Skip Navigation

Cardiovascular Research 2007 73(3):521-530; doi:10.1016/j.cardiores.2006.11.025
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Thomsen, M. B.
Right arrow Articles by Vos, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thomsen, M. B.
Right arrow Articles by Vos, M. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2006, European Society of Cardiology

Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation

Morten B. Thomsen1, Avram Oros1, Marieke Schoenmakers, Jurren M. van Opstal, Joep N. Maas, Jet D.M. Beekman and Marc A. Vos*

Department of Medical Physiology, Yalelaan 50, NL-3584 CM Utrecht, The Netherlands

* Corresponding author. Tel.: +31 302 538 900; fax: +31 302 539 036. Email address: m.a.vos{at}umcutrecht.nl

Received 3 July 2006; revised 30 October 2006; accepted 20 November 2006


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Acquired long-QT syndrome in combination with increased beat-to-beat variability of repolarisation duration (BVR) is associated with lethal torsades de pointes arrhythmias (TdP) in dogs with remodelled heart after atrioventricular block (AVB). We evaluated the relative contributions of bradycardia and ventricular remodelling to proarrhythmic BVR with and without pharmacological IKr block in order to identify the individual at risk.

Methods: Three groups of dogs were used: sinus rhythm dogs (n=12), dogs with acute AVB (n=8), and dogs with >3 weeks chronic AVB (n=27). Under anaesthesia, ECG and monophasic action potential duration (MAPD) were measured. Local BVR was quantified as short-term variability from 30 consecutive left ventricular MAPD (STV={sum}|Dni–Dn+1|/[30x{surd}2]). All dogs received dofetilide iv.

Results: The slower ventricular rate acutely after AVB affected neither QTc nor STV (288±18 to 293±38 ms and 0.7±0.1 to 0.7±0.1 ms, respectively; P=NS for both), whereas ventricular remodelling increased both (to 376±46 and 2.3±0.6 ms, respectively; P<0.05 for both). Neither dogs in sinus rhythm nor acute AVB showed any TdP, whereas dofetilide induced TdP in 74% of the chronic-AVB dogs. Dofetilide increased the QTc interval in all groups (19–24%; P<0.05 for all groups), whereas STV was elevated in chronic-AVB dogs only (to 4.2±1.5 ms; P<0.05) and further confined to inducible chronic-AVB dogs (5.0±0.8 versus 1.9±0.4 ms for resistant dogs; P<0.05). Variability of the idioventricular rate was increased directly after AVB and did not influence BVR.

Conclusions: Under drug-free circumstances, a persistent high BVR in chronic-AVB dogs is remodelling dependent rather than a direct consequence of bradycardia acutely after AVB. Variability of this slower rate does not influence BVR. Dofetilide causes a transient increase in BVR only in proarrhythmic dogs. Thus, BVR may aid the identification of the TdP-susceptible patient.

KEYWORDS ECG; Heart-rate variability; Remodelling; Repolarisation; Ventricular arrhythmias


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Torsades de pointes arrhythmia (TdP) is a serious ventricular polymorphic tachycardia, which may herald fatal ventricular fibrillation and sudden death. By definition, the arrhythmia is associated with a prolonged QT interval of the ECG [1]. Drug-induced TdP can be induced by various pharmacological medications, but occurs almost exclusively in patients with an underlying cardiac pathology elevating their vulnerability to repolarisation-dependent arrhythmias [2,3]. Instead of prohibiting beneficial medical treatments to avoid drug-induced TdP, identification of the vulnerable patient could be an advantageous strategy [4].

Recently, several studies have concluded that QT prolongation on its own is not a reliable predictor of drug-induced TdP, whereas alternative or additional surrogate parameters have been proposed [5–8]. We have suggested temporal beat-to-beat variability of repolarisation duration (BVR) as a candidate parameter [5]. Our research was performed in anaesthetised dogs with chronic atrioventricular block (AVB), with a ~70% incidence in TdP provoked by class-III antiarrhythmic drugs [9,10]. This enhanced susceptibility results from ventricular remodelling following the onset of chronic bradycardia [11,12]. The electrophysiological fraction of the remodelling processes features primarily a heterogeneous prolongation of repolarisation duration manifested by QTc prolongation in vivo. Furthermore, a chronically increased BVR is observed at baseline [13]. In this model, baseline BVR has been successfully employed to identify predisposition of individual animals: those showing large BVR die suddenly in the absence of anaesthesia and drugs [13].

In the present study, we evaluate the relative contributions of bradycardia and ventricular electrical remodelling to the persistently increased baseline BVR present in anaesthetised chronic-AVB dogs. Furthermore, we analyse the influence of physiological heart-rate variability on BVR and the response of BVR to pharmacological IKr block. Finally, we compared values of BVR in dogs with and without drug-induced proarrhythmia.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health and is in accordance with the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (86/609/EU). The local animal-care committees of Maastricht and Utrecht Universities approved all experiments.

2.1. General
Experiments from 47 mongrel dogs of either sex were included in this investigation. 12 Experiments in dogs in sinus rhythm and 9 experiments in dogs in chronic AVB have been reported upon previously [9,10], whereas 11 chronic-AVB dogs are part of ongoing pharmacological studies on novel experimental drugs, where dofetilide serves as reference drug for proarrhythmia. BVR has not been reported for any of these dogs previously. Generally, inclusion criteria were: (1) anaesthesia induced by sodium pentobarbital (25 mg/kg i.v.) and maintained by 0.5% halothane in a mixture of O2 and N2O (1:2); (2) high quality recordings of monophasic action potentials (MAP, EP technologies, CA) from the left (LV) and right ventricle (RV); and (3) administration of 25 µg/kg dofetilide i.v. over 5 min.

Steerable MAP recording catheters were placed under fluoroscopic guidance at the endocardium of each ventricle. Endocardial location was selected based on MAP amplitude and reproducibility. In all experiments, 6 ECG leads from the limbs and the 2 MAPs were recorded continuously. Signal processing, recording and animal care have been described in detail earlier [10]. In 35 dogs, complete AVB had been created by radiofrequency ablation as previously described [14]. Of these, 8 were studied acutely, 20–30 min after AV-nodal ablation, whereas the remaining 27 animals were studied after a minimum of 3 weeks, a sufficient time period for stabilisation of electrical remodelling [14].

2.2. Experimental protocol
Dofetilide was dissolved in 100 µl 0.1 M HCl and diluted in 0.9% saline to a final volume of 0.5 ml/kg bodyweight and administered over 5 min or until TdP appeared. The acute electrophysiological effects of dofetilide were studied for 15 min covering the time-points of both maximal plasma concentration [9] and maximal cardiac effect [10]. Any TdP that degenerated into ventricular fibrillation was stopped by electrical cardioversion.

2.3. Data analysis
Applying a custom-made computer programme (ECGview, Maastricht University, The Netherlands), we measured the following parameters offline at a resolution of 2 ms: RR and QT intervals from lead II and LV and RV MAP duration to 100% repolarisation (MAPD). All measurements were performed on 30 consecutive beats with the same focus of activation before and 10 min after the start of dofetilide administration. Due to substantial extrasystolic activity of the ventricles in chronic-AVB dogs after dofetilide, analysis was performed immediately prior to the first extrasystolic beat. Interventricular dispersion of repolarisation duration ({Delta}MAPD) was defined as LV minus RV MAPD. Heart-rate corrected QT intervals were calculated according to van de Water's formula [15]. BVR was determined according to earlier publications [5]. Briefly, Poincaré plots were drawn from 30 consecutive LV MAPD measurements and short-term variability (STVLV={sum}|Dn–Dn–1|/[30x{surd}2], where Dn represents the LV MAPD of the nth beat), representing the mean orthogonal distance to the line-of-identity, was calculated. Additionally, STV of the RR, PP, and QT intervals (STVRR, STVPP, and STVQT respectively) was determined using the same algorithm.

Torsades de pointes was defined as a polymorphic ventricular tachycardia of at least 5 beats with a typical twisting around the isoelectric line in the setting of a prolonged QT interval. A dog was considered inducible when 3 or more TdP occurred as a consequence of dofetilide administration. A second investigator confirmed all observations and measurements.

2.4. Statistical analysis
Pooled data are expressed as mean±SD. All comparisons of electrophysiological data were performed with a one- or two-way ANOVA followed by a Bonferroni t-test when appropriate. Inducibility was compared using Fisher's Exact Test. Association between pairs of variables was analysed with Pearson product moment correlation test. SigmaStat (v. 2.03; SPSS Inc.) was used for statistical analysis. Significance was set at P<0.05. The area under the receiver-operating characteristics was used to asses the proarrhythmic-predictive power of electrophysiological values. Furthermore, we determined the predictive power of electrophysiological parameters combined through multiplication (AxB, where A and B are 2 different electrophysiological parameters).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Electrophysiological parameters defining the 3 groups
As expected, the sinus rhythm group was characterised by a faster ventricular rate than the AVB groups (Table 1). In contrast, the shortest PP intervals were seen in the acute-AVB dogs. Although repolarisation duration in general showed a trend towards prolongation after AVB, this was entirely due to the slowed ventricular rate, as the QTc intervals were equal at sinus rhythm and acute AVB. Electrical remodelling after AVB quantified as QTc prolongation relative to sinus rhythm was 2±34 ms (1%; P=NS; n=8) and 95±49 ms (34%; P<0.05; n=27) for acute and chronic AVB, respectively. Prolonged repolarisation times at chronic AVB were also observed in the group comparison of Table 1. Representative examples of the electrophysiological parameters are given in Fig. 1.


View this table:
[in this window]
[in a new window]

  		Table 1 Electrophysiological parameters before and after administration of 25 µg/kg dofetilide in the 3 groups of dogs

 

Figure 1
View larger version (84K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Electrophysiological characteristics of the 3 phenotypes used in the current study. Shown in each trace are lead II and the LV and RV MAP recordings. Measured RR intervals and QT interval are above and below the ECG, respectively. MAPD is noted adjacent to the measured action potential. All measurements are mean of 30 beats (all ms). ECG calibrated to 1 mV/cm and a paper speed of 20 mm/s (horizontal scale bar). MAP signals calibrated to 30 mV/cm. Dots above the ECG are aligned with P waves. Right-most panels are Poincaré plots depicting 30 consecutive LV MAPD from around the traces to the left. Black arrows indicate Poincaré plots under the influence of dofetilide. Sinus rhythm (A) is characterised by synchrony between P waves and QRS complexes indicating normal AV-node conduction. There is no bradycardia and repolarisation duration at baseline is relatively short. Administration of dofetilide prolongs repolarisation duration but does not increase the size of the Poincaré plot. Acute AVB (B) causes prolongation of the RR interval and rate-dependent prolongation of repolarisation durations. There is complete asynchrony between P waves and QRS complexes. Dofetilide has the same effects on repolarisation duration and on the Poincaré plot size as in sinus rhythm. At chronic AVB (C), ventricular remodelling has caused pronounced prolongation of repolarisation duration. Dofetilide causes a further increase in both the QT interval and the ventricular MAPD and increases beat-to-beat variability of repolarisation as is obvious from the Poincaré plot. TdP arrhythmias were only seen after dofetilide in dogs with chronic AVB.

 
The dofetilide challenge prolonged the RR and QT intervals as well as LV and RV MAPD in all 3 groups (Table 1). The absolute increase in ventricular repolarisation duration was comparable between the 3 groups (Table 1), although maximum values were higher in chronic-AVB dogs. Torsades de pointes arrhythmia was neither observed at baseline nor after dofetilide in dogs in sinus rhythm or in acute AVB (Fig. 1), whereas the incidence of dofetilide-induced TdP in the chronic-AVB group was 74%.

3.2. Parameters of temporal dispersion in the 3 groups
Short-term variability of the LV MAPD increased as a consequence of remodelling after AVB, whereas bradycardia alone did not alter STVLV (Fig. 2A). Variability of the beat-to-beat cycle length (STVRR) during idioventricular rhythm was larger than when the RR interval was measured during sinus rhythm, but it was not affected by ventricular remodelling. Dofetilide caused an increase in the STVLV only in the remodelled chronic-AVB dogs and not in the other 2 groups. STVRR was only affected by dofetilide when the ventricles were under sinus-node control (Fig. 2A).


Figure 2
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 (A) Temporal variability of ventricular repolarisation and rate at baseline (open bars) and after administration of 25 µg/kg dofetilide i.v. (gray bars) in anaesthetised dogs in sinus rhythm, acute (AAVB) and chronic (CAVB) AVB. At baseline, STVLV is increased in the chronic-AVB group, and dofetilide only elevates STVLV in this group. *, P<0.05. Ventricular-rate variability quantified by STVRR is increased after AV-node ablation, but this is not remodelling dependent. Dofetilide increases the sinus rhythm STVRR, but has no effect on STVRR after AVB. Actual values are noted within bars. Panel (B) shows STVLV as a function of RR interval and STVRR for individual dogs. There was a statistical significant correlation between the RR interval and STVLV (r=0.6; P<0.05; n=94; left), but not between STVRR and STVLV (r=0.1; P=NS; n=94; right).

 
In sinus rhythm, the dofetilide-induced increase in STVRR (1.3±0.8 to 2.9±1.7 ms; P<0.05; Fig. 2), had no effect on STVQT (1.0±0.2 to 1.2±0.4 ms; P=NS) or STVLV (0.7±0.1 to 0.7±0.1 ms; P=NS; Fig. 2A). Representative examples of Poincaré plots are shown in Fig. 3. Even when performing a beat-to-beat heart-rate correction of the QT interval, the STV of these QTc intervals was not increased (STVQTc: 1.1±0.3 to 1.3±0.4 ms; P=NS).


Figure 3
View larger version (27K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Four pairs of representative Poincaré plots of the RR, QT, and QTc intervals and LV MAPD for the same 30 consecutive beats in sinus rhythm. Open arrow, baseline; closed arrow, dofetilide. Only the variability of the RR interval is increased by dofetilide, whereas the QT, QTc, and LV MAPD plots are virtually unchanged.

 
STVPP was comparable to STVRR in sinus rhythm and increased with dofetilide (STVPP: 2.0±0.9 to 3.4±1.9 ms; P<0.05; n=12). To evaluate the effect of ventricular bradycardia and remodelling on the atria, we determined STVPP, which increased to 12.0±18 ms (P<0.05; n=27) after 3-week AVB. This increase was based on a heterogeneous response, as evidenced by a range of STVPP between 1.5 and 71 ms (Fig. 4). Dofetilide did not significantly affect STVPP after AVB (7.6±7.8 and 17.5±15 ms after acute and chronic AVB, respectively; P=NS for both).


Figure 4
View larger version (9K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Beat-to-beat variability of sinus rhythm cycle length. Under baseline conditions, STVPP is increased after 3-week AVB, however a large inter-individual variability within the chronic-AVB dogs (CAVB) is present. Note the logarithmic STVPP scale. *, P<0.05 versus sinus rhythm and acute AVB (AAVB).

 
3.3. Electrophysiological characteristics of the TdP-prone dog
Seven of the 27 dogs with chronic AVB were resistant to dofetilide-induced TdP. Compared to the inducible chronic-AVB dogs, RR and QT intervals, LV and RV MAPD and STVLV were all significantly lower at baseline in the resistant dogs (Table 2). Dofetilide increased most electrophysiological parameters in both sub-groups, and both RR and QT intervals reached higher maximal values in the inducible sub-group. STVRR or STVPP was not affected by dofetilide, however STVLV was only increased in the TdP-inducible dogs (Table 2; Fig. 5).


View this table:
[in this window]
[in a new window]

  		Table 2 Electrophysiological effects of dofetilide in chronic-AVB dogs divided into resistant and inducible dogs on the basis of dofetilide-induced TdP

 

Figure 5
View larger version (11K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Temporal development of STVLV obtained as a 30-beat moving average in 2 dogs with chronic AVB. Arrow indicates start of dofetilide administration. Only the inducible dog has an instantaneous increase in STVLV as a consequence of dofetilide infusion.

 
The TdP-predictive value of the different electrophysiological parameters was determined from the chronic-AVB dogs (Table 3). This analysis was performed by calculating the area under the curve of the receiver-operating characteristics (Fig. 6). This area for STVLV after dofetilide administration was 1.0 indicating total separation of STVLV values. As illustrated in Fig. 6, all TdP-inducible chronic-AVB dogs had an acute dofetilide-induced elevated STVLV reaching values above 3.0 ms. On the other hand, all resistant dogs had values below 3.0 ms. A combination of 2 of the electrophysiological parameters by simple multiplication increased the area under the curve considerably in several incidences (Table 4).


View this table:
[in this window]
[in a new window]

  		Table 3 Proarrhythmic predictive values of single electrophysiological parameters analysed for Table 2

 

Figure 6
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 6 Proarrhythmic-predictive value of various parameters as determined by receiver-operating characteristics (ROC), plotting specificity as a function of sensitivity over a wide range of cut-off values. The area under the curve of these plots quantifies the predictive value (Table 3). Only chronic-AVB dogs are included in the analysis. ROC plots (above) for the RR and QT interval and the STVLV at baseline (dotted lines) and after dofetilide (solid lines). In this study with limited group sizes of inducible and resistant dogs with chronic AVB, there is a perfect ROC plot with an area of 1, indicating failsafe predictive value. This is due to total separation of the dofetilide-elevated STVLV in the 2 groups (below). Thus, a cut-off value of 3.0 ms (dashed line) discriminates between TdP inducible and resistant dogs in anaesthetised dogs with chronic AVB and dofetilide challenge.

 

View this table:
[in this window]
[in a new window]

  		Table 4 Proarrhythmic predictive values of electrophysiological parameters combined by multiplication

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
With the present study we confirm that baseline STVLV is persistently increased in chronic-AVB dogs with remodelled hearts, when compared to dogs in acute AVB. The novel findings are that the increased STVLV is a result of ventricular remodelling and independent of heart rate or STVRR. Secondly, STVRR is significantly increased immediately after AVB, which persists over weeks during cardiac remodelling, whereas STVPP is only elevated secondary to the ventricular remodelling. This is the first study to document that IKr block causes comparable QTc prolongation across a range of cardiac pathologies from healthy to compensated hypertrophy, whereas STVLV is transiently increased only in the individual that later develops TdP.

4.1. Cardiac ventricular remodelling and BVR
Volume-overload induced cardiac remodelling after AVB has been a subject of intense interest over the years. Next to the structural and functional remodelling processes in dogs, a profound electrical remodelling takes place, contributing to the increased proarrhythmic phenotype present after 3 weeks of AVB. Table 1 shows that the AV-nodal ablation causes bradycardia, whereas the repolarisation-dependent parameters are not altered at this acute stage, especially when corrected for heart rate. Earlier studies have shown that cardiac output is momentarily decreased at this point despite an adrenergically induced increase in stroke volume [16,17]. Over weeks, cardiac output is restored as biventricular eccentric hypertrophy develops to facilitate an increase in stroke volume and the adrenergic drive levels off [14,17,18]. At this point, electrical remodelling has prolonged the ventricular repolarisation partly through a downregulation of IKr and IKs, an upregulation of the sodium–calcium exchange current, and increased calcium release from the sarcoplasmic reticulum [11,19]. The results of the present study strongly suggest that increased BVR is another hallmark of ventricular electrical remodelling. Together, the remodelling processes render the dogs with chronic AVB susceptible to drug-induced and spontaneous TdP arrhythmias [9,10,13,14,16,20]. In Table 1, we confirm our earlier results that the repolarisation-dependent parameters like QT, QTc, LV and RV MAPD alongside interventricular dispersion of repolarisation duration are all increased at chronic AVB. Fig. 2A shows that BVR is independent of the acute bradycardia and only increases as a consequence of ventricular remodelling, like the other repolarisation parameters in Table 1. Interestingly, beat-to-beat variability of the ventricular rate (STVRR) is significantly increased after AVB but does not alter further during remodelling to chronic AVB. Thus, the present study shows for the first time that the increased STVLV seen at chronic AVB is a consequence of the remodelling processes rather than directly induced by a decreased ventricular rate, whereas an increased STVRR is intrinsic of the idioventricular rate and not affected by cardiac remodelling (Fig. 2A). Furthermore, this implies that bradycardia does not contribute to BVR in non-remodelled circumstances.

4.2. Drug-induced TdP in chronic-AVB dogs
Administration of QT-prolonging drugs causes a significant increase in STVLV prior to the occurrence of TdP (Fig. 5), as have been shown previously [5,20,21]. Furthermore, QT-prolonging agents free of proarrhythmia in the chronic-AVB dogs do not induce an increase of STVLV [5,20]. The present study was not undertaken to demonstrate the proarrhythmic properties of dofetilide, which has been identified previously by ourselves and in large clinical trials [10,22]. Rather, we wished to investigate the relationship between various electrophysiological parameters, including BVR, and individual susceptibility to drug-induced TdP.

The theory of multiple hits on repolarisation suggests that several consecutive reductions of repolarisation reserve are required for the initiation of TdP [20,23]. In our setting, the first perturbation of repolarisation is the AV-nodal ablation causing bradycardia. Secondly, weeks of cardiac remodelling sets the stage for TdP. Finally, a combination of anaesthesia and fast intravenous administration of a proarrhythmic drug triggers a series of events, including increased BVR, prolonged and increased spatial heterogeneity of repolarisation duration, occurrence of early afterdepolarisations and extrasystoles, often culminating in reproducible TdP arrhythmias.

The difference between resistant and inducible chronic-AVB dogs (Table 2) despite identical hits on repolarisation reserve is likely to be dependent on the genetic background of the dogs, although further investigations into this area are needed before this remains clear. Table 2 shows that resistant dogs have a faster idioventricular rate than TdP-inducible dogs, raising the possibility that these animals experience less electrical remodelling. This could be secondary to different levels of contractile or structural remodelling in the two groups, however these remodelling aspects were not determined in the present study. Nevertheless, cardiac remodelling is essential for the induction of arrhythmia.

4.3. Beat-to-beat variability
By using Poincaré plots, STV is one way of analysing BVR. A dose-dependent TdP occurrence after d-sotalol was tightly associated with the transient increase in STVLV, whereas the absence of TdP after a QT prolonging drug is reflected in an unchanged STVLV [5]. Later, we documented that anti-torsadogenic preventive or interventional treatments are associated with stabilised or even decreased STVLV [20].

In the sinus rhythm dogs, dofetilide increased STVPP and STVRR but had no effect on either STVQT or STVLV (Figs. 2 and 3Go). Thus, the repolarisation in these dogs is strong enough to compensate for the irregular diastolic intervals and keeping action-potential duration constant. Furthermore, the overall range of RR changes within the 30 beats in a dog is <10% of the mean RR interval, probably too small to significantly influence action potential duration. Interestingly, the beat-to-beat heart-rate correction did not transfer the dofetilide-induced increase in STVRR to differences in STVQTc. Caution should be taken in interpreting these results, as heart-rate correction formulas have not been designed to work on an immediate beat-to-beat basis. Furthermore, changes in repolarisation tend to lag behind the heart-rate change [24,25].

In an awake study using telemetry monitoring of 6 dogs in sinus rhythm, dofetilide (30 µg/kg i.v.) prolonged the QT interval by 15% without significant effect on the heart rate [26]. STVQT calculated over 100 beats did not change significantly (6.5±3.7 versus 10.4±3.9 ms; P=NS) as a consequence of dofetilide administration. Thus, compared to the present study (Table 1), the awake situation shows a shorter QT at baseline and a smaller dofetilide-induced increase in the QT interval, however a larger baseline STVQT. Unfortunately, STVRR was not quantified in the awake study, as a considerable respiration-induced RR interval variability in conscious dogs is known to exist [27], which could contribute to a higher STVQT at baseline. We and others have shown that this dose of dofetilide does not cause TdP arrhythmia in sinus rhythm dogs either with or without anaesthesia [10,26].

Beat-to-beat QT interval measurements in dogs with AVB are hampered by P waves coinciding with the end of the T wave (Fig. 1). When such beats are skipped in the analysis, the direct beat-to-beat consecutiveness is lost and sensitivity declines [5]. Furthermore, we have previously shown that STVRV is a poor predictor of drug-induced TdP [5,13]. In the anaesthetised dogs with AVB, STVLV is thus the preferable measure of repolarisation lability.

The shortened PP interval directly after AVB (Table 1) has been shown earlier [14,17,18] and is generally attributed to the increased adrenergic activity compensating the acute drop in cardiac output. The PP intervals are normalized to pre-AVB levels after 2 weeks of AVB [14,17,18]. Still, long PP intervals seem to be a proarrhythmic risk factor in the chronic-AVB dogs (Table 2), which could indicate that either low adrenergic or high vagal tone contributes to the proarrhythmic trigger. A high adrenergic tone, suggested by a short PP interval, would theoretically imply a β-adrenoceptor-mediated activation of the partly downregulated IKs, preventing an excessively prolonged and unstable action potential, thereby possibly serving as a safety factor, reducing TdP inducibility. This is probably a delicate balance of the autonomic nervous system, as intense and acute β-adrenergic stimulation is proarrhythmic [28].

Interestingly, the wide range of STVPP values in the dogs with chronic AVB (Fig. 4) indicates different levels of atrial remodelling despite comparable ventricular remodelling after AVB. This could possibly be based on atrial vulnerability to stretch as the atria are regularly contracting against closed valves after complete AVB. The chronic-AVB dogs with the largest STVPP are thus sensitive to atrial stretch induced by ventricular contraction. Further research is needed to quantify and understand this atrial remodelling in detail.

4.4. Electrophysiological parameters predicting TdP
Fig. 6 illustrates receiver-operating characteristics (ROC) for RR, QT, and STVLV with and without pharmacological challenge showing the specificity as a function of sensitivity over a large range of cut-off points to avoid the bias of choosing artificial cut-off points. The area under the curve indicates the predictive value of the given parameter, where an area of 1 indicates 100% specificity and 100% sensitivity for at least 1 cut-off point. At baseline, the most powerful predictors of individual susceptibility to TdP are long PP intervals and elevated STVLV (Table 3). By combining 2 electrophysiological parameters through simple multiplication, the predictive power could be increased in many instances (Table 4). At baseline, multiplication of the PP interval and STVLV gives a rather arbitrary value but a high TdP-predictive power. Dofetilide caused a significant increase in STVLV in the TdP-inducible dogs only (Table 2), but more importantly all values of STVLV increased to over 3.0 ms in the group, whereas none of the resistant dogs reached this level. Hence, there is a total separation of the 2 groups by means of STVLV (Fig. 6) and the resulting area under the ROC curve is 1 (Table 3). This finding is further accentuated by the presence of persistently elevated BVR above 3.0 ms in retrospectively analysed chronic-AVB dogs that died suddenly under conscious, drug-free circumstances [13].

In the present study, {delta}MAPD represented spatial dispersion of repolarisation duration, whereas temporal dispersion was characterised by BVR. Interventricular dispersion of MAPD may not directly represent the spatial dispersion required for the perpetuation of triggered TdP [29]. Nevertheless, increased {delta}MAPD is likely to suggest steeper gradients of spatial repolarisation dispersion that could infringe an early afterdepolarisation-triggered extrasystole. Generally, interventricular dispersion is larger that intraventricular dispersion of repolarisation duration [30], however the latter was not assessed in the present study. Discrete ventricular areas with substantial discordant BVR could give rise to moments of significant intraventricular dispersion setting the stage for TdP arrhythmias. Administration of dofetilide to chronic-AVB dogs (Table 2) increases the proarrhythmic substrate (e.g., QT interval and spatial dispersion of repolarisation), whereas triggers (e.g., elevated BVR and extra systoles) are only present in the inducible dogs.

4.5. Limitations
This study limits BVR measurements to anaesthetised dogs, suggesting precaution when extrapolating TdP-predictive values to the clinical setting. Presently, there is no satisfactory cellular explanation for the mechanism underlying BVR. As this was not a serial investigation, the electrophysiological characteristics of a dofetilide-challenge in a chronic-AVB dog cannot be tracked back to the sinus rhythm situation. STVQT after AVB could not be determined as precise measurements occasionally are hampered by P waves (Fig. 1).

4.6. Clinical implications
Identification of the patient susceptible to drug-induced life threatening TdP arrhythmias is difficult, and the list of available drugs prolonging cardiac repolarisation is increasing, especially among non-cardiovascular drugs [31]. In-hospital initiation of therapy is standard for an increasing number of drugs to minimise the risk of TdP-induced cardiac mortality. Novel proarrhythmic parameters may enhance the quality and reduce the costs of the pre-treatment evaluation of the individual patient receiving potentially torsadogenic medication.

Pharmacological pre-screening of patients is not ideal [4], however in the present study, dofetilide was used as a tool to elicit proarrhythmic individuals. Our study suggests that baseline BVR, possibly in combination with other electrophysiological parameters, may contribute to the individual risk stratification of patients. Preliminary results suggest that this may be feasible also in the clinical setting [32].

4.7. Conclusions
Beat-to-beat variability of repolarisation duration quantified by STVLV is persistently increased by ventricular remodelling but not directly by the slower ventricular rate after AVB. Neither RR intervals nor variability of the RR interval influence BVR. Only hearts prone to TdP express a transient increase in BVR upon dofetilide challenge. Thus, BVR may aid the identification of the TdP-susceptible patient before manifest proarrhythmia.


   Notes
 
1 Contributed equally as first authors. Back

Time for primary review 16 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Dessertenne F. La tachycardie ventriculaire à deux foyers opposés variables. Arch des Mal du Cœur (1966) 59:263–272.
  2. Roden D.M. Taking the "idio" out of "idiosyncratic": predicting torsades de pointes. Pacing Clin Electrophysiol (1998) 21:1029–1034.[CrossRef][Medline]
  3. Thomsen M.B., Matz J., Volders P.G., Vos M.A. Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacol Ther (2006) 112:150–170.[CrossRef][ISI][Medline]
  4. Kaab S., Hinterseer M., Nabauer M., Steinbeck G. Sotalol testing unmasks altered repolarization in patients with suspected acquired long-QT-syndrome – a case-control pilot study using i.v. sotalol. Eur Heart J (2003) 24:649–657.[Abstract/Free Full Text]
  5. Thomsen M.B., Verduyn S.C., Stengl M., Beekman J.D., de Pater G., Van Opstal J.M., et al. Increased short-term variability of repolarization predicts D-sotalol-induced torsades de pointes in dogs. Circulation (2004) 110:2453–2459.[Abstract/Free Full Text]
  6. Antzelevitch C., Sun Z.Q., Zhang Z.Q., Yan G.X. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. J Am Coll Cardiol (1996) 28:1836–1848.[Abstract]
  7. Hondeghem L.M., Carlsson L., Duker G. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation (2001) 103:2004–2013.[Abstract/Free Full Text]
  8. Gbadebo T.D., Trimble R.W., Khoo M.S., Temple J., Roden D.M., Anderson M.E. Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes. Circulation (2002) 105:770–774.[Abstract/Free Full Text]
  9. Thomsen M.B., Volders P.G., Stengl M., Spätjens R.L., Beekman J.D., Bischoff U., et al. Electrophysiological safety of sertindole in dogs with normal and remodeled hearts. J Pharmacol Exp Ther (2003) 307:776–784.[Abstract/Free Full Text]
  10. van Opstal J.M., Leunissen J.D., Wellens H.J., Vos M.A. Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of torsade de pointes arrhythmias. Eur J Pharmacol (2001) 412:67–76.[CrossRef][ISI][Medline]
  11. Sipido K.R., Volders P.G., de Groot S.H., Verdonck F., Van de Werf F., Wellens H.J., et al. Enhanced Ca(2+) release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis. Circulation (2000) 102:2137–2144.[Abstract/Free Full Text]
  12. Volders P.G., Sipido K.R., Vos M.A., Kulcsar A., Verduyn S.C., Wellens H.J. Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation (1998) 98:1136–1147.[Abstract/Free Full Text]
  13. Thomsen M.B., Truin M., van Opstal J.M., Beekman J.D., Volders P.G., Stengl M., et al. Sudden cardiac death in dogs with remodeled hearts is associated with larger beat-to-beat variability of repolarization. Basic Res Cardiol (2005) 100:279–287.[CrossRef][ISI][Medline]
  14. Schoenmakers M., Ramakers C., van Opstal J.M., Leunissen J.D., Londono C., Vos M.A. Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog. Cardiovasc Res (2003) 59:351–359.[Abstract/Free Full Text]
  15. Van de Water A., Verheyen J., Xhonneux R., Reneman R.S. An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. J Pharmacol Methods (1989) 22:207–217.[CrossRef][ISI][Medline]
  16. Vos M.A., de Groot S.H., Verduyn S.C., van der Zande J., Leunissen H.D., Cleutjens J.P., et al. Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation (1998) 98:1125–1135.[Abstract/Free Full Text]
  17. Donker D.W., Volders P.G., Arts T., Bekkers B.C., Hofstra L., Spatjens R.L., et al. End-diastolic myofiber stress and ejection strain increase with ventricular volume overload – serial in-vivo analyses in dogs with complete atrioventricular block. Basic Res Cardiol (2005) 100:372–382.[CrossRef][ISI][Medline]
  18. de Groot S.H., Schoenmakers M., Molenschot M.M., Leunissen J.D., Wellens H.J., Vos M.A. Contractile adaptations preserving cardiac output predispose the hypertrophied canine heart to delayed afterdepolarization-dependent ventricular arrhythmias. Circulation (2000) 102:2145–2151.[Abstract/Free Full Text]
  19. Volders P.G., Sipido K.R., Vos M.A., Spatjens R.L., Leunissen J.D., Carmeliet E., et al. Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes. Circulation (1999) 100:2455–2461.[Abstract/Free Full Text]
  20. Thomsen M.B., Volders P.G., Beekman J.D., Matz J., Vos M.A. Beat-to-beat variability of repolarization determines proarrhythmic outcome in dogs susceptible to drug-induced torsades de pointes. J Am Coll Cardiol (2006) 48:1768–1776.
  21. Wu L., Shryock J.C., Song Y., Belardinelli L. An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT – prolonging drugs in female rabbit hearts. J Pharmacol Exp Ther (2006) 316:718–726.[Abstract/Free Full Text]
  22. Torp-Pedersen C., Moller M., Bloch-Thomsen P.E., Kober L., Sandoe E., Egstrup K., et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med (1999) 341:857–865.[Abstract/Free Full Text]
  23. Roden D.M. Drug-induced prolongation of the QT interval. N Engl J Med (2004) 350:1013–1022.[Free Full Text]
  24. Janse M.J., van der Steen A.B., van Dam R.T. Refractory period of the dog's ventricular myocardium following sudden changes in frequency. Circ Res (1969) 24:251–262.[Abstract/Free Full Text]
  25. Franz M.R., Swerdlow C.D., Liem L.B., Schaefer J. Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest (1988) 82:972–979.[ISI][Medline]
  26. Schneider J., Hauser R., Andreas J.O., Linz K., Jahnel U. Differential effects of human ether-a-go-go-related gene (HERG) blocking agents on QT duration variability in conscious dogs. Eur J Pharmacol (2005) 512:53–60.[CrossRef][ISI][Medline]
  27. Ettinger S.J., Suter P.F. Canine cardiology. (1970) London: W. B. Saunders Company. 272.
  28. Stengl M., Ramakers C., Donker D.W., Nabar A., Rybin A.V., Spatjens R.L., et al. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: focus on IKs downregulation and blunted beta-adrenergic activation. Cardiovasc Res (2006) 72:90–100.[Abstract/Free Full Text]
  29. Kozhevnikov D.O., Yamamoto K., Robotis D., Restivo M., El Sherif N. Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery patterns. Circulation (2002) 105:1128–1134.[Abstract/Free Full Text]
  30. Verduyn S.C., Vos M.A., van der Zande J., van der Hulst F.F., Wellens H.J. Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium. Cardiovasc Res (1997) 34:453–463.[Abstract/Free Full Text]
  31. Haverkamp W., Breithardt G., Camm A.J., Janse M.J., Rosen M.R., Antzelevitch C., et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. Cardiovasc Res (2000) 47:219–233.[Free Full Text]
  32. Hinterseer M., Beckmann B.M., Thomsen M.B., Pfeufer A., Perz S., Wichmann H.E., et al. Beat-to-beat variability of QT intervals is increased in drug-induced and congenital long-QT syndromes. Heart Rhythm (2006) 3:S269–S270.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Thomsen, M. B.
Right arrow Articles by Vos, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Thomsen, M. B.
Right arrow Articles by Vos, M. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?