Abnormal excitability of myocardial cells may give rise to ectopic beats and initiate re-entry around an anatomical or functional obstacle. As K+ currents control the repolarization process of the cardiac action potential (AP), the K+ channel function determines membrane potential and refractoriness of the myocardium. Both gain and loss of the K+ channel function can lead to arrhythmia. The former because abbreviation of the active potential duration (APD) shortens refractoriness and wave length, and thereby facilitates re-entry and the latter because excessive prolongation of APD may lead to torsades de pointes (TdP) arrhythmia and sudden cardiac death. The pro-arrhythmic consequences of malfunctioning K+ channels in ventricular and atrial tissue are discussed in the light of three pathophysiologically relevant aspects: genetic background, drug action, and disease-induced remodelling. In the ventricles, loss-of-function mutations in the genes encoding for K+ channels and many drugs (mainly hERG channel blockers) are related to hereditary and acquired long-QT syndrome, respectively, that put individuals at high risk for developing TdP arrhythmias and life-threatening ventricular fibrillation. Similarly, down-regulation of K+ channels in heart failure also increases the risk for sudden cardiac death. Mutations and polymorphisms in genes encoding for atrial K+ channels can be associated with gain-of-function and shortened, or with loss-of-function and prolonged APs. The block of atrial K+ channels becomes a particular therapeutic challenge when trying to ameliorate atrial fibrillation (AF). This arrhythmia has a strong tendency to cause electrical remodelling, which affects many K+ channels. Atrial-selective drugs for the treatment of AF without affecting the ventricles could target structures such as IKur or constitutively active IK,ACh channels.
Torsades de pointes
Regular excitation is generated in the sino-atrial node and spreads throughout the heart in an orderly manner, whereas disorganization of electrical activity is the basis of atrial or ventricular fibrillation. Arrhythmias are caused by the perturbation of physiological impulse formation, impaired impulse conduction, or disturbed electrical recovery. Abnormal excitability of myocardial cells may give rise to ectopic beats and initiate re-entry around an anatomical or functional obstacle (reviewed in Jalife1).
The long-lasting action potential (AP) of the working myocardium maintains a refractory state for as long as the muscle contracts and thus ensures rhythmic pump function. Typical cardiac APs consist of five distinct phases (Figure 1). In phase 0, Na+ influx triggers a rapid depolarization followed by an early fast repolarization phase (phase 1) and a plateau phase (phase 2), in which repolarization is slowed due to the activation of inward Ca2+ current. During the final rapid repolarization phase (phase 3), membrane potential returns to the resting level (phase 4). The various potassium (K+) currents are repolarizing outward currents. Their major contributions to the cardiac AP are control of stable resting membrane potential and termination of the AP.
Inward, depolarizing and outward, repolarizing currents that underlie the atrial and ventricular action potential. Inward currents: INa sodium current; ICa,L L-type calcium current; Ito transient outward current; IKur ultra rapidly activating delayed rectifier current; IKr and IKs rapidly and slowly activating delayed rectifier current; IK1 inward rectifier current; IK,ACh acetylcholine-activated potassium current. Note that IKur is present in atria only. Phase 0, rapid depolarization; phase 1, rapid early repolarization phase; phase 2, slow repolarization phase (‘plateau’ phase); phase 3, rapid late repolarization phase; phase 4, resting membrane potential. Adapted from The Sicilian gambit.28
Ions traverse the lipid bilayer of the plasmalemma along their electrochemical gradient via hydrophilic ion channels. These ion channels open and close in a voltage- and time-dependent manner (activation, inactivation, or deactivation) and pass ions only in the open state. After-repolarization, some channels must recover from inactivation before they become available for re-opening, and during this time, the myocardial cells remain refractory for re-excitation.
Potassium channels form the largest family of ion channel proteins. Determining and depending on membrane potential, K+ channels can also be activated by ligand binding, and hence are divided into voltage- and ligand-gated channels. The ion-conducting pore of a K+ channel is formed by four α-subunits that co-assemble as homo- or hetero-tetramers with different biophysical properties. Their gating characteristics are further modulated by ancillary subunits.
Cardiac K+ channels are further classified according to their function (cf. Figure 1). (i) The transient outward currentIto exhibits rapid activation and subsequent inactivation during the early repolarization phase. (ii) The delayed rectifier channels conduct at least three different currents IKur, IKr, and IKs. All three currents activate at positive potentials with distinct time courses, i.e. ultrarapid, rapid, and slow, respectively. Inactivation of IKur and IKs is slow, whereas that of IKr is extremely fast. Contribution of each of these currents to repolarization depends on the number of open channels and the electrochemical driving force that declines as the membrane potential returns to its resting level. In the course of repolarization, IKr recovers rapidly from inactivation into an open state which deactivates very slowly, so that this current exhibits inward rectification.2 Therefore, IKr increases again at negative potentials and strongly accelerates final repolarization. (iii) The major classical cardiac inward rectifier K+current is IK1. This channel is always open and conducts K+ better into than out of the cell. Atrial myocytes also express an acetylcholine-dependent channel that conducts IK,ACh in response to the stimulation of G-protein-coupled muscarinic (M2) and adenosine (A1) receptors. The activation of IK,ACh hyperpolarizes the membrane and shortens the active potential duration (APD). The third inward rectifier channel in cardiomyocytes is closed under physiological metabolic conditions and is activated when the cells are deprived of intra-cellular adenosine triphosphate. Similar to IK,ACh, IK,ATP causes profound APD shortening.
Potassium channels—differences between atrium and ventricle
Despite general similarity in the mechanisms of AP generation, APs exhibit distinct shapes in atrial and ventricular myocardium (Figure 1). The most striking differences are that (i) the plateau phase occurs at more negative potentials and (ii) overall APD is shorter in atrial when compared with ventricular cells. These differences are due to the non-uniform distribution of ion channels, including K+ channels. For instance, IKur is detected only in atrial but not in ventricular myocytes, although the Kv1.5 protein is abundant in both chambers. Rapid activation of IKur in the positive potential range following the AP upstroke may offset depolarizing ICa,L and hence leads to the less positive plateau phase in atrial than ventricular cells. The acetylcholine-activated inward rectifying current IK,ACh, too, is not detected in ventricle.
Contribution of K+ channel function to arrhythmias
Because of their impact on membrane potential and refractoriness, K+ currents play a prominent role in arrhythmogenesis. An increase in K+ currents abbreviates APD and thereby facilitates re-entry. Conversely, impaired K+ current amplitudes prolong APD with contrasting outcome, whereas moderate prolongation maintains the myocardium in a refractory state and is actually considered an anti-arrhythmic mechanism (class III anti-arrhythmic action according to the classification of Vaughan Williams), excessive prolongation predisposes to early after-depolarizations that may trigger torsades de pointes arrhythmias (TdP). This form of arrhythmia may either resolve spontaneously or deteriorate into ventricular fibrillation causing sudden cardiac death.
Therefore, both gain and loss of K+ channel function can lead to arrhythmia. Malfunction of K+ channels may be due to diverse causes such as mutations in the encoding genes for any of the subunits, drug actions, or remodelling in adaptation to heart disease. These three factors will be discussed first for ventricular and, subsequently, for atrial arrhythmias.
Arrhythmogenic potential of K+ channel mutations
The number of mutations identified in K+ channel-encoding genes that have been related to arrhythmias is increasing rapidly. The consequences of missense mutations include faulty protein folding and disturbed co-assembly between subunits and therefore early degradation, disruption of trafficking or defects in plasmalemmal integration, altered voltage dependency, or impaired ion selectivity of the channel. These adverse effects reduce repolarizing K+ currents and thereby delay the repolarization process. The resulting long-cardiac APD or long-QT interval in the electrocardiogram predisposes a patient to TdP arrhythmias. Therefore, patients with the hereditary long-QT syndrome (LQTS) are at increased risk for sudden cardiac death. Mutations in the genes for KvLQT1 (IKs) and hERG (IKr) account for 80–90% of all hereditary LQTS, although mutations that cause LQTS were also discovered in other ion channels, in ion-handling, or associated proteins (for recent review, see Saenen and Vrints3). As mentioned above, rare gain-of-function mutations in hERG and KvLQT1 shorten cardiac APs and also give rise to potentially lethal arrhythmias (short-QT syndrome).
Arrhythmogenic potential of K+ channel blockers
Many drugs used in cardiac and non-cardiac diseases prolong APs and give rise to acquired LQTS. Besides underlying heart disease, several factors predispose to drug-induced TdP. These include female gender, long-QT interval at baseline, bradycardia, low K+ and Mg2+ plasma levels, old age, and the increased incidence of heart disease. Similar to congenital LQTS, the actual incidence of drug-induced TdP is low and that of proven drug-associated syncope or sudden cardiac death is even lower.4 The absolute incidence of cardiotoxicity of any drug must be judged in relation to the severity of the treated disease: a high risk may be perfectly acceptable when treating a life-threatening condition, whereas even a very low incidence as reported for non-sedating antihistaminic drugs is not acceptable as these drugs are widely prescribed for minor complaints. Nevertheless, the increasing number of drugs recognized to cause acquired LQTS has become a concern for patients, physicians, and safety regulation authorities.
Almost all drugs with reported QT-prolongation and TdP are blockers of potassium channels, particularly IKr channels.5 In fact, hERG channels are sensitive to block by a surprisingly large variety of agents, and block of hERG channels is so common that drug safety agencies require data on hERG channel block for new drugs when filed for registration. hERG screening tests are performed at very early stages in drug development and even promising new compounds are usually abandoned when testing positive. This is not always justified, because the block of IKr may in part be compensated by changes in opposing currents (increase in ‘repolarization reserve’).6,7 Although there appears to be no strict concentration–response relationship for triggering TdP, drug plasma concentrations should not be allowed to rise above the therapeutic level and interference with drug metabolism or excretion should be avoided.
Even in asymptomatic patients, a genetic predisposition related to congenital LQTS may exacerbate drug action that turns the otherwise borderline QT interval into overt prolongation. Some polymorphisms, for instance, in the gene encoding for a common ancillary subunit (i.e. the KCNE2 gene) have normal function at baseline, but are susceptible to block by sulfamethoxazole that imposes no prolongation in healthy individuals.8
Arrhythmogenic exacerbation frequently occurs due to pharmacokinetic interactions by co-administered drugs that interfere with biotransformation and excretion of a previously tolerated drug resulting in excessive plasma concentrations. If the parent compound is more effective than the metabolite in producing a pro-arrhythmic event, inhibition of drug metabolizing enzymes will enhance arrhythmogenicity. Conversely, if the metabolite is more effective, induction of enzymes is pro-arrhythmogenic. The antifungal agent, ketoconazole for instance, interferes with biotransformation of the non-sedating antihistaminic terfenadine into a metabolite that does not prolong the AP. Thus, co-medication of the two drugs results in a high plasma concentration of terfenadine leading to acquired LQTS. Such an interaction applies for many drugs that inhibit cytochrome P450 enzymes and even grapefruit juice may interfere (reviewied in Priori et al.4).
Intuitively, cardiac drugs and, in particular, anti-arrhythmics that prolong APD (class III action according to the Vaughan Williams classification) are expected to produce an increased risk not only because of their mechanism of action but also because they are given to patients with diseased hearts that are per se at a high risk for rhythm disturbances. However, drugs for treating non-cardiac diseases such as antihistamines, antibiotics, antipsychotic, or prokinetic agents also may increase risk. Comprehensive lists of drugs with reported or suspected risk for TdP are available in the internet (for instance, http://www.qtdrugs.org/).
Heart failure is associated with a plethora of ventricular ionic changes that predispose to arrhythmias (for recent review, see Nass et al.9). These remodelling processes include electrophysiological changes that lead to APD prolongation, especially in the endocardial region. We and others have shown that Ito amplitude is down-regulated, but other K+ currents (IKr, IKs, and IK1) are depressed as well.10,11 Reduced K+ currents increase the propensity for early after-depolarizations, dispersion of repolarization, and ventricular arrhythmias, thereby significantly increasing the risk of sudden cardiac death in heart failure patients. In contrast, delayed after-depolarizations occurring at high intra-cellular Ca2+ load may initiate triggered activity and induce ventricular tachycardia, particularly in non-ischaemic heart failure patients, and decreased IK1 enhances the propensity for triggered activity.12 K+ channel down-regulation also contributes to enhanced sensitivity of failing myocardium to other triggering factors such as hypokalaemia, ischaemia, and anti-arrhythmic agents with class III effects. In addition, overexpression of pacemaker channels may predispose ventricular myocytes from failing hearts to enhanced automaticity.13
Atrial fibrillation (AF) is initiated when a suitable trigger meets an appropriate substrate. The underlying pathophysiological mechanisms include ectopic electrical activity and single or multiple re-entry circuits. Re-entry often develops in large fibrotic atria associated with valvular disease or heart failure, whereas in seemingly healthy hearts, rapid local ectopic activity initiating in the pulmonary veins can give rise to re-entry circuits.
Arrhythmogenic potential of K+ channel mutations
In contrast to the vast majority of several hundreds of known K+ channel mutations being associated with LQTS, there are, but a few, mutations directly linked to familial AF (Table 1). Nevertheless, LQTS patients may also exhibit polymorphic atrial tachyarrhythmias.14 Although in the ventricles loss-of-function mutations predominantly predispose to chaotic electrical activity, the K+ channel mutations associated with AF exhibit—with one exception—gain-of-function, leading to abbreviation of the APD and facilitating re-entry. In the individual studies, gain-of-function was verified by expressing mutated channels in cell lines and measuring increased K+ current density when compared with wild-type channels (reviewed in Roberts15). For the loss-of-function mutation, it was demonstrated that mice expressing the mutated channels had long APs with early after-depolarizations and were more prone to stress-induced arrhythmias.16 Recent evidence from a genome-wide association study identified three novel single nucleotide polymorphisms that confer predisposition to AF.17 Moreover, a systematic candidate gene-based analysis of the gene encoding for hERG discovered a hitherto unknown variant, which strongly associated with AF.18
Mutations in genes encoding for potassium channel proteins associated with familial atrial fibrillation
Amino acid change
Olson et al.16
Hong et al.29
Chen et al.30
Hong et al.31
Otway et al.32
Yang et al.33
Xia et al.34
Arrhythmogenic potential of drugs acting on K+ channels
Vagal nerve stimulation induces AF because of shortening of the refractory period due to acetylcholine release and subsequent activation of IK,ACh. In analogy, drugs that shorten APD by activating K+ currents are expected to predispose to AF. However, much less is known about the actual incidence of drug-induced AF than of TdP in the case of LQTS. As outlined above, prolongation of atrial APD by the block of K+ channels, as, for instance, with cesium, may also induce AF;19 however, unlike ventricular fibrillation, this arrhythmias is not immediately life threatening.
Atrial fibrillation has a strong tendency to become persistent. Persistent AF is thought to develop because of ‘remodelling’, which refers to any change in the atrial function that promotes AF or occurs as a consequence of the arrhythmia20 and involves alterations in myocardial structural and electrophysiological properties. Structural remodelling includes interstitial fibrosis and is closely related to the renin–angiotensin–aldosterone system.21 Electrical remodelling comprises triangularization of the AP shape, shortening of APD, and lack of adaptation of APD to cycle length and is due to alterations in the ion channel function as well as changes in Ca2+ handling of the cardiomyocytes.11,22 Reduced refractoriness supports multiple wavelet re-entry and generation of sustained, high-frequency spiral waves (‘rotors’) with fibrillatory conduction, which are thought to contribute to sustained AF.23
Electrical remodelling by AF affects depolarizing currents (with reduced ICa,L, unaffected conventional INa, and activated sodium/calcium exchanger) as well as repolarizing K+ currents with Ito and IKur current densities being decreased. The contribution of IKr and IKs to electrical remodelling is less clear, because their presence in the human atrium is difficult to assess experimentally.24 Basal activity of the inwardly rectifying IK1 current is enhanced, but acetylcholine-activated IK,ACh current is reduced. Moreover, a component of constitutively active IK,ACh that activates in the absence of any agonist is detected in persistent AF and may contribute to AP shortening.25 The contribution of other ion channels (chloride channels, TASK-1, and so on) to AF pathophysiology is still unknown.
Atrial fibrillation-induced changes in K+ current amplitude need not necessarily be due to corresponding alteration in the gene expression, but can be caused by AF-induced effects on protein kinases and phosphatases that modify channel phosphorylation status (see, for instance, Christ et al.6) or by enhanced protein degradation through proteases.21 There is some controversy in the literature concerning the expression of K+ channels in remodelled atria (see Dobrev and Ravens,22 for references): mRNA and protein expression of Ito channels are always found depressed, IKur channels are not changed or decreased; IKr channels are not altered or decreased and IKs channels are decreased or increased; inward rectifier K+ channels for IK1 are enhanced, for IK,ACh and IK,ATP decreased.26,27 Moreover, these discrepant findings do not always go in line with the actually measured changes in the current amplitude, indicating that AF-induced channel dysregulation must have occurred. Although ancillary subunits of K+ channels profoundly affect their expression and biophysical properties, little is presently known about AF-induced remodelling in these regulatory proteins.
The K+ currents, IKur and IK,Ach, have recently attracted special attention because they are confined to atrial myocardium and hence their blockade is not expected to cause pro-arrhythmic effects in the ventricles. In the past decade, several new compounds were developed for the prolongation of effective refractory period by the block of IKur, however, the efficacy of most of these new drugs in converting AF back to SR has been rather disappointing, possibly due to low IKur amplitude in AF. With regard to IK,ACh channels, we have recently reported that these channels develop constitutive activity during human AF, i.e. these channels become activated, despite the absence of stimulating acetylcholine.25 Constitutively active IK,ACh can hyperpolarize the membrane and hence contribute to persistence of AF by stabilization of rotors. Therefore, selectively targeting constitutively active IK,ACh channels only may preserve physiological stimulation by vagal nerves and could serve as a promising remodelling-related drug target.
This work was supported by a grant from the Fondation Leducq and by a European Union grant (NORMACOR, LSHM-CT-2006-018676).
The authors gratefully acknowledge helpful comments by Dobromir Dobrev and Niels Voigt.
. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels. J Am Coll Cardiol 2001;37:926-32.
. Molecular basis of downregulation of G-protein-coupled inward rectifying K+ current (IK,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced I(K,ACh) and muscarinic receptor-mediated shortening of action potentials. Circulation 2001;104:2551-7.
The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991;84:1831-51.