Transient outward potassium current and Ca2+ homeostasis in the heart: beyond the action potential

R.A. Bassani About the author


Normal central nervous system development relies on accurate intrinsic cellular programs as well as on extrinsic informative cues provided by extracellular molecules. Migration of neuronal progenitors from defined proliferative zones to their final location is a key event during embryonic and postnatal development. Extracellular matrix components play important roles in these processes, and interactions between neurons and extracellular matrix are fundamental for the normal development of the central nervous system. Guidance cues are provided by extracellular factors that orient neuronal migration. During cerebellar development, the extracellular matrix molecules laminin and fibronectin give support to neuronal precursor migration, while other molecules such as reelin, tenascin, and netrin orient their migration. Reelin and tenascin are extracellular matrix components that attract or repel neuronal precursors and axons during development through interaction with membrane receptors, and netrin associates with laminin and heparan sulfate proteoglycans, and binds to the extracellular matrix receptor integrins present on the neuronal surface. Altogether, the dynamic changes in the composition and distribution of extracellular matrix components provide external cues that direct neurons leaving their birthplaces to reach their correct final location. Understanding the molecular mechanisms that orient neurons to reach precisely their final location during development is fundamental to understand how neuronal misplacement leads to neurological diseases and eventually to find ways to treat them.

Extracellular matrix; Central nervous system; Cerebellum; Neuron; Migration

Braz J Med Biol Res, March 2006, Volume 39(3) 393-403 (Review)

Transient outward potassium current and Ca2+ homeostasis in the heart: beyond the action potential

R.A. Bassani

Centro de Engenharia Biomédica, Universidade Estadual de Campinas, Campinas, SP, Brasil


Correspondence and Footnotes


The present review deals with Ca2+-independent, K+-carried transient outward current (Ito), an important determinant of the early repolarization phase of the myocardial action potential. The density of total Ito and of its fast and slow components (Ito,f and Ito,s, respectively), as well as the expression of their molecular correlates (pore-forming protein isoforms Kv4.3/4.2 and Kv1.4, respectively), vary during postnatal development and aging across species and regions of the heart. Changes in Ito may also occur in disease conditions, which may affect the profile of cardiac repolarization and vulnerability to arrhythmias, and also influence excitation-contraction coupling. Decreased Ito density, observed in immature and aging myocardium, as well as during several types of cardiomyopathy and heart failure, may be associated with action potential prolongation, which favors Ca2+ influx during membrane depolarization and limits voltage-dependent Ca2+ efflux via the Na+/Ca2+ exchanger. Both effects contribute to increasing sarcoplasmic reticulum (SR) Ca2+ content (the main source of contraction-activating Ca2+ in mammalian myocardium), which, in addition to the increased Ca2+ influx, should enhance the amount of Ca2+ released by the SR during systole. This change usually takes place under conditions in which SR function is depressed, and may be adaptive since it provides partial compensation for SR deficiency, although possibly at the cost of asynchronous SR Ca2+ release and greater propensity to triggered arrhythmias. Thus, Ito modulation appears to be an additional mechanism by which excitation-contraction coupling in myocardial cells is indirectly regulated.

Key words: Action potential, Repolarization, Ca2+ current, K+ current, Excitation-contraction coupling


The action potential (AP) is the triggering signal for contraction in striated muscle. Ion currents through sarcolemmal voltage- and ligand-dependent channels, as well as electrogenic ion transporters, determine the AP waveform. In a typical mammalian cardiac myocyte, 4 phases of the AP (Figure 1) can be identified (1,2):

Figure 1.
Action potential (AP) and ion currents in a rabbit ventricular myocyte. A, AP waveform, in which phases zero (upstroke), 1 (early repolarization), 2 (plateau), and 3 (late repolarization) are indicated. B, Voltage-dependent ion currents that contribute to membrane depolarization during the AP: Na+ current (INa) and L-type Ca2+ current (ICa,L). Note: the actual INa density is 10-fold greater than that shown in the figure. C, Voltage-dependent K+ currents that contribute to membrane repolarization during the AP: transient outward current (Ito), total delayed rectifier K+ current (IK) and inwardly rectifying K+ current (IK1). For clarity, IK components (IKr and IKs) were combined, and currents carried by ion transporters (e.g., Na+-Ca2+ exchanger, Na+-K+ ATPase), as well as ICl(Ca), were omitted. Traces were obtained by simulation with the LabHEART 4.9.5 program (Ref. 3).

Phase zero (upstroke): during this brief phase, the rapidly activating Na+ current drives the membrane potential (Em) from its diastolic level (~ -80 mV) to positive values (20-50 mV). The AP peak is limited mainly by Na+ channel inactivation and decrease in the transsarcolemmal Na+ electrochemical gradient.

Phase 1 (early repolarization): the rapid, transient outward current (Ito) is the predominant contributor to the partial membrane repolarization.

Phase 2 (plateau): this usually long phase may last up to a few hundred milliseconds, and is characterized by slow Em variation, which is dependent on the delicate balance between depolarizing (mostly L-type Ca2+ current, ICa,L) and repolarizing (mainly mediated by delayed rectifier K+ channels) currents.

Phase 3 (late repolarization): this phase relies on both a decrease in ICa,L due to ICa,L inactivation/deactivation, and activation of delayed rectifier K+ channels. As repolarization proceeds, K+ efflux through inwardly rectifying K+ channels (IK1) becomes greater (Figure 1C) due to relief of channel rectification and contributes to late restoration and stabilization of the diastolic Em.

Recent investigation has provided evidence that the early repolarization phase may considerably influence the AP waveform. Ito, the main current responsible for this phase, has been shown to be carried by distinct ionic components: in addition to the Ca2+-independent, voltage- and time-dependent K+ current (Ito-1), a Ca2+-dependent Cl- current (ICl(Ca) or Ito-2) was also identified. In this review, I will refer to the 4-aminopyridine-sensitive, Ca2+-insensitive transient outward K+ current (Ito-1) as Ito. More information on ICl(Ca) can be found in a recent review (4).

Ito, in turn, is the net result of K+ flux through at least two different types of channel associated with different isoforms of the pore-forming protein. The behavior of these channels differs especially in the time course of voltage-dependent inactivation and steady-state recovery from inactivation. Fast Ito (Ito,f) is mediated by channels that recover from inactivation in less than 100 ms, whereas for channels that carry slow Ito (Ito,s) recovery from inactivation takes a few seconds (5,6).

Both experimental data and mathematical models have shown that Ito magnitude and composition (i.e., the relative contributions of Ito,f and Ito,s to total Ito) may markedly affect AP duration and shape (7-13). Expression of Ito,f and Ito,s channel proteins is highly regulated, and may vary with species, developmental stage, and region of the heart (6,11). For instance, Ito,f is more prominent in ventricular epicardial myocytes than in endocardial myocytes. In the former, the AP waveform displays the so-called spike-and-dome configuration, with distinct phases 1 and 2, while in the latter AP duration tends to be greater and repolarization to the plateau level is slower and more gradual. Differences in Ito,f density correlate with differences in the AP profile within and between ventricles (e.g., 5,11,14,15). The Ito,f and AP duration gradients across and along the ventricular wall have been proposed to contribute to the dispersion of ventricular refractoriness, which markedly influences ventricular repolarization path, direction and time course. It has been proposed that region-dependent changes in Ito reported in certain disease states (e.g., post-myocardial infarction, ventricular hypertrophy, heart failure) may underlie increased susceptibility to repolarization abnormalities and reentry arrhythmias (11,16,17). However, in this brief review, I will not deal with the influence of Ito on cardiac electric conduction (see Ref. 16 for further discussion), but its indirect effects, via the AP waveform, on Ca2+ homeostasis, which is of paramount importance for the development of adequate ventricular mechanical function and blood pumping.

Myocardial Ca2+ cycling

Ca2+-induced Ca2+ release (CICR) is the most accepted mechanism underlying excitation-contraction coupling (ECC) in the mammalian myocardium (18,19). Ca2+ influx through voltage-dependent, sarcolemmal ICa,L during the AP is the main trigger for the release of a greater amount of Ca2+ by the sarcoplasmic reticulum (SR), which is the source of most Ca2+ that activates contraction. SR Ca2+ release causes an increase in the cytosolic free Ca2+ concentration ([Ca2+]i), which results in greater interaction of the ion with myofilament proteins and development of force and cell shortening. Thus, the AP is the signal for contraction development, and Ca2+ acts as the second messenger in the electro-mechanical coupling process. Contraction is limited by Ca2+ removal from the cytosol by several transporters, which promote [Ca2+]i decline, Ca2+ dissociation from myofilaments and cell relaxation. The dominant transporter that ultimately determines relaxation is the SR Ca2+-ATPase (SERCA), which is responsible for 70-90% of cytosolic Ca2+ clearance and repletion of the SR Ca2+ store. Ca2+ efflux is mainly mediated by the Na+-Ca2+ exchanger (NCX), a sarcolemmal counter-transporter that is driven by the transsarcolemmal Na+ and Ca2+ electrochemical gradients. NCX accounts for 7-30% of total cytosolic Ca2+ removal during relaxation, which is approximately equivalent to the amount of Ca2+ entering the cell via ICa,L during excitation (1,20,21).

The Ca2+ transient amplitude is an important determinant of contraction amplitude and is greatly dependent on the amount of Ca2+ released by the SR during ECC. During each AP, the SR releases a fraction of its content, which increases with increasing trigger (i.e., ICa,L) amplitude and/or SR Ca2+ content (12,22,23). Moreover, ECC efficiency may be modulated by additional regulation of the SR Ca2+ channel activity by ions (e.g., Mg2+) and proteins (e.g., Ca2+-

calmodulin-dependent protein kinase II, FK506-binding protein, sorcin) (1).

It is important to note that Ca2+ transport by the main influx (ICa,L) and efflux (NCX) pathways during the cardiac cycle is strongly influenced by Em: the former because of the voltage dependence of ICa,L activation and inactivation (and also because of the driving force for Ca2+ flux), and the latter because the direction and driving force for Ca2+ transport are determined by the difference between Em and the exchanger reversal potential (ENCX = 3ENa - 2ECa, where ENa and ECa are the Nernst equilibrium potentials for Na+ and Ca2+, respectively (24)). The consequences of the voltage dependence of ICa,L and NCX operation for ECC, [Ca2+]i and contraction amplitude are many. The amplitude and time course of the trigger Ca2+ signal were shown to markedly affect its ability to induce SR Ca2+ release (19) and the so-called fractional SR Ca2+ release, i.e., the fraction of the SR Ca2+ content that is released at a twitch (22). On the other hand, Ca2+ efflux by the NCX is thermodynamically favored by membrane repolarization. Changes in NCX function may influence SR Ca2+ content and vulnerability to triggered arrhythmias (1). Thus, one can conclude that the AP does not represent simply an impulse to trigger ECC, but a complex input waveform that can modulate directly or indirectly ECC efficiency. On the other hand, Ca2+ cycling may conversely modulate the AP waveform, because of the effects of SR-released Ca2+ on membrane currents, for instance, inactivation of ICa,L, activation of Ca2+-dependent Cl- channels and NCX-mediated current (25).

Transient outward K+ current (Ito)

Ito is characteristic of neurons and cardiac muscle, and its voltage-dependent activation and inactivation kinetics is much faster than that of other cardiac K+ currents. The channel is a macromolecular protein complex composed of pore-forming subunits a (which belong to the Kv gene subfamily), accessory ß subunits (several types of ß subunit have been identified) and other regulatory proteins, such as minimal K+ channel subunit homologues, K+ channel-associated proteins (possibly chaperone proteins) and K+ channel-interacting proteins (KChIP, which belong to a family of neuronal Ca2+ binding proteins). KChIP2 is present in the heart, and its co-expression with Kv4.2, but not with Kv1.4, increases current amplitude, changes the biophysical channel properties and allows the channel to be regulated by protein kinase A. The a subunit presents 6transmembrane domains, a K+-selective pore region and a highly charged S4 domain, which is considered to be the region where the voltage sensor is located. The functional channel consists of the assembly of 4 a subunits. In rodent heart, it seems that the channel that mediates Ito,f consists of Kv4.2 and/or 4.3 subunits co-assembled with KChIP2. A detailed description of the molecular aspects of the channels that mediate Ito can be found elsewhere (2,6,11,17).

Two types of a subunits may form channels with different kinetic properties. Kv4.2/4.3 expression correlates with Ito,f, which shows fast inactivation and recovery from steady-state inactivation (milliseconds). Kv4.2 appears to be the pore-forming subunit in rodent atria, whereas Kv4.3 mediates Ito,f in canine and human ventricle. Kv1.4 is thought to form the channels that mediate Ito,s, which displays a longer time course, especially of recovery from steady-state inactivation (seconds) (5,6,11,17).

The expression of these rapidly activating K+ channels is influenced by several factors.


Kv4.2/4.3 and Ito,f are strongly expressed in the ventricular myocardium of adult rodents, ferrets, dogs, and humans, with a lesser contribution of Kv1.4 and Ito,s (6,12). Ito,f has been considered to be responsible for the typically brief rodent ventricular AP (6,26). In other species (e.g., rabbit), Ito,s and Kv1.4 are the dominant Ito component and channel isoform, respectively (6,12). In the guinea pig ventricle, Ito is absent, a fact that may contribute to the prolonged AP in this species (6).

Developmental stage

In several species, even those in which the heart presents large Ito expression during adulthood, Ito density is considerably small or absent during the fetal and neonatal period. In neonatal rodent ventricle, Ito,f and Ito,s (whose density is paralleled by Kv4.2/4.3 and Kv1.4 expression, respectively) show similar contributions to total Ito, while in adults the former contributes over 90% (2,11,27,28). In the neonatal myocardium, the AP is longer than in the adult, and AP shortening with maturation coincides with an increase in myocardial Ito density and channel isoform switch (28). Rabbit ventricle also shows a developmental increase in Ito, but in this species the dominant component shifts from Ito,f to Ito,s (29). On the other hand, aging is associated with a decrease in Ito density and AP prolongation (30).

Region of the ventricle

Ito density (particularly Ito,f) is greater in epicardium vs endocardium, in the apex vs base, and in right vs left ventricle. This variation is considered to underlie the regional differences in the AP profile, as well as in the dispersion of repolarization (5,11,14,15). While in rodents this regional variation may rely on a gradient of Kv4.3 expression only, it has not yet been established whether the origin of this variation in canine and human ventricle depends on the expression of Kv4.3, KChIP2, or both (17,31,32).


Ito,f down-regulation associated with AP prolongation has been reported following myocardial infarction, in hypertension, diabetic cardiomyopathy, ventricular hypertrophy, and heart failure (7-9,32-35), although in some cases AP lengthening is not accompanied by changes in Ito density (36). The mechanisms responsible for these changes have not been ascertained, but it is possible that they involve increased activity of the sympathetic and renin-angiotensin-aldosterone systems, since norepinephrine (via a-adrenoceptors), angiotensin II and aldosterone may negatively regulate Ito,f-mediating channels (11,17,35,37,38). Although in most cases a decrease in Ito,f is accompanied by Kv4.2/4.3 down-regulation, sometimes with an increase in Ito,s and Kv1.4 up-regulation (9,32,33,38), the functional change may be also associated with direct modification of the biophysical properties of the current (e.g., by angiotensin II) (37). Because of the decrease in Ito,f in the epicardium (where current density is greater) during disease, the transmural heterogeneity of AP duration is largely suppressed or even reversed, an event that may lead to repolarization abnormalities and possibly increase the predisposition to reentry arrhythmias (11,15).

How Ito can affect Ca2+ homeostasis

In the physiological context, Ito regional variability within the heart is thought to partially underlie regional differences in Ca2+ transient amplitude (15,39). The role of Ito magnitude and composition in cell Ca2+ homeostasis and contraction is mediated by Ito influence on AP waveform, especially the rate at which a plateau is attained, as well as its amplitude and duration. These AP features affect voltage-dependent Ca2+ transport pathways involved in ECC, in relaxation and in general regulation of cell Ca2+ load, such as ICa,L and NCX (Figure 2).

Figure 2.
How lengthening of the action potential (AP) plateau by transient outward current (Ito) suppression may affect excitation-contraction coupling in mammalian cardiac myocytes. Prolonged depolarization increases Ca2+ influx mainly by voltage-dependent L-type Ca2+ channels, and decreases the driving force of Ca2+ extrusion via the sarcolemmal Na+-Ca2+ exchanger (NCX). Both changes enhance Ca2+ availability for uptake by the sarcoplasmic reticulum (SR) Ca2+-ATPase, leading to an increase in SR Ca2+ content. Both increased Ca2+ influx and SR Ca2+ load synergistically increase the fractional SR Ca2+ release during systole, which causes greater myofilament activation and contraction. Increased Ca2+ influx can also permit a greater direct contribution to myofilament activation by Ca2+ originating from the extracellular medium.

Most of ICa,L develops during the AP plateau, in the voltage range at which the current peak is nearly maximal (1). A decrease in Ito density results in AP prolongation, especially of the plateau phase. It is expected that a longer AP is associated with greater total Ca2+ influx, and this has been confirmed by experimental evidence (12, 21,40). Paucity of Ito and prolonged AP are observed in some conditions in which the SR function is depressed, such as immaturity and senescence, ventricular hypertrophy and heart failure. In these cases, increased Ca2+ influx may contribute not only to the contraction-activating cytosolic Ca2+ pool, but also to facilitating ECC by enhancement of the fractional SR Ca2+ release (22,23). It is tempting to speculate whether there is a negative relationship between Ito functional expression and the SR relative contribution to ECC. Ito density has been found to be higher in cardiomyocytes in which Ca2+ cycling between the SR and cytosol is more prominent, such as rodents and ferrets vs rabbits, and adults vs neonates (6,11,12,41). In adult rodents and ferrets, a short AP would allow large and short-lived ICa,L, better suited for triggering synchronized SR Ca2+ release than for providing Ca2+ for contraction and SR loading (see below).

During early postnatal development, SR contribution to Ca2+ cycling, although important, is smaller than in adult myocardium (1,41), probably due to structural SR underdevelopment and paucity of sarcolemma-SR specialized junctions, as well as to diminished sensitivity of the CICR mechanism (18). Because of the small volume and reduced Ca2+ buffering capacity in immature myocytes (42), a greater Ca2+ influx should have a considerable impact directly on cytosolic [Ca2+] and/or indirectly via the induction of SR Ca2+ release, and thus on contractile activity. It has been recently shown that immature human myocytes (in which AP is long) stimulated with a waveform similar to the adult AP show depressed Ca2+ transients, which indicates that prolonged AP in developing myocytes is of paramount importance for proper Ca2+ cycling (43). Similar results were observed in myocytes from senescent animals (44), which present, as neonatal cells, reduced Ito density and prolonged AP (30).

In adults, enhanced cardiac workload due to increased hemodynamic load and/or decreased myocardial contractile function, such as in chronic ventricular hypertrophy induced by pressure overload, myocardial infarction and heart failure, are commonly associated with diminished total Ito or selectively Ito,f, and AP prolongation (7-9,35). These changes are accompanied by greater total Ca2+ influx during the long AP waveform, which may result in maintenance of Ca2+ transient amplitude, just as observed in immature and senescent ventricle. Interestingly, in these conditions the SR function is depressed, usually in association with SERCA down-regulation and diminished CICR sensitivity (1). One could thus interpret these findings from the viewpoint that Ito reduction may enable a presumably adaptive increase in Ca2+ influx during the long AP, so as to maintain Ca2+ cycling and contractile function compatible with survival.

Kassiri et al. (45) reported that Ito inhibition in cultured cardiac myocytes was effective in inducing myocyte hypertrophy by a Ca2+ influx-dependent mechanism. Expression and function of Kv4.2/4.3 channels are inhibited by signaling pathways normally activated during cardiac overload, possibly via phosphorylation by protein kinase C resulting from stimulation of angiotensin, a1-adrenergic and endothelin-1 receptors (11, 37,46). Additionally, mineralocorticoid receptor activation has been implicated in early channel down-regulation following myocardial infarction (35). Thus, it has been speculated whether hypertrophy induction by activation of these pathways would partially involve enhanced Ca2+ influx resulting from Ito depression (45). Greater cell Ca2+ cycling, in addition to contributing to the preservation of cardiac mechanical function, might also play a role in excitation-transcription coupling, for instance via Ca2+-calmodulin-dependent kinases and phosphatases (calcineurin), in the development of ventricular hypertrophy and remodeling, which may eventually deteriorate to heart failure (1,36,45). However, although there is strong evidence of the implication of Ca2+-dependent biochemical pathways in hypertrophy development (see, e.g., 1,36,38), Ito,f reduction may not be the only way by which cell Ca2+ cycling can be increased. A few days after aortic banding (before hypertrophy development), Ca2+ cycling is enhanced by augmented SR function, without signs of increased Ca2+ influx (47), whereas a few weeks later the observed AP prolongation may be associated with an increase in ICa,L density, rather than a decrease in Ito (36). Also, Bodi et al. (38) observed that Ito suppression, reversal of Kv4.2/4.3 vs Kv1.4 dominance and AP prolongation in transgenic mice overexpressing ICa,L occurred only several months after hypertrophy development. Thus, Ito suppression may also be a consequence, rather than a cause, of greater Ca2+ cycling. For instance, enhancement of Ca2+ transient amplitude by SERCA overexpression has been shown to cause Kv4.2/4.3 and KChIP2 down-regulation, a decrease in Ito density and AP lengthening, even in the absence of hypertrophy or heart failure (48). In summary, there is no compelling evidence supporting the hypothesis that Ito suppression is necessarily involved in hypertrophy signaling. Part of the discrepancies among studies might be due to the multiplicity of experimental hypertrophy models and of the signaling pathways involved.

Although greater Ca2+ influx during a long AP may help prevent a dramatic depression of Ca2+ cycling in disease conditions, this compensation may be only partial in heart failure, because: a) a decrease in SR Ca2+ content in this condition (49) probably limits the amount of released Ca2+, even though influx is increased, and b) the slow AP phase 1 to phase 2 transition may slow down the ICa,L time course. To investigate the latter aspect, Sah et al. (50) employed stimulating AP waveforms of similar total duration, but with different rates of phase 1 repolarization. They observed that when early repolarization is slowed, ICa,L shows a decreased peak and slower kinetics, in spite of similar or greater total Ca2+ influx compared to that with fast early repolarization. Slow-developing ICa,L results in asynchronous SR Ca2+ release, which is less efficient to rapidly increase [Ca2+]i at systole (50,51). This alteration may become more accentuated, with progression to heart failure, when intrinsic reduction of ICa,L amplitude may occur (51). One of the expected consequences would be slower and weaker contraction activation. Thus, an increase in Ca2+ influx due to Ito suppression and AP prolongation may provide a partial adaptation that is eventually offset by decreased ECC efficiency with maintenance and worsening of the disease condition.

Thus, the kinetic aspect involves an additional, subtler aspect of ICa,L modulation by Ito, i.e., the timing and rate of early repolarization. Linz and Meyer (52) showed that, during the respective AP waveforms, ICa,L is briefer and attains greater amplitude in rat (strong Ito) than in guinea pig myocyctes (where Ito and AP phase 1 are absent), even though the plateau is much shorter in the former. This difference was attributed to the ability of the large rodent Ito to rapidly drive Em to a range at which the driving force for ICa,L is greater, before the channels rapidly inactivate and deactivate, causing ICa,L to assume a quasi impulse-like waveform. Although total Ca2+ influx is lower, it develops much faster in the rat than in the guinea pig, which is consistent with an optimal triggering signal for SR Ca2+ release. On the other hand, comparing epicardial vs endocardial canine ventricular myocytes (both of which present much longer APs than observed in rodents), the greater Ito density in the former causes the AP to assume the spike-and-dome configuration, which apparently favors Ca2+ channel reopening during the plateau (see secondary ICa,L peak in Figure 1B), resulting in greater Ca2+ influx (53). Thus, it appears that the fine-tuning of Ca2+ influx by the modulation of the AP waveform by Ito strongly depends on the type, density and behavior of the ion current profile present in a specific cell type and/or animal species.

An important side effect of Ito down-regulation and AP prolongation present in disease states may be the greater vulnerability to arrhythmias. In addition to reentry-predisposing changes in refractoriness dispersion (16), triggered activity is often associated with increased AP duration (1). Prolonged depolarization may result in diminished Ca2+ efflux via NCX (due to a decreased driving force), which, in combination with greater Ca2+ influx, leads to a greater cell and SR Ca2+ load. Although this might cause a further increase in Ca2+ transient and contraction amplitude because SR Ca2+ content greatly influences the fractional SR Ca2+ release (22,23), it may also facilitate arrhythmogenesis. SR Ca2+ overload is often accompanied by enhanced diastolic SR Ca2+ release (1,54) that results in the generation of a depolarizing, inward membrane current by electrogenic efflux of the leaked Ca2+ via NCX (stoichiometry of 1 Ca2+:3 Na+) (24). If of sufficient magnitude, this current can drive Em to the excitation threshold and give rise to triggered arrhythmias. In the particular case of heart failure, arrhythmogenesis by this mechanism would be additionally favored by NCX up-regulation and Em instability due to decreased IK1 density (1).

Finally, it is also worthwhile to consider the relationship between AP duration and cycle length. This relation seems to stem from multifactorial mechanisms: Ito may be one of the underlying mechanisms in some species, in addition to modulation of ICa,L and other Ca2+-dependent currents by SR-released Ca2+, and a rate-dependent increase in density of delayed-rectifier K+ currents (e.g., 25,55). In most large mammals, including man, which present marked Kv4.2/4.3-dependent Ito, AP duration is decreased or little affected by increasing rate, especially in epicardial cells (16,56,57). This response might be important to allow adequate relaxation and ventricular filling during the shortened diastole. However, in rabbit and hamster myocardium, in which total Ito density is lower and Ito,s is the dominant component, the AP is lengthened with increasing rate (12,56,58). This might be due, at least in part, to the slow Ito,s recovery from inactivation, which would decrease channel availability at short intervals (2,55,56). A positive relationship between AP duration and rate may limit ventricular function and predispose the heart to triggered arrhythmias at high rates. As pointed out earlier, Ito,f down-regulation has been described in canine and human hypertrophied and failing ventricle. However, this event per se does not seem to affect the AP duration-rate relation, since the AP is prolonged at long, but not short cycle lengths (16,25). Recent results from computer simulations predicted that the positive rate-AP duration relationship relies on the presence of Ito,s, rather than on a decrease in Ito,f, since a negative relation is still present if Ito is totally suppressed (12). Interestingly, our prediction is in agreement with experimental data that show a negative AP duration-rate curve in the guinea pig ventricle (in which Ito is absent (55,59)) which is not changed by chronic ventricular hypertrophy induced by pressure overload (59). The finding that diabetic cardiomyopathy is associated with a frankly positive AP duration-rate relationship in the rat is intriguing, in contrast with the weak rate dependence observed in controls (60). However, information on Ito,s or Kv1.4 expression in this condition is lacking, and thus a possible link between Ito,s dominance and positive AP duration-rate still requires experimental confirmation.

Changes in Ito density and profile caused by pathological cardiovascular conditions may be overall adaptive, as they contribute to increase Ca2+ influx and may confer some protection against reentry due to prolonged refractoriness, although excessive Ca2+ loading, in conjunction with a decrease in membrane electrical stability, may favor the appearance of triggered arrhythmias. However, the fact that these changes are superimposed on the naturally occurring regional heterogeneity of this current (and its components) in the adult ventricle makes it difficult to predict their net effect on vulnerability to arrhythmia. This also complicates the development of pharmacological and gene therapy strategies targeted to Ito channels. Hopefully, this might be overcome with novel information to be gathered in the coming years.


I am grateful to Dr. José W.M. Bassani for helpful criticism and comments about this manuscript, and to Mr. Rafael A. Ricardo for assistance with the illustrations, both from Departamento de Engenharia Biomédica, FEEC, UNICAMP, Campinas, SP, Brazil.

  • Correspondence and Footnotes
  • Address for correspondence: R.A. Bassani, Centro de Engenharia Biomédica, UNICAMP, Caixa Postal 6040, 13084-971 Campinas, SP, Brasil. Fax: +55-19-3289-3346. E-mail:

    Publication supported by FAPESP. Received May 18, 2005. Accepted November 24, 2005.

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    Correspondence and Footnotes

    Publication Dates

    • Publication in this collection
      06 Mar 2006
    • Date of issue
      Mar 2006


    • Accepted
      24 Nov 2005
    • Received
      18 May 2005
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