© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block
Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
* Corresponding author. Tel.: +31-43-387-5097; fax: +31-43-387-5104 m.vos{at}cardio.azm.nl
Received 7 September 2000; accepted 25 January 2001
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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Background: The dog model of chronic complete AV-block (CAVB) demonstrates a considerable incidence of (witnessed) sudden death (16/117 dogs). In this study we tried to: (1) elucidate the mechanisms of sudden death using an ECG telemetry device and (2) identify retrospectively the risk parameters indicative of this arrhythmogenic death. Methods: Between 1994 and 1998, 78 anesthetized dogs underwent an extensive electrophysiological study including: (1) left- (LV) and right ventricular (RV) monophasic action potential (MAP) recordings to assess
MAPD (LV APD minus RV APD) and (2) pacing protocols (PES) to induce torsade de pointes arrhythmias (TdP) at 4–6 weeks CAVB. Eight animals experienced sudden cardiac death (SCD) during the follow-up period (mean 7±3 weeks CAVB). Since the response of the CAVB dog to class III drugs is not uniform we also made comparisons among the SCD group, TdP drug responders and non-responders. For this purpose we selected all animals which (1) received almokalant (n = 15, 0.12 mg/kg/5 min) or ibutilide (n = 9, 0.025 mg/kg/5 min) as an additional challenge to induce TdP and (2) had a follow-up period of at least 4 weeks. Results: Six out of eight SCD dogs showed inducible TdP at baseline. Two of eight dogs had telemetric ECG surveillance and both revealed polymorphic VT as the cause of SCD. Baseline MAPD of the SCD (90±15 ms) was significantly higher than the non-scD group (n = 70, 60±30 ms). Of the 24 dogs which received class III drugs, 12 belonged to the TdP responder group. MAPD of the TdP responder group (80±15 ms) was similar to the SCD group and significantly higher compared to the non-responder group (n = 12, 40±25 ms). QT-time and cycle length of idioventricular rhythm were not different. Conclusion: In the CAVB dog model, SCD is (1) most probably related to TdP while (2) inducible TdP and the measure of MAPD at baseline indicate susceptibility to SCD.
KEYWORDS Arrhythmia (mechanisms); Bradycardia; Long QT syndrome; Repolarization; Sudden death; Ventricular arrhythmias
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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In Maastricht, the chronic AV-block (CAVB) dog has been studied extensively to understand its enhanced susceptibility to ventricular arrhythmias [1–5]. The bradycardia induced volume overload by acute AV-block initiates rapidly a number of adaptation processes to compensate for the decreased cardiac output and the increased end-diastolic pressure [5]. These remodeling processes are completed within 4 weeks of CAVB and include (1) development of biventricular eccentric hypertrophy, (2) compensated cardiac hemodynamics and (3) heterogeneous prolongation of the ventricular repolarization time, resulting in an increased dispersion of repolarization (i.e. electrical remodeling) [1,2,5]. These adaptations, alone or synergistically, increase the risk of early afterdepolarizations (EAD) — respectively, delayed afterdepolarization-dependent triggered arrhythmias and drug-induced torsade de pointes arrhythmias (TdP) [1,2,4–10]. Moreover, a number of (witnessed) sudden deaths occur in the cages after 4 weeks of CAVB.
To assess if sudden death could be attributed to ventricular arrhythmias, a two-lead electrocardiagram (ECG) telemetric device was implanted prospectively. As telemetry revealed sudden death to be arrhythmogenic, our large canine database at baseline CAVB was used to identify retrospectively the electrophysiological parameters which could predict susceptibility to sudden cardiac death (SCD).
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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Between 1994–1998, the CAVB dog (n = 117) was investigated to determine (1) the different remodeling processes in relation to ventricular arrhythmias and (2) to compare the ability of different anti-arrhythmic drugs to induce TdP. During this period 16 out of 117 dogs experienced sudden death.
Before discussing the employment of the telemetry device, the definition of sudden cardiac death and the use of our electrophysiological database, the general methodology will be described briefly.
2.1 General methods
Animal handling was in accordance with the Dutch Law on Animal Experimentation (WOD) and the European Directive for the Protection of Vertebrae Animals used for Experimental and other Scientific Purposes (European Union Directive #86/609/CEE). The experiments were approved by The Committee for Experiments on Animals (DEC) of Maastricht University, The Netherlands.
The methods used for induction of anesthesia, creation of AV-block and the electrophysiological studies performed at 4–6 weeks of AV-block are detailed in previous publications [1,5,6,8,9]. In short, anesthesia was induced by premedication and sodium pentobarbital (20–25 mg/kg) and the dogs were ventilated artificially using a mixture of oxygen, nitrous oxide and 0.5% halothane. AV-block was created by injection of formaldehyde in the AV-groove after a right-sided thoracotomy. Proper care was taken before and after the experiments including antibiotics and analgesics. During the time period between the AV-block operation and the actual experiments at 4–6 weeks of AV-block, the dogs were checked daily to assess their physical condition and a weekly surface ECG was made to verify persistence of CAVB.
During the electrophysiological studies at 4–6 weeks of AV-block six surface ECGs and two endocardial monophasic action potentials (MAPs) were simultaneously registered and stored on hard disk. MAP catheters (EP Technologies Inc., CA, USA) were placed endocardially, under fluoroscopic guidance, in the left- (LV) and right (RV) ventricular cavity. MAPs were positioned in such a way that a qualitatively good, stable and reproducible signal could be obtained.
Two different pacing modes (PES) were used to induce TdP at baseline circumstances: (1) a short-long-short sequence (400, 800+ extrastimulus, or 4x600,1200+ extrastimulus, (2) eight basic stimuli with a cycle length of 600 ms followed by an extrastimulus. Pacing was performed from a left epicardial electrode which had been implanted during the AV-block operation. A number of dogs received class III drugs to provoke TdP. TdP was considered significant if the arrhythmia occurred 
3 times.
After completion of the follow-up period, or SCD, the heart was excised to determine the heart to body weight ratio.
2.2 Sudden cardiac death
SCD was defined as unexpected death occurring in the cage. To exclude all other non-cardiac causes of death an autopsy was performed. To record the circumstances of SCD, a custom made 24-h telemetry device was developed in collaboration with M. Janssen, Wageningen, Netherlands and L. Dohmen, Maastricht University. In the same session as the electrophysiological study, the telemetry device, 8x5x2 cm, was placed in a total of five dogs in a subcutaneous pocket at the left side of the thorax. Three electrodes (each 10 cm long) were positioned in an Y-shape configuration under the skin to record a two-lead ECG, one lead to inferior, one to the sternum and one to the left scapula. We made sure that one of these leads was similar to lead II of the surface ECG. The transmitter unit contained a radio-frequency transmitter and a battery. The cage had a receiver and both output signals (lead 1 and 2) were connected to an analog to digital converter interface of a PC-based data acquisition system to process signals. Multiple cages could be connected simultaneously to the computer. Signals were displayed in real-time on a PC monitor and stored continuously (24 h/day) and processed off line.
2.3 Electrophysiological database: composition of the subgroups
Of the total of 117 CAVB dogs, 78 underwent an extensive electrophysiological study at 4–6 weeks of CAVB consisting of: (1) recordings of two qualitatively good MAP signals to assess interventricular dispersion [7], and (2) completion of a PES protocol to provoke TdP at baseline.
Eight of these 78 animals experienced SCD during the follow-up period (SCD group) and were compared to the 70 non-scD dogs. Since the response of the CAVB dog to class III drugs is not uniform, we also made electrophysiological comparisons at baseline among the SCD group, drug TdP responders and drug non-responders. For this purpose we selected all dogs which as well (1) showed no (inducible) TdP at baseline, (2) received almokalant (0.12 mg/kg/5 min) or ibutilide (CorvertTM, 0.025 mg/kg/5 min) as an additional challenge to induce TdP, and (3) had a follow-up period of at least 4 weeks after the electrophysiological study performed at 4–6 weeks of CAVB. Part of the almokalant-treated dogs have been published previously [9], although the results are now used for a different purpose.
2.4 Data analysis at CAVB baseline
Applying a custom made computer program (ECG View, Maastricht University), with a resolution of 2 ms and adjustable gain and time scale, the following parameters were measured off line: cycle length of idioventricular rhythm (CL-IVR), QT-time, the duration of the monophasic action potential (MAPD) of the LV and RV at 100% of repolarization. From these measurements, the interventricular dispersion (MAPD) was calculated, defined as LV MAPD minus RV MAPD.
Electrophysiological data were measured during a stable CL-IVR after at least 1 h of anesthesia and are the mean of five consecutive beats. Both at baseline and during class III drugs, the electrophysiological measurements were done beat to beat to determine maximum values.
2.5 Statistics
Pooled data are expressed as mean±standard deviation (S.D.). Two group comparisons between the SCD and the non-scD group were analyzed by unpaired Student's t-test. Multiple comparisons between the SCD-, drug TdP-responders, and non-responders groups were performed by one-way analysis of variance (ANOVA) test with a post-hoc Bonferroni t-test. Chi-square test was used when the data were presented as a proportion.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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3.1 Sudden cardiac death group: electrophysiological and arrhythmogenic parameters
Mean time of SCD was 7±3 weeks of CAVB. Gender, age and the amount of cardiac hypertrophy in the SCD dogs (heart/body weight 12.6±1.5 g/kg) was not different from the non-scD dogs (heart/body weight 11.5±2.4 g/kg). Two of the eight SCD dogs had a telemetric device implanted and revealed a polymorphic ventricular tachycardia as cause of death. As can be seen in Fig. 1, the tachycardia was preceded by an acceleration in heart rate and the occurrence of ventricular ectopic activity. This particular animal also showed a substantial amount of ectopic activity and a self terminating polymorphic ventricular tachycardia in the hours preceding its death. In the other six SCD animals, having no telemetric device, other causes of death could be excluded. Two of these six animals were witnessed to have SCD while excited, dying in front of the animal technician. Resuscitation equipment was not available in the stables.
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In Table 1 (left part), it can be seen that CL-IVR, QT-time and RV MAPD did not differ between the SCD dogs and the non-scD dogs (n = 70). LV MAPD and
MAPD were however significantly different between the two groups.
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When looking at the arrhythmia incidence in the SCD group, six of eight animals (75%) already demonstrated TdP at baseline: in four dogs multiple episodes of spontaneous TdP were seen during the (preparation of the) electrophysiological study (Fig. 2) while in five dogs TdP could be induced by PES. In the non-scD group the incidence of TdP at baseline was 11/70 (16%, P<0.001 SCD vs. non-scD group).
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3.2 TdP responder versus non-responder group
Twenty four dogs met the inclusion criteria of which 15 received almokalant and nine ibutilide. Half of them (n = 6 ibutilide, n = 6 almokalant) responded with TdP to the drug challenge (i.e. TdP responders) while the other half did not (non-responders).
As previously described [8,9] and visualized in Fig. 3, class III drugs increased significantly (1) CL-IVR, (2) QT-time, and (3) all MAP-derived durations, including MAPD (data not shown).
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3.3 Arrhythmogenic and electrophysiological parameters of the subgroups at baseline: SCD, TdP responders and non-responders
In Table 1 (right part), the electrophysiological parameters of the SCD group, TdP responders and non-responders at baseline are compared. No significant differences existed between the three subgroups in CL-IVR, QT-time and RV MAPD. LV MAPD and
MAPD were however significantly different between the SCD and TdP responders versus non-responders. Although LV MAPD and MAPD appeared somewhat larger in the SCD compared to the TdP responder group, these differences did not reach significance. Fig. 4 shows the individual data points of the MAPD in the three groups, which revealed clearly the distinction between the SCD and TdP responder groups on the one hand versus the non-responder group on the other.
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Thus, in fact we can distinguish two groups: arrhythmogenic and non-arrhythmogenic, on the basis of their LV MAPD and
MAPD during baseline. In Table 2, the different specificity and sensitivity values for MAPD cut-off points of 40, 65, and 90 ms can be seen in relation to the occurrence of ventricular arrhythmias.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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This study demonstrates that in the dog with CAVB, SCD can most probably be attributed to (polymorphic) ventricular tachycardias. The ability to induce TdP at baseline and the measure of LV MAPD and
MAPD indicate susceptibility to SCD.
4.1 Telemetry device
The observation period started following the electrophysiological study, which was performed after at least 4 weeks of CAVB. From this time on, we assume that the (electrical) remodeling processes are completed and stable in time [11,12].
To record the mode of death, we developed a telemetry system which provides a two-lead ECG recording for 24 h a day for a maximum of 2 months in a dog which can move freely in his cage. The first analysis of these telemetry recordings in the two dogs dying suddenly, revealed in both cases that the arrhythmia was preceded by an acceleration in idioventricular rhythm which was accompanied by ventricular ectopic activity (Fig. 1). The latter pattern shows similarities with the initiation sequence of drug-induced TdP (Fig. 3) in which EADs trigger ectopic beats, setting the stage for a TdP arrhythmia. The observed acceleration in rate and the fact that the two witnessed deaths occurred when the dogs were excited suggest an adrenergic contribution to the initiation of the arrhythmia.
4.2 Predictive parameters of SCD
In our retrospective study we looked at 78 CAVB dogs, including eight SCD dogs. The group of 24 dogs which received almokalant or ibutilide, showed a TdP responders versus non-responders ratio comparable to other anti-arrhythmic drugs used in the model [10].
An arrhythmogenic parameter indicative of SCD was the ability to evoke TdP already under baseline circumstances. In some anesthetized dogs TdP arose spontaneously (Fig. 2), while in others our short-long-short mimicking pacing protocols were able to initiate TdP.
One of the other electrophysiological parameters we focused on was MAPD, as we recently demonstrated that the amount of MAPD is strongly associated with drug induced TdP [1,8–10]. Also in other models of hypertrophy and heart failure, inter- and intraventricular inhomogeneity in action potential duration has been described [13,14], while Antzelevitch et al. [15] described the concept of transmural dispersion of repolarization. In Table 1 it can be seen that the MAPD of the SCD group is significantly larger compared to the non-scD group.
Interestingly the SCD group and the TdP responder group show many similarities. The MAPD at baseline of these two groups was significantly different from the non-responder group (Table 1 and Fig. 4). A MAPD of 65 ms had a sensitivity of 85% and a specificity of 92% for the occurrence of ventricular arrhythmias (Table 2). Besides MAPD, the only other electrophysiological parameter which showed a significant difference was LV MAPD. This suggests that the length of the LV MAPD plays an important role, either in creating dispersion between the ventricles (MAPD) or in generating early afterdepolarizations triggering arrhythmias [16,17]. It was surprising to find that QT-time did not discriminate sufficiently to become predictive. Also CL-IVR was similar in the different group comparisons excluding bradycardia as an arrhythmogenic factor.
4.3 Basis of the enhanced sensitivity to SCD in the CAVB dog
QT prolongation or repolarization lability are regarded as risk factors for ventricular arrhythmias and SCD in patients with cardiac hypertrophy or failure [18]. Recently the concept of a decreased repolarization reserve was introduced [19,20]. Arrhythmias would then occur when the reduced repolarization is challenged, e.g. by drugs or adrenergic stimulation [19–21].
We have described that the prolonged repolarization in the CAVB dog can be attributed to a decrease in IK and an upregulation of the Na–Ca exchanger current in both ventricles [3,4]. All other currents which we have measured so far (e.g. ICaL, Ito, IK1) did not show any change. These electrical adaptations result in a more pronounced interventricular dispersion and a higher susceptibility to TdP [1,8,9]. The electrical remodeling is accompanied by an eccentric biventricular hypertrophy and by a maintained cardiac output (compensated function) [1,4,5].
To some degree the above mentioned characteristics in cardiac hypertrophy and/or failure may be regarded as a form of acquired long QT syndrome [3,19,21]. The fact that the CAVB population can now be divided further in an arrhythmogenic and a non-arrhythmogenic group is new and it is tempting to suggest that arrhythmogenic dogs would have the least repolarization reserve. To test this hypothesis, ion channel expression levels of arrhythmogenic versus non-arrhythmogenic dogs will be part of future investigations.
Besides possessing a substrate (MAPD), the arrhythmogenic group needed an additional trigger to start the arrhythmia. This trigger which is likely to be related to triggered activity or abnormal automaticity can be provided by the addition of a challenging factor. So far these include: increased adrenergic state (excitement), anesthesia, pacing, and/or class III drugs. Whether other factors are involved will be part of ongoing investigations.
4.4 Relevance of the model
Only few studies have been able to demonstrate arrhythmogenic consequences of the mentioned repolarization abnormalities in hypertrophy and heart failure [13,14,22–26].
The presumed adrenergically induced TdP in the conscious CAVB dog in which the IK current is decreased shows similarities with some forms of the congenital long QT syndrome (LQT1 and LQT2) in which SCD is related to IKr or IKs downregulation and adrenergic stimulation [27]. Also patients with ‘forme fruste’ congenital LQT syndrome show an increased TdP susceptibility to class III drugs [28].
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5 Limitations |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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SCD is a complex phenomenon whose appearance is unpredictable. In this respect our follow-up period of
4 weeks could have been too short. The scope of the study prevents us from drawing conclusions about the cause of the increased susceptibility to SCD in a subgroup of CAVB dogs. Cellular electrophysiological studies on sudden death could not be performed because cells can only be obtained from freshly arrested hearts. Placement of MAPs at only two sites (LV and RV) ignores possible transmural and intraventricular differences. However, we have shown with multisite transmural needle electrodes that APD is present within the CAVB dog heart [29]. |
6 Conclusion |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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In the CAVB dog model, SCD is (1) most probably related to TdP while (2) inducible TdP and the measure of LV MAPD and
MAPD at baseline indicate susceptibility to SCD. Time for primary review 26 days.
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Acknowledgements |
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The authors would like to express their gratitude to Dr. Stengl for helpful comments and advice on the manuscript and to Leon Dohmen, BSc for developing and maintaining the telemetry equipment. Financial support by The Netherlands Heart Foundation (#98.042) and Netherlands Organization for Scientific Research (#950.10.647) is gratefully acknowledged.
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References |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 Limitations6 ConclusionReferences |
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- Vos M.A., de Groot S.H., Verduyn S.C., 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] - 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] - Volders P.G., Sipido K.R., Vos M.A., 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] - Sipido K.R., Volders P.G.A., de Groot S.H.M., et al. Enhanced Ca2+ release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes. Circulation (2000) 102:2137–2144.
[Abstract/Free Full Text] - de Groot S.H., Schoenmakers M., Molenschot M.M.C., Leunissen H.D.M., Wellens H.J.J., Vos M.A. Contractile adaptations preserving cardiac output predispose the hypertrophied canine heart to delayed afterdepolarization dependent ventricular arrhythmias. Circulation (2000) 102:2145–2155.
[Abstract/Free Full Text] - Vos M.A., Verduyn S.C., Gorgels A.P., Lipcsei G.C., Wellens H.J. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation (1995) 91:864–872.
[Abstract/Free Full Text] - Vos M.A., Verduyn S.C., Wellens H.J.J. Monophasic action potentials. Bridging cell and bedside. Franz M.R., ed. (2000) Armonk, NY: Futura Press. 553–569.
- 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] - Verduyn S.C., Vos M.A., van der Zande J., Kulcsar A., Wellens H.J. Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: a comparison between almokalant and d-sotalol using the dog as its own control. J Am Coll Cardiol (1997) 30:1575–1584.[Abstract]
- van Opstal J.M., Leunissen H.D.M., Wellens H.J.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][Web of Science][Medline]
- Verduyn SC, Vos MA, Snoep G, Leunissen HDM, Wellens HJJ. Bradycardia induced volume overload leads to rapid structural and electrophysiological changes in the AV-block dog. Am J Physiol 2001 (in press).
- Peschar M., Vanagt W.Y.R., Vos M.A., Prinzen F.W. Lack of reverse electrical remodeling during regression of volume overload hypertrophy [abstract]. Pacing Clin Electrophysiol (1999) 22:881.
- Kowey P.R., Friechling T.D., Sewter J., et al. Electrophysiological effects of left ventricular hypertrophy. Effect of calcium and potassium channel blockade. Circulation (1991) 83:2067–2075.
[Abstract/Free Full Text] - Pak P.H., Nuss H.B., Tunin R.S., et al. Repolarization abnormalities, arrhythmia and sudden death in canine tachycardia-induced cardiomyopathy. J Am Coll Cardiol (1997) 30:576–584.[Abstract]
- Antzelevitch C., Shimizu W., Yan G.X., et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol (1999) 10:1124–1152.[Web of Science][Medline]
- January C.T., Riddle J.M. Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res (1989) 64:977–990.
[Abstract/Free Full Text] - Volders P.G., Vos M.A., Szabo B., et al. Progress in the understanding of cardiac early afterdepolarizations and torsade de pointes: time to revise current concepts. Cardiovasc Res (2000) 46:376–392.
[Free Full Text] - Zipes D.P., Wellens H.J. Sudden cardiac death. Circulation (1998) 98:2334–2351.
[Free Full Text] - Marban E. Heart failure: the electrophysiologic connection. J Cardiovasc Electrophysiol (1999) 10:1425–1428.[Web of Science][Medline]
- Roden D.M. Taking the ‘idio’ out of ‘idiosyncratic’: predicting torsades de pointes. Pacing Clin Electrophysiol (1998) 21:1029–1034.[CrossRef][Medline]
- Nabauer M., Kaab S. Potassium channel down-regulation in heart failure. Cardiovasc Res (1998) 37:324–334.
[Abstract/Free Full Text] - Hsieh M.H., Chen Y.J., Lee S.H., Ding Y.A., Chang M.S., Chen S.A. Proarrhythmic effects of ibutilide in a canine model of pacing induced cardiomyopathy. Pacing Clin Electrophysiol (2000) 23:149–156.[CrossRef][Medline]
- Sabbah H.N., Goldberg A.D., Schoels W., et al. Spontaneous and inducible ventricular arrhythmias in a canine model of chronic heart failure: relation to haemodynamics and sympathoadrenergic activation. Eur Heart J (1992) 13:1562–1572.
[Abstract/Free Full Text] - Sabbah H.N., Stein P.D., Kono T., et al. A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. Am J Physiol (1991) 260:H1379–1384.[Web of Science][Medline]
- Pogwizd S.M. Nonreentrant mechanisms underlying spontaneous ventricular arrhythmias in a model of nonischemic heart failure in rabbits. Circulation (1995) 92:1034–1048.
[Abstract/Free Full Text] - Rials S.J., Wu Y., Ford N., et al. Effect of left ventricular hypertrophy and its regression on ventricular electrophysiology and vulnerability to inducible arrhythmia in the feline heart. Circulation (1995) 91:426–430.
[Abstract/Free Full Text] - Priori S.G., Barhanin J., Hauer R.N., et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation (1999) 99:518–528.
[Abstract/Free Full Text] - Napolitano C., Schwartz P.J., Brown A.M., et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol (2000) 11:691–696.[Web of Science][Medline]
- Vos M.A., de Bakker J.M.T., Jungschleger J.J., van der Hulst F.F., et al. The importance of the septum for ventricular dispersion in the dog with chronic AV-block [abstract]. Circulation (1999) 100:51.
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 Y. Tsuji, T. Opthof, K. Yasui, Y. Inden, H. Takemura, N. Niwa, Z. Lu, J.-K. Lee, H. Honjo, K. Kamiya, et al. Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block Circulation, October 8, 2002; 106(15): 2012 - 2018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. van Opstal, M. Schoenmakers, S. C. Verduyn, S.H. M. de Groot, J. D.M. Leunissen, F. F. van der Hulst, M. M.C. Molenschot, H. J.J. Wellens, and M. A. Vos Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome Circulation, November 27, 2001; 104(22): 2722 - 2727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Spooner, S. G Priori, and R. J Myerburg Spotlight on sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 173 - 176. [Full Text] [PDF]
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