Atrial fibrillation (AF) is the most common arrhythmia in adults; it affects approximately 0.8 million patients in Japan alone. Yet despite many years of basic and clinical research, the exact mechanisms underlying the initiation and maintenance of AF remain poorly understood. In this review article, we summarize recent high-resolution optical mapping studies in isolated sheep hearts, which have provided new insights into the dynamics and mechanisms of AF. We focus on 3 models of AF. First, we discuss results from experiments on AF induced by atrial stretch that revealed the presence of spatio-temporally organized waves emerging from the posterior wall of the left atrium. In the presence of adreno-cholinergic stimulation and stretch, AF was governed by evolving interactions between reentry and spontaneous focal discharges. Next, we outline the results obtained from a persistent AF model (average AF duration: 21.3 day) induced by intermittent rapid atrial pacing. By using simultaneous optical mapping of epicardial and endocardial activation patterns, we demonstrated that AF in this model was maintained by 3-dimensional scroll waves with I-shaped filaments anchored to junctions between thin and thick myocardium. Numerical simulation results predicted that wall thickness-dependent activation of stretch-activated channels and the filament tension dynamics were sufficient to explain the specific localization of the I-shaped filament. In a final set of studies discussed herein, we investigated AF in sheep with tachypacing-induced heart failure and found that micro-reentry in the left atria was a major mechanism of AF maintenance, although focal discharges at the pulmonary vein area also played a role. Large fibrotic patches in failing hearts may serve as potential anchoring sites for micro-reentry in this model. Thus, the 3 different experimental results in isolated sheep hearts presented here clearly suggest that self-sustained rotors do exist in the atria and that such rotors are in fact the high frequency sources that determine the complex patterns of activation that characterize AF.

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Atrial fibrillation (AF) is the most common arrhythmia. Although AF is known to develop during the course of various cardiac pathological conditions, including valvular heart diseases, congestive heart failure, and hypertension, recent clinical data implicate the additional contribution of genetic factors in the pathogenesis of AF. A familial form of AF has been noted, and 8 loci and 6 responsible genes have been identified. In non-familial AF, genetic risks were originally investigated by the candidate gene approach, and recently by genome-wide association studies (GWASs). GWASs executed in other countries have identified 3 loci: 4q25 near Pitx2, 1q21 in KCNN3, and 16q22 in ZFHX3. Several AF-associated SNPs in 4q25 are also associated with the recurrence rate of AF after catheter pulmonary vein isolation. This review will discuss the genetic underpinnings of AF, in both familial AF and non-familial AF.

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We have experimentally established appropriate models of atrial fibrillation (AF) with atrial interstitial fibrosis. Two approaches were adopted. Firstly, left atrial fibrosis was induced by continuous infusion of angiotensin II (AII). In an electrophysiological study using isolated perfused heart, AF was easily induced following AII treatment. Repeated whole-body hyperthermia led to the induction of heat-shock protein 72, which resulted in attenuation of AII-induced left atrial fibrosis and suppression of AF inducibility. Secondly, atrial fibrosis was induced by pressure overload by abdominal aortic constriction (AAC). AAC enhanced left atrial expression of monocyte chemoattractant protein-1 and activity of matrix metalloproteinase-9. Treatment with pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, resulted in attenuation of pressure overload-induced left atrial fibrosis and suppression of AF inducibility. In the same AAC model, the effects of candesartan on gap junction remodeling were investigated. Connexin 43 (Cx43) of the left atria was firmly located in the intercalated disks in control rats. A progressive redistribution of Cx43 from the intercalated disk to the lateral surface (lateralization) was observed in AAC rats. Candesartan prevented left Cx43 lateralization. Thus, heat-shock proteins, pioglitazone, and candesartan could be novel therapeutic approaches to prevent atrial fibrosis and AF.

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Non-pharmacological rhythm control of atrial fibrillation (AF) is becoming increasingly important in our aging society. Advancement of catheter ablation techniques in the last decade has provided a cure for AF patients, with a nearly established efficiency for paroxysmal cases. However, since ablation of persistent/chronic AF cases is still challenging, early treatment of paroxysmal AF before transformation to the persistent/chronic form is mandatory. Although there is a consensus that pulmonary vein isolation is the first-line approach for ablation of long-standing persistent AF, similar to that for paroxysmal AF, there are still wide variations in the adjunctive approach to modify the atrial substrate of persistent AF (anatomical linear ablation, electrogram-based complex fractionated atrial electrogram ablation, ganglionated plexus ablation, etc.). Since data comparing the effectiveness of these adjunctive approaches are still lacking, large-scale controlled trials evaluating the effect of catheter ablation in diverse patient populations on a long-term basis are needed to establish the appropriate approach for long-standing persistent AF. Furthermore, the development of de novo ablation methods (new energies, new targets, etc.) is expected to improve ablation outcome in patients with long-standing persistent AF.

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Atrial fibrillation is now recognized as a significant medical and social problem. Atrial fibrillation not only causes cardiovascular complications, including thromboembolism and heart failure, but also decreases the survival of patients with impaired left ventricular function; thus, it is considered an independent factor for cardiovascular death. The goal of antiarrhythmic drug therapy for atrial fibrillation is improvement of daily quality of life and cardiovascular prognosis in maintaining sinus rhythm, while ensuring the safety of antiarrhythmic drugs. Antiarrhythmic drugs are prescribed to prevent recurrence of atrial fibrillation; however, they demonstrate limited efficacy. Recently, catheter ablation has been established as a promising new therapy to prevent recurrence of atrial fibrillation, even though this procedure would be difficult to apply clinically because of its complications and the large number of patients requiring treatment. Since the antiarrhythmic drugs remain the first-line, primary therapy for paroxysmal atrial fibrillation, clinicians should select appropriate antiarrhythmic drugs for treatment of paroxysmal atrial fibrillation based on individual patient characteristics.
Herein, I review the current strategies of antiarrhythmic drug therapy for paroxysmal atrial fibrillation from the point of view of pharmacological prevention of atrial fibrillation recurrence, improvement of patient quality of life, and cardiovascular prognosis.

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Background: Anti-arrhythmic drugs (AADs) are often administered following catheter ablation (CA) for persistent atrial fibrillation (peAF) to maintain sinus rhythm (SR). It remains unclear whether AADs can be withdrawn in patients showing no recurrence after CA.
Method: We administered hybrid therapy consisting of CA and AAD (bepridil) in 75 patients with peAF. Withdrawal of AADs was attempted in patients who had no recurrence of AF for ≥6 months. We followed them for 22±16 months.
Results: Patients received 1.2±0.4 sessions of CA and a mean bepridil dose of 131±46 mg/day. After a 3-month "blanking period," 62 (83%) patients maintained SR without recurrence of tachyarrhythmia for ≥6 months. AADs were discontinued in 41 patients who agreed to medication withdrawal. Ten of these (24%) experienced a relapse of tachycardia, and these patients had a higher incidence of residual inducibility of tachyarrhythmia at the end of the CA procedure (70% vs. 32%; P=0.03) and required a higher dose of bepridil to maintain SR (170±48 mg vs. 106±30 mg; P<0.0001) than those without relapse.
Conclusions: Discontinuation of AADs occasionally results in recurrence, especially in patients with residual inducibility and in those requiring higher doses of AADs.

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Introduction: Endurance sports have recently been recognized as a risk factor for atrial fibrillation (AF). This study aimed to characterize AF in endurance athletes and to examine the efficacy of pulmonary vein antrum isolation (PVAI) in an attempt to clarify the mechanism.
Methods and results: Twenty-two men (46±8 years old) with AF, who had no risk factors other than participation in long-term endurance sports, were examined; 12 patients had paroxysmal AF, 9 had persistent AF, and 1 had long-standing AF. Twelve patients (55%) were asymptomatic at rest. Nineteen patients (86%) experienced less exercise tolerance during AF than during sinus rhythm; exercise-induced paroxysmal AF was noted in 14 of these patients (64%). Antiarrhythmic drugs (AADs) were used in 18 patients, but were effective in only 3 patients (16%). Eleven patients underwent PVAI; in these patients, AF was eliminated without AADs in 9 patients (82%) and with AADs in 2 patients over an average follow-up period of 21±9 months.
Conclusion: AF in endurance athletes is frequently asymptomatic at rest, but manifests as reduced exercise tolerance. AF originates from the pulmonary veins; PVAI could be an effective non-pharmacologic therapy.

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Introduction: Lone atrial fibrillation (AF) is defined as AF occurring in the absence of any other cardiovascular disease. The prognosis of patients with lone AF varies in previous studies, and the clinical and electroanatomical characteristics of lone AF are unclear. The purpose of this study was to investigate the clinical characteristics of lone AF.
Methods: This study included 203 patients (52±13 years old, 144 males) that underwent circumferential pulmonary vein isolation (CPVI) for paroxysmal AF. The mean voltage and total activation time of the individual atria were obtained by using a NavX mapping system and were compared for patients with lone and non-lone AF. Several parameters, including the age, gender, AF duration, and left atrial (LA) diameter were analyzed.
Results: Compared with non-lone AF patients, lone AF patients were significantly younger (49±13 years old vs. 58±11 years old, p<0.001) and had lower body-mass index (BMI, 24.60±2.96 vs. 26.07±3.29, p=0.02), lesser cholesterol level (169.06±31.41 vs. 183.63±31.12, p=0.014), smaller LA diameter (35.89±4.90 vs. 40.86±4.62, p±0.001), and higher LA bipolar voltage (2.10±0.50 vs. 1.83±0.73 mV, p±0.05). Furthermore, a dramatic voltage reduction was observed for 60-year-old patients.
Conclusion: Patients with lone AF have unique clinical and electroanatomical characteristics.

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The aim of this study was to evaluate the clinical significance of serum bepridil (Bep) concentration (SBC) for safely managing patients with atrial tachyarrhythmias (AT).
Methods and results: SBC was measured in 37 patients with AT, including atrial fribrillation (AF) (31 cases), AF+atrial flutter (AFL) (4 cases), AFL (1 case), and atrial tachycardia (1 case). The patients were administrated Bep for more than 4 weeks at the same dose. SBC was positively correlated with Bep dose per kilogram of body weight (p=0.015), QT interval (p=0.019), and QTc (p=0.034). The patients were divided into 2 groups according to their SBC: the high-SBC (HSBC) group of 8 patients with an SBC ≥500 ng/ml and a low-SBC (LSBC) group of 29 patients with an SBC <500 ng/ml. There was no difference in maintenance of sinus rhythm between the groups. For clinical variables, QT and QTc were significantly longer in the HSBC than in the LSBC group (p=0.004 and p=0.016, respectively). Patients with QT >0.5 were more prominent in the HSBC group (37.5% vs. 3.4%, p=0.026), and torsade de points (TdP) occurred in only one patient in the HSBC group. However, there were several patients with normal QT/QTc despite having high SBC.
Conclusions: In patients treated with Bep, measurement of SBC is useful for preventing proarrhythmias.

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A 65-year-old man with a history of refractory paroxysmal atrial fibrillation (AF) underwent catheter ablation for persistent AF lasting 2 months. AF was not terminated after complete isolation of the 4 pulmonary veins (PV). Instead, it was transformed to a sustained atrial tachyarrhythmia with beat-to-beat variability in the atrial cycle length. A 12-lead electrocardiogram during tachycardia showed negative flutter-like waves in the inferior leads. Entrainment pacing along the tricuspid annulus confirmed the diagnosis of irregular cavotricuspid isthmus (CTI)-dependent typical atrial flutter (AFL). Linear ablation of the CTI terminated AFL and restored sinus rhythm.

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A 54-year-old man with a surgically repaired double-outlet right ventricle (DORV) presented with palpitations and worsening right heart failure. His 12-lead ECG showed atrial tachycardia (AT) with an atrial cycle length (CL) of 300 ms and an inverted saw-tooth F-wave pattern in the inferior leads II, III, and aVF typical of atrial flutter. Electrophysiological study and radiofrequency catheter ablation were performed. A total of 3 sustained ATs (AT1–AT3) were induced. Using the electroanatomical mapping system, CARTO3, and conventional mapping techniques, the ATs were identified as macroreentrant tachycardias circling around an incisional line on the free wall of the right atrium (AT1), the tricuspid annulus (AT2), and low voltage area in the lateral wall including the right septum (AT3). Accuracy of CARTO3 in three-dimensional reconstruction was sufficient to elucidate anatomical features (including catheter sites, incision, and low voltage areas) and macroreentrant circuits. However, conventional mapping techniques were also necessary to identify the mechanism of the tachycardias, and therefore to eliminate all of them successfully. This case demonstrates that the use of combined conventional and electroanatomical mapping techniques, such as CARTO3, can be helpful in identifying the critical isthmus for catheter ablation of macroreentrant AT in patients with surgically corrected congenital heart disease (CHD).

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