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Am J Physiol Heart Circ Physiol 292: H1782-H1788, 2007. First published December 1, 2006; doi:10.1152/ajpheart.00932.2006
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IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits

Fumiaki Suto,1 Wei Zhu,1 Alice Chan,1 and Gil J. Gross1,2,3

1Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute; 2Cardiology Division, Hospital for Sick Children; and 3Department of Pediatrics and Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada

Submitted 28 August 2006 ; accepted in final form 25 November 2006


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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Bradycardic ventricular electrical remodeling predisposes to lethal tachyarrhythmias. We investigated the early temporal sequence and reversibility of electrical remodeling in a rabbit complete heart block model subjected to bradycardic ventricular pacing for either 2 or 8 days, with a third group of animals undergoing 8 days of bradycardic pacing followed by 8 days of physiological-rate pacing. At specified time points after complete heart block induction and pacing initiation, steady-state QT interval measurements and variability as well as dynamic QT interval adaptation to abrupt heart rate acceleration were assessed in the absence and presence of isoproterenol. Rapidly (IKr) and slowly (IKs) activating delayed rectifier repolarizing K+ tail current densities were evaluated using whole cell patch clamp in isolated right ventricular myocytes. Steady-state QT interval prolongation at both 2 and 8 days was associated with moderate IKr reduction. IKs downregulation was apparent by day 2 but more profound at day 8. Dynamic QT interval adaptation was impaired under baseline conditions at day 8 but only during isoproterenol administration at day 2. Both in vivo and cellular manifestations of remodeling reverted toward control values after 8 days of physiological-rate pacing. In conclusion, in this bradycardic model, IKs downregulation 1) proceeds more gradually but more extensively than that of IKr and 2) is most prominently associated with impaired dynamic QT interval adaptation to heart rate acceleration. Isoproterenol blunts the dynamic QT interval response in animals with partially downregulated IKs, consistent with stress-related phenomena in known IKs-impaired states. Relative early sparing of IKs could explain the delay in the onset of lethal tachyarrhythmia predisposition in bradycardic electrical remodeling. Reversibility of remodeling supports the potential utility of preventive pacing intervention soon after bradycardia onset.

bradycardia; ion channels; repolarization; ventricular arrhythmias

VENTRICULAR REPOLARIZATION abnormalities and predisposition to torsades des pointes ventricular tachycardia are established concomitants of chronic bradycardia in humans (10). Our laboratory (23) and others (27, 28, 30) have shown that downregulation of ventricular myocyte rapidly (IKr) and slowly (IKs) activating delayed rectifier repolarizing K+ currents underlies electrocardiographic QT interval (QTi) prolongation and predisposition to torsades des pointes following at least 1 wk of bradycardia in animal models of ventricular electrical remodeling.

In the present study, we explore the very early time course of IKr and IKs downregulation and its phenotypic manifestations during bradycardic remodeling in a rabbit complete heart block (CHB) model (22). The reversibility of these changes with short-term ventricular pacing at near-physiological rate is also demonstrated.


   METHODS
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 METHODS
RESULTS
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This investigation conformed with the Guide to the Care and Use of Experimental Animals, published by the Canadian Council on Animal Care (2nd edition, 1993), and was approved by the Hospital for Sick Children Animal Care Committee.

CHB model. Transcatheter radiofrequency atrioventricular node ablation and permanent right ventricular (RV) endocardial demand (VVI) pacing in healthy young (3.0–3.5 kg) adult male New Zealand White rabbits have been described previously (22). Animals undergoing atrioventricular node ablation were paced at 140 beats/min, approximately half of their physiological resting sinus heart rate (22). Bradycardic pacing was maintained for 2 days in 11 rabbits and for 8 days in 13 rabbits. Steady-state QTi and whole cell patch-clamp data from 8 of these 13 rabbits that were reported previously (23) are not included here.

An additional group of six animals was subjected to bradycardic pacing for 8 days, followed by 8 days of pacing at the near-physiological rate of 280 beats/min to assess the reversibility of remodeling changes induced by bradycardia. Control rabbits underwent intracardiac catheter manipulation without conduction system disruption, and an endocardial pacing system was implanted but not activated.

Steady-state QTi measurement and dynamic QTi adaptation to abrupt rate change. QTi measurements were obtained on day 0 and either on day 2 or on day 8 post-CHB induction from six-lead surface electrocardiograms recorded with a sampling interval of 1.2 ms in anesthetized animals (ketamine, 33 mg/kg; and acepromazine, 1.1 mg/kg iv) after at least 5 min of continuous pacing at 140 beats/min (23). Animals in the remodeling reversal protocol underwent ECG recording on days 0, 8, and 16. Steady-state QTi was measured manually off-line in blinded fashion using averaged values from three consecutive beats in the lead with the most readily discernible T-wave termination that was usually lead II. A modification of the approach described by Thomsen and colleagues (25) was used to assess short-term (beat-to-beat) QTi variability, applying the formula QTi variability = {sum} (QTn – QTn+1)/10 x 21/2, where QTn and QTn+1 are QTi values of 2 consecutive beats among a series of 10 consecutive beats recorded during steady-state pacing at 140 beats/min.

To assess dynamic QTi adaptation to abrupt rate change, a surface ECG was recorded continuously for 10 s before and 2 min after a pacing rate shift from 140 to 210 beats/min. Beat-by-beat QTi values measured manually off-line were plotted against time after rate shift and fitted with a single exponential decay equation to generate an adaptation time constant ({tau}).

Steady-state QTi recording and the QTi adaptation protocol were repeated after 5 min of intravenous isoproterenol infusion at 0.03 µg·kg–1·min–1. This infusion rate was chosen as the maximum at which the 140-beat/min pacing rate could be reliably maintained without isoproterenol-induced competition from ectopic foci.

Ventricular myocyte isolation. RV myocytes were isolated as described elsewhere (23). Briefly, the excised heart was retrogradely perfused for 10 min with nominally Ca2+ free HEPES-buffered saline (HBS). Perfusate was then switched to Ca2+ free HBS containing collagenase 1 mg/ml (Worthington Class 2, Lakewood, NJ) and protease 0.1 mg/ml (Sigma type XIV, St. Louis, MO) for 15–20 min, followed by 4 min of washout with Ca2+ free HBS. All perfusates were gassed with 100% O2 and maintained at 37°C. Ventricles were removed and teased apart with forceps. After gauze filtration, dispersed myocytes were resuspended in sequentially higher Ca2+ concentrations (0.05, 0.1, 0.2, 1.0, and 1.8 mM Ca2+ HBS) and stored at room temperature for study within 10 h of isolation.

Cellular electrophysiologic recording. Conventional whole cell patch clamp was performed as previously described (2, 5, 23). Delayed rectifier currents were measured as peak density of tail current elicited by repolarization to –30 mV following 3-s depolarizing voltage steps from a holding potential of –80 mV. IKr and IKs were measured as the E4031- (5 µM; Wako, Osaka, Japan) and chromanol 293B- (10 µM; Hoechst, Frankfurt, Germany) (12) sensitive tail current components, respectively. All experiments were carried out at physiological temperature (35–37°C).

Data analysis. Results are reported as means (SD). Curve-fitting and statistical procedures were performed by using Origin 7.0 (Microcal Software, Northampton, MA), yielding time constants and midpoint potentials for pooled data where appropriate. Statistical analysis was based on the paired or unpaired Student's t-test or on one-way ANOVA followed by Bonferroni's test for multiple pairwise comparisons. Differences were considered significant when P < 0.05.


   RESULTS
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Steady-state QTi prolongation. We previously observed significant steady-state QTi prolongation in rabbits paced for 8 days post-CHB induction at 140 beats/min but not at the near-physiological rate of 280 beats/min (23). In the present study, we found that steady-state QTi prolongation at day 2 had already proceeded essentially to the extent noted at day 8, with QTi values increasing from 203 (SD 12) on day 0 to 247 ms (SD 30) on day 2 (P < 0.01; Fig. 1).


Figure 1
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  		Fig. 1. QT interval (QTi) during steady-state pacing at 140 beats/min increased from 203 (SD 12) on day 0 to 247 ms (SD 30) on day 2 (A), with comparable values of 244 ms (SD 34) recorded on day 8 (B). Two points joined by a line represent paired measurements recorded in one animal (N, number of animals).

 
Impaired dynamic repolarization response to abrupt rate change. We assessed the dynamic repolarization response to abrupt heart rate acceleration by measuring beat-to-beat QTi shortening over 2 min following a shift in the ventricular pacing rate from 140 to 210 beats/min. Representative QTi adaptation curves obtained on post-CHB induction days 0, 2, and 8 are shown in Fig. 2, A and B. The curve is flattened after 8 days of bradycardic pacing at 140 beats/min. Whereas the steady-state QTi duration had already shifted by day 2 of bradycardic pacing, the time course of QTi adaptation to abrupt rate change was still preserved at that time point, with {tau} on day 0 [35 s (SD 18)] showing no significant change by day 2 [38 s (SD 15), P = not significant; Fig. 2C]. In contrast, by day 8 there was marked slowing in QTi adaptation {tau} from 36 (SD 16) to 72 s (SD 42) (P = 0.01; Fig. 2D).


Figure 2
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  		Fig. 2. Representative plots of QTi adaptation to an abrupt ventricular pacing rate shift from 140 to 210 beats/min on days 2 (A) and 8 (B) of bradycardic pacing. A: QTi adaptation curves recorded from a single animal on complete heart block (CHB) days 0 and 2. B: QTi adaptation curves recorded from a different animal on CHB days 0 and 8. Beat-by-beat QTi measurements were plotted against time after rate shift and fitted with a single exponential decay model (R2 > 0.95). Although the steady-state QTi had already lengthened significantly by day 2, the time course of adaptation was initially preserved [time constant ({tau}) = 38 (SD 15) on day 2 vs. 35 s (SD 18) on day 0; C] but slowed significantly by day 8 of bradycardic pacing [72 (SD 42) on day 8 vs. 36 s (SD 16) on day 0; D]. Two points joined by a line represent paired measurements recorded in one animal (N, number of animals). NS, not significant.

 
IKr and IKs current reduction. Bradycardic electrical remodeling extending over 8 days in this rabbit CHB model is associated with significant biventricular downregulation of both IKr and IKs but not of the inwardly rectifying (IK1) or transient outward (Ito) K+ currents (23). We therefore assessed the expression of IKr and IKs in whole cell patch-clamp studies of RV myocytes isolated after either 2 or 8 days of bradycardic pacing. Interestingly, IKr at 2 days was reduced to an extent comparable with that seen after 8 days of bradycardic remodeling, whereas IKs expression at day 2 was intermediate between that observed on days 0 and 8 of pacing at 140 beats/min (Fig. 3).


Figure 3
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  		Fig. 3. Tail current density-voltage relations for rapidly (IKr) and slowly (IKs) activating delayed rectifier repolarizing K+ currents elicited with 3-s depolarizing voltage steps to membrane potential indicated from a holding potential of –80 mV, followed by repolarization to –30 mV, in right ventricular myocytes obtained from 6 control rabbits (control) or CHB rabbits paced for either 2 (day 2; 8 rabbits) or 8 (day 8; 5 rabbits) days at 140 beats/min or from 5 rabbits subjected to 8 days of bradycardia followed by 8 days of physiological-rate pacing (day 16). N, number of data points (myocytes) for each group.

 
Isoproterenol effects in remodeled myocardium. IKs is known to be autonomically modulated through a protein kinase A-dependent signaling pathway and is typically enhanced in the presence of the beta-adrenergic receptor agonist isoproterenol (31). We assessed the effects of isoproterenol on repolarization parameters immediately after CHB induction and again after 2 days of continuous bradycardic pacing. There was no clearly discernible isoproterenol effect either on mean steady-state QTi or on the time course of dynamic QTi adaptation to abrupt pacing rate increase immediately after CHB induction. Interestingly, however, after 2 days of bradycardic remodeling, beta-adrenergic stimulation had a pronounced and reproducible effect on dynamic QTi adaptation but not on the mean steady-state QTi. In animals on the 2 day protocol, the time constant of adaptation increased from 38 (SD 15) to 77 s (SD 29) (P < 0.01; n = 7 animals), whereas steady-state QTi in the presence of isoproterenol [249 ms (SD 29)] did not differ significantly from that recorded in the absence of the drug [247 ms (SD 30)]. After 8 days of bradycardic pacing, QTi adaptation {tau} increased from 92 (SD 48) to 101 s (SD 58) during isoproterenol administration (P = not significant; n = 5), whereas steady-state QTi was similar in the presence and absence of the drug. The paired QTi adaptation {tau} data are illustrated graphically in Fig. 4.


Figure 4
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  		Fig. 4. Intravenous isoproterenol (Iso) administration (0.03 µg·kg–1·min–1) "unmasked" latent impairment of dynamic QTi adaptation to an abrupt pacing rate shift from 140 to 210 beats/min that was not apparent under baseline conditions at day 2 but did subsequently manifest by day 8 (see text and Fig 2). Iso had no consistent effect on steady-state QTi values obtained either immediately after CHB induction or following 2 days of bradycardic remodeling when the baseline QTi was already prolonged (not shown). Control indicates values obtained in the absence of Iso. Two points joined by a line represent paired measurements recorded in one animal.

 
Although isoproterenol had no discernible effect on mean steady-state QTi values, it did increase the beat-to-beat variability of steady-state QTi after both 2 and 8 days of bradycardic remodeling but not immediately after CHB induction (Fig. 5).


Figure 5
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  		Fig. 5. QTi beat-to-beat variability increases in response to Iso as bradycardic electrical remodeling proceeds. QTi variability was calculated from the formula QTi variability = {sum} (QTn – QTn+1)/10 x 21/2, where QTn and QTn+1 are QTi values of 2 consecutive beats among a series of 10 consecutive beats recorded during steady-state pacing at 140 beats/min. Under baseline conditions, a slight but statistically insignificant increase in short-term QTi variability was apparent after 8 but not after 2 days of bradycardic remodeling. However, Iso administration increased QTi variability at both time points of bradycardic remodeling (P = 0.04 at day 2 and 0.007 at day 8, Iso vs. control).

 
Reversibility of remodeling changes with 8 days of near-physiological rate pacing. As shown in Fig. 6, there was an essentially complete reversal of in vivo bradycardia-induced remodeling changes when animals underwent ventricular pacing at 280 beats/min for 8 days. Both the steady-state QTi and the time course of dynamic QTi adaptation to abrupt rate change showed typical prolongation after 8 days of bradycardia, followed by reversion to prebradycardia values after a further 8 days spent at near-physiological heart rate. Interestingly, RV myocyte IKr recovery was not fully complete at the end of the reversal protocol, whereas IKs tail current densities did not differ significantly from those recorded in control animals (Fig. 3).


Figure 6
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  		Fig. 6. Reversibility of bradycardic electrical remodeling. Rabbits with CHB subjected to 8 days of bradycardic (140 beats/min) ventricular demand pacing were subsequently paced for a further 8 days at the near-physiological rate of 280 beats/min. A: sequence of QTi measurements obtained during steady-state pacing at 140 beats/min. Steady-state QTi prolonged from 191 (SD 12) on day 0 to 203 ms (SD 10) on day 8 (P = 0.004) and then normalized to 188 ms (SD 15) on day 16 (P = 0.002 vs. day 8, NS vs. day 0). B: sequence of QTi adaptation time constants ({tau}) obtained with abrupt pacing rate shift from 140 to 210 beats/min. {tau} increased from 38 (SD 11) on day 0 to 58 s (SD 17) on day 8 (P = 0.001) and then shortened to 31 ms (SD 12) on day 16 (P = 0.002 vs. day 8, NS vs. day 0). {tau} did not change in the rabbit which showed minimum QTi prolongation on day 8 (*). Points joined by lines represent measurements recorded sequentially in a single animal.

 

   DISCUSSION
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Staged downregulation of repolarizing K+ currents. This investigation extends our understanding of the earliest physiological and cellular manifestations of mammalian bradycardic ventricular electrical remodeling. We and others have previously observed similar degrees of bradycardia-mediated downregulation of IKr and IKs after at least 1 wk of heart block in rabbits (23, 27, 28) as well as in dogs (30). By advancing the earliest time point of study of bradycardic remodeling to just 2 days after induction of heart block, we now begin to see time-dependent differences in the downregulation of these delayed rectifier currents. IKr reduction is fully manifest within 48 h of bradycardia onset in this model. In contrast, the initial diminution of IKs is relatively modest but shows additional progression to the 8-day mark (23), when it is downregulated more substantially than IKr and essentially to the extent previously observed by Tsuji et al. (27) in rabbits after 3 wk of unpaced bradycardia. It thus appears that stepwise regulatory change occurs during the first week after bradycardia onset, with IKr downregulation reaching its full expression before that of IKs and with IKs reduction ultimately reaching more profound levels, in relative terms, than those attained by IKr.

Stengl and associates (21) recently used a novel serial myocardial needle biopsy approach to longitudinally characterize the early time course of IKs and beta-adrenergic receptor downregulation in their bradycardic canine CHB model. Of greatest relevance to the results we report here, their observations showed decreased levels of KCNQ1 mRNA and protein expression after 3 days of CHB, the earliest time point that they sampled. Thus it appears that transcriptional downregulation of IKs likely begins almost immediately after bradycardia onset.

In vivo correlates of differential IKr and IKs downregulation. Our data reveal that significant steady-state QTi prolongation is already manifest after just 2 days of bradycardic pacing to the extent previously observed at 8 days post-CHB induction (23). The time course of this phenomenon seems to parallel that of IKr downregulation.

In marked contrast to early steady-state QTi prolongation, the physiological response of QTi shortening to abrupt heart rate acceleration is still preserved at day 2 of bradycardic pacing, whereas it is decidedly blunted by day 8. Interestingly, the reduction of IKs is not yet fully developed by day 2, consistent with the proposed role of IKs in the adaptive repolarization response to heart rate shifts (3, 15, 17, 20). Although IKr likely plays a role in dynamic action potential heart rate adaptation (7), recent modeling studies by Choe and associates (4) seem to confirm the predominance of IKs in the QTi adaptive response. This might be particularly relevant in species such as the rabbit where IKs does not participate prominently in cardiac myocyte action potential repolarization under stable physiological conditions (11) and could assume additional importance in settings of IKr impairment, as demonstrated by Volders et al. (31) and as elegantly modeled by Silva and Rudy (20).

In this context, it is noteworthy that spontaneous torsades des pointes in bradycardic rabbits has been observed predominantly at least 1 wk after CHB induction (27). Moreover, these findings are consistent with clinical observations in humans affected by impaired IKs function in congenital long QT syndrome type 1, in whom baseline QTi is often indistinguishable from that of healthy individuals (24), but torsades des pointes is typically induced in settings of heart rate acceleration such as exercise (19).

Importance of beta-adrenergic stimulation with reduced repolarization reserve. The responsiveness of cardiac myocyte IKs to beta-adrenergic stimulation has been explored in a number of studies (14, 18, 31) and is presumably central to its function as a repolarizing current reservoir in settings of action potential prolongation. Sanguinetti and colleagues (18) showed that isoproterenol-mediated IKs augmentation could counter the action potential prolonging effect of pharmacological IKr blockade in guinea pig ventricular myocytes.

When IKs availability is reduced, the effect of beta-adrenergic stimulation is to delay rather than accelerate cardiac myocyte repolarization. The combination of pharmacological IKs blockade and beta-adrenergic stimulation prolongs the action potential in canine cardiac Purkinje cells (6) and enhances arrhythmogenicity in arterially perfused canine left ventricular wedge preparations (1). Repolarization abnormalities reminiscent of long QT syndrome were exacerbated by isoproterenol administration in a mouse knockout model lacking the Kcnq1 gene that encodes the pore-forming protein underlying IKs (9, 26).

Conversely, the combined pharmacological blockade of IKs and beta-adrenergic receptors reduced ventricular tachyarrhythmia inducibility in a canine myocardial infarction model (13). Among patients with genotyped congenital long QT syndrome, the efficacy of beta-blocker therapy is reportedly greatest in those with KCNQ1 mutations (long QT syndrome type 1) (8, 29).

In our bradycardic rabbit model, the effect of isoproterenol administration 2 days after induction of heart block is to "unmask" the abnormal QTi adaptive response seen at day 8 in the absence of isoproterenol. This speaks directly to the issue of repolarization reserve, suggesting that even moderate reduction of IKs availability against a backdrop of downregulated IKr could result in a severely impaired stress-induced repolarization response. When IKs is more substantially diminished, as at 8 days post-heart block induction in our model, the abnormal QTi adaptation to heart rate acceleration becomes fully manifest even in the absence of beta-adrenergic stimulation.

Moreover, administration of isoproterenol after both 2 and 8 days of bradycardic electrical remodeling had the effect of destabilizing ventricular repolarization even under steady-state pacing conditions, as evidenced by increased short-term QTi variability. Thomsen and colleagues (25) correlated increased beat-to-beat QTi variability with the incidence of torsades des pointes among CHB dogs exposed to d-sotalol. Stengl et al. (21) found that canine bradycardic remodeling evolving from 3 to 30 days after CHB induction is associated with progressively greater isoproterenol effects on QTi instability.

Reversibility of early bradycardic electrical remodeling with physiological-rate pacing. Scant information is available with respect to the reversibility of bradycardic ventricular electrical remodeling. Peschar et al. (16) observed that QTi prolongation induced in dogs with CHB with 8 wk of profound, essentially unpaced, bradycardia persisted even after a subsequent 8-wk period of physiological-rate ventricular pacing, notwithstanding that bradycardia-induced structural changes showed evidence of regression. Among human CHB patients who had previously experienced torsades des pointes, Kurita and colleagues (10) noted that evidence of delayed repolarization persisted even after at least 2 mo of appropriate permanent pacing. However, these clinical data are difficult to interpret because the duration of bradycardia before pacing was not specified and because other conditions associated with repolarization abnormalities such as congenital long QT syndrome were not systematically excluded.

In contrast to the foregoing evidence of remodeling irreversibility following prolonged, severe bradycardia, our findings suggest that significant reversal of repolarization abnormalities can be achieved when appropriate pacing intervention is instituted relatively soon after onset of bradycardic remodeling. While they raise interesting questions about mechanisms underlying remodeling and its reversibility, these observations could potentially impact upon clinical decision making with respect to the optimal timing of pacing intervention for bradycardic patients. However, the presence and nature of a "threshold" bradycardic interval beyond which electrical remodeling becomes entrenched remain to be demonstrated in humans and further defined in our animal model.

Study limitations. Whereas the present study documents the early time course, in vivo manifestations, and reversibility of IKr and IKs downregulation in bradycardic rabbits, it does not specifically address mechanisms underlying the reduced expression of these currents. Reports published by others have essentially excluded shifts in voltage dependence of activation (27, 28) or deactivation kinetics (28) as major factors in either IKr or IKs downregulation in the rabbit with profound and prolonged bradycardia. Confirmatory evidence with respect to IKs has come from the canine model (21). Transcriptional downregulation of pore-forming K+ channel subunits appears to play a significant role in each of these cases (21, 28). Intriguingly, Stengl and colleagues (21) did demonstrate reduced ventricular myocyte beta1-adrenergic receptor expression and reduced IKs responsiveness to isoproterenol in addition to IKs downregulation in their canine model of bradycardic electrical remodeling.

Although we previously observed no significant difference in bradycardic electrical remodeling between myocytes isolated from the right and left ventricles (23), our exclusive reliance on RV myocytes in the present study precludes a detailed regional or transmural evaluation of repolarizing current changes.

We have not assessed the inducibility of tachydysrhythmias through provocative testing in this model of early bradycardic electrical remodeling. Reversibility of less lethal manifestations of remodeling as demonstrated here might not encompass the predisposition to torsades des pointes observed in humans or animals with more developed or malignant variants of bradycardic remodeling.

In conclusion, in this rabbit CHB model of very early bradycardic ventricular electrical remodeling, IKr downregulation proceeds earlier and to a smaller extent than that of IKs. The time course of steady-state QTi prolongation appears to correspond to that of IKr reduction, at least with respect to the limited number of time points assessed in this investigation. This contrasts with the more gradual and profound downregulation of IKs that is expressed phenotypically in impaired QTi adaptation to abrupt heart rate acceleration. Whereas this important physiological response is superficially preserved very early in the remodeling process when IKs reduction is still relatively slight, isoproterenol administration can unmask significant adaptive impairment comparable with its effects in other settings of genetically and pharmacologically reduced IKs availability. The reversibility of bradycardic electrical remodeling with timely pacing intervention at physiological heart rates is clearly demonstrated for the first time.


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F. Suto was the recipient of a research fellowship and of the Evelyn McGloin Award from the Heart and Stroke Foundation of Ontario (HSFO). This work was supported by HSFO Grants-in-Aid NA5044 and T5387.


   ACKNOWLEDGMENTS
 
We thank Marvin Estrada and Kristine Rehner for expert technical assistance. Permanent pacing equipment was generously provided by Medtronic Canada, and C293B was a gift from Drs. Uwe Gerlach and Hans-Jochen Lang of Aventis.


   FOOTNOTES
 

Address for reprint requests and other correspondence: G. J. Gross, Cardiology Div., The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada (e-mail: ggross{at}sickkids.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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  1. Burashnikov A, Antzelevitch C. Block of IKs does not induce early afterdepolarization activity but promotes beta-adrenergic agonist-induced delayed afterdepolarization activity. J Cardiovasc Electrophysiol 11: 458–465, 2000.[Web of Science][Medline]
  2. Cahill SA, Gross GJ. Propafenone and its metabolites preferentially inhibit IKr in rabbit ventricular myocytes. J Pharmacol Exp Ther 308: 59–65, 2004.[Abstract/Free Full Text]
  3. Cheng JH, Kodama I. Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarization. Acta Pharmacol Sin 25: 137–145, 2004.[Web of Science][Medline]
  4. Choe CU, Schulze-Bahr E, Neu A, Xu J, Zhu ZI, Sauter K, Bähring R, Priori S, Guicheney P, Mönnig G, Neapolitano C, Heidemann J, Clancy CE, Pongs O, Isbrandt D. C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14–3-3{epsilon}. Hum Mol Genet 15: 2888–2902, 2006.[Abstract/Free Full Text]
  5. Gross GJ, Burke RP, Castle NA. Characterisation of transient outward current in young human atrial myocytes. Cardiovasc Res 29: 112–117, 1995.[CrossRef][Web of Science][Medline]
  6. Han W, Wang Z, Nattel S. Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells. Am J Physiol Heart Circ Physiol 280: H1075–H1080, 2001.[Abstract/Free Full Text]
  7. Hua F, Gilmour RF Jr. Contribution of IKr to rate-dependent action potential dynamics in canine endocardium. Circ Res 94: 810–819, 2004.[Abstract/Free Full Text]
  8. Itoh T, Kikuchi K, Odagawa Y, Takata S, Yano K, Okada S, Haneda N, Ogawa S, Nakano O, Kawahara Y, Kasai H, Nakayama T, Fukutomi T, Sakurada H, Shimizu A, Yazaki Y, Nagai R, Nakamura Y, Tanaka T. Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome. J Hum Genet 46: 38–40, 2001.[CrossRef][Web of Science][Medline]
  9. Knollmann BC, Casimiro MC, Katchman AN, Sirenko SG, Schober T, Rong Q, Pfeifer K, Ebert SN. Isoproterenol exacerbates a long QT phenotype in Kcnq1-deficient neonatal mice: possible roles for human-like Kcnq1 isoform 1 and slow delayed rectifier K+ current. J Pharmacol Exp Ther 310: 311–318, 2004.[Abstract/Free Full Text]
  10. Kurita T, Ohe T, Marui N, Aihara N, Takaki H, Kamakura S, Matsuhisa M, Shimomura K. Bradycardia-induced abnormal QT prolongation in patients with complete atrioventricular block with torsades de pointes. Am J Cardiol 69: 628–633, 1992.[CrossRef][Web of Science][Medline]
  11. Lengyel C, Iost N, Virág L, Varró A, Lathrop DA, Papp JG. Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration. Br J Pharmacol 132: 101–110, 2001.[CrossRef][Web of Science][Medline]
  12. Lu Z, Kamiya K, Opthof T, Yasui K, Kodama I. Density and kinetics of IKr and IKs in guinea pig and rabbit ventricular myocytes explain different efficacy of IKs blockade at high heart rate in guinea pig and rabbit: implications for arrhythmogenesis in humans. Circulation 104: 951–956, 2001.[Abstract/Free Full Text]
  13. Lynch JJ Jr, Salata JJ, Wallace AA, Stump GL, Gilberto DB, Jahansouz H, Liverton NJ, Selnick HG, Claremon DA. Antiarrhythmic efficacy of combined IKs and beta-adrenergic receptor blockade. J Pharmacol Exp Ther 302: 283–289, 2002.[Abstract/Free Full Text]
  14. Marx SO, Kurokawa J, Reiken S, Motoike H, D'Armiento J, Marks AR, Kass RS. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295: 496–499, 2002.[Abstract/Free Full Text]
  15. Nattel S. Specific potassium channel blockade for arrhythmia prevention in the ionically remodeled failing heart: peril or panacea? Heart Rhythm 2: 739–740, 2005.[CrossRef][Web of Science][Medline]
  16. Peschar M, Vernooy K, Vanagt WY, Reneman RS, Vos MA, Prinzen FW. Absence of reverse electrical remodeling during regression of volume overload hypertrophy in canine ventricles. Cardiovasc Res 58: 510–517, 2003.[Abstract/Free Full Text]
  17. Roden DM. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Pacing Clin Electrophysiol 21: 1029–1034, 1998.[CrossRef][Medline]
  18. Sanguinetti MC, Jurkiewicz NK, Scott A, Siegl PK. Isoproterenol antagonizes prolongation of refractory period by the class III antiarrhythmic agent E-4031 in guinea pig myocytes. Mechanism of action. Circ Res 68: 77–84, 1991.[Abstract/Free Full Text]
  19. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 103: 89–95, 2001.[Abstract/Free Full Text]
  20. Silva J, Rudy Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation 112: 1384–1391, 2005.[Abstract/Free Full Text]
  21. Stengl M, Ramakers C, Donker DW, Nabar A, Rybin AV, Spätjens RL, van der Nagel T, Wodzig WK, Sipido KR, Antoons G, Moorman AF, Vos MA, Volders PG. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: focus on IKs downregulation and blunted beta-adrenergic activation. Cardiovasc Res 72: 90–100, 2006.[Abstract/Free Full Text]
  22. Suto F, Cahill SA, Wilson GJ, Hamilton RM, Greenwald I, Gross GJ. A novel rabbit model of variably compensated complete heart block. J Appl Physiol 92: 1199–1204, 2002.[Abstract/Free Full Text]
  23. Suto F, Zhu W, Cahill SA, Greenwald I, Navarro AL, Gross GJ. Ventricular rate determines early bradycardic electrical remodeling. Heart Rhythm 2: 293–300, 2005.[CrossRef][Web of Science][Medline]
  24. Swan H, Saarinen K, Kontula K, Toivonen L, Viitasalo M. Evaluation of QT interval duration and dispersion and proposed clinical criteria in diagnosis of long QT syndrome in patients with a genetically uniform type of LQT1. J Am Coll Cardiol 32: 486–491, 1998.[Abstract/Free Full Text]
  25. Thomsen MB, Verduyn SC, Stengl M, Beekman JD, de Pater G, van Opstal J, Volders PG, Vos MA. Increased short-term variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation 110: 2453–2459, 2004.[Abstract/Free Full Text]
  26. Tosaka T, Casimiro MC, Rong Q, Tella S, Oh M, Katchman AN, Pezzullo JC, Pfeifer K, Ebert SN. Nicotine induces a long QT phenotype in Kcnq1-deficient mouse hearts. J Pharmacol Exp Ther 306: 980–987, 2003.[Abstract/Free Full Text]
  27. Tsuji Y, Opthof T, Yasui K, Inden Y, Takemura H, Niwa N, Lu Z, Lee JK, Honjo H, Kamiya K, Kodama I. Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block. Circulation 106: 2012–2018, 2002.[Abstract/Free Full Text]
  28. Tsuji Y, Zicha S, Qi XY, Kodama I, Nattel S. Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes. Circulation 113: 345–355, 2006.[Abstract/Free Full Text]
  29. Villain E, Denjoy I, Lupoglazoff JM, Guicheney P, Hainque B, Lucet V, Bonnet D. Low incidence of cardiac events with beta-blocking therapy in children with long QT syndrome. Eur Heart J 25: 1405–1411, 2004.[Abstract/Free Full Text]
  30. Volders PG, Sipido KR, Vos MA, Spätjens RL, Leunissen JD, Carmeliet E, Wellens HJ. Downregulation of delayed rectifier K+ currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. Circulation 100: 2455–2461, 1999.[Abstract/Free Full Text]
  31. Volders PG, Stengl M, van Opstal JM, Gerlach U, Spätjens RL, Beekman JD, Sipido KR, Vos MA. Probing the contribution of IKs to canine ventricular repolarization: key role for beta-adrenergic receptor stimulation. Circulation 107: 2753–2760, 2003.[Abstract/Free Full Text]




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