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Background Brugada syndrome is a rare inherited arrhythmic syndrome with a coved type 1 ST-segment elevation on ECG and an increased risk of sudden death. Many studies have evaluated risk stratification performance based on ECG-derived parameters. However, since historical Brugada patient cohorts included mostly paper ECGs, most studies have been based on manual ECG parameter measurements. We hypothesized that it would be possible to run automated algorithm-based analysis of paper ECGs. We aimed: 1) to validate the digitization process for paper ECGs in Brugada patients; and 2) to quantify the acute class I antiarrhythmic drug effect on relevant ECG parameters in Brugada syndrome. Methods A total of 176 patients (30% female, 43 ± 13 years old) with induced type 1 Brugada syndrome ECG were included in the study. All of the patients had paper ECGs before and during class I antiarrhythmic drug challenge. Twenty patients also had a digital ECG, in whom printouts were used to validate the digitization process. Paper ECGs were scanned and then digitized using ECGScan software, version 3.4.0 (AMPS, LLC, New York, NY, USA) to obtain FDA HL7 XML format ECGs. Measurements were automatically performed using the Bravo (AMPS, LLC, New York, NY, USA) and Glasgow algorithms. Results ECG parameters obtained from digital and digitized ECGs were closely correlated (r = 0.96 ± 0.07, R2 = 0.93 ± 0.12). Class I antiarrhythmic drugs significantly increased the global QRS duration (from 113 ± 20 to 138 ± 23, p Conclusions Automated algorithm-based measurements of depolarization and repolarization parameters from digitized paper ECGs are reliable and could quantify the acute effects of class 1 antiarrhythmic drug challenge in Brugada patients. Our results support using computerized automated algorithm-based analyses from digitized paper ECGs to establish risk stratification decision trees in Brugada syndrome.

Gain-of-function (GOF) pathogenic variants of KCNT1, the gene encoding the largest known potassium channel subunit, KNa1.1, are associated with developmental and epileptic encephalopathies accompanied by severe psychomotor and intellectual disabilities. Blocking hyperexcitable KNa1.1 channels with quinidine, a class I antiarrhythmic drug, has shown variable success in patients in part because of dose-limiting off-target effects, poor blood–brain barrier (BBB) penetration, and low potency. In recent years, high-resolution cryogenic electron microscopy (cryo-EM) structures of the chicken KNa1.1 channel in different activation states have been determined, and animal models of the diseases have been generated. Alongside increasing information about the functional effects of GOF pathogenic variants on KNa1.1 channel behaviour and how they lead to hyperexcitability, these tools will facilitate the development of more effective treatment strategies. We review the range of KCNT1 variants and their functional effects, the challenges posed by current treatment strategies, and recent advances in finding more potent and selective therapeutic interventions for KCNT1-related epilepsies.

Xin Su Ning (XSN) is a China patented and certified herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. A recent completed clinical trial of 861 patients showed that XSN had similar PVC inhibition rate to the class I antiarrhythmic drug mexiletine, at 65.85% for XSN and 63.10% for mexiletine. We have previously reported that XSN prolongs action potential duration (APD) and suppresses action potential amplitude (APA) of the cardiac ventricular myocytes. In this report we aim to reveal the effect of XSN on the ionic channels that govern APD and APA, which would help to explain the cellular electrophysiological mechanism of XSN. Our main findings are: (1) On ECG recorded in isolated rat, in the presence of XSN the amplitude of R wave was significantly decreased and the amplitude of T wave was increased significantly; (2) XSN blocked hNaV1.5 channel stably transfected cell line in a dose-dependent manner with an IC50 of 0.18 ± 0.02 g/L; and (3) XSN suppresses hERG channels in a dose-dependent manner with an IC50 of 0.34 ± 0.01 g/L. In conclusion, the clinical antiarrhythmic efficacy of XSN is based on its class I and Class III antiarrhythmic properties by suppression hNaV1.5 channel and hERG channels, which are directly responsible for XSN’s effect on APA suppression and APD prolongation.

The effect of cibenzoline, a class I antiarrhythmic drug, on Na+/Ca2+ exchange current (INCX) was investigated using the patch-clamp method. Cibenzoline inhibited the bi-directional INCX in a concentration-dependent manner. The IC50 values of cibenzoline for the outward and inward components of INCX were 77 and 84 μM, respectively, with Hill coefficients of 1. Intracellular application of trypsin via the pipette solution did not change the inhibitory effect of cibenzoline. The inhibitory effect of cibenzoline on INCX at pHo 6.5 was smaller than those at pHo 7.4 and pHo 8.2. We conclude that cibenzoline inhibits INCX in supra-therapeutic concentrations. Keywords:: antiarrhythmic drug, cibenzoline, Na+/Ca2+ exchange (NCX)

Background: Class I antiarrhythmic drugs can promote the organization of atrial fibrillation (AF) and sometimes converts AF into atrial flutter (AFL) concomitant with difficulty of rate control. We studied the usefulness of Bepridil, which exhibits a class III-like effect, for class I drug-induced AFL in patients with paroxysmal AF. Methods: The study population consisted of 17 consecutive patients (15 men, mean age 65 ± 8 years) with AFL converted from paroxysmal AF following oral treatment of class IA or IC antiarrhythmic agents including pilsicainide (n = 8), cibenzoline (n = 5), flecainide (n = 2), aprindine (n = 1), and propafenone with cibenzoline (n = 1). After the occurrence of AFL, class I drug was replaced by bepridil with a dose of 100–200 mg per day in all patients. Results: After the treatment with bepridil, 15 (88%) out of the 17 patients restored sinus rhythm after 1 to 68 days (average of 21 days). In 12 (80%) of the 15 patients, sinus rhythm was maintained for an average of 23.6 months (range of 1 to 62 months) follow-up period. Although torsade de pointes was not recognized, a marked QT prolongation (0.60 sec) was observed in one patient during the administration of bepridil at a daily dose of 200 mg. In this patient, QT interval was normalized (0.45 sec) after reduction of bepridil to 150 mg daily. Conclusion: Bepridil treatment may be safe and effective for class I drug-induced AFL in patients with paroxysmal AF to restore and maintain sinus rhythm as an alternative therapy for catheter ablation. However, the QT interval must be carefully monitored during this medication.

The aim of this study was to investigate the mechanism of spontaneous termination of atrial fibrillation (AF) by comparing it with drug-induced termination on the basis of changes in fibrillation cycle length (FCL). Fast Fourier transform analysis was carried out on the electrocardiogram (ECG) records of 27 patients with paroxysmal AF without organic heart disease. In 8 patients with drug-induced termination of AF, spectral analysis of the data from surface ECG lead V1 was performed before and after class I antiarrhythmic drug infusion for 10 min. In 19 patients with spontaneous termination of AF, the analysis used the Holter ECG recordings at 10 min before the spontaneous termination and at the termination. FCL was calculated from the peak frequency of each epoch and the mean FCL and the coefficient of variation (CV) of FCL were determined from the data of 20 epochs. In the 8 episodes of drug-induced AF termination, the mean FCL increased significantly with class I drugs (from 151±17 to 203±21 ms, p

I群薬の心室性不整脈に対する催不整脈作用の原因は不明な点が多い.そこで不整脈の機序が明らかな房室回帰性頻拍 (AVRT) を対象にI群薬の催不整脈作用を電気生理学的に検討した.対象は頻拍に副伝導路が関与した14例で顕性WPW症候群6例, 不顕性WPW症候群8例.いずれもI群薬投与にかかわらずAVRT (房室結節を順伝導し副伝導路を逆伝導する) が誘発可能であった.顕性WPW症候群における心房刺激時の誘発促進の機序はI群薬により副伝導路の順伝導のみが抑制され逆伝導が保たれ―方向性伝導が容易に生じるためと考えられた.不顕性WPW症候群のI群薬による誘発促進は比較的まれだが, 誘発zoneが拡大しinoessant型頻拍となる例もあり, 不応期延長に比べ伝導時間延長作用が強いことが原因と考えられた.AVRTに対するI群薬の催不整脈作用の機序には旋回路内の―方向性伝導の促進, 伝導時間延長が関与した.

Mechanisms of Class I Drugs in AF. Sodium channel blocking drugs (Class I antiarrhythmic agents) have been used for the termination of atrial fibrillation (AF) and for sinus rhythm maintenance for almost 100 years. Despite this long history, the mechanisms that underlie their efficacy in AF remain poorly understood. Classic notions about the determinants of cardiac reentry, as embodied in leading circle theory, and of AF, as reflected in the multiple wavelet hypothesis, suggest that cardiac conduction slowing should promote, rather than prevent, AF. This article reviews the evidence (both clinical and experimental) for the efficacy and mechanisms of action of Class I antiarrhythmic agents in AF. Application of mathematical models of AF to the evaluation of Class I mechanisms is discussed, and recent insights into the latter are presented. A better understanding of the ways in which Na + channel blockers affect AF will be useful, not only for new antiarrhythmic drug development but also for gaining insight into the mechanisms of the arrhythmia. (J Cardiovasc Electrophysiol, Vol. 14, pp. S133-S139, October 2003, Suppl.)

A 46-year-old man with type II Brugada electrocardiogram pattern changed to a type I Brugada type electrocardiogram pattern by class I antiarrhythmic drug (pilsicainide) underwent electrophysiologic study. Ventricular fibrillation was induced by double extrastimuli from the right ventricular (RV) apex. Monophasic action potentials (MAPs) were then recorded from the high right atrium. Duration of MAP at a coupling interval of 220 milliseconds was 122 milliseconds, and local activation of S2 spread to the left atrium. However, MAP at a coupling interval of 210 milliseconds was 112 milliseconds, and local activation of S2 failed to spread to the rest of atrium.

The most common mechanism of sustained ventricular tachycardia (VT) is re-entry with an excitable gap, but the electrophysiologic properties and response to antiarrhythmic drugs in the area of slow conduction are not yet fully known. The purpose of this study was to assess the effects of a class I antiarrhythmic drug (procainamide) and class III agents (amiodarone, E-4031, and MS-551) on re-entrant VT using the width of the zone of entrainment. The cycle length (CL) of VT (VTCL) , the block CL that was the longest paced CL that interrupted the VT, and the width of the zone of entrainment, defined as the difference between VTCL and block CL, were compared before and after treatment with antiarrhythmic drugs. The VTCL was prolonged significantly from 308±63 to 410±77 msec after procainamide (p

Class I antiarrhythmic drug infusion has been established as the standard test to unmask Brugada syndrome. This report presents two patients with Brugada syndrome with positive flecainide response which was not reproducible in a subsequent test.

The antiarrhythmic effect of flecainide acetate (FCN), a newly developed class I antiarrhythmic drug, was evaluated on epinephrine (E)-halothane induced arrhythmias in dogs. The arrhythmogenic dose of E (ADE) under 1% of halothane was significantly increased from 0.71 +/- 0.08 to 1.08 +/- 0.11 and 1.84 +/- 0.23 micro g.kg(-1).min(-1) by the administration of 2 and 4 mg.kg(-1) of FCN, respectively. The arrhythmias induced by ADE in the absence of FCN were stopped by 1.78 +/- 0.29 mg.kg(-1) of FCN in bolus injections. These results suggest that FCN can be used for the treatment of arrhythmias that E contributes to under halothane anesthesia.

As part of a continuing program of systematically modifying the structure of the class I antiarrhythmic drug changrolin, we synthesized 15 analogues in which the linkage between the two aromatic regions was altered. High antiarrhythmic activity and low parasympatholytic activity was found when the linkage region, designated region 3, contained a carbonyl moiety, including ketones, amides, and ureas. Secondary amides were superior to tertiary amides, while amide reversal resulted in no change in activities. One compound in this series, 7, 2,6-bis(1-pyrrolidinyl-methyl)-4-benzamidophenol (ACC-9358), is undergoing preclinical evaluations.

As part of a continuing program of systematically modifying the structure of the class I antiarrhythmic drug changrolin, we synthesized 15 analogues in which the linkage between the two aromatic regions was altered. High antiarrhythmic activity and low parasympatholytic activity was found when the linkage region, designated region 3, contained a carbonyl moiety, including ketones, amides, and ureas. Secondary amides were superior to tertiary amides, while amide reversal resulted in no change in activities. One compound in this series, 7, 2,6-bis(1-pyrrolidinyl-methyl)-4-benzamidophenol (ACC-9358), is undergoing preclinical evaluations.

[3H]EO-122, a radiolabeled class I antiarrhythmic drug, has been used to characterize a new specific binding system to rat heart membranes. The binding is saturable and competitive with unlabeled EO-122 and other antiarrhythmic drugs. In this system, [3H]EO-122 binds to two sites. Site A with an apparent Kd of 33.5 ± 1.5 n m , Bmax of 1.05 ± 0.15 pmol/mg protein and Hill coefficient nH = 4. Site B with an apparent Kd of 233 ± 25 n m , Bmax equals 5.7 ± 0.61 pmol/mg proteins and nH = 6. The binding to site B indicates that this site is pharmacologically relevant to known class IA antiarrhythmic drugs such as quinidine and procainamide. Lidocaine (class IB) does not interact with this site. Interpretation of the high Hill coefficient suggests that the binding of an antiarrhythmic drug to its pharmacologically relevant binding site exposes additional binding sites and/or modulates the affinity of adjacent binding sites.