Further Observations to Elucidate the Role of Interventricular Dispersion
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector JACC Vol. 30, No. 6 1575 November 15, 1997:1575–84 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 S. CORA VERDUYN, PHD, MARC A. VOS, PHD, JOLANDA VAN DER ZANDE, BS, ATILLA KULCSA` R, PHD, HEIN J. J. WELLENS, MD, FACC Maastricht, The Netherlands Objectives. We sought to further elucidate the role of early 60 ms; d-sotalol: 80 6 45 ms, p < 0.05). The incidence of EADs (18 afterdepolarizations (EADs) and interventricular dispersion of of 22 vs. 11 of 24, p < 0.05) and single ectopic beats (EBs) (1.5 6 repolarization (DAPD) in the genesis of acquired torsade de 2 vs. 24 6 32, p < 0.01) was more frequently observed after pointes (TdP) arrhythmias. almokalant than after d-sotalol. Moreover, multiple EBs only Background. Administration of class III agents can be associ- occurred after almokalant. These beats interfered with the basic ated with TdP. We developed a dog model in which TdP can be rhythm, leading to dynamic changes in left ventricular APD and to reproducibly induced by pacing after d-sotalol. This model shows additional increases in DAPD. Spontaneous TdP was observed in reproducible results over weeks. 9 of 14 dogs after almokalant and could be increased to 12 of 14 Methods. In 14 anesthetized dogs with chronic complete atrio- with programmed electrical stimulation. After d-sotalol, TdP ventricular block, two separate experiments were performed in could only be induced by programmed electrical stimulation (5 of which d-sotalol (2 mg/kg body weight) or almokalant (0.12 mg/kg) 14, p < 0.05). was administered. Monophasic action potentials were simulta- Conclusions. In the same dog, almokalant induced more delay neously recorded from the endocardium of the right and left in repolarization, more EADs, multiple EBs and more ventricular ventricle to register EADs and to measure the action potential inhomogeneity in APD than d-sotalol. These changes were related duration (APD). DAPD was defined as the APD of the left to a higher incidence of TdP and thereby confirm a strong ventricle minus that of the right ventricle. association of the occurrence of EADs, multiple EBs and DAPD in Results. Baseline conditions were identical in the serially the genesis of TdP. These findings also show the possible value of performed experiments. The cycle length and QT time increased our model for evaluating the proarrhythmic potential of different by 16% and 26% after d-sotalol and by 15% and 31% after drugs. almokalant, respectively. After both drugs the action potential of (J Am Coll Cardiol 1997;30:1575–84) the left ventricle prolonged more than that of the right ventricle, ©1997 by the American College of Cardiology thereby increasing DAPD (almokalant [mean 6 SD]: 110 6 Antiarrhythmic drugs that prolong repolarization without af- sade de pointes (TdP) arrhythmias in ;1% to 5% of patients fecting conduction have attracted interest because of their (1,2,4–9). possible value in the prevention and suppression of reentrant Many reports have pointed to the relevance of early after- tachycardias (1–3). However, class III drugs do produce tor- depolarizations (EADs) and EAD-dependent ectopic beats (EBs) for the initiation of TdP arrhythmias (9–13). Whether they are solely responsible for the initiation of TdP arrhyth- From the Department of Cardiology, Cardiovascular Research Institute, mias or whether other factors such as ventricular dispersion of University of Limburg, Maastricht, The Netherlands. This study was supported by Grant 91.104 from The Netherlands Heart Foundation, The Hague. ASTRA repolarization also contribute is still a matter of discussion Nederland, Rijswijk, The Netherlands provided the almokalant; Bristol Myers (14,15). Regional differences in the duration of the action Squibb, Woerden, The Netherlands provided the d-sotalol; and the Bakken potential can be present within the ventricular wall (transmu- Research Institute (Medtronic), Maastricht, The Netherlands provided the epicardial electrodes used in this study. ral), within one ventricle (intraventricular) or between ventri- Manuscript received August 17, 1995; revised manuscript received July 18, cles (interventricular). 1997, accepted August 12, 1997. In anesthetized dogs with chronic complete atrioventricular Address for correspondence: Dr. Marc A. Vos, Department of Cardiology, Cardiovascular Research Institute Maastricht, University of Limburg, P.O. Box (AV) block, TdP could be reproducibly initiated using the 5800, 6202 AZ Maastricht, The Netherlands. E-mail: [email protected]. combination of d-sotalol and pacing in 50% of experiments ©1997 by the American College of Cardiology 0735-1097/97/$17.00 Published by Elsevier Science Inc. PII S0735-1097(97)00333-1 1576 VERDUYN ET AL. JACC Vol. 30, No. 6 RELEVANT FACTORS FOR THE INITIATION OF TdP November 15, 1997:1575–84 agents (0.015 mg/kg of intramuscular buprenorfine). A tempo- Abbreviations and Acronyms rary ventricular pacemaker (VVI) was sometimes placed after APD 5 action potential duration the AV block operation and after the experiments. Pacing was AV 5 atrioventricular switched off after a maximum of 24 h. EADs 5 early afterdepolarizations Determination of almokalant dose. In dogs in sinus EBs 5 ectopic beats LV 5 left ventricular rhythm, other investigators have shown (19) that 0.35 mg/kg of MAP 5 monophasic action potential almokalant had approximately two times the effect on repolar- RV 5 right ventricular ization as 3 mg/kg of d-sotalol. In our previous studies (16–18) TdP 5 torsade de pointes we used 2 mg/kg d-sotalol to induce TdP by pacing. Because we DAPD 5 interventricular dispersion wanted to obtain a similar effect on action potential duration (APD) prolongation, a dose of 0.12 mg/kg of almokalant (1/3 of 0.35 mg/kg 5 0.12) was chosen. In the 14 dogs tested, d-sotalol was given first ([mean 6 SD] 4 6 2.2 weeks after creation of complete AV block) in 11 dogs, (16). We compared inducible versus noninducible TdP in this followed by almokalant 3 6 2.1 weeks later. In three dogs the canine model and demonstrated (17) that the number of EADs order was reversed, with almokalant given at 5 6 2.6 weeks and is higher and the amount of interventricular dispersion larger d-sotalol at 9 6 3.1 weeks of chronic complete AV block. than in inducible dogs. Because the response is maintained Induction of TdP arrhythmias. A detailed description of over weeks (16), we compared the effects of two antiarrhythmic the TdP protocol is described elsewhere (16). In short, at least drugs, d-sotalol and almokalant, in their ability to induce TdP 2 weeks after creation of complete AV block, anesthetized arrhythmias in the same dog. In this way we could assess whether differences in the occurrence of EADs, EAD- animals received two defibrillation patches that were attached dependent EBs or interventricular dispersion or repolarization to both sides of the chest and connected with a defibrillator. At could explain spontaneous initiation of TdP. least 30 min after the onset of anesthesia, programmed elec- trical stimulation was performed from the epicardial electrode. Stimulation was done with a programmable stimulator capable Methods of pacing synchronously to the QRS complexes. Unipolar stimuli were given using a pulse of 2 ms and a stimulus strength The study protocol was approved by the Committee for of twice diastolic threshold. As an indifferent electrode, a Experiments on Animals of the University of Limburg, Maas- tricht, The Netherlands and was conducted in accordance with needle was placed through the skin. the guidelines of the American Physiological Society. Programmed electrical stimulation consisted of two differ- General protocol. The experiments were performed in ent pacing protocols: 1) a short–long–short sequence (400 anesthetized adult male and female mongrel dogs with a body 800 1 extrastimulus, or 4p600 1,200 1 extrastimulus), and 2) weight between 20 and 31 kg. In a preliminary operation, a eight basic stimuli followed by an extrastimulus. The inter- right thoracotomy was performed to induce a permanent stimulus intervals were 600 or 1200 ms. The extrastimulus complete AV block by injection of 37% formaldehyde into the interval in both pacing protocols was shortened from 500 ms AV junction (18). During the same session, a pacing electrode using steps of 50 ms until 300 ms. After completion of the basic (Bakken Research Center, Medtronic) was inserted at the apex pacing protocol, d-sotalol (2 mg/kg for 5 min) or almokalant of the left ventricle. The wire was exteriorized through the (0.12 mg/kg for 10 min) was administered. back of the neck of the dog. Six surface electrocardiographic Pacing was resumed 10 min after the start of the infusion, leads and two endocardial monophasic action potential (MAP) unless spontaneous TdP had occurred during the observation signals were simultaneously registered and stored on optical period. When TdP occurred, we tried to perform the pacing disc. All drugs were administered through a cannula in the protocol at 15 min. Pacing was always performed in random cephalic vein. order. A TdP arrhythmia was defined as a polymorphic ventric- Anesthesia was induced by 1) intramuscular premedication ular tachycardia consisting of $5 beats twisting around the (1 ml/5 kg: 10 mg of oxycodon, 1 mg of acepromazine and baseline in the setting of a prolonged QT(U) duration. TdP 0.5 mg of atropine), and 2) sodium pentobarbital (20 mg/kg was terminated using cardioversion (60 to 70 J) when it lasted body weight intravenously).