medicine but also it is familiar as the "multiple" hit hypotheses in cancer biology. The 2 IKs-focused article in this week’s issue of Circulation serve to reiterate the message that unraveling such complex systems biology requires multiple highly complementary approaches, including a focus on individual molecules, integrated physiological behaviors, and appropriately constructed computational models to validate current hypotheses and to point to new experiments.
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Acknowledgments |
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This work was supported in part by grants from the US Public Health Service (HL46681, HL49989, HL65962) and the American Heart Association (0565306B). Dr Roden is the holder of the William Stokes Chair in Experimental Therapeutics, a gift from the Dai-ichi Corporation.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionSeparating IK Into IKr...IKr Block Causes Torsade...At First Glance, IKs...What Does KCNE1 Do...Approaches to the Study...References |
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1. Hodgkin AL, Huxley AF. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol (Lond). 1952; 116: 449–472.
2. McAllister RE, Noble D. The time and voltage dependence of the slow outward current in cardiac Purkinje fibres. J Physiol. 1966; 186: 632–662.
3. Shigenobu K, Sperelakis N. Calcium current channels induced by catecholamines in chick embryonic hearts whose fast sodium channels are blocked by tetrodotoxin or elevated potassium. Circ Res. 1972; 31: 932–952.
4. Bennett PB, McKinney L, Begenisich T, Kass RS. Adrenergic modulation of the delayed rectifier potassium channel in calf cardiac Purkinje fibers. Biophys J. 1986; 49: 839–848.[Medline] [Order article via Infotrieve]
5. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current: differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990; 96: 195–215.
6. Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A. 2000; 97: 12329–12333.
7. Viskin S, Justo D, Halkin A, Zeltser D. Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis. 2003; 45: 415–427.[Medline] [Order article via Infotrieve]
8. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004; 350: 1013–1022.
9. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995; 80: 795–803.[CrossRef][Medline] [Order article via Infotrieve]
10. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995; 81: 299–307.[CrossRef][Medline] [Order article via Infotrieve]
11. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Towbin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996; 12: 17–23.[CrossRef][Medline] [Order article via Infotrieve]
12. Petersen CI, McFarland TR, Stepanovic SZ, Yang P, Reiner DJ, Hayashi K, George AL, Roden DM, Thomas JH, Balser JR. In vivo identification of ether-a-go-go related gene-interacting proteins in Caenorhabditis elegans that affect cardiac arrhythmias in humans. Proc Natl Acad Sci U S A. 2004; 101: 11773–11778.
13. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999; 97: 175–187.[CrossRef][Medline] [Order article via Infotrieve]
14. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium current. Nature. 1996; 384: 78–80.[CrossRef][Medline] [Order article via Infotrieve]
15. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature. 1996; 384: 80–83.[CrossRef][Medline] [Order article via Infotrieve]
16. Takumi T, Ohkubo H, Nakanishi S. Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science. 1988; 242: 1042–1045.
17. Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA. 1993; 269: 1532–1536.
18. Roden DM. Taking the idio out of idiosyncratic—predicting torsades de pointes. Pacing Clin Electrophysiol. 1998; 21: 1029–1034.[CrossRef][Medline] [Order article via Infotrieve]
19. Jost N, Virag L, Bitay M, Takacs J, Lengyel C, Biliczki P, Nagy Z, Bogats G, Lathrop DA, Papp JG, Varro A. Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation. 2005; 112: 1392–1399.
20. Silva J, Rudy Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation. 2005; 112: 1384–1391.
21. Gintant GA. Two components of delayed rectifier current in canine atrium and ventricle: does IKs play a role in the reverse rate dependence of class III agents? Circ Res. 1996; 78: 26–37.
22. Wang Z, Fermini B, Nattel S. Rapid and slow components of delayed rectifier current in human atrial myocytes. Cardiovasc Res. 1994; 28: 1540–1546.[Medline] [Order article via Infotrieve]
23. Virag L, Iost N, Opincariu M, Szolnoky J, Szecsi J, Bogats G, Szenohradszky P, Varro A, Papp JG. The slow component of the delayed rectifier potassium current in undiseased human ventricular myocytes. Cardiovasc Res. 2001; 49: 790–797.[CrossRef][Medline] [Order article via Infotrieve]
24. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003; 348: 1866–1874.
25. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQTt1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. 1998; 98: 2314–2322.
26. Volders PG, Stengl M, van Opstal JM, Gerlach U, Spatjens RL, Beekman JD, Sipido KR, Vos MA. Probing the contribution of IKs to canine ventricular repolarization: key role for beta-adrenergic receptor stimulation. Circulation. 2003; 107: 2753–2760.
27. Luo CH, Rudy Y. A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. Circ Res. 1991; 68: 1501–1526.
28. Lu Z, Kamiya K, Opthof T, Yasui K, Kodama I. Density and kinetics of I(Kr) and I(Ks) in guinea pig and rabbit ventricular myocytes explain different efficacy of I(Ks) blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans. Circulation. 2001; 104: 951–956.
29. Balser JR, Bennett PB, Roden DM. Time-dependent outward current in guinea pig ventricular myocytes. Gating kinetics of the delayed rectifier. J Gen Physiol. 1990; 96: 835–863.
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