[Show abstract][Hide abstract] ABSTRACT: We reported that experimental autoimmune myocarditis (EAM) rats showed dramatic changes in ventricular action potential and enhanced arrhythmogenicity in the acute phase, but mechanisms for this are still unclear. To investigate the mechanisms of cardiac remodeling in acute myocarditis and subsequent heart failure, physiological and molecular changes were evaluated along the time course of EAM.
Six-week-old Lewis rats were immunized with porcine cardiac myosin. On days 14, 21, 35 and 60 after immunization, histology, hemodynamics and electrophysiological parameters (i.e., effective refractory period (ERP), monophasic action potential duration (MAPD) and PVC inducibility) were evaluated and compared with control rats. After these studies, the expression levels of Kv(+) and L-Ca(2+) channels, ion transporters and BNP expressions in the left ventricle were examined by quantitative real time RT-PCR and Western blot analysis.
EAM rats showed acute myocarditis with massive infiltration of the mononuclear cells on days 14 and 21. Subsequently, a chronic dilated cardiomyopathy (DCM)-like structural change was observed on day 60. Hemodynamic parameters were worse in EAM than controls. ERP and MAPD were longer in EAM than controls, with a peak on day 21, which was parallel to PVC inducibility. mRNA levels of Kv4.2, Kv1.5, KChIP2, frequenin and SERCA2a, and the protein levels of Kv4.2 and Kv1.5, were reduced, especially in the acute phase.
The initial reduction of Ito-related molecules, such as the expression levels of Kv4.2, 1.5, frequenin and KChIP2, and the prolongation of MAPD are considered to be a key mechanism of ventricular remodeling and cause the characteristic clinical findings in EAM in the acute inflammatory phase and chronic DCM phase.
Cardiovascular Research 10/2004; 63(4):689-99. · 5.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The heterogeneous process of atrial electrical remodeling (AER) in the canine rapid atrial stimulation model has been previously reported although it has been reported that a sodium channel blocker might suppress the shortening of the atrial effective refractory period (AERP), its effect on long-term electrical remodeling is unknown. In the present study, the effect of pilsicainide on AER was evaluated. The right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. In the RAA, Bachmann's bundle (BB), the right atrium near the inferior vena cava (IVC) and in the left atrium (LA), AERP, AERP dispersion (AERPd) and the inducibility of atrial fibrillation (AF) were evaluated at several time points of the pacing phase and the recovery phase (1 week). The same protocol was performed during the administration of pilsicainide (4.5 mg/kg per day) and the parameters were compared with the controls. In the control dogs, the AERP was significantly shortened by rapid pacing at all atrial sites studied and the AERP shortening (DeltaAERP) was larger at the RAA and LA sites (p<0.03). However, pilsicainide decreased these DeltaAERPs at all 4 atrial sites. AERPd was increased during the pacing phase whereas it was decreased during the recovery phase in the control dogs. In contrast, this pacing-induced AERPd was attenuated by the administration of pilsicainide. The AF inducibility was highest at the LA site in both groups, and the inducibility was lower in the pilsicainide group than the control group at all atrial sites. During the rapid pacing phase, the ventricular heart rate was significantly lower in the pilsicainide group than the control because of intra-atrial conduction block. In a canine rapid right atrial stimulation model, pilsicainide suppressed the shortening of the AERP at all atrial sites, possibly through the improvement of the hemodynamics as well as the action of the Na - Ca exchanger.
[Show abstract][Hide abstract] ABSTRACT: It is important to clarify how electrical remodeling develops in clinical cases of paroxysmal atrial fibrillation (PAF), because it has been suggested that this electrophysiological phenomenon promotes an increase in the frequency of PAF. In the present study, the f-f interval during PAF was analyzed from the ambulatory ECG recordings of 21 patients with PAF (total PAF duration >2/24 h with normal atrial size) to monitor the atrial electrophysiological changes. The patients were clinically followed-up for 6 months without any antiarrhythmic drugs. Before and after the follow-up period 24-h Holter monitoring was carried out and the duration of both the PAF and the f-f intervals during the PAF episode were evaluated. In selected cases, the atrial effective refractory period (ERP) was evaluated in an electrophysiologic study before and after the follow-up period. The total PAF duration was prolonged from 187+/-50 to 223+/-79 min (p=0.034) and the f-f interval was shortened from 0.14+/-0.03 to 0.12+/-0.02 ms (p=0.003). There was an inverse relationship between the changes in total PAF duration and f-f interval (p=0.027). The ERP was shortened from 214+/-15 to 194+/-5 ms (n=5, p=0.025) and there was a direct correlation between the changes in ERP and f-f interval (p=0.048). In clinical cases, the prolongation of the PAF was related to the shortening of the f-f interval during the PAF episodes and to the shortening of the atrial ERP. Electrical remodeling plays a role in promoting the development of the atrial fibrillation in patients with PAF.
[Show abstract][Hide abstract] ABSTRACT: Bepridil, a multi-ion channel blocker, is effective for some types of cardiac arrhythmias, and so its effect on the paroxysmal atrial fibrillation (PAF) was evaluated in the present study, comparing it with class Ic antiarrhythmic drugs. The relationship between efficacy and the f-f interval in the surface ECG recording was also analyzed. Sixty-one symptomatic PAF patients were randomized to a bepridil group (200 mg/day, n=23) or class Ic drug group (flecainide 100-200 mg/day or pilsicainide 75-150 mg/day, n=38). The drug was considered effective for PAF prevention when symptomatic episodes of PAF were decreased to less than 50% during the follow-up period of 2-6 months. The f-f interval in the surface 12-lead ECG trace was evaluated during a PAF episode. Both bepridil and the class Ic drugs were effectively prevented PAF (15/23 (65.2%) vs 24/38 (63.1%) patients, NS). In the class Ic drug group, the f-f interval was longer in the effective cases (114+/-48 ms) than in the non-effective cases (68+/-26 ms, p=0.0002). In contrast, in the bepridil group the f-f interval was shorter in the effective cases (85+/-26 ms) than in the non-effective ones (152+/-45 ms, p=0.0005). When comparing the non-effective cases in the 2 groups, the bepridil group showed a significantly longer f-f interval than the class Ic drug group (p=0.0003). As a result of drug administration, the class Ic drugs prolonged the f-f interval from 78+/-33 ms to 128+/-46 ms (p=0.0004) whereas bepridil showed no change (109+/-39 ms vs 135+/-47 ms). For clinical PAF prevention, the effect of bepridil matched that of class Ic antiarrhythmic drugs. Because bepridil was effective in PAF patients with relatively shorter f-f intervals without prolonging the f-f interval, bepridil is considered to work mainly as a class III antiarrhythmic drug.
[Show abstract][Hide abstract] ABSTRACT: [corrected] Bepridil, a multiple ion-channel blocker, has been reported to prevent paroxysmal atrial fibrillation (PAF). The f-f interval of PAF during treatment with bepridil versus class Ic antiarrhythmic drugs was compared.
Fifty-two patients with PAF were randomized to bepridil, 200 mg/day (n = 14) versus flecainide, 100 to 200 mg/day (n = 15) or pilsicainide, 75 to 150 mg/day (n = 23). The drug was considered effective when symptomatic episodes of PAF were decreased to < 50% during a follow-up of 2 to 6 months. The f-f interval was measured in 12-lead ECGs of initial PAF episodes.
Bepridil and Ic were effective in 10 of 14 (71.4%) and 24 of 38 patients (63.2%), respectively (ns). In the Ic group, the f-f interval was longer in successfully (114 +/- 48 ms) than in unsuccessfully (68 +/- 25 ms) treated patients (P = 0.002). In the bepridil group, the f-f interval was shorter in successfully (84 +/- 27 ms) than unsuccessfully (155 +/- 68 ms) treated patients (P = 0.015). When comparing unsuccessfully treated patients, the f-f interval in the bepridil group was significantly longer than in the Ic group (P = 0.007).
Bepridil was as effective as Ic drugs in the prevention of PAF. Because it was more effective in smaller (functional) than larger (anatomical) reentrant circuits, the effect of bepridil was considered to be mainly attributable to a class III antiarrhythmic action.
[Show abstract][Hide abstract] ABSTRACT: Leakage of electrical current from the body surface during a defibrillation shock delivery by an ICD device was evaluated in 27 patients with life-threatening ventricular tachyarrhythmias. All patients underwent the implantation of the Medtronic Jewel Plus ICD system, and the defibrillation shocks were delivered between the active can implanted in the left subclavicular region and the endocardial lead placed in the right ventricle. At the time of measurement of the effect of electrical energy delivery for defibrillation, the shocks were delivered in a biphasic form at the energy level of 20 or 30 J. During each delivery of the defibrillation shock, the electrical current to the body surface was measured through large skin electrodes (6.2 cm2) that were pasted at the following positions: (1) parallel position: the electrodes were placed at the left shoulder and the right low-chest, and the direction of the electrode vector was parallel to the direction of the defibrillation energy flow, and (2) cross position: the electrodes were placed at the right shoulder and the left low-chest, and the vector of the electrodes was roughly perpendicular to the direction of the energy flow. The energy leakages were measured in 80 defibrillation shocks. The peak leakage current during the shock delivery at energy of 30 J was 48 +/- 26 mA at the parallel position and 19 +/- 15 mA at the cross position (P = 0.0002). The energy leakage at a 30-J shock was 7.4 +/- 7.2 mJ at the parallel position and 1.4 +/- 2.3 mJ at the cross position (P = 0.0002). The actual maximum energy leakage was 105 mA, 29 mJ, and 106 V that appeared at the parallel position. The body surface leakage of the defibrillation energy of the ICD device was evaluated. The power of the energy leakage strongly depended on the angle between the alignment of the recording electrodes and the direction of the energy flow. The highest current leakage to the body surface reached a considerable level, but the energy leakage was small because of the short duration of the defibrillation shock.
Pacing and Clinical Electrophysiology 09/2002; 25(8):1212-8. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ATP-sensitive K+ (KATP) channel openers have a cardioprotective effect and so mexiletine (Mex), a class Ib anti-arrhythmic drug, may also be cardioprotective because of its KATP channel-opening effect. The present study examined the effect of Mex on acute myocardial ischemia in a closed-chest acute ischemia and reperfusion model in rabbits. The rabbits were divided into 3 groups: (1) control (n=8); (2) Mex (n=8), continuous infusion of mexiletine (24 mg x kg(-1) h(-1)); and (3) Mex+Gli (n=8), pre-administration of glibenclamide (Gli; 0.5mg/kg) followed by mexiletine infusion. The incidence of arrhythmia, the hemodynamics and left ventricular ejection fraction (LVEF), and the infarct size were evaluated and compared among the 3 groups. The incidence of fatal ventricular fibrillation (VF) was least in the Mex group. The LVEF at 30 min after reperfusion was least in the Mex group, but at 360 min after reperfusion, it was least in the Mex+Gli group. The area of myocardial infarction determined by 2,3-triphenyltetrazolium chloride (TTC) staining was smallest in the Mex group. In this model, Mex reduced infarct size and improved left ventricular function during the late phase after reperfusion, although the effect was totally negated by the addition of glibenclamide.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the electrical remodeling of the ventricular myocardium in the experimental autoimmune myocarditis (EAM) model in Lewis rats. EAM was induced by immunization with cardiac myosin. During the active myocarditis phase, the effective refractory period (ERP), the duration of the monophasic action potential (MAPD) was extracted from the left ventricular free wall, and the mRNA levels of Kv1.4, 4.2, 4.3 and L type Ca2+ channel were determined by RNase protection assays. The inducibility of ventricular arrhythmia was higher in EAM rats than in the control rat, and the direct relationship between the coupling intervals of the premature stimulus and the ventricular arrhythmia in EAM rats. The ERP was prolonged in EAM rats compared with the control group. The MAPDs determined as 20% and 90% repolarization time, were both longer in EAM rats than in the controls. The level of expression of Kv4.2 mRNA was reduced in EAM rats in comparison with the controls, whereas those of Kv1.4, 4.3 and the L type Ca2+ channel were unchanged. Ventricular vulnerability was higher in EAM rats than in the control rats, and some of the ventricular arrhythmias observed in the EAM group seemed to be based on triggered activity. The level of expression of Kv4.2 mRNA was significantly reduced, and this change was compatible with prolongation of the action potential duration.
[Show abstract][Hide abstract] ABSTRACT: The post-repolarization refractoriness (PRR) is an important factor to determine the conduction block in cardiac muscle. Recently, we proposed the block coupling interval (BCI) as an useful electrophysiological index for evaluating the PRR. In the present study, the effect of procainamide on PRR was evaluated using the BCI and the effective refractory period (ERP). In five beagle dogs, radiofrequency linear ablation was performed on the right atrial surface parallel to the AV groove, forming an artificial isthmus (8-10 mm width and 15-20 mm length). Bipolar recordings were performed in the isthmus at a resolution of 1.2 mm and single extrastimuli with eight basic drive trains were delivered to cause conduction blocks in the isthmus. When a conduction block occurred, the recorded coupling interval at the recording site just proximal to the site of block was defined as BCI. At the site of the block, the ERP and duration of the monophasic action potential (MAP) at each drive cycle length was measured. The PRR was calculated using two different formulas: (1) [ERP-MAP] and (2) [BCI-MAP]. Procainamide was administrated intravenously at a dose of 15 mg/kg after the control study and the whole study protocol was repeated. The site of the block in an individual dog was always the same. BCI, ERP, and MAP were all shortened in accordance with the shortening of the basic drive cycle length, and the BCI was always the longest, ERP the middle, and the MAP was the shortest. The administration of procainamide prolonged each parameter, but the order of BCI > ERP > MAP remained unchanged. The PRR calculated as [BCI-MAP] was prolonged from 15 +/- 10 ms to 29 +/- 8 ms by the administration of procainamide (P = 0.048), but [ERP-MAP] was unchanged (8 +/- 10 ms vs 8 +/- 4 ms). In the conduction block model in the canine right atrium, procainamide prolonged the [BCI-MAP], but did not change the [ERP-MAP]. The procainamide effect of prolonging the PRR might be expressed better by the change in the BCI than the ERP.
Pacing and Clinical Electrophysiology 08/2001; 24(7):1100-7. · 1.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Post-repolarization refractoriness (PRR) is an important factor in determining conduction block and is the difference between the effective refractory period (ERP) and the duration of the monophasic action potential (MAPD). In the present study, conduction block in an artificial isthmus in the canine atrium was evaluated and the coupling interval of a premature beat, which caused the block, was defined as the block coupling interval (BCI). The usefulness of this value was also evaluated. Radiofrequency linear ablation was performed on the right atrial surface parallel to the atrioventricular groove in 5 mongrel dogs, and an artificial isthmus (8-10mm wide and 25-30mm long) was created. Fourteen simultaneous unipolar recordings were performed in the isthmus with a resolution of 1.2 mm. Single extra-stimuli with basic drive train were delivered to induce conduction block in the isthmus and when it occurred, the coupling interval at the recording site just proximal to the site of the block was defined as the BCI. At the site of the block, the ERP and MAPD at each drive cycle length were measured. The PRR was calculated using 2 different formulae: (1) [ERP-MAPD], and (2) [BCI-MAPD]. It was found that each value was shortened in accordance with the shortening of the basic drive cycle length. In all basic drive trains, BCI>ERP>MAPD, and [ERP-MAPD] was always shorter than [BCI-MAPD]. In the shorter cycle length of basic drives, the difference between [ERP-MAPD] and [BCI-MAPD] was more prominent. In the artificial isthmus model in the canine atrium, BCI was always longer than the ERP measured at the same site as the block. Because the ERP may not directly reflect the block phenomenon, the electrophysiologic evaluation should use the BCI instead, as in the PRR evaluation.