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Cardiovascular Research 1998 37(2):324-334; doi:10.1016/S0008-6363(97)00274-5
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Potassium channel down-regulation in heart failure

Michael Näbauer* and Stefan Kääb

Department of Medicine I, University of München, Klinikum Großhadern, Marchioninistrasse 15, München 81377, Germany

* Corresponding author. Tel. (+49-89) 70951; Fax (+49-89) 7095 8830.

Received 28 July 1997; accepted 17 October 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Diversity of cardiac...
 3 Down-regulation of potassium...
 4 Future aspects
 References
 
Prolongation of action potential duration is the most consistent electrophysiological abnormality in myocardium and myocytes from hypertrophied and failing hearts. Measurements of currents in myocytes from hypertrophied and failing hearts indicate that, in most cases, this is due to a decrease in outward potassium currents. If present, a calcium-independent transient outward current is usually substantially reduced, but delayed rectifier and inward rectifier currents have also been found to be diminished. There is increasing evidence that potassium current down-regulation contributes significantly to the enhanced lability of the repolarization process in heart failure, predisposing to early after-depolarizations, dispersion of repolarization and ventricular arrhythmias. The reduction of outward potassium currents may also be involved in the enhanced sensitivity of failing myocardium to triggering factors like hypokalemia, ischemia, and antiarrhythmic agents with Class III effects. A thorough understanding of the mechanisms of cardiac excitability and arrhythmogenesis at the cellular and molecular level under normal and pathological conditions will be essential for the development of new pharmacological strategies to prevent sudden cardiac death in heart failure.

KEYWORDS Potassium channel; Hypertrophy; Heart failure; Repolarization; Long-QT syndrome; Arrhythmia; Sudden cardiac death


   1 Introduction
Top
 Abstract
 1 Introduction
2 Diversity of cardiac...
 3 Down-regulation of potassium...
 4 Future aspects
 References
 
Electrical instability is a characteristic feature of the failing heart. Despite advances in the treatment of heart failure in recent years, annual mortality remains high, reaching up to 50%, 35–50% of which die suddenly presumably due to ventricular tachyarrhythmias [1–3]. The exact mechanism of the increased electrical instability of the failing heart is not known and, depending on etiology, different mechanisms including ischemia in coronary heart disease or structural alteration such as fibrosis or myocardial scarring after myocardial infarction may be prominent. However, one of the most important predictors of sudden cardiac death is depressed left ventricular function [4–6], suggesting that, despite etiological heterogeneity, common mechanisms may be involved in the propensity of failing myocardium to potentially fatal arrhythmias. Altered intracellular and transmembrane calcium handling [7, 8], stretch-induced mechanisms due to altered ventricular loading conditions [9–11]and changes in myocyte electrical properties [9, 12–14]have been implicated in the increased electrical instability of the failing heart.

Several lines of evidence indicate an important role of abnormalities in repolarization for the increased risk of sudden cardiac death in heart failure. Prolongation of action potential duration is a consistent finding in experimental models of cardiac hypertrophy and failure, causing by itself the repolarization process to be more labile [13, 14]. Spatial and temporal inhomogeneity of repolarization, measured as dispersion of repolarization, has been described in patients with increased risk of sudden cardiac death [15–17]. Recent data from experimental models of cardiac hypertrophy or failure, and terminal heart failure in man, indicate that down-regulation of potassium currents, particularly a transient outward current (Ito1), may cause abnormalities in repolarization and contribute to the increased electrical instability of failing hearts [13].

This review is to give an overview on available evidence for alteration of potassium channels in cardiac hypertrophy and failure. More general reviews on the cellular electrophysiology in cardiac hypertrophy and failure have been recently presented by Pye and Cobbe [9], Hart [18], and Boyden and Jeck [19].


   2 Diversity of cardiac potassium channels and their role in repolarization
Top
 Abstract
 1 Introduction
 2 Diversity of cardiac...
3 Down-regulation of potassium...
 4 Future aspects
 References
 
Voltage-gated ion channels open in response to a change in membrane potential to permit transmembrane passage of specific ions (such as potassium ions) according to inherent voltage- and time-dependent properties. At least four major potassium channels (Ito1, IKr, IKs, IK1) with different density and voltage- and time-dependent properties contribute to repolarization in ventricular myocardium (Fig. 1) [20–23]. In addition to potassium channels, chloride channels and currents generated by ion pumps and Na/Ca exchange influence the repolarization process. It is important to note that the plateau of the cardiac action potential is a phase of low conductance [13, 24], where even small current changes can markedly influence the balance between inward and outward currents and alter the time course of repolarization. The late repolarization phase is therefore a labile condition highly sensitive to alterations of the ionic environment (e.g. hypokalemia), block of potassium channels by antiarrhythmic drugs (Class Ia, Ic, III [20]) or other drugs blocking potassium channels (such as Erythromycin [25], Terfenadine [26]), and alterations of ion channel function or density. Delay of the repolarization process may initiate arrhythmias by causing abnormal impulse generation due to early after-depolarizations and triggered activity or, when spatial or temporal inhomogeneity of repolarization ensues, to abnormal impulse conduction which promotes re-entrant arrhythmias. Genetic alterations of various ion channels involved in repolarization (HERG, KvLQT1, SCN5A) have recently been shown to underlie the propensity to ventricular tachyarrhythmias and sudden cardiac death in congenital forms of the Long-QT syndrome [27]. Similarly, disease processes such as increased hemodynamic load may lead to alterations in channel density or function providing a substrate for arrhythmias in cardiac hypertrophy or failure.


Figure 1
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  		Fig. 1 Ventricular action potential and time-dependent contribution of major inward currents (INa, ICa,L), Na/Ca-exchange current, and outward currents (Ito1, IKs, IKr, IK1). Filled tracings are graphical representations of the time dependence of the contribution of various currents to the depolarization and repolarization process. The relative size of the currents is not correctly represented; downward deflections indicate contribution of an inward current. The initial depolarization is induced by rapid activation of INa, followed by activation of the L-type calcium current. While Ito1 causes early repolarization of the action potential plateau leading to a notch in the action potential shape, activation of the delayed rectifier currents IKr and IKs, together with a decrease in ICa, control final repolarization. The late phase of the final repolarization is further supported by current contributed by IK1.

 

   3 Down-regulation of potassium channels in heart failure
Top
 Abstract
 1 Introduction
 2 Diversity of cardiac...
 3 Down-regulation of potassium...
4 Future aspects
 References
 
3.1 Alterations of potassium channels in left ventricular hypertrophy
Usually, some degree of hypertrophy is present during the development of heart failure, often due to pressure or volume overload. Furthermore, the presence of compensatory hypertrophy in the noninfarcted myocardium in ischemic heart failure and in myocytes from hearts with dilated cardiomyopathy suggests similarities between electrophysiological changes in cardiac hypertrophy and failure [7, 9]. Prolongation of action potential duration has been the most consistent finding in models of pressure overload in a variety of experimental models and species. Using microelectrode studies, an increase in action potential plateau and duration was observed in cat hearts failing due to right ventricular pressure overload [28], while in the same model, Tritthart et al. observed action potential prolongation already during hypertrophy [29]. Action potential duration was prolonged in rat hearts with renovascular hypertension [30–32]and in chronically infarcted rat hearts with myocyte hypertrophy [33]. However, some reports indicated no changes or even shortening of the action potential duration in hypertrophied myocardium [28, 34], which may have been due to differences in the model or degree and duration of hypertrophy.

In principle, any increase in inward or decrease in outward current during the plateau phase of the action potential is capable of causing a prolongation of the cardiac action potential. Use of the patch-clamp technique in single myocytes facilitated the identification of ion currents responsible for the observed prolongation of the action potential and confirmed that these changes were due to altered intrinsic properties of the cells. However, while the major inward currents (INa, ICa,L) appeared to be rather consistent throughout different species, a large diversity of potassium channels has been observed with expression of different potassium channel types and densities in different species and myocardial regions [23, 35–37]. Thus, depending on the species studied, different channels may be involved in a similar phenotypic prolongation of the action potential in cardiac hypertrophy or failure.

3.1.1 Transient outward current
As noted earlier by Hart [18], comparison of action potential configuration generally shows that the action potential in hypertrophy diverges from control soon after the maximal overshoot, indicating that currents active during the early plateau are at least in part responsible for the action potential prolongation. Major currents active during that time include ICa,L and Ito1, even though other currents (Ito2, IKr) may also be important. Available data on ICa,L (mostly referring to unstimulated peak ICa,L) has recently been reviewed in detail by Hart [18], indicating that ICa,L may be increased in mild hypertrophy, unchanged in moderate degrees of hypertrophy, and reduced in severe hypertrophy with failure.

While the rapid inactivation kinetics of Ito1 (time constant of decay ~8 ms at physiological temperatures [38]) make a direct contribution to the final phase of repolarization unlikely, Ito1 is very important during early repolarization in setting the level of the plateau, thereby affecting activation of other plateau currents [39]. In species expressing a significant Ito1 (e.g. rat, ferret, hamster, rabbit, dog, cat, man), a decrease in this current may thus contribute to early deviation of action potential configuration and action potential prolongation.

Various models of pressure overload hypertrophy have been utilized to delineate the role of Ito1 in prolongation of action potential duration. In hypertrophied myocardium from spontaneously hypertensive rat, a prolongation of the action potential duration was reported in tissue [40]and single isolated myocytes [41]. Action potential prolongation and decrease in Ito1 depended on the degree of hypertrophy and were more pronounced at 18 month (decrease in Ito1 48%) than at 3 month (37%) after development of hypertension. No changes in the properties of Ito1, late outward current, or IK1 were noted. When left ventricular hypertrophy was induced by abdominal aortic ligation, Tomita et al. observed a decrease in Ito1 by 35% without change in current properties [42], while Benitah et al. found Ito1 to be decreased and activation shifted to more positive potentials [43].

When pharmacological means were applied to induce cardiac hypertrophy, Xu and Best [44], using growth hormone in rats, found a decrease of Ito1 by 37.7%. In DOCA-salt treated rats, Ito1 density was reduced depending on the severity of hypertrophy amounting to 53% in moderately hypertrophic and 94% in severely hypertrophic hearts, with no changes in sustained outward currents or calcium-handling systems [45, 46]. Catecholamine stimulated cardiac hypertrophy in rat also resulted in a 50% reduction of Ito1 with no change in voltage-dependent or kinetic properties [47].

Similar reductions in Ito1 during hypertrophy were observed in other species expressing Ito1. In ferrets with pulmonary artery banding, Potreau [48]demonstrated a decrease of Ito1 by {approx}35% (Fig. 1 in [48]), as initially suggested based on the observation of an unchanged ICa [49]. Activation and inactivation parameters were not altered, but recovery from inactivation was found to be slowed, further reducing the available current at physiological frequencies [48].

Notable exceptions form this almost uniform reduction of Ito1 in cardiac hypertrophy were reported by Brooksby et al. [50], where ICa,L and outward currents were unchanged in spontaneously hypertensive rats despite prolongation of action potential duration. In an one clip/two kidney model of renovascular hypertension, action potential duration was prolonged, but the transient component of the transient outward current was increased by {approx}35% [51]. Action potential prolongation was reported to be due to an increased ICa,L in this model [51, 52]. This indicates that the same phenotype of a prolonged action potential in hypertrophy may be due to diverse changes in ionic channels. Ten Eick et al. reported an increase in Ito1 in myocytes from hypertrophied feline right ventricles after pulmonary artery banding [53]without changes in channel kinetics. The reason for these findings of an unchanged or increased Ito1 in cardiac hypertrophy is unknown but may be related to different species and models used, or degree and time course of development of hypertrophy.

However, if generalizations can be made from these observations, there is a strong tendency of Ito1 to be reduced in hypertrophied myocardium of several species and reduction appears to be correlated to the degree of hypertrophy at least in some of the experimental models.

3.1.2 Inward rectifier current (IK1)
Only few observations on changes of the inward rectifier current, IK1, also termed background potassium current, in cardiac hypertrophy are available. Kleiman and Houser [54]reported IK1 to be increased in mildly hypertrophied feline right ventricular myocytes after pulmonary artery banding, whereas in rat with spontaneous hypertension [41]and guinea pig with mild hypertrophy due to abdominal aortic constriction [55], no changes in IK1 density could be observed.

3.1.3 Delayed rectifier potassium currents
Data on alteration of delayed rectifier type currents in cardiac hypertrophy is also limited, and there is no study available discriminating the two components of the delayed rectifier current, IKs and IKr, as described recently [23]. This is of special importance as the relative contribution of the two channels to repolarization may vary in different species, with IKr appearing to be more prominent in cat [56]than rabbit [57]or guinea pig [23].

In isolated myocytes from cats with right ventricular hypertrophy due to pulmonary artery banding, IK was found to be reduced in hypertrophied cells, which was accompanied by slower activation, more rapid deactivation and steeper rectification properties [54, 58]. Together with an increase in ICa,L, this was considered to be responsible for the prolongation of action potential duration. In feline left ventricular hypertrophy due to abdominal aortic constriction, density of IK was also found to be reduced (by {approx}31%, Fig. 3 in [59]), together with delayed activation and faster deactivation kinetics. The decreased delayed rectifier current was considered to be involved in prolongation of action potential duration and propensity to early after-depolarizations during reperfusion in hypertrophied cells [60].

Data in mild hypertrophy in guinea pig with abdominal aortic constriction indicated no changes in density of IK [55], and prolongation of action potential duration was attributed to an increased ICa,L and Na/Ca-exchange current. Similarly, in hearts from spontaneously hypertensive rats, Brooksby found no evidence for altered delayed rectifier currents measuring at the end of a 500 ms depolarizing pulse [50].

3.2 Alterations of potassium channels in cardiac failure
Evidence for down-regulation of cardiac potassium currents in heart failure has been derived from studies of a hereditary cardiomyopathy of the Syrian hamster [61], rabbit and dog models of pacing-induced heart failure [39, 62, 63], and from terminally failing human myocardium studied at the time of cardiac transplantation [64](Table 1). Common to these conditions is prolongation of action potential duration, similar to what has been found in most models of pressure overload cardiac hypertrophy. A notable exception occurs in heart failure due to chronic doxorubicin administration where shortening of the action potential duration is a typical finding [65, 66], indicating that different mechanisms may be operative [9].


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  		Table 1 Alterations of potassium currents in heart failure

 
3.2.1 Cardiomyopathic hamster
A number of structural, biochemical and electrophysiological alterations have been reported in hereditary cardiomyopathy of the Syrian hamster, including fibrosis [67], increase in ICa,T and Na/Ca-exchange current [68, 69], and alterations in sarcoplasmic reticulum calcium handling [70]. Hypertrophy of the myocytes, however, may not be a prominent feature [71]. Prolongation of action potential duration has been observed in multicellular preparations [67, 72]and isolated myocytes [72], indicating alterations of intrinsic properties of the cells. Analysis of ion currents revealed a decrease in ICa,L by 37%, and a dramatic decrease in Ito1 by 70.6% which was considered to be responsible for the prolongation of the action potential duration. Deviation of action potential configuration in failing myocardium and myocytes from control traces was evident immediately after the upstroke and in the voltage range above 0 mV, where Na/Ca-exchange current is unlikely to play a major role. However, increased T-Type calcium channel expression may also contribute to the delay of repolarization [68].

3.2.2 Guinea pig
In a guinea pig model of heart failure induced by banding of the ascending aorta [73], action potential duration was prolonged only at 50% repolarization but unchanged at 90% repolarization. This corresponds to findings of unchanged delayed rectifier currents in this model. Even though a decrease in unstimulated peak ICa,L by 21% was observed, due to a shift in activation and steady-state inactivation parameters, L-Type calcium window current would be expected to increase which might have offset the decrease in ICa,L with respect to the late repolarizing phase of the action potential.

3.2.3 Pacing-induced heart failure in dog
Two models of heart failure induced by rapid ventricular pacing have recently been implemented and analyzed, both displaying a significant prolongation of action potential duration together with a dramatic decrease in Ito1 [39, 63]. In a dog model, heart failure was induced by rapid ventricular pacing at a frequency of 240/min for 3–4 weeks, when animals developed clinical signs of cardiac failure [39]. These hearts showed an increased LVEDP, depressed dP/dtmax, and delayed relaxation time. Hearts were considered to be in terminal failure when analyzed. In addition, these animals showed a propensity to die from sudden cardiac death and electrophysiological testing revealed increased dispersion of repolarization [62]. QT-time, the surface manifestation of action potential duration, and monophasic action potential duration were prolonged and dispersion of repolarization increased in failing hearts. When action potential duration was measured in single isolated cells, action potential prolongation was preserved even under conditions where intracellular calcium transient were reduced or eliminated. Analysis of inward currents revealed no changes in INa and unstimulated peak ICa,L, suggesting that these currents may not be responsible for the prolonged action potential duration. IK1 was found to be reduced slightly but significantly, mostly at voltages negative to –90 mV which would not affect repolarization. In the voltage range positive to the potassium reversal potential, a significant difference from control was observed only at –60 mV, indicating that a reduced IK1 may be responsible for some slowing of terminal repolarization. A substantial reduction in Ito1 density by 65.5% was found in myocytes from failing hearts without differences in kinetic and voltage-dependent properties (Fig. 2). Using single channel conductance measurements and nonstationary noise fluctuation analysis, the reduction in Ito1 density could be attributed to a reduction in the number of functional channels. The observed action potential changes in failing myocytes could be reproduced by block of Ito1 with 4-aminopyridine in myocytes from nonfailing hearts, as well as reversed by introduction of an Ito-like repolarizing current pulse during the early plateau of the action potential in cells from failing myocardium [39]. This indicates that Ito1, despite its transient nature, is strongly influencing shape and duration of the ventricular action potential.


Figure 2
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  		Fig. 2 Comparison of alterations of action potential configuration and Ito1 current density in myocytes from (A) failing and nonfailing dog left ventricle and from myocytes isolated from (B) nonfailing (upper panels) and terminally failing human hearts (lower panels). There is a close similarity with respect to prolongation of action potential duration and reduction of Ito1 in failing hearts. Short bars indicate zero voltage/current level. (Figures from [39]with modifications and [13]with permission.)

 
3.2.4 Pacing-induced heart failure in rabbit
In pacing-induced heart failure in rabbits, similar changes in Ito1 were reported [63]. After 2–3 weeks of rapid ventricular pacing, animals were considered to be in an early stage of heart failure. When cellular hypertrophy was assessed by measuring cell dimensions, little evidence was found for cellular hypertrophy, possibly due to the short time to development of cardiac failure. Analysis of ion currents revealed ICa,L and IK1 to be unchanged while Ito1 was reduced by 65% in myocytes from failing myocardium. Therefore, the reduction in Ito1 was considered to partly account for the changes in action potential duration observed in this model.

3.2.5 Human tissue studies
Considering human tissue studies it must be kept in mind that end-stage heart failure in man is a highly variable clinical entity with respect to etiology, duration and clinical course, patient's age, treatment and clinical condition at the time of transplantation. Nevertheless, prolongation of the action potential has been reported for isolated cardiac preparations from failing hearts [8]as well as in isolated myocytes derived from failing as compared to nonfailing hearts [64]. While action potential duration in the latter study was determined under conditions where intracellular calcium transients would have been suppressed, action potential prolongation was also noted under conditions of maintained calcium transients and contraction [74].

As unstimulated peak ICa,L was found to be unchanged in failing and nonfailing myocytes [75], potassium channels were studied to clarify the mechanisms of action potential prolongation. Analysis of IK1 indicated a small reduction in current significant only at voltages negative to the potassium reversal potential. However, a marked decrease in Ito1 (by 37%) was observed in failing myocytes which was considered responsible for the prolongation of action potential duration (Fig. 2). A comparison of delayed rectifier currents was not conducted in this study. Evaluation of regional differences of Ito1 also demonstrated a decrease in Ito1 (by 26%) in epicardial myocytes from failing hearts [38].

In contrast, Wettwer et al. [76]found Ito1 density and channel properties not to be different in myocytes from failing and nonfailing human myocardium. However, myocytes used in this study were not derived from identified sites and regional heterogeneity may have had influenced the results. In a further study, regional heterogeneity was addressed indicating no change in Ito1 density on the epicardial side but a significant reduction by 47% in subendocardial tissue [77].

Thus, even though reports differ with respect to the regions where Ito1 is reduced in human tissue, available data strongly support down-regulation predominantly of Ito1 in experimental models of heart failure as well as failing human ventricular myocardium.

With respect to IK1, Koumi et al. studied alterations of whole-cell current density and single channel properties in isolated myocytes from human hearts with a variety of diseases [78, 79]. IK1 density was found to be smaller in cells from hearts with dilated cardiomyopathy and single channel properties altered as compared to ischemic cardiomyopathy, indicating that specific diseases may affect density and properties in a different way [79]. Another study did not find significant differences in basal IK1 density in cells isolated from failing as compared to nonfailing human hearts [78].

3.3 Molecular mechanisms of potassium channel regulation
At present, little is known on the mechanisms involved in regulation of potassium channel expression in cardiac hypertrophy and failure. Adaptive changes may be initiated by pathways intrinsic to the myocytes, e.g. mechanical stress or electrical activity, or occur in response to neurohumoral signals [80, 81]. While in the short term, cardiac output can be adjusted by heart rate, Frank–Starling–Mechanism and β-adrenergic stimulation, chronic cardiac overload alters gene expression inducing changes at the cellular and molecular level. Similarly, gene expression is altered in heart failure [80, 81]. One of the main cellular features of the adaptation process in hypertrophy and failure is slowing of the kinetics of contraction, presumably driven by improved contractile economy [82–84]. In addition, trans-sarcolemmal calcium cycling may be increased to compensate for the depressed SR–Ca-ATPase function in heart failure, evidence for which has recently been provided [69, 80, 85]. Both the prolonged time course of the mechanical cycle and increased trans-sarcolemmal calcium transport would be facilitated by a prolonged action potential duration, so that potassium channel down-regulation might seem a useful adaptive change in cardiac hypertrophy and failure.

There is evidence that signalling systems known to be activated in cardiac hypertrophy and failure differentially influence potassium channel expression, as shown for cAMP– [86]and protein kinase C-dependent pathways [87, 88], or elevation of intracellular calcium [87]. Alpha-receptor stimulation was shown to produce hypertrophy and a profound decrease in Ito1 in rat neonatal myocytes [89]. In addition, potassium channel expression may be affected by membrane potential [87, 90]and activation of the renin–angiotensin system [91]. While in chronic heart failure in humans, myocyte hypertrophy is usually present [7], it does not appear to be required for potassium channel down-regulation to occur, since in dog and rabbit pacing-induced heart failure, myocyte hypertrophy is small or absent [63].

As several different potassium channels are involved in repolarization with species-dependent differences, altered repolarization may be due to changes in expression of various genes coding for potassium channels. Present data indicate that mRNA transcripts coding for Ito1 in rat (presumably encoded by Kv4.2 [92]) are reduced in parallel with current density of Ito1 in hypertrophied myocytes of the chronically infarcted rat heart [33]. In failing human left ventricular myocardium, mRNA for Kv4.3 (the putative gene coding for Ito1 in man [93]) was reduced by a similar extent as Ito1, indicating that functional expression of Ito1 is at least in part transcriptionally regulated [94]. However, other steps before incorporation of functional channel protein into the membrane may also be altered. In addition to the channel protein itself, β-subunits may be altered and significantly affect properties of the ion channel [95–97].

3.4 Functional implications of potassium channel down-regulation
Adaptive changes to cardiac hypertrophy or failure, originating as a compensatory response, have been shown to be not only beneficial [80, 98], and there is increasing evidence that this may also be true for changes in ionic currents, particularly repolarizing potassium currents. Heart failure results in a high risk of cardiac death, which can be reduced by interfering with mechanisms involved in the adaptation processes [81]. Even though deterioration of heart failure may be responsible for a significant number of deaths, almost 50% of the patients die suddenly, mostly due to ventricular tachyarrhythmias [13, 99], with depressed left ventricular function being the strongest predictor of arrhythmic death [4–6, 80]. However, even at the stage of hypertrophy, when hemodynamics are not compromised, risk of sudden cardiac death is significantly increased [100]. Interestingly, as shown above, cardiac hypertrophy is also characterized by prolonged action potential duration and increased lability of the repolarization process.

Animal studies have provided a close correlation between delayed repolarization, reduction of potassium currents and increased propensity to ventricular arrhythmias in cardiac hypertrophy and failure. Earlier studies have shown that hypertrophied rat hearts had a longer action potential duration and higher incidence of early after-depolarizations, and triggered activity after block of potassium channels by TEA was facilitated [14, 32]. In feline left ventricular hypertrophy, an enhanced sensitivity to metabolic inhibition could be attributed to decreased delayed rectifier currents [59], and reperfusion-induced early after-depolarizations and arrhythmias could be related to decreased outward potassium currents [60]. Ventricular tachyarrhythmias during ischemia in dogs were also facilitated by left ventricular hypertrophy [101]. A postinfarct model of myocyte hypertrophy in rat demonstrated increased susceptibility to ventricular tachycardia, increased dispersion of repolarization, and triggered activity from early and delayed after-depolarizations and re-entrant excitation. This was shown to be accompanied by decreases of Ito1 and a slowly decaying transient outward current, Ito–s [33]. In hypertrophied canine ventricle, prolongation of action potential duration was shown to be related to enhanced predisposition to early after-depolarizations that appeared to trigger ventricular tachyarrhythmias [102]. These correlations suggest that reduction of potassium currents may in fact contribute to the propensity to ventricular arrhythmias in cardiac hypertrophy.

For failing myocardium, substantial evidence connecting potassium channel down-regulation to abnormalities of repolarization, arrhythmias and sudden cardiac death has recently been provided in dogs with pacing-induced cardiac failure [39, 62, 103]. Action potential prolongation and a dramatic decrease in Ito1 by 65% was shown to be accompanied by a prolonged effective refractary period, monophasic action potential duration and dispersion of repolarization, and increased incidence in ventricular arrhythmias and sudden cardiac death. In addition, sensitivity to CsCl, which causes further block of potassium currents, was greatly enhanced leading to excessive monophasic action potential prolongation and dispersion, and generation of early after-depolarizations in failing myocardium. This was reflected at the cellular level by a similar propensity to excessive action potential prolongation and early after-depolarizations in response to CsCl [62]. Thus, potassium channel down-regulation appears to predispose to enhanced sensitivity of myocardial cells to interventions disturbing repolarization, suggesting greater susceptibility to factors known to trigger arrhythmias such as transient neurohumoral activation, electrolyte changes or transient ischemia.

Even though this does by no means exclude the contribution of other ion currents (such as increased sodium window current, L-type calcium currents [73], or Na/Ca-exchange current [69]), any decrease in outward current will shift the repolarization process towards later repolarization and greater lability for any given inward currents. Even if a simultaneous reduction of inward currents counteracts action potential prolongation, membrane impedance at the action potential plateau would still be increased implicating an increased lability of the repolarizing process. Furthermore, changes in electrical properties in hypertrophy and failure may not necessarily be homogenous. There is evidence to the contrary [104], and outward potassium currents may also be involved, e.g. due to different loading conditions. Clearly, any inhomogeneity in repolarizing currents will cause inhomogeneity in repolarization and subsequently excitability, facilitating re-entry.

Present evidence on potassium channel down-regulation in heart failure clearly indicates involvement of Ito1. With respect to IK1, alterations reported [39, 64]did not extend to the voltage range positive to the potassium reversal potential relevant of the final repolarization process. Others reported a difference in current density in cells from failing hearts with dilated cardiomyopathy when compared to ischemic cardiomyopathy or valvular heart disease [79], while no differences were found when cells from failing versus nonfailing human myocardium were studied [78]. Further studies will be required to clarify potential alterations in IK1 in heart failure. Preliminary reports suggest a reduction of mRNA levels of HERG in failing human myocardium [105]; if these findings translate into reduced functional expression of IKr, a more widespread reduction in potassium currents may occur in heart failure.

The recent discovery of a causative role of decreased or altered repolarizing potassium currents in congenital LQT Syndrome (LQT1, LQT2, LQT4) [27]provides strong arguments for a link of potassium channel down-regulation and action potential prolongation to enhanced lability of repolarization and sudden cardiac death. Genetic alteration of IKs (KvLQT1) and IKr (HERG) are probably responsible for the majority of LQT syndromes [27], which is characterized by repolarization abnormalities with prolongation and increased lability of the action potential duration as manifested by an increased dispersion of repolarization, and sudden cardiac death. Even more importantly, QT prolongation and dispersion appeared to be reversible by interventions increasing IKr (such as elevation of extracellular potassium concentration) [106], demonstrating the crucial involvement of the reduced potassium outward current.

To some degree, action potential prolongation in cardiac hypertrophy and failure may be viewed as a form of acquired LQT syndrome, sharing the characteristics of action potential prolongation with increased lability and dispersion, reduction of outward potassium currents (or possibly increased inward currents such as INa in LQT3) and propensity to early after-depolarizations, polymorphic ventricular tachycardia or torsade de pointes and sudden cardiac death. As in LQT syndrome, heart failure shows a greater sensitivity to further prolongation of action potential duration in hypokalemia [62]or following exposure to antiarrhythmic agents like sotalol, which has been shown to exert greater proarrhythmic effects in failing hearts and to cause excess mortality [15]. Further validation of a contribution of reduced potassium currents to electrical instability in heart failure might be obtained by demonstration of stabilization of repolarization after increasing outward potassium currents, as in a genetic LQT syndrome [106]. Recent preliminary data suggest that this may indeed be true as increasing IKr (by elevation of [K+]o) was capable of reducing QT prolongation and dispersion in congestive heart failure in man [107].

The clinical efficacy of elevation of extracellular potassium in stabilizing ventricular arrhythmias in LQT syndrome and congestive heart failure suggests that despite disappointing results with most current antiarrhythmic drugs, there may be a potential for new strategies, possibly by increasing potassium currents or specific current components. However, a much deeper level of understanding of the electrical activity in myocardium under normal and pathological conditions, and structure and function of the ion channels will be an essential prerequisite.


   4 Future aspects
Top
 Abstract
 1 Introduction
 2 Diversity of cardiac...
 3 Down-regulation of potassium...
 4 Future aspects
References
 
Most cardiac potassium channels exhibit a pronounced regional heterogeneity throughout the ventricular wall, from base to apex and between septum, left and right ventricle [37, 108, 109]. Therefore, when studying current densities and properties or mRNA levels of ion currents and channels, great care has to be taken to prevent any influence possibly arising from tissue sampling. Even in rat heart, regional differences in action potential configuration and current densities have clearly been recognized [43]. As evident from the rapid changes in Ito1 density towards the deeper subendocardium [110], even a small local sampling error may cause ‘significant’ differences in current density.

As shown recently, the delayed rectifier current IK consists of two components which can be separated based on kinetic criteria and pharmacologic sensitivity [23]. Considering that the two channels are encoded by different genes [27]and may be regulated independently, these two channels need to be evaluated separately. However, at present no study attempted to separately quantify alterations in current density of IKr and IKs in hypertrophied or failing myocardium.

Finally, little is known as to the mechanisms regulating the altered expression of potassium currents in cardiac hypertrophy and failure, such as mechanical stress, neurohumoral activation, or membrane potential. Identification of the systems involved may provide specific options to interfere with potentially detrimental adaptive changes.

Time for primary review 34 days.


   Acknowledgements
 
These studies were supported in part by the Deutsche Forschungsgemeinschaft and Friedrich–Baur–Stiftung.


   References
Top
 Abstract
 1 Introduction
 2 Diversity of cardiac...
 3 Down-regulation of potassium...
 4 Future aspects
 References
 

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S. Brunet, F. Aimond, H. Li, W. Guo, J. Eldstrom, D. Fedida, K. A. Yamada, and J. M. Nerbonne
Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult mouse ventricles
J. Physiol., August 15, 2004; 559(1): 103 - 120.
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Y. Shimoni and X.-F. Liu
Sex differences in the modulation of K+ currents in diabetic rat cardiac myocytes
J. Physiol., July 15, 2003; 550(2): 401 - 412.
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R. Sah, R. J. Ramirez, and P. H. Backx
Modulation of Ca2+ Release in Cardiac Myocytes by Changes in Repolarization Rate: Role of Phase-1 Action Potential Repolarization in Excitation-Contraction Coupling
Circ. Res., February 8, 2002; 90(2): 165 - 173.
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K S Thorneloe, X F Liu, M P Walsh, and Y Shimoni
Transmural differences in rat ventricular protein kinase C epsilon correlate with its functional regulation of a transient cardiac K+ current
J. Physiol., May 15, 2001; 533(1): 145 - 154.
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J. M Nerbonne
Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium
J. Physiol., June 1, 2000; 525(2): 285 - 298.
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B. C Knollmann, B. E C Knollmann-Ritschel, N. J Weissman, L. R Jones, and M. Morad
Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin
J. Physiol., June 1, 2000; 525(2): 483 - 498.
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W. Guo, H. Xu, B. London, and J. M Nerbonne
Molecular basis of transient outward K+ current diversity in mouse ventricular myocytes
J. Physiol., December 15, 1999; 521(3): 587 - 599.
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T. Volk, T. H.-D. Nguyen, J.-H. Schultz, and H. Ehmke
Relationship between transient outward K+ current and Ca2+ influx in rat cardiac myocytes of endo- and epicardial origin
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