Search

Background: Low-invasive stereotactic body radiation therapy is a novel anti-arrhythmic strategy. The mechanisms underlying its effects against ventricular tachycardia/fibrillation (VT/VF) are gradually becoming clear, whereas those underlying atrial tachycardia/fibrillation (AT/AF) remain unknown. This study investigated the effects of carbon ion beam on gap junction expression and sympathetic innervation., Methods and results: Atrial and ventricular tachyarrhythmia models was established in 26 hypercholesterolemic (HC) 3-year-old New Zealand white rabbits; 12 rabbits were irradiated with a single 15-Gy carbon ion beam (targeted heavy ion irradiation [THIR]) and 14 were not (HC group). Eight 3-month-old rabbits (Young) were used as a reference group. In vivo induction frequencies in the Young, HC, and HC+THIR groups were 0%, 9.9%, and 1.2%, respectively, for AT/AF and 0%, 7.8%, and 1.2%, respectively, for VT/VF (P<0.01). The conduction velocity of the atria and ventricles on optical mapping was significantly reduced in the HC group; this was reversed in the HC+THIR group. Connexin-40 immunolabelling in the atria was 66.1-78.7% lower in the HC than Young group; this downregulation was less pronounced in the HC+THIR group (by 23.1-44.4%; P<0.01). Similar results were obtained for ventricular connexin-43. Sympathetic nerve densities in the atria and ventricles increased by 41.9-65.3% in the HC vs. Young group; this increase was reversed in the HC+THIR group., Conclusions: Heavy ion radiation reduced vulnerability to AT/AF and VT/VF in HC elderly rabbits and improved cardiac conductivity. The results suggest involvement of connexin-40/43 upregulation and suppression of sympathetic nerve sprouting.

Background: The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF)., Methods and results: In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS2score, were detected among the regions. The highest mean CHADS2score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P<0.001), with lower frequencies observed in Hokkaido and Shikoku. Baseline prothrombin time international normalized ratio differed slightly but significantly between the regions (P<0.05). On univariate analysis, frequency of thromboembolic events differed among the regions (P<0.001), with the highest rate seen in Shikoku. An inverse correlation was detected between frequency of thromboembolic and of major hemorrhagic events (P=0.062). On multivariate analysis, region emerged as an independent risk for thromboembolism., Conclusions: Thromboembolic risk, frequency of warfarin use, and intensity and quality of warfarin treatment differed significantly between geographic regions of Japan. Region was found to be an independent predictor of thromboembolic events. (Circ J 2016; 80: 1548-1555).

Background: Concomitant use of vitamin K antagonist (VKA) and aspirin (ASA) is becoming increasingly prevalent among atrial fibrillation (AF) patients. We quantified the net clinical benefit of adding ASA to a VKA using nationwide prospective AF registry data., Methods: We studied 6074 patients (VKA monotherapy: 83% and VKA+ASA: 17%) between January 2009 and July 2009, and followed them for a mean follow-up period of 2years. The risk of strokes and bleeding was calculated by the CHA2DS2-VASc and HAS-BLED scores. The net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by VKAs minus intracranial hemorrhages attributable to the VKA+ASA, multiplied by an impact weight of 1.5., Results: Patients on a VKA+ASA were older with more medical comorbidities than those on VKA alone. Using VKA monotherapy as a reference, higher major bleeding rates and all-cause death were evident in those on VKA+ASA. The net clinical benefit of VKA+ASA for the overall cohort was -0.1%/year (95% confidence interval, -0.74% to 0.46%). There was a trend toward a negative net clinical benefit from VKA+ASA in patients with a CHA2DS2-VASc≥2 and HAS-BLED≤2 (-1.17%/year). The VKA+ASA yielded a positive net clinical benefit in patients with a CHA2DS2-VASc≥2 and HAS-BLED≥3 (1.16%/year). The result patterns were relatively constant using impact weight of 1.0 and 2.0., Conclusions: Our estimates of the net clinical benefit can provide a useful anchoring point for adding ASA to VKA in patients with AF., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Recently, direct-acting oral anticoagulants (DOACs) have been introduced, with increasing use in patients with non-valvular atrial fibrillation (NVAF). However, warfarin continues to be widely used and the benefits and risks of warfarin in NVAF patients warrant closer inspection., Materials and Methods: Thromboembolism, major hemorrhage, and total and cardiovascular mortalities were analyzed in 7,406 NVAF patients in the J-RHYTHM Registry from January to July 2009, prior to DOAC introduction. Propensity score matching analysis was performed to reduce the differences in clinical characteristics between non-anticoagulant (n=1002) and warfarin (n=6404) cohorts to reassess warfarin outcomes over 2years., Results: The incidence of thromboembolism was significantly greater in the non-anticoagulant cohort (3.0%) than in the warfarin cohort (1.5%, P<0.001) with less frequent major hemorrhage in the non-anticoagulant cohort (0.8%) than in the warfarin cohort (2.1%, P=0.009). Using propensity score matching, new subsets (n=896 each) were obtained, with matching of the clinical characteristics between warfarin and non-anticoagulant subsets. The warfarin subset had lower risk factors compared with the total warfarin cohort. The incidence of thromboembolism was higher in the non-anticoagulant subset (2.9%) than in the warfarin subset (0.7%, P<0.001). However, major hemorrhage was not significantly different between the two subsets., Conclusions: Although warfarin was associated with a significantly higher incidence of hemorrhage in the unmatched cohorts, propensity score matching revealed that warfarin reduced thromboembolism without a significant increase in hemorrhage in the matched subsets with lower risks. Propensity score matching reduced selection bias and provided rational comparisons although it had indwelling limitations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Atrial fibrillation (AF) is associated with metabolic stress, which activates adenosine monophosphate-regulated protein kinase (AMPK)., Objectives: This study sought to examine AMPK response to AF and associated metabolic stress, along with consequences for atrial cardiomyocyte Ca(2+) handling., Methods: Calcium ion (Ca(2+)) transients (CaTs) and cell shortening (CS) were measured in dog and human atrial cardiomyocytes. AMPK phosphorylation and AMPK association with Ca(2+)-handling proteins were evaluated by immunoblotting and immunoprecipitation., Results: CaT amplitude and CS decreased at 4-min glycolysis inhibition (GI) but returned to baseline at 8 min, suggesting cellular adaptation to metabolic stress, potentially due to AMPK activation. GI increased AMPK-activating phosphorylation, and an AMPK inhibitor, compound C (CompC), abolished the adaptation of CaT and CS to GI. The AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) increased CaT amplitude and CS, restoring CompC-induced CaT and CS decreases. CompC decreased L-type calcium channel current (ICa,L), along with ICa,L-triggered CaT amplitude and sarcoplasmic reticulum (SR) Ca(2+) content under voltage clamp conditions in dog cells and suppressed CaT and ICa,L in human cardiomyocytes. Small interfering ribonucleic acid-based AMPK knockdown decreased CaT amplitude in neonatal rat cardiomyocytes. L-type Ca(2+) channel α subunits coimmunoprecipitated with AMPKα. Atrial AMPK-activating phosphorylation was enhanced by 1 week of electrically maintained AF in dogs; fractional AMPK phosphorylation was increased in paroxysmal AF and reduced in longstanding persistent AF patients., Conclusions: AMPK is activated by metabolic stress and AF, and helps maintain the intactness of atrial ICa,L, Ca(2+) handling, and cell contractility. AMPK contributes to the atrial compensatory response to AF-related metabolic stress; AF-related metabolic responses may be an interesting new therapeutic target., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The aim of this study was to investigate the role of gap junctions in atrial fibrillation (AF) by analysing the effects of a gap junction enhancer and blocker on AF vulnerability and electrophysiological properties of isolated hearts., Methods and Results: The acute atrial stretch model of AF in the isolated rabbit heart was used. Sustained AF (SAF) was induced by a burst of high-frequency stimulation of the Bachmann's bundle. The effective refractory period (ERP) was measured, and the total conduction time (TCT) and the pattern of conduction of the anterior surface of the left atrium were monitored by using an optical mapping system. The effect of enhancing gap junction function by 100-1000 nM rotigaptide (ZP123) and block by 30 μM carbenoxolone on these parameters was measured. SAF inducibility was increased with an elevation of intra-atrial pressure. Enhanced gap junction conductance induced by treatment with 100-1000 nM rotigaptide reduced SAF inducibility, and the gap junction blocker carbenoxolone increased SAF inducibility. In the absence of gap junction enhancer or blocker, normal conduction was observed at 0 cmH2O. When intra-atrial pressure was raised to 12 cmH2O, the conduction pattern was changed to a heterogeneous zig-zag pattern and TCT was prolonged. Conduction pattern was not affected by either agent. Rotigaptide shortened TCT, whereas carbenoxolone prolonged TCT. ERP was significantly shortened with an increase in intra-atrial pressure, but ERP was unaffected by either agent., Conclusion: Gap junction modulators changed AF inducibility through their effects on atrial conduction, not by altering ERP., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Treatment guidelines for atrial fibrillation (AF) used in Western countries describe female gender as a risk factor for thromboembolic events in patients with nonvalvular AF (NVAF). The present study aimed to determine the impact of gender on prognosis of Japanese patients with NVAF. A subanalysis of 7,406 patients with NVAF (mean age 70 years) who were followed-up prospectively for 2 years was performed using data from the J-RHYTHM registry. The primary end points were thromboembolic events, major hemorrhaging, total mortality, and cardiovascular mortality. Compared with male subjects (n = 5,241), female subjects (n = 2,165) were older and displayed greater prevalences of paroxysmal AF, heart failure, and hypertension but less prevalences of diabetes, previous cerebral infarction, and coronary artery disease. Male and female patients had mean CHADS2 (Congestive heart failure, Hypertension, Age of 75 years or more, Diabetes mellitus and prior Stroke or transient ischemic attack) scores of 1.6 and 1.8, respectively (p <0.001). Warfarin was given to 87% of male patients and 86% of female patients (p = 0.760), and the 2 genders displayed similar mean international normalized ratio of prothrombin time values at baseline (1.91 vs 1.90, respectively, p = 0.756). Multivariate logistic regression analysis indicated that male gender was an independent risk factor for major hemorrhaging (odds ratio 1.59, 95% confidence interval 1.05 to 2.40, p = 0.027) and all-cause mortality (odds ratio 1.78, 95% confidence interval 1.25 to 2.55, p <0.002) but not for thromboembolic events (odds ratio 1.24, 95% confidence interval 0.83 to 1.86, p = 0.297) or cardiovascular mortality (odds ratio 0.96, 95% confidence interval 0.56 to 1.66, p = 0.893). In conclusion, female gender is not a risk factor for thromboembolic events among Japanese patients with NVAF who were treated mostly with warfarin. However, male gender is a risk factor for major hemorrhaging and all-cause mortality., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The mechanisms by which acute left atrial ischemia (LAI) leads to atrial fibrillation (AF) initiation and perpetuation remain unclear., Objective: To investigate the electrophysiological mechanisms of AF perpetuation in the presence of regional atrial ischemia., Methods: LAI (90-minute ischemia) was obtained in isolated sheep hearts by selectively perfusing microspheres into the left anterior atrial artery. Two charge-coupled device cameras and several bipolar electrodes enabled recording from multiple atrial locations: with a dual-camera setup (protocol 1, n = 10, and protocol 1', n = 4, for biatrial or atrioventricular camera setups, respectively), in the presence of propranolol/atropine (1 μM) added to the perfusate after LAI (protocol 2, n = 3) and after a pretreatment with glibenclamide (10 μM; protocol 3, n = 4)., Results: Spontaneous AF occurred in 41.2% (7 of 17) of the hearts that were in sinus rhythm before LAI. LAI caused action potential duration shortening in both the ischemic (IZ) and nonischemic (NIZ) zones by 21% ± 8% and 34% ± 13%, respectively (pacing, 5 Hz; P<.05 compared to baseline). Apparent impulse velocity was significantly reduced in the IZ but not in the NIZ (-65% ± 19% and 9% ± 18%; P = .001 and NS, respectively). During LAI-related AF, a significant NIZ maximal dominant frequency increase from 7.4 ± 2.5 to 14.0 ± 5.5 Hz (P<.05) was observed. Glibenclamide, an ATP-sensitive potassium current (IKATP) channel blocker, averted LAI-related maximal dominant frequency increase (NIZ: LAI vs glibenclamide 14.0 ± 5.5 Hz vs 5.9 ± 1.3 Hz; P<.05). An interplay between spontaneous focal discharges and rotors, locating at the IZ-NIZ border zone, maintained LAI-related AF., Conclusions: LAI leads to an IKATP conductance-dependent action potential duration shortening and spontaneous AF maintained by both spontaneous focal discharges and reentrant circuits locating at the IZ border zone., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Target anticoagulation levels for warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF) are unclear., Methods and Results: Of 7,527 patients with NVAF, 1,002 did not receive warfarin (non-warfarin group), and the remaining patients receiving warfarin were divided into 5 groups based on their baseline international normalized ratio (INR) of prothrombin time (≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Patients were followed-up prospectively for 2 years. Primary endpoints were thromboembolic events (cerebral infarction, transient ischemic attack, and systemic embolism), and major hemorrhage requiring hospital admission. During the follow-up period, thromboembolic events occurred in 3.0% of non-warfarin group, but at lower frequencies in the warfarin groups (2.0, 1.3, 1.5, 0.6, and 1.8%/2 years for INR values of ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0059). Major hemorrhage occurred more frequently in warfarin groups (1.5, 1.8, 2.4, 3.3, and 4.1% for INR values ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0041) than in non-warfarin group (0.8%/2 years). These trends were maintained when the analyses were confined to patients aged ≥70 years., Conclusions: An INR of 1.6-2.6 is safe and effective at preventing thromboembolic events in patients with NVAF, particularly patients aged ≥70 years. An INR of 2.6-2.99 is also effective, but associated with a slightly increased risk in major hemorrhage. (UMIN Clinical Trials Registry UMIN000001569)

Background: Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential canonical-3 (TRPC3) channels., Methods and Results: Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca(2+) influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca(2+) removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5' promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression., Conclusions: TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca(2+) influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.

Aims: Atrial dilatation and myocardial stretch are strongly associated with atrial fibrillation (AF). However, the mechanisms by which the three-dimensional (3D) atrial architecture and heterogeneous stretch contribute to AF perpetuation are incompletely understood. We compared AF dynamics during stretch-related AF (pressure: 12 cmH(2)O) in normal sheep hearts (n = 5) and in persistent AF (PtAF, n = 8)-remodelled hearts subjected to prolonged atrial tachypacing. We hypothesized that, in the presence of stretch, meandering 3D atrial scroll waves (ASWs) anchor in regions of large spatial gradients in wall thickness., Methods and Results: We implemented a high-resolution optical mapping set-up that enabled simultaneous epicardial- and endoscopy-guided endocardial recordings of the intact atria in Langendorff-perfused normal and PtAF (AF duration: 21.3 ± 11.9 days) hearts. The numbers and lifespan of long-lasting ASWs (>3 rotations) were greater in PtAF than normal (lifespan 0.9 ± 0.5 vs. 0.4 ± 0.2 s/(3 s of AF), P< 0.05). Than normal hearts, focal breakthroughs interacted with ASWs at the posterior left atrium and left atrial appendage to maintain AF. In PtAF hearts, ASW filaments seemed to span the atrial wall from endocardium to epicardium. Numerical simulations using 3D atrial geometries (Courtemanche-Ramirez-Nattel human atrial model) predicted that, similar to experiments, filaments of meandering ASWs stabilized at locations with large gradients in myocardial thickness. Moreover, simulations predicted that ionic remodelling and heterogeneous distribution of stretch-activated channel conductances contributed to filament stabilization., Conclusion: The heterogeneous atrial wall thickness and atrial stretch, together with ionic and anatomic remodelling caused by AF, are the main factors allowing ASW and AF maintenance.

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).

Background: There is evidence that verapamil promotes the persistence of paroxysmal atrial fibrillation (AF). Little is known about the underlying mechanisms., Objective: The purpose of this study was to determine the effect of verapamil on dominant frequencies (DFs) in the pulmonary veins (PVs) and atria during paroxysmal AF with reference to its potential arrhythmogenicity., Methods: Forty-three patients with paroxysmal AF were studied. Bipolar electrograms were recorded simultaneously during AF from the right atrial free wall (RAFW), coronary sinus (CS) and three PVs, or two PVs and the left atrial appendage (LAA). The DFs were obtained by fast Fourier transform analysis before and after infusion of verapamil (0.1 mg/kg, intravenously)., Results: At baseline, the maximum DF among the PVs (6.9 +/- 0.9 Hz) was significantly higher than the DF in the RAFW (6.2 +/- 0.7 Hz), CS (5.7 +/- 0.5 Hz), or LAA (5.9 +/- 0.7 Hz) (P<.01); there was a substantial PV-to-atrial DF gradient (RAFW 0.7 +/- 0.9, CS 1.1 +/- 0.7, LAA 0.7 +/- 0.9 Hz). Verapamil increased the atrial DF to 6.9 +/- 0.8, 6.6 +/- 0.7, and 7.2 +/- 1.0 Hz in the RAFW, CS, and LAA, respectively (P<.0001) but did not affect the maximum PV DF (7.1 +/- 0.7 Hz). The PV-to-atrial DF gradient was eliminated after verapamil (RAFW 0.2 +/- 0.8, CS 0.5 +/- 0.6, LAA -0.4 +/- 0.8 Hz; P<.01 vs. baseline)., Conclusion: Verapamil increases the activation frequency in the atria but not in the PVs, eliminating the PV-to-atrial DF gradient during paroxysmal AF., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The mortality and morbidity rates of various cardiovascular diseases differ between Western countries and Japan. The age- and gender-specific prevalence rate of atrial fibrillation (AF) in the general population of Japan was determined using the data from periodic health examinations in 2003., Methods: Data of 630,138 subjects aged 40 years or more (47% were men and 34% were employees of companies and local governments) were collected from northern to southern Japan. The prevalence of diagnosed AF in each 10-year age group of both men and women was determined. Based on these prevalence rates and the Registry of Residents, the number of people having AF in Japan was estimated., Results: The prevalence rate of AF increased as both male and female subjects aged, and it was 4.4% for men but only 2.2% for women aged 80 years or more (p<0.0001). As a whole, the AF prevalence of men was three times that of women (1.35 versus 0.43%, p<0.0001). There may be approximately 716,000 people (95% confidence interval (CI), 711,000-720,000) with AF in Japan, an overall prevalence of 0.56%. The number of people having AF was projected to be 1.034 (95% CI, 1.029-1.039) million, an overall prevalence of 1.09%, in 2050., Conclusions: The prevalence of AF increased in Japan as the population aged, as in Western countries. The overall prevalence of AF in Japan is approximately two-thirds of that in the USA. The projected increase in the number of people having AF is modest in Japan in 2050.

Background: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action., Methods and Results: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172 +/-26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD(90S) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD(90) was greater in RVOT (approximately 13%) than RVA (approximately 8%). Bepridil flattened the MAPD(90) restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65 +/-0.22 vs 0.95 +/-0.38) and RVA (0.65 +/-0.14 vs 0.94 +/-0.29). The T(peak-end) interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response., Conclusions: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization.

Background: Both atrial stretch and combined adrenocholinergic stimulation (ACS) have been shown to favor initiation and maintenance of atrial fibrillation (AF). Their respective contributions to the electrophysiological mechanism remains, however, incompletely understood., Objective: This study endeavored to determine the mechanism of maintenance of stretch-related AF (SRAF) in the presence and absence of ACS and to assess how focal discharges interact with rotors to modify the level of complexity in the activation patterns to perpetuate AF., Methods: Video imaging of AF dynamics was carried out using a SRAF model in isolated sheep hearts (n = 24). Pharmacological approaches were used to (1) mimic ACS with acetylcholine (1 microM) plus isoproterenol (0.03 microM), and (2) abolish triggered activity, in response to sarcoplasmic reticulum calcium release, with caffeine (5 mM, CA) or ryanodine (10 to 40 microM, RYA)., Results: In the absence of ACS, on perfusion of CA or RYA, focal discharges were abolished and SRAF was terminated in most of the cases (10 of 13 experiments). In the presence of ACS, multiple drifting rotors as well as a large number of focal discharges were identified and only 1 of 11 AF episodes was terminated., Conclusions: In the absence of ACS, SRAF is maintained by high-frequency focal discharges that generate fibrillatory conduction and wave breaks. In the presence of ACS, SRAF dynamics is characterized by multiple high frequency rotors that are rendered unstable by spatially distributed focal discharges.

Introduction: Increasing evidence suggests that high-frequency excitation in the pulmonary vein (PV) plays a dominant role in the maintenance of paroxysmal atrial fibrillation (AF). However, in a certain population of patients, AF remains inducible after PV isolation (PVI). We sought to clarify whether dominant frequency (DF) analysis of atriopulmonary electrograms can predict paroxysmal AF maintained by non-PV sources., Methods and Results: Sixty-one patients with paroxysmal AF (aged 59 +/- 12 years) were studied. Before PVI, bipolar electrograms during AF were recorded simultaneously from three PV ostia, the coronary sinus (CS), and the septum and free wall of the right atrium (RA). DF was obtained by fast Fourier transform (FFT) analysis. AF was rendered noninducible after PVI in 39 of the 61 patients (noninducible group), but was still inducible in the remaining 22 (inducible group). Among the six recording sites, the highest DF was documented in the PV in all of the patients in the noninducible group; the maximum DF among the three PVs (PV-DF(max)) was higher than that among the CS and two RA sites (atrial DF(max); 7.2 +/- 1.0 Hz vs 5.8 +/- 0.7 Hz, P < 0.0001). In contrast, the highest DF was documented in the CS or RA in 45.5% of the patients in the inducible group; PV-DF(max) was comparable with atrial DF(max) (6.6 +/- 0.8 Hz vs 6.6 +/- 0.6 Hz). AF inducibility after PVI was predicted by a PV-to-atrial DF(max) gradient of <0.5 Hz, with a sensitivity of 90.9% and a specificity of 89.7%., Conclusion: Paroxysmal AF maintained by non-PV sources can be predicted by the PV-to-atrial DF gradient.

Background Although previous clinical trials demonstrated the non-inferiority of a rate control to rhythm control strategy for management of atrial fibrillation (AF), the optimal treatment strategy for paroxysmal AF (PAF) remains unclear. Methods and Results A randomized, multicenter comparison of rate control vs rhythm control in Japanese patients with PAF (the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study) was conducted. The primary endpoint was a composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy. In the study, 823 patients with PAF were followed for a mean period of 578 days. The primary endpoint occurred in 64 patients (15.3%) assigned to rhythm control and in 89 patients (22.0%) to rate control (P=0.0128). No significant differences between the treatment strategies were observed in the incidences of death, stroke, bleeding and heart failure. Meanwhile, significantly fewer patients requested changes of assigned treatment strategy in the rhythm control vs the rate control group, which was accompanied by improvement in AF-specific quality of life scores. Conclusion The J-RHYTHM study showed that rhythm control was associated with fewer primary endpoints than rate control. However, mortality and cardiovascular morbidity were not affected by the treatment strategy (umin-CTR No. C000000106).

Background: The incidence of various cardiovascular diseases is known to exhibit seasonal variations, but seasonal patterns of paroxysmal atrial fibrillation (AF) have not been well characterized., Objective: The objective of this study was to determine whether seasonal variation affects the incidence of paroxysmal AF and whether this pattern is affected by patient age., Methods: We identified 258 paroxysmal AF episodes in 237 patients (age 65 +/- 14 years, mean +/- standard deviation; age range 16-95 years) among 12,390 consecutive 24-hour Holter electrocardiogram recordings obtained from 2001 to 2005 at our institute. Seasonal variations were analyzed by both month and by season. The relative risk (RR) of AF for each period was determined as being high or low in relation to the overall mean incidence. The association among clinical covariates and risk of paroxysmal AF was tested by logistic regression analysis., Results: The incidence of paroxysmal AF was highest in September (RR = 1.40, 95% confidence interval [CI] 1.36-1.44) and lowest in June (RR = 0.52, 95% CI 0.50-0.54), with an RR difference of 63% (P < .001) among all patients. Patients aged > or =65 years demonstrated a peak incidence in September (RR = 1.46, 95% CI 1.41-1.51) and a minimum in June (RR = 0.55, 95% CI 0.52-0.58), while those aged <65 years showed a peak incidence in December (RR = 1.33, 95% CI 1.27-1.39) and a minimum in June (RR = 0.49, 95% CI 0.45-0.53). The incidence of paroxysmal AF also showed an autumn peak (RR = 1.21, 95% CI 1.16-1.27) and a summer minimum (RR = 0.66, 95% CI 0.62-0.70), with an RR difference of 53% (P < .001) among all patients. This seasonal variation in paroxysmal AF did not differ between patients of different age ranges. Clinical covariates including underlying disease or medications did not influence the monthly or seasonal variation in paroxysmal AF. There was a significant inverse relationship between the incidence of paroxysmal AF and the length of daylight in patients aged <65 years (r = -0.57, P < .05)., Conclusion: There was a significant seasonal variation in paroxysmal AF, with maximum and minimum incidences in autumn and summer, respectively, and this pattern was not age dependent.

Background: Mega trials of rhythm vs rate control could not demonstrate the usefulness of available antiarrhythmic drugs, so a more effective and safer therapy for atrial fibrillation (AF) is now required. One candidate is the so-called "upstream therapy", which refers to the blockade of upstream modifying elements (renin - angiotensin system, cathecholamines, oxidative stress etc) that contribute to the arrhythmogenic substrate., Methods and Results: The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is a randomized comparative evaluation of an angiotensin II type 1 blocker (candesartan) and a dihydropiridine calcium blocker (amlodipine), both combined with antithrombotic therapy, as an antiarrhythmic therapy for the treatment of paroxysmal AF (PAF) associated with hypertension. To test the usefulness of this therapy, this study will reveal the recurrence rate of asymptomatic as well as symptomatic PAF during 1-year of treatment with candesartan or amlodipine, using daily transtelephonic monitoring., Conclusions: The J-RHYTHM II study will follow 400 patients with PAF and hypertension who were treated at approximately 50 sites throughout Japan, and will provide clinically important information.

Background: Atrial fibrillation (AF) is an arrhythmia associated with functional and morphological remodeling of atria. We investigated the distribution and the expression of connexins in atrial tissues from patients with chronic AF and left atrial dilatation (AD)., Methods and Results: Immunohistochemistry was performed in atrial tissues obtained during cardiac surgery from patients with chronic AF + AD (n = 11), sinus rhythm (SR, n = 11) and SR + AD (n = 4). In SR patients (control), the connexin (Cx) 43 labeling of the intercalated disks seen en-face was characterized by small central spots surrounded by larger spots at the periphery. In the left atria from AF + AD patients, the area of the intercalated disk was significantly enlarged. Although peripheral Cx43 labeling was preserved, there was a striking loss of central labeling spots. The area occupied by gap junctions was slightly but significantly larger than that of the control. The left atria from patients with SR + AD showed gap junction disorganization analogous to AF + AD. The labeling patterns of Cx40 were essentially similar to those of Cx43. Conclusions In chronic AF with AD, gap junctions at the intercalated disk are disorganized, resulting most likely from AD but not from AF itself. This gap junction remodeling might be involved in altered atrial conduction properties, but its potential arrhythmogenic role remains unclear.

Background: Cardioversion for atrial fibrillation (AF) is the most effective treatment for the restoration of sinus rhythm (SR). Recently, an elevated level of hs-CRP has been shown to be associated with AF burden, suggesting that inflammation increases the propensity for persistence of AF. We examined whether the level of high-sensitivity C-reactive protein (hs-CRP) was predictive of the outcome of cardioversion for AF., Methods and Results: One hundred and six patients with a history of symptomatic AF lasting > or =1 day (age 63+/-14 years, mean+/-S.D.) underwent cardioversion. Echocardiography and hs-CRP assay were performed immediately prior to cardioversion. SR was restored in 84 patients (79%). By using selected cutoff values, multiple discriminant analysis revealed significant associations between successful cardioversion and a shorter duration of AF (AF duration< or =36 days, odds ratio (OR), 0.98; 95% confidence interval (CI), 0.97-0.99), smaller left atrial diameter (left atrial diameter< or =40 mm, OR 0.82, 95% CI 0.71-0.94), better-preserved left ventricular ejection fraction (left ventricular ejection fraction> or =60%, OR 0.92, 95% CI 0.86-0.99), and lower hs-CRP level (hs-CRP< or =0.12 mg/dL, OR 0.33, 95% CI 0.21-0.51). During a follow-up period of 140+/-144 days, AF recurred in 64 patients (76%). By using a cutoff value of hs-CRP> or =0.06 mg/dL, Cox proportional-hazards regression model found that only hs-CRP level was an independent predictor of AF recurrence (OR 5.30, 95% CI 2.46-11.5) after adjustment for coexisting cardiovascular risks. When patients were divided by the hs-CRP level of 0.06 mg/dL, percentage of maintenance of SR below and above the cutoff was 53% and 4%, respectively (log-rank test, p<0.0001)., Conclusions: hs-CRP level determined prior to cardioversion represents an independent predictor of both successful cardioversion for AF and the maintenance of SR after conversion.

Background: A multicenter investigational survey (Japanese Guideline for Arrhythmia Management By Individual Therapy) was conducted to evaluate the validity of using CD-ROM guidelines vs physician choice for the selection of antiarrhythmic drugs., Methods and Results: Patients with paroxysmal atrial fibrillation (PAF, n=274) or premature ventricular contractions (PVC, n=216) were enrolled. The rate of concordance for drug selection between the treating physician and the CD-ROM was 216 of 274 patients (78.8%) with PAF. Of these, 168 (61.3%) were concordant for first-line agents and the remaining 48 (17.5%) were concordant for second-line agents. The concordance for the treatment of PVC was 154/216 cases (71.3%). Of these, 106 (49.1%) were concordant for first-line agents and the remaining 48 (22.2%) were concordant for second-line agents. Nonconcordance for PAF therapy was more likely to occur for patients with underlying heart disease (p<0.05), depressed cardiac function (p<0.001), and with more frequent ECG abnormalities and renal dysfunction. These differences were not seen in patients with PVC., Conclusion: The CD-ROM guidelines appear to be valid in the selection of antiarrhythmic drugs for both PAF and PVC, but their usefulness is influenced by the patient's clinical characteristics.

Introduction: Recurrence of atrial fibrillation (AF) may be related to AF-induced electrical remodeling characterized by shortening of the atrial action potential duration (APD) and loss of its rate adaptation. We investigated the effects of pretreatment with oral d,l-sotalol on rate-dependent changes in atrial monophasic action potential (MAP) duration after cardioversion of chronic AF with reference to the efficacy in preventing the arrhythmia recurrence., Methods and Results: MAPs were recorded from the right atrium at six pacing cycle lengths (CLs) from 300 to 750 ms in 19 chronic AF patients after electrical cardioversion; 9 had been pretreated with oral d,l-sotalol (196 +/- 42 mg/day) for 7 days and 10 were untreated. MAP duration at 90% repolarization (MAPD90) in 11 control patients increased progressively with increases in CLs from 209 +/- 19 ms at CL = 300 ms to 264 +/- 28 ms at CL = 750 ms. In AF patients without sotalol, the CL-MAPD relation was shifted downward and flattened at longer CLs; MAPD90 values were 206 +/- 11 ms and 227 +/- 16 ms at CLs of 300 and 750 ms, respectively. MAPD90 values at CLs > or =500 ms in AF were significantly shorter than controls. In AF patients with sotalol, the normal CL-MAPD relation was preserved; MAPD90 increased from 226 +/- 19 ms to 282 +/- 46 ms in the CL range. AF recurred within 2 weeks after cardioversion in 14 of 24 patients pretreated with d,l-sotalol (216 +/- 51 mg/day) despite of continuation of sotalol treatment., Conclusion: Sotalol reverses AF-induced decrease in MAPD adaptation to rate in the atria of chronic AF patients, but this effect does not lead to prevention of AF recurrence.

The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM study) is a randomized comparative evaluation of rate control and rhythm control, both combined with antithrombotic therapy, as therapeutic strategies for the treatment of atrial fibrillation (AF). This study differs from the earlier AFFIRM and RACE studies in that it has a composite primary end-point representing mortality and also physical/psychological disablement (total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure requiring intravenous administration of diuretics, and patient disablement). Patients' will to change the therapeutic strategy to the other is also considered as an end-point representing disablement under the assigned strategy. The secondary end-point includes quality of life scores and the efficacy and safety of drugs used in treating AF. The J-RHYTHM study emphasizes patient-reported experience and perception of AF-specific disablement, and the safety of antiarrhythmics available in Japan; it will follow 2600 patients treated at more than 150 sites in Japan for a 3-year period.

It has been shown in animal experiments that recurrent induction of atrial fibrillation (AF) or long-lasting atrial pacing causes a shortening of the atrial effective refractory period (ERP) and action potential duration (APD) and a loss of their physiological adaptation to rate. Much remains to be clarified as to the electrical remodeling in human patients with chronic AF. We recorded monophasic action potentials (MAPs) from the right atrium at pacing cycle lengths (CLs) of 300, 333, 400, 500, 600, and 750 ms after external cardioversion in 13 patients with chronic lone AF. Their configuration was compared with those obtained from 13 control patients. APDs at 50% and 90% repolarization (APD50, APD90) at the shortest CL (300 ms) in control and AF patients were 131 +/- 14, 211 +/- 19 ms and 136 +/- 12, 210 +/- 22 ms, respectively (mean +/- SD). APDs in control patients increased linearly with increases of CL, reaching maximal values of 174 +/- 30 ms (APD50) and 277 +/- 38 ms (APD90) at a CL of 750 ms. In AF patients, the steady-state CL-APD relation was shifted downward and flattened at CLs > 500 ms; APD50 and APD90 at a CL of 750 ms were 158 +/- 19 ms, 232 +/- 28 ms, respectively. APD90s at CLs of 600 and 750 ms were significantly shorter in AF than in control patients. No statistically significant difference was obtained in APD50 between the two groups at any CL tested. MAP configuration in AF patients was characterized by an acceleration of the late repolarization. The difference between APD90 and APD50 (APD90-50) in control patients was increased with increases of CL, reaching a plateau at a CL of 600 ms. This CL dependent slowing of the late repolarization of MAPs was abolished in AF patients. The atrial ERP, measured at CLs of 400 and 600 ms, showed changes parallel to those of APD90. ERP at a CL of 600 ms in AF patients (224 +/- 13 ms) was significantly shorter than that in control patients (247 +/- 25 ms). We conclude that chronic lone AF leads to electrical remodeling in the human atrium, which causes a loss of rate response of the late repolarization of action potential, leading to a shortening of APD and ERP at slower heart rates.