Cardioprotective effects of sarcolemmal and mitochondrial K-ATP channel openers in an experimental model of autoimmune myocarditis. Role of the reduction in calcium overload during acute heart failure.

It has been reported that K-ATP channel openers have a cardioprotective effect in acute ischemia as a pharmacological preconditioning effect. In the present study, the chronic effects of clinical K-ATP channel openers, ie, nicorandil (Nic) and mexiletine (Mex), on cardiac function were evaluated in a rat model of experimental autoimmune myocarditis (EAM). Nicorandil (3 or 10 mg/kg/day) or Mex (10 or 25 mg/kg/day) was administered to the EAM rats, and the effects were compared with those in untreated EAM rats (control EAM) and sham rats without EAM on day 21 (acute phase) or day 60 (chronic phase). In the acute phase, the control EAM rats exhibited a reduced left ventricular ejection fraction (LVEF) and prolonged monophasic action potential duration (MAPD). Neither drug had an affect on the LVEF or degree of myocarditis, but Mex 25 mg suppressed the MAPD prolongation. In the chronic phase, EAM+Nic and EAM+Mex 25 mg exhibited a higher LVEF than the control EAM. Although the control EAM exhibited sustained MAPD prolongation, the other groups showed recovery of the MAPD in the chronic phase. The mitochondorial redox state was lower in the control EAM than in the sham, and EAM+Nic exhibited a similar level of the redox state as the sham in the chronic phase. Nicorandil exhibited a cardioprotective effect through the protection of mitochondrial function. Mexiletine exhibited a cardioprotective effect possibly through a reduction in the calcium overload by shortening the MAPD in the acute phase.

N-acetylcysteine suppresses the progression of ventricular remodeling in acute myocarditis: studies in an experimental autoimmune myocarditis (EAM) model.

BACKGROUND: Electrical and structural remodeling, characterized by prolonged action potential duration (APD), Kv4.2 downregulation and cellular infiltration were studied in rat experimental autoimmune myocarditis (EAM). Because the reactive oxygen species (ROS) has been speculated to play a role in the promotion of such remodeling, the effect of N-acetylcysteine (NAC) on the progression of ventricular remodeling was evaluated. METHODS AND RESULTS: Six-week-old Lewis rats were immunized with porcine cardiac myosin. On Days 10-11 after the immunization, NAC (0, 1, 10, or 100mg) was injected intraperitoneally to EAM and control rats. On Day 14, the electrophysiological parameters were evaluated and the expression levels of the mRNA were examined by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR).The EAM rats exhibited a typical acute myocarditis with prolonged APD and reduced Kv4.2 expression as previously reported. The myocarditis and electrical changes were significantly suppressed by NAC-treatment in a dose-dependent manner (P<0.05). In rats with 100mg NAC, the myocarditis was almost totally negated although the mortality increased. In rats with 1mg NAC, the suppression of myocarditis was not obvious, but APD prolongation and Kv4.2 reduction was attenuated (P<0.05). CONCLUSIONS: The NAC treatment suppressed ventricular remodeling in the EAM rats. This may indicate the role of oxidative stress in causing remodeling and myocarditis itself in the acute phase of myocarditis.

Clinical usefulness of electrophysiologic study (EPS)-guided risk stratification for life-threatening arrhythmia in patients with heart failure.

BACKGROUND: Ventricular tachyarrhythmia is one of the most important factors determining the prognosis of patients with heart failure and sudden death can be observed even during stable therapy controlling clinical heart failure. In this study, the usefulness of electrophysiologic study (EPS) for the prediction of a future arrhythmic event was evaluated in patients with heart failure. METHODS AND RESULTS: The patient population consisted of 474 patients with a history of clinical heart failure but without an episode of spontaneous sustained ventricular tachycardia or fibrillation (VT/VF). A Holter ECG was performed in all patients, and 177 of the 474 patients underwent EPS because of a recording of nonsustained VT (NSVT, > 5 beats). When sustained VT/VF was inducible in EPS, the patient was assigned to implantation of a defibrillation device. The patients were divided into 3 groups, ie, 1) no NSVT (n = 297), 2) NSVT + no inducible VT/VF (n = 134), and 3) NSVT + inducible VT/VF (n = 43), and were followed-up for > 12 months. All patients were followed-up under standard therapy for heart failure. There were no significant differences in basic clinical characteristics and therapies among the 3 groups. During the follow-up period of 32 +/- 18 months, 56/474 patients suffered a VT/VF episode, ie, 21/297 in no NSVT, 14/134 in NSVT + no inducible VT/VF, and 21/43 in NSVT + inducible VT/VF patients (P = 0.032). All patients were rescued from sudden death among patients with an implanted defibrillator, but 11 patients without a defibrillator died. CONCLUSION: In patients with heart failure, future arrhythmic events could be predicted by EPS and Holter ECG. EPS-guided risk stratification seems to be useful in managing patients with heart failure.

Predictive impact of the inducibility of ventricular fibrillation in patients with Brugada-type ECG.

The natural history of asymptomatic individuals with a Brugada-type electrocardiogram (ECG) is still controversial. In this study, we evaluated ventricular fibrillation (VF) inducibility in Brugada-type ECG patients and compared it with other risk factors to clarify the significance of these data on their prognosis. The study population consisted of 38 patients who presented with a typical ST-segment elevation in the precordial leads and underwent an electrophysiological study (EPS). The patients were divided into 3 groups; group A: patients with spontaneous ventricular fibrillation (VF) (n = 5), group B: patients without clinical VF but with inducible VF in EPS (n = 16), and group C: patients with neither clinical nor inducible VF (n = 17). The clinical features, diagnostic results, and prognosis were compared among these groups. During the follow-up period of 26 +/- 19 months, 2/5 (group A), 1/16 (group B), and 0/17 (group C) patients suffered fatal arrhythmic events. None of the clinical features showed any significant difference, although the incidence of positive results in a drug challenge test was higher in groups A and B than in group C (P < 0.05). On the other hand, VF inducibility was higher in patients with positive results in the drug challenge test than in patients with negative results (59% versus 13%; P < 0.05). No VF episodes were observed in patients without VF induction, although one was observed in 1 of 16 patients with VF induction in asymptomatic Brugada syndrome. The drug challenge test appears to be useful for predicting VF inducibility even though it is a noninvasive test.

Long-term follow-up of changes in fibrillation waves in patients with persistent atrial fibrillation: spectral analysis of surface ECG.

BACKGROUND: Little is known about the shortening of atrial refractoriness as a result of electrical remodeling in atrial fibrillation (AF) in clinical cases, especially in terms of long-term follow-up, because of a lack of noninvasive testing methods. METHODS AND RESULTS: The present study population comprised 38 consecutive patients with persistent AF (PAF, >1 month). Before and after the follow-up period of 1-14 months, surface ECGs were recorded for analysis. In each case, the fibrillation wave was purified by subtracting the QRS-T complex template and then power spectral analysis was performed. The mean fibrillation cycle length (FCL) and FCL coefficient of variation (FCL-CV) were determined from peak power frequency in 20 epochs in each recording. The change in FCL (FCL) was calculated by subtracting the baseline FCL from the FCL after the follow-up period. To correct for the difference in the follow-up period, DeltaFCL was divided by the follow-up period in each case. In 38 cases, mean FCL decreased from 160+/-20 ms to 151+/-19 ms (p<0.05), and the FCL-CV also decreased from 15+/-9% to 12+/-5% (p<0.05). The corrected DeltaFCL was -2.4+/-7.6 (ms/month) and there was a significant negative correlation between corrected DeltaFCL and baseline FCL (p<0.01). CONCLUSION: Shortening of the FCL during a relatively long-term follow-up period was observed in patients with PAF.

Bepridil inhibits sub-acute phase of atrial electrical remodeling in canine rapid atrial stimulation model.

Background The effect of bepridil, a multichannel blocker, on atrial electrical remodeling was evaluated in a canine rapid atrial stimulation model. Methods and Results In 10 beagle dogs, the right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. The atrial electrophysiological parameters, including effective refractory period (AERP), were evaluated at three atrial sites: RAA, the right atrium close to the inferior vena cava (IVC) and the left atrium (LA), during the time course of rapid pacing. Five of the dogs were given bepridil (10 mg . kg (-1) . day(-1) po). In the control group, AERP was significantly shortened at all atrial sites and the AERP shortening (DeltaAERP) was larger for the RAA and LA than at the IVC site (p<0.05). In the bepridil group, DeltaAERP was smaller than that of the controls at all atrial sites, and the AERP started to return slowly to the pre-pacing level in the second week, regardless of the continuation of rapid pacing. Conclusions In a canine rapid atrial stimulation model, bepridil suppressed AERP shortening. Bepridil might have a reverse electrical remodeling effect, at least for AERP shortening, because it showed slow recovery of AERP in the subacute phase of rapid atrial pacing. (Circ J 2006; 70: 206 - 213).