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Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and D,L-Sotalol on the Human Atrium

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Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and D,L-Sotalol on the Human Atrium CLINICAL INVESTIGATIONS Jpn Circ J 2001; 65: 1–6 Frequency-Dependent Electrophysiological Effects of Flecainide, Nifekalant and d,l-Sotalol on the Human Atrium Hiromi Watanabe, MD; Ichiro Watanabe, MD; Toshiko Nakai, MD; Naohiro Oshikawa, MD; Satoshi Kunimoto, MD; Riko Masaki, MD; Toshiaki Kojima, MD; Satoshi Saito, MD; Yukio Ozawa, MD; Katsuo Kanmatuse, MD To compare the effects of class Ic and III antiarrhythmic agents on the termination and prevention of atrial fibril- lation, the present study investigated the use-dependent electrophysiological effects of flecainide, nifekalant and d,l-sotalol on the human atrium. Flecainide significantly prolonged effective refractory period (ERP), intra-atrial conduction time (IACT) and monophasic action potential duration (MAPD), and its effects on ERP and IACT were use-dependent. Nifekalalant significantly prolonged ERP and MAPD, and these effects were reverse use- dependent; however, there was no significant change in IACT. d,l-Sotalol significantly prolonged MAPD and the effect was reverse use-dependent. It significantly prolonged ERP, but the effect was not reverse use-dependent. d,l-Sotalol increased IACT in a use-dependent manner. Thus, for atrial fibrillation, class Ic antiarrhythmic agents might be more effective in termination and class III antiarrhythmic agents might be more effective in prevention. (Jpn Circ J 2001; 65: 1–6) Key Words: Antiarrhythmic drugs; Atrial muscle; Monophasic action potential; Reverse use-dependency; Use-dependency lass I antiarrhythmic drugs have use-dependent diac dysfunction comprised the study population. Of these effects on ventricular conduction; that is, intraven- 23 patients, 4 had paroxysmal atrial flutter or fibrillation, 4 C tricular conduction time increases according to had concealed Wolf-Parkinson-White (WPW) syndrome, 5 heart rate.1 By contrast, many class III antiarrhythmic drugs had atrial flutter or fibrillation, 5 had atrioventricular nodal have reverse use-dependent effects on the ventricular reentrant tachycardia (AVNRT), 2 had atrioventricular (AV) action potential duration (APD); that is, a decrease in the block, 2 had sick sinus syndrome (SSS), 1 had syncope, extent of prolongation of ventricular APD according to and 1 had ventricular tachycardia (VT). None of the patient heart rate.2,3 However, there are few studies on the use- had had an episode of atrial fibrillation, flutter or paroxysmal dependent effects of class I and III antiarrhythmic drugs on supraventricular tachycardia for at least 2 weeks prior to atrial APD, effective refractory period (ERP) and intra- the study and all antiarrhythmic drugs had been withdrawn atrial conduction time (IACT) in humans. Therefore,we for a period equivalent to at least 5 half-lives prior to the investigated the use-dependent electrophysiological effects study. Patients who had a left atrial diameter greater than of a class Ic antiarrhythmic drug, flecainide, and 2 class III 40mm on transthoracic echocardiography were excluded antiarrhythmic drugs, nifekalant and d,l-sotalol, on the from the study. right atrium by measuring APD, ERP and IACT. The subjects were divided in 3 groups: flecainide group (n=10), nifekalant group (n=5) and d,l-sotalol group (n=8). Prior to the study, the patients and their families gave Methods consent to the assessment of the efficacy of the new antiar- Subjects rhythmic drugs. Twenty three subjects aged 18–70 years (44±16 years, mean±SD) who underwent an electrophysiological study Techniques (EPS) and who did not have ischemic heart disease or car- A Franz-combination catheter (EPT Ltd, Sunnyvale, CA, USA) was used to record the monophasic action potential (Received February 28, 2000; revised manuscript received August 24, (MAP). A quadripolar electrode with 2-mm interelectrode 2000; accepted September 19, 2000) space was used for atrial pacing, which was performed The Second Department of Medicine, Nihon University School of using 2-ms rectangular pulses at twice the late diastolic Medicine, Tokyo, Japan threshold. A Franz-combination catheter was introduced A summary of this article was presented at the 12th Meeting of the through the right femoral vein and pushed against the high Japanese Society of Electrocardiology and at the 61st Annual Scientific right atrium to record the atrial MAP with a band pass filter Meeting of Japanese Circulation Society. Mailing address: Hiromi Watanabe, MD, The Second Department of of 0.05–500Hz. MAPs were recorded at a paper speed of Medicine, Nihon University School of Medicine, 30-1 Ohyaguchikami- 200mm/s. MAP duration was measured at 90% repolariza- machi, Itabashi-ku, Tokyo 173-0186, Japan. E-mail: iwatanab@med. tion (MAPD90) and calculated as the average of 5 consecu- nihon-u.ac.jp tive complexes. IACT was measured from the pacing spike Japanese Circulation Journal Vol.65, January 2001 2 WATANABE H et al. Fig1. Recording of the right atrial monophasic action potential at a pacing cycle length of 600ms, and AV sequential pacing interval of 100ms. I, II, III, V1: surface ECG leads; CSd, coronary sinus distal potential; RA MAP, right atrial muscle monophasic action potential; RA MAPD90, RA MAP duration at 90% repolarization; IACT, intra-atrial conduction time. Fig2. Electrophysiological effects of flecainide on atrial muscle (1). ERP, effective refractory period of the right atrium; MAPD, monophasic action potential duration in the right atrium; IACT, intra-atrial conduction time. Fig3. Electrophysiological effects of flecainide on atrial muscle (2). ∆ERP, change in ERP before and after flecainide; ∆MAPD, change in MAPD before and after flecainide; ∆ERP/MAPD, change in ERP/MAPD before and after flecainide; ∆IACT, change in IACT before and after flecainide. at the high right atrium (St) to the distal coronary sinus administration of flecainide, nifekalant and d,l-sotalol were atrium potential during AV sequential pacing with the AV measured. interval varying from 50 to 150ms (Fig1). (1) With 120beats of AV sequential pacing at a basic Electrophysiological indices before and after intravenous cycle length (BCL) of 600 and 350ms, the right atrial Japanese Circulation Journal Vol.65, January 2001 Flecainide, Nifekalant and d,l-Sotalol on Human Atrium 3 Fig4. Use-dependent electrophysiological effects of nifekalant on atrial muscle (1). Fig5. Use-dependent electrophysiological effects of nifekalant on atrial muscle (2). MAPD90 and IACT were measured between 110 and 120 beats of pacing at which the MAP duration reaches a steady Results state.4 Flecainide Group (2) The right atrial ERP was measured at the site adja- Changes in right atrial ERP, MAPD, ERP/MAPD and cent to where the MAP recordings were obtained. An extra IACT are shown in Figs2 and 3. Flecainide prolonged ERP stimulus was applied during late diastole after 12beats of from 193.0±12.3ms to 233.5±29.1ms at a BCL of 600ms basic drive (BCL 600 and 350ms) with successive decre- (p<0.01) and from 176.0±15.2 ms to 222.5±36.8 ms at a ments of the coupling interval of the extra stimulus by 5ms. BCL of 350 ms (p<0.01). Flecainide prolonged MAPD (3) ERP/MAPD was measured as an index of post repo- from 215.9±17.9ms to 239.1±27.9ms at a BCL of 600ms larization refractoriness. (p<0.05) and from 186.7±20.2 ms to 207.1±15.4 ms at a (4) ∆ERP, MAPD and IACT show the changes in these BCL of 350ms (p<0.01). Although there was no significant parameters following the administration of the drug at each change in the ERP/MAPD ratio at BCL 600ms (0.90±0.07 cycle length. ms to 0.94±0.08 ms), it increased from 0.95±0.14 ms to (5) Drugs were administered intravenously in the follow- 1.07±0.15ms at BCL 350ms (p<0.05). IACT was prolonged ing dose rates: 2mg/kg of flecainide; 0.5mg/kg of saline- at both BCL 600 and 350ms from 125.2±16.5ms to 162.4± dissolved nifekalant followed by a continuous infusion of 24.8ms, and from 132.4±18.6ms to 194.6±35.3ms respec- 0.017 mg·kg–1·min–1; 1.5 mg/kg of saline-dissolved d,l- tively (p<0.01). Changes in ERP (∆ERP) before and after sotalol. flecainide were 30.5±27.4ms at BCL 600ms, and 46.5±29.0 ms at BCL 350 ms, the latter being significantly greater Statistics (p<0.05). Changes in MAPD (∆MAPD) before and after All data are expressed as mean±SD. Student’s paired and flecainide were 23.2±24.3ms at BCL 600ms, and 20.4±13.9 unpaired t test and Wilcoxon signed rank test were used for ms at BCL 350ms with no statistical difference. Changes in data analysis. A p value <0.05 was considered statistically IACT (∆IACT) before and after flecainide were 37.2±17.9 significant. at BCL 600 ms, and 62.1±28.3 ms at BCL 350 ms, the former being significantly greater (p<0.01). Changes in Japanese Circulation Journal Vol.65, January 2001 4 WATANABE H et al. Fig6. Use-dependent electrophysiological effects of d,l-sotalol on atrial muscle (1). Fig7. Use-dependent electrophysiological effects of d,l-sotalol on atrial muscle (2). ERP/MAPD (∆ERP/MAPD) before and after flecainide ∆ERP/MAPD between BCL 600ms and 350ms (–0.08±0.07 were 0.04±0.10 at a BCL of 600ms, and 0.12±0.15 at a and –0.05±0.14, respectively). BCL of 350ms, which was not statistically different despite the change being much greater at BCL of 350ms than at d,l-Sotalol Group BCL 600ms. Changes in right atrial ERP, MAPD, ERP/MAPD and IACT are shown in Figs6 and 7. d,l-Sotalol prolonged ERP Nifekalant Group from 195.0±21.8ms to 234.0±21.0ms at a BCL of 600ms Changes in right atrial ERP, MAPD, ERP/MAPD and (p<0.05), and from 181.0±16.7ms to 212.0±17.9ms at a IACT are shown in Figs4 and 5.
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