Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model.

Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller (P=0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group (P=0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group (P=0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.

Precise Signals with a High-Density Grid Mapping Catheter Are Useful for an Entrainment Study.

Complex atrial tachycardias (ATs) after catheter ablation or a MAZE procedure is sometimes difficult to determine the circuits of the tachycardia. A high-density, grid-shapes mapping catheter has been launched, which can be useful for detecting the detail circuits of tachycardias on three-dimensional mapping systems. The signal quality is also important for performing electrophysiological studies (EPSs), such as entrainment mapping, to identify the circuit. This unique mapping catheter has 1 mm electrodes on 2.5 Fr shafts, which improve the signal quality. The high-quality intracardiac electrograms facilitate differentiating small critical potentials, which allows us to perform detailed entrainment mapping in targeted narrow areas. Here, we describe a patient with a perimetral AT with epi-endocardium breakthrough after a MAZE surgery and catheter ablation, which was treated successfully along with detailed entrainment mapping using the HD Grid. This catheter with high-quality signals could be a significant diagnostic tool for a classic EPS as well as for the construction of 3D mapping.

Linagliptin Suppresses Electrical and Structural Remodeling in the Isoproterenol Induced Myocardial Injury Model.

The effect of DPP-4 inhibitor on the electrical and structural remodeling in myocardial injury has not been evaluated. We hypothesized that linagliptin, DPP-4 inhibitor, suppresses myocardial remodeling in the isoproterenol (ISP)-induced myocardial injury model.Sprague-Dawley rats were assigned to 3 groups: 1) sham group, 2) ISP group (subcutaneous ISP injection of 70 mg/kg), and 3) ISP + linagliptin (ISP + Lin) (5 mg/kg/day, p.o.) group. Serum was sampled on day 1 (acute phase) and day 7 (sub-acute phase) to evaluate derivatives of reactive oxidative metabolites (d-ROMs). The electrophysiological study was performed in sub-acute phase for the evaluation of the ventricular effective refractory period (VERP) and monophasic action potential duration (MAPD). The VERP and MAPD were markedly prolonged in the ISP group in comparison with the sham (MAPD20: 14 ± 6 versus 11 ± 3 ms, MAPD90: 57 ± 8 versus 44 ± 7 ms, VERP: 74 ± 22 versus 38 ± 10 ms, P < 0.05). In contrast in the ISP + Lin group, such prolongations were suppressed, and the parameters were shorter than the ISP group (MAPD20: 9 ± 2 ms, MAPD90: 35 ± 6 ms, VERP: 52 ± 13 ms, P < 0.05). ISP treatment induced myocardial injury. The injured area was reduced in the ISP + Lin group in comparison with the ISP group (P < 0.05). Serum d-ROMs level in acute phase was higher in ISP group than the other 2 groups (sham: 214 ± 55 versus ISP: 404 ± 45 versus ISP + Lin: 337 ± 20 U.CARR, P < 0.05).Linagliptin suppressed structural and electrical changes, possibly through the antioxidative effect, in this myocardial injury model.

Safety of neuromuscular electrical stimulation in patients implanted with cardioverter defibrillators.

Neuromuscular electrical stimulation (NMES) is one of the few exercise modes that have been confirmed to be effective for advanced heart failure patients. Previous clinical trials that verified the effects of NMES excluded patients with implantable cardioverter defibrillators (ICDs). We investigated whether NMES to leg muscles could be applied in heart failure patients implanted with ICDs. As a result, we found that NMES could be conducted without any instances of electromagnetic interference. NMES to leg muscles could be applied safely to ICD patients if the aforementioned common stimulation methods were used with sufficient monitoring during NMES.

Predicting the efficacy of antiarrhythmic agents for interrupting persistent atrial fibrillation according to spectral analysis of the fibrillation waves on the surface ECG.

BACKGROUND: Spectral analysis of the fibrillation waves was performed in patients with persistent atrial fibrillation (PAF) to clarify the usefulness of this method of predicting the efficacy of antiarrhythmic agents. METHODS AND RESULTS: The 59 patients with PAF were randomly assigned to pilsicainide (150 mg/day) or bepridil (200 mg/day) therapy for 4 weeks under optimal anticoagulation therapy. When the first therapy did not interrupt PAF, the drugs were changed in a cross-over manner. The fibrillation cycle length (FCL) was calculated using spectral analysis of the fibrillation waves on the body-surface ECG every 2 weeks. Pilsicainide and bepridil were effective in 19 and 20 patients, respectively. The FCL at the basic state was longest in the pilsicainide-effective group, moderate in the bepridil-effective group and shortest in the failure group (P<0.05). The change in FCL with drug administration (DeltaFCL) was larger in the effective than in the ineffective cases (P<0.01). Successful interruption of the atrial fibrillation (AF) with pilsicainide could be expected for patients with a FCL >148 ms (sensitivity =0.917, specificity =0.612, P=0.007) and DeltaFCL >41 ms (sensitivity =0.875, specificity =0.833, P=0.001). CONCLUSIONS: The FCL reflects the electrophysiological properties of the AF substrate and is considered useful for predicting the efficacy of antiarrhythmic agents.

Role of electrophysiologic study (EPS)-guided preventive therapy for the management of ventricular tachyarrhythmias in patients with heart failure.

BACKGROUND: Ventricular tachyarrhythmias (VT/VF) are 1 of the most important factors determining the prognosis of patients with heart failure (HF). Although priority is given to implantable cardioverter defibrillator (ICD) therapy for the prevention of sudden cardiac death, electrophysiologic-study (EPS)-guided preventive therapy could be important for reducing the number of cardiac events. METHODS AND RESULTS: Of 864 patients with a history of HF, an EPS was performed in 168 and 121 had inducible VT/VF. Under the basic therapy of an ICD, additional catheter ablation was attempted for 95 of 124 monomorphic VT foci in 74 patients, and 78 of the VT were successfully ablated. The prognoses were compared among 5 patient groups with different results for the EPS and catheter ablation: (1) success group (n=43), (2) failure group (n=15), (3) not attempted group (n=16), (4) VF group (n=47), and (5) no inducible VT/VF group. During a follow-up period of 31+/-22 months, the incidence of VT/VF was lower in the success and no inducible VT/VF groups than in the other groups (p=0.0018), although a significant difference was not observed for the total deaths. CONCLUSION: EPS-guided preventive therapy using an ICD and catheter ablation can be useful, at least for the reduction of arrhythmic events in patients with HF.

Arrhythmogenic difference between the left and right atria during rapid atrial activation in a canine model of atrial fibrillation.

BACKGROUND: Continuous rapid atrial stimulation causes atrial remodeling, but little is known about the difference in the arrhythmogenicity of the left (LA) and right atria (RA). METHODS AND RESULTS: In 14 beagle dogs, continuous rapid pacing (400 beats/min) was delivered from the right (n=7) or left (n=7) atrial appendage (RAA or LAA) for 2 weeks. The atrial effective refractory period (ERP), ERP dispersion, and inducibility of atrial fibrillation (AF) were evaluated along the time course from 4 atrial sites: (1) RAA, (2) area close to the inferior vena cava (IVC), (3) Bachmann's bundle (BB) and (4) LA. The ERP exhibited progressive shortening at all sites, but the degree of shortening differed among them. In the RA stimulation group, ERP shortening was more prominent in the RAA and LA than in the IVC or BB. In contrast, in the LA stimulation group, ERP shortening was more prominent in the LA than in the other sites. As a result, ERP dispersion was larger in the LA stimulation group than in the RA stimulation group and the AF inducibility was higher in the LA stimulation group than in the RA stimulation group, especially at the LA site (p<0.05). CONCLUSION: LAA stimulation was more arrhythmogenic than RAA stimulation in this model. This result may partly explain the importance of premature contractions occurring from the pulmonary veins in clinical cases of AF.

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.

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.

Prediction of clinical recurrence of atrioventricular-nodal reentrant tachycardia (AVNRT) after successful slow pathway ablation.

BACKGROUND: Even after successful slow pathway (SP) ablation for atrioventricular-nodal reentrant tachycardia (AVNRT), there may be clinical recurrence in certain patients and it is clinically important to be able to predict that. METHODS AND RESULTS: In 97 patients with common type AVNRT, the effective refractory period (ERP) of the fast pathway (FP), SP-ERP, and prolongation of the atrio-His (AH) interval (AH) at the time of jump-up phenomenon were investigated. In patients with residual SP, parameters were re-evaluated in a similar manner. SP was successfully ablated and AVNRT was not inducible in all the patients, but residual SP was observed in 54 of the 97 patients, and there was late clinical recurrence in 10 patients (10/54 patients with residual SP and 0/43 without residual SP, p=0.002). The changes in FP-ERP before and after ablation (DeltaFP-ERP) did not differ between recurrent and non-recurrent patients. Among the patients with residual SP, DeltaSP-ERP did not differ between the groups. However, the changes in DeltaAH before and after ablation (DeltaDeltaAH) were larger in non-recurrent (24+/-30 ms) than in the recurrent patients (4+/-7 ms, p=0.042). CONCLUSIONS: In patients with AVNRT, the residual SP and changes in DeltaAH after successful SP ablation might be useful indices of clinical recurrence.

Monitoring the progression of the atrial electrical remodeling in patients with paroxysmal atrial fibrillation.

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.