Koichiro Kumagai

Angiotensin II Antagonist Prevents Electrical Remodeling in Atrial Fibrillation

BACKGROUND The blockade of angiotensin II (Ang II) formation has protective effects on cardiovascular tissue; however, the role of Ang II in atrial electrical remodeling is unknown. The purpose of this study was to investigate the effects of candesartan and captopril on atrial electrical remodeling. METHODS AND RESULTS In 24 dogs, the atrial effective refractory period (AERP) was measured before, during, and after rapid atrial pacing. Rapid atrial pacing at 800 bpm was maintained for 180 minutes. The infusion of saline (n=8), candesartan (n=5), captopril (n=6), or Ang II (n=5) was initiated 30 minutes before rapid pacing and continued throughout the study. In the saline group, AERP was significantly shortened during rapid atrial pacing (from 149+/-11 to 132+/-16 ms, P<0.01). There was no significant difference in AERP shortening between the saline group and the Ang II group. However, in the candesartan and captopril groups, shortening of the AERP after rapid pacing was completely inhibited (from 142+/-9 to 147+/-12 ms with candesartan, from 153+/-15 to 153+/-14 ms with captopril, P=NS). Although rate adaptation of the AERP was lost in the saline group, this phenomenon was preserved in the candesartan and captopril groups. CONCLUSIONS The inhibition of endogenous Ang II prevented AERP shortening during rapid atrial pacing. These results indicate for the first time that Ang II may be involved in the mechanism of atrial electrical remodeling and that the blockade of Ang II may lead to the better therapeutic management of human atrial fibrillation.

Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation

UNLABELLED The purpose of the present study was to evaluate the effect of angiotensin II type 1 receptor (AT1R) antagonist on chronic structural remodeling in atrial fibrillation (AF). BACKGROUND We previously reported that an AT1R antagonist, candesartan, prevents acute electrical remodeling in a rapid pacing model. However, the effect of candesartan on chronic structural remodeling in AF is unclear. METHODS Sustained AF was induced in 20 dogs (10 in a control group and 10 in a candesartan group) by rapid pacing of the right atrium (RA) at 400 beats/min for five weeks. Candesartan was administered orally (10 mg/kg/day) for one week before rapid pacing and was continued for five weeks. The AF duration, atrial effective refractory period (AERP) at four sites in the RA, and intra-atrial conduction time (CT) from the RA appendage to the other three sites were measured every week. RESULTS The mean AF duration in the control group after five weeks was significantly longer than that with candesartan (1,333 +/- 725 vs. 411 +/- 301 s, p < 0.01). The degree of AERP shortening after five weeks was not significantly different between the two groups. The CT from the RA appendage to the low RA after five weeks with candesartan was significantly shorter than that in the control (43 +/- 14 vs. 68 +/- 10 ms, p < 0.05). The candesartan group had a significantly lower percentage of interstitial fibrosis than the control group (7 +/- 2% vs. 16 +/- 1% at the RA appendage, p < 0.001). CONCLUSIONS Candesartan can prevent the promotion of AF by suppressing the development of structural remodeling.

Simultaneous Multisite Mapping Studies During Induced Atrial Fibrillation in the Sterile Pericarditis Model: Insights Into the Mechanism of its Maintenance

BACKGROUND Chronic atrial fibrillation (AF) is thought to be due to multiple, simultaneously circulating wavelets. In the canine sterile pericarditis model, the mechanisms of maintenance of AF are not yet understood. METHODS AND RESULTS During six induced AF episodes in six dogs with sterile pericarditis, 372 unipolar electrograms were recorded simultaneously from an electrode array placed around both atrial free walls, along with 10 to 24 electrodes from the atrial septum, by use of a multiplexing system. Activation maps during 12 consecutive 100-ms windows were analyzed from an episode of sustained AF in each dog (mean duration, 32 +/- 24 minutes). In two dogs, two such activation maps during the same episode of AF were analyzed. During AF, multiple unstable reentrant circuits (mean number, 1.4 +/- 0.1 per 100-ms analysis window) with very short cycle lengths (mean, 111 +/- 8 ms) present primarily in the atrial septum and right atrium were responsible for maintenance of AF. The unstable reentrant circuits frequently disappeared and re-formed. Wave fronts traveling from one atrium to the other and/or from the atrial septum play an important role in re-formation of unstable reentrant wave fronts. CONCLUSIONS In this model of paroxysmal AF, unstable reentrant circuits of very short cycle length principally involving the atrial septum appear to be critical for maintenance of AF. Some reentrant circuits disappear as others re-form, so that at least one reentrant circuit is always present. Because the atria cannot follow their very short cycle lengths in a 1:1 manner, AF is maintained.

Electrophysiological properties in chronic lone atrial fibrillation.

BackgroundAlthough the electrophysiological mechanisms underlying self-sustaining atrial fibrillation (AF) are unclear, recent studies suggest that one requirement for reentry, slow conduction, is frequently present in patients with AF. However, these observations limited to paroxysmal AF may not necessarily apply to chronic AF. Therefore, electrophysiological properties of the atrium and sinus nodal function in chronic lone AF were evaluated. Methods and ResultsElectrophysiological studies were performed after electrocardioversion in 12 patients with chronic lone AF. Atrial enlargement was absent in the patients with AF. Twelve patients without atrial arrhythmias served as the control group. The patients with AF had a higher incidence of sinus nodal dysfunction, a shorter atrial effective refractory period (215 ± 19 msec versus 238 ± 23 msec, p < 0.02), and a longer P wave duration than control patients (115 ± 16 msec versus 86 ± 16 msec, p < 0.01). The conduction delay zone was significantly greater in patients with AF (60 ± 12 msec) than that in the control patients (8 ± 13 msec, p < 0.01), and the maximal conduction delay was also greater in the study patients than those in the control group, both to the His bundle region (31 ± 12 msec versus 10 ± 15 msec, p < 0.01) and to the coronary sinus (41 + 15 msec versus 15 ± 11 msec, p < 0.01). The fragmented atrial activity zone was wider in the study group (23 ± 25 msec) than in control subjects (1.7 ± 4 msec, p < 0.02). Repetitive atrial firing was observed in four patients with AF but it was not seen in the control group. ConclusionsThese electrophysiological features, which are manifestations of the abnormal atrial electrophysiology, would favor production of atrial reentry in chronic lone AF.

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation

During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic. The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B. In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations. The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended. The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group. Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient. The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.

2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design

This is a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation, developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology and the European Cardiac Arrhythmia Society (ECAS), and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). This is endorsed by the governing bodies of the ACC Foundation, the AHA, the ECAS, the EHRA, the STS, the APHRS, and the HRS.

Role of rapid focal activation in the maintenance of atrial fibrillation originating from the pulmonary veins.

Most episodes of focal atrial fibrillation (AF) can be initiated by premature beats originating from the pulmonary veins (PV). However, the role of rapid focal activation in the maintenance of AF is unclear. Thirty‐two patients with focal AF who underwent focal ablation of triggering ectopic beats were studied. Bipolar electrograms from all four PVs were recorded simultaneously. The cycle length (CL) of RFA at sites that triggered AF was measured at AF onset, after 5 minutes of sustained AF, and just before the spontaneous termination of 32 episodes of nonsustained AF. Fifteen episodes of sustained AF (> 10 minutes) and 17 episodes of nonsustained AF (5–120 seconds, mean 56 ± 59 seconds) were analyzed. In sustained AF, the mean CL of RFA in the PV from which it originated was not significantly different than in the other PVs, and RFA was continuously observed. In nonsustained AF, the mean CL of RFA in a PV from which it originated was significantly shorter than in other PVs and, when RFA disappeared, AF terminated. RFA in 1 PV induced RFA in another PV. In conclusion, widespread conduction of RFA from a PV at its source to the other sites may be necessary for the sustenance of AF. A PV interaction, a RFA triggering another, may be involved in the maintenance of AF. RFA arising from PVs is important not only as a trigger of onset, but also in the maintenance of AF.

Antiarrhythmic Effects of JTV-519, a Novel Cardioprotective Drug, on Atrial Fibrillation/Flutter in a Canine Sterile Pericarditis Model

Introduction: A new cardioprotective drug, JTV‐519, blocks Na+ current and inwardly rectifying K+ current and inhibits Ca2+ current. However, its role in atrial electrophysiology is unknown. We investigated the antiarrhythmic effects of JTV‐519 on atrial fibrillation/flutter in the canine sterile pericarditis model.

Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)

AIMS Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. METHODS AND RESULTS The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. CONCLUSIONS In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

Low energy synchronous transcatheter cardioversion of atrial flutter/fibrillation in the dog

The feasibility and effectiveness of low energy synchronous transcatheter cardioversion of atrial flutter and fibrillation were examined in dogs with talc-induced pericarditis. A conventional electrode catheter was positioned transvenously in the right atrial appendage. Atrial flutter/fibrillation was induced by using the train pulse method, and the tachyarrhythmia-inducing threshold was determined. The minimal effective cardioversion energy levels were compared in three different cardioversion methods: method A = delivery of shock between the proximal electrode (cathode) and the backplate (anode), method B = delivery between the proximal electrode (cathode) and the distal electrode (anode) and method C = conventional external cardioversion. In both methods A and B, all 149 cardioversion attempts were successful with shocks of less than or equal to 5 J. Shocks of less than or equal to 1 J resulted in successful cardioversion in 57 (70%) of 81 attempts, 50 (74%) of 68 attempts and 5 (12%) of 41 attempts with methods A, B and C, respectively. The mean minimal effective cardioversion energy levels were not significantly different between methods A and B (0.62 +/- 0.67 versus 0.58 +/- 0.71 J). Transcatheter cardioversion decreased the defibrillation threshold 3- to 75-fold (mean 6- to 7-fold) from that of transthoracic cardioversion. The defibrillation threshold was not influenced by the inducibility of atrial flutter/fibrillation. There were no complications of heart block, ventricular fibrillation or pathologic evidence of severe shock-induced atrial injury. Thus, low energy synchronous transcatheter cardioversion of atrial flutter/fibrillation is considered feasible and effective. This technique may also be useful in managing the atrial flutter/fibrillation that can occur during electrophysiologic studies.