View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector JACC Vol. 29, No. 7 1639 June 1997:1639–44 Electrophysiologic Effects of Sodium Channel Blockade on Anisotropic Conduction and Conduction Block in Canine Myocardium Preferential Slowing of Longitudinal Conduction by Flecainide Versus Disopyramide or Lidocaine TSUNEHIRO KONDO, MD, MICHIYASU YAMAKI, MD, ISAO KUBOTA, MD, HIDETADA TACHIBANA, MD, HITONOBU TOMOIKE, MD Yamagata, Japan Objectives. The purpose of this study was to determine the Results. High dose flecainide (100 mg/kg body weight per min) effects of sodium channel blockade on anisotropic excitation delayed the AT along the L direction markedly (mean [6SE] propagation in the intact canine left ventricle. 227 6 38%, p < 0.02) and mildly (121 6 10%, p < 0.02) along the Background. Anisotropic ventricular conduction—electric con- T direction in regular beats (p < 0.007, L vs. T). Lidocaine and ductivity dependent on the myocardial fiber direction—is one of disopyramide did not show direction-dependent prolongation of the important mechanisms of ventricular arrhythmia. However, the AT on regular beats. When examined on premature beats, AT the effects of sodium channel blockade, especially the differential was delayed, depending on the coupling interval and the fiber effect of a subclass of this agent, on the anisotropic properties direction when saline, flecainide or lidocaine was infused. The remain unknown. conduction blocks along the L direction were observed in three of Methods. In 28 anesthetized, open chest dogs, a small cannula seven dogs on regular beats after flecainide and ventricular was inserted into the left anterior descending coronary artery. fibrillation ensued in two of these three dogs. Saline (control), disopyramide, lidocaine or flecainide was infused Conclusions. A peculiar slowing of L conduction by flecainide selectively into the cannula. An array of 64 epicardial electrodes may relate to the character of proarrhythmia. was placed on the anterior surface of the ventricle. Activation time (J Am Coll Cardiol 1997;29:1639–44) (AT) was measured along the longitudinal (L) and transverse (T) ©1997 by the American College of Cardiology directions. Excitation conduction on the myocardium is dependent on duration (APD) (6). Recently, heterogeneity of class I agents myocardial fiber direction (1–5), which is known as “aniso- was emphasized on use dependency and state dependency tropy.” Anisotropic properties of cardiac muscle cause block of (activation or inactivation) on sodium blocking action (7–9). an electric excitation owing to a reduced safety factor for Such heterogeneity in sodium channel blockade possibly af- conduction along with longitudinal (L) fiber orientation, al- fects anisotropic electric propagation. Nevertheless, the effect though conduction velocity is faster (2,3). Such conduction of each subclass of sodium channel blockers on anisotropism block contributes to the induction of reentrant activity as a remains unknown. The purpose of this study was to evaluate component of the reentry circuit (2,3). the directional differences in ventricular conduction caused by Sodium channel blockade suppresses electric conductivity sodium channel blockade. We examine the effects of disopyr- and is used to block the reentrant circuit as a class I antiar- amide, lidocaine and flecainide on both L and transverse (T) rhythmic agent. The class I agent was traditionally subclassified electric propagation. into Ia, Ib and Ic, mainly depending on the action potential Methods From the First Department of Internal Medicine, Yamagata University Surgical preparation. Twenty-eight adult mongrel dogs School of Medicine, Yamagata, Japan. This study was supported in part by Grant were anesthetized with sodium pentobarbital (30 mg/kg intra- 07670749 from the Ministry of Education, Science and Culture, Tokyo, Japan venously), intubated and ventilated by a respirator with room and by grants from the Japan Research Foundation for Clinical Pharmacology, Tokyo and the Suzuken Memorial Foundation, Nagoya. air supplemented with oxygen (3 to 5 liters/min). The thorax Manuscript received March 20, 1996; revised manuscript received February was opened in the fifth intercostal space; the pericardium was 19, 1997, accepted February 26, 1997. opened; and a pericardial cradle was made to support the heart Address for correspondence: Dr. Michiyasu Yamaki, First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, at an appropriate position. The chest cavity was covered with Yamagata 990-23, Japan. E-mail: [email protected]. plastic wrap to prevent cooling or dehydration. The body ©1997 by the American College of Cardiology 0735-1097/97/$17.00 Published by Elsevier Science Inc. PII S0735-1097(97)00095-8 1640 KONDO ET AL. JACC Vol. 29, No. 7 SODIUM CHANNEL BLOCKADE AND ANISOTROPIC CONDUCTION June 1997:1639–44 Formalin was injected into the atrioventricular conduction Abbreviations and Acronyms system, according to a previously described method, to inter- APD 5 action potential duration rupt atrioventricular conduction (11). Electric stimulation of AT 5 activation time 2-ms current pulses with twice the voltage of the threshold L 5 longitudinal potential (model 8EN-7203, Nihon Koden, Tokyo, Japan) was LAD 5 left anterior descending coronary artery T 5 transverse applied to a bipolar electrode fixed at the corner of the array. VF 5 ventricular fibrillation Activation time (AT) was defined as the time instant of the minimal derivative of the local electric potentials (2). Activa- tion time maps with 2-ms of isochronism were constructed for each activation array using the computerized devise, where the temperature was maintained at 37 to 38°C. An arterial line was time zero was taken at the pacing artifact. The presence of inserted into the right femoral artery to continuously monitor conduction block was defined as a slowing of the conduction the mean arterial pressure. Another polyvinyl catheter was velocity ,0.05 m/s between adjacent electrode sites. The inserted into the left ventricular cavity to measure left ventric- percent difference of AT was calculated from the beat of the ular pressure. Lead II of the electrocardiogram as well as blood baseline measurement in protocol 1 or from the regular basic pressure was recorded simultaneously throughout the study beat in protocol 2. The AT on lead A8 was used to assess the (NEC Sanei, model 2G66, Tokyo, Japan). L conduction, and those on lead H1 the T conduction. A 24-gauge plastic cannula was inserted into the left Experimental protocol. Protocol 1: examination on basal anterior descending coronary artery (LAD) at the distal site of regular beats. Physiologic salt solution (saline; n 5 7), disopyr- the second diagonal branch (Fig. 1). Heparin (10,000 IU) was amide (low dose: 20 mg/kg body weight per min; high dose: intravenously administered before the LAD cannulation. The 200 mg/kg per min; n 5 7), lidocaine (low dose: 0.12 mg/kg per cannula was kept open by continuous infusion of saline in min; high dose: 0.6 mg/kg per min; n 5 7) or flecainide (low 1 ml/min. dose: 10 mg/kg per min; high dose: 100 mg/kg per min; n 5 7) Electrodes for recording and pacing. An array of 64 unipo- was intracoronarily infused. A lower dose of disopyramide, lar electrodes (;14 3 14 mm) was placed on the anterior lidocaine or flecainide was almost 1% of that used intrave- surface of the left ventricle (Fig. 1). Each electrode was made nously in experimental studies (12–14), and a higher dose was of fine silver wires (0.005-in. [0.013-cm] diameter) and was 5% to 10%. After the baseline measurement, the low dose insulated, except at the point of attachment. All recordings infusion was loaded during the first 20 min, and the high dose were referenced to the Wilson central terminal, and multichan- infusion was continued for the next 20 min. The heart was nel electrograms were digitized every millisecond using a paced at a basic cycle length of 500 ms. Sixty-four epicardial multichannel data processing system (CD-G015, Chunichi electrograms were simultaneously recorded every 5 min. When Denshi, Nagoya, Japan), as described in a previous study (10). spontaneous ventricular tachyarrhythmias occurred, the elec- trograms were also recorded. Protocol 2: effect of coupling interval on anisotropic conduc- Figure 1. An experimental model. A 64-electrode array is placed on tion. After the heart was paced by a basic cycle length of the anterior epicardial surface of the left ventricle. Columns (A to H) 500 ms for 1 min or longer, a single extrastimulus was applied and rows (1 to 8) of the epicardial electrodes are 2 mm apart. A small cannula is inserted into the distal LAD as a route of drug administra- on the same pacing site. The coupling interval of the extra- tion. AO 5 aorta; IVC 5 inferior vena cava; L 5 longitudinal stimuli was 300, 240, 220, 200, 195, 190 and 185 ms, if propagation; LV 5 left ventricle; PA 5 pulmonary artery; RA 5 right applicable, and 64 epicardial electrograms were simultaneously atrium; RV 5 right ventricle; SVC 5 superior vena cava; T 5 recorded during the stimulation. These procedures are re- transverse propagation. peated after loading the low dose of disopyramide, lidocaine, flecainide or saline. Statistical analysis. Data are presented as mean value 6 SE. Comparisons of dose-dependent or coupling interval– dependent changes in ATs were made by using analysis of variance for repeated measures and the Wilcoxon signed-rank test. Comparisons of ATs between L and T conduction or among the three types of sodium channel blockers and saline infusion were performed by analysis of variance, followed by the Sheffe´test. Differences were considered significant at p , 0.05. Results Twenty-eight dogs were studied: seven were given disopy- amide, seven lidocaine, seven flecainide and seven saline.