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.

Combined effects of up- and downstream therapies on atrial fibrillation in a canine rapid stimulation model.

BACKGROUND: Recent reports suggest angiotensin receptor blockers (ARBs) and some antiarrhythmic agents affect atrial remodeling in atrial fibrillation (AF). We evaluated the effect of combination therapy with olmesartan (Olm) and bepridil (Bep) in a canine model of AF. METHODS AND RESULTS: An atrial stimulation device was implanted in 10 dogs undergoing 6-week pacing at 400 bpm. They were divided into Olm (2 mg/kg/day) (n=5) and Olm+Bep (Olm, 2 mg/kg/day; Bep, 10 mg/kg/day) groups (n=5). Atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated weekly, and hemodynamics, atrial histology, and mRNA expression and protein expression of ion-channel and gap junction-related molecules at 6 weeks. Data were compared between groups and with non-pacing control and pacing-control groups from our previous report. The pacing-control group exhibited shortened AERP, decreased CV, increased AF inducibility and tissue fibrosis, and down-regulated L-type Ca(2+) channel (LCC), SCN5A, Kv4.3 and connexin43 (Cx43). By comparison, the Olm group exhibited suppression of the decrease in CV and of the increase in AF inducibility, but no change in AERP shortening. The Olm+Bep group exhibited suppression of AERP shortening as well as the greatest decrease in AF inducibility. Histologically, tissue fibrosis was suppressed in Olm and Olm+Bep groups. Down-regulation of Cx43 was partly suppressed in the Olm group while that of LCC, SCN5A, and Cx43 was suppressed in the Olm+Bep group. CONCLUSION: Olm and Bep in combination suppressed AF inducibility more strongly than Olm alone, and may be more useful in the suppression of AF.

Acute myocardial infarction involving double vessel total occlusion of the left anterior descending and left circumflex arteries: A case report.

A 66-year-old Japanese man complained of chest pain consistent with acute myocardial infarction (AMI). His electrocardiogram showed ST segment elevation in the anterior and inferior leads. Emergency coronary angiography revealed occlusion of the proximal left anterior descending artery (LAD) and middle left circumflex artery (LCx). An intra-aortic balloon pump (IABP) was inserted to restore antegrade coronary flow in these vessels. Coronary stents were subsequently implanted at the culprit lesions. Although previous reports of multivessel coinstantaneous AMI are rare and indicate a poor prognosis, he had a relatively benign course and was discharged with New York Heart Association functional class I without post-operational complications.

Evaluation of exercise-induced T wave changes in patients with idiopathic dilated cardiomyopathy before and after beta-blocker therapy.

INTRODUCTION: Ventricular repolarization abnormalities are thought to contribute to lethal ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy (DCM). The purpose of this study was to evaluate exercise-induced T wave changes in DCM patients before and after beta-blocker therapy to investigate repolarization abnormalities. METHODS AND RESULTS: Treadmill exercise testing was performed in 20 DCM patients and 50 normal subjects. T wave amplitude (TA: baseline to T wave apex; mV) and recovery time (RT: QRS onset to the maximum dV/dt point of the T wave; msec) were measured before and 1 minute after peak exercise. TA was averaged in the right and left precordial leads (TA(V1-3), TA(V4-6)). RT was normalized to the maximum QT interval in the 12-lead ECG and expressed as the %RT (%RT). %RT was also averaged in the precordial leads (%RT(V1-3), %RT(V4-6)). After exercise, TA increased and %RT decreased in both groups. In DCM patients, TA(V1-3) was greater and TA(V4-6) was less than in normal subjects before and after exercise. There was no difference in %RT(V1-3) between the groups, but %RT(V4-6) was greater in DCM patients both before and after exercise. DCM patients repeated the same evaluation after 6 months of oral beta-blocker therapy. Compared with measurements before beta-blocker therapy, TA(V1-3) and %RT(V1-3) did not change. However, TA(V4-6) increased and %RT(V4-6) decreased significantly both before and after exercise. CONCLUSION: DCM patients showed small TA and large %RT in the left precordial leads at rest as well as after exercise. Chronic beta-blocker therapy in DCM patients normalized these ventricular repolarization abnormalities.

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.

Clinical significance of the electrophysiologic study (EPS)-guided therapy for the secondary prevention of ventricular tachycardia.

BACKGROUND: Although electrophysiologic study (EPS) is one of the most reliable methods for selecting preventive therapy for patients with sustained ventricular tachycardia (VT), VT may recur during EPS-guided effective therapy; therefore, the importance of implantable cardioverter-defibrillator (ICD) has been emphasized. In this study, the prognoses of VT patients were evaluated to clarify the importance of EPS-guided therapy for the secondary prevention of VT. METHODS AND RESULTS: The study population consisted of 99 consecutive patients with a history of sustained VT, which was inducible in EPS. The VT induction protocol used 1-3 extrastimuli and rapid ventricular pacing at 2 right ventricular sites and included additional isoproterenol infusion. ICD implantation was applied to all patients with an episode of hemodynamically unstable VT, regardless of the result of preventive therapy. For preventive therapy, an antiarrhythmic drug and/or catheter ablation were selected, and they were defined as being effective in the EPS-guided therapy when the induction of VT was completely prevented. When no therapy was effective for prevention, an antiarrhythmic drug was prescribed under ICD implantation. During the follow-up period of 19+/-20 months, VT recurred in 17 of 32 patients (53%) in the ineffective group and in 10 of 67 patients (15%) in the effective group (p=0.0001). The therapies used in the effective group were class I antiarrhythmic drug in 9, class III in 15, and catheter ablation in 35 patients. Between the patients with and without VT recurrence, there were no significant differences in the left ventricular ejection fraction and the maximum number of repetitive ventricular responses that remained in VT induction in EPS. CONCLUSIONS: Although VT may recur in up to 15% of patients with EPS-guided effective therapy, the recurrence rate was significantly reduced in comparison to that in the ineffective group. EPS-guided therapy may be useful to reduce the clinical recurrence of VT, as well as the action of ICD.

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).

Structural and electrical ventricular remodeling in rat acute myocarditis and subsequent heart failure.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.