Comparison of High- and Low-Dose Rivaroxaban Regimens in Elderly East Asian Patients With Atrial Fibrillation.

BACKGROUND: In the Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban 20 mg was the on-label dose, and the dose-reduction criterion for rivaroxaban was a creatinine clearance of < 50 mL/min. Some Asian countries are using reduced doses label according to the J-ROCKET AF trial. The aim of this study was to assess the safety and efficacy of a high-dose rivaroxaban regimen (HDRR, 20/15 mg) and low-dose rivaroxaban regimen (LDRR, 15/10 mg) among elderly East Asian patients with atrial fibrillation (AF) in real-world practice. METHODS: This study was a multicenter, prospective, non-interventional observational study designed to evaluate the efficacy and safety of rivaroxaban in AF patients > 65 years of age with or without renal impairment. RESULTS: A total of 1,093 patients (mean age, 72.8 ± 5.8 years; 686 [62.9%] men) were included in the analysis, with 493 patients allocated to the HDRR group and 598 patients allocated to the LDRR group. A total of 765 patients received 15 mg of rivaroxaban (203 in the HDRR group and 562 in the LDRR group). There were no significant differences in the incidence rates of major bleeding (adjusted hazard ratio [HR], 0.64; 95% confidential interval [CI], 0.21-1.93), stroke (adjusted HR, 3.21; 95% CI, 0.54-19.03), and composite outcomes (adjusted HR, 1.13; 95% CI, 0.47-2.69) between the HDRR and LDRR groups. CONCLUSION: This study revealed the safety and effectiveness of either dose regimen of rivaroxaban in an Asian population for stroke prevention of AF. Considerable numbers of patients are receiving LDRR therapy in real-world practice in Asia. Both regimens were safe and effective for these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04096547.

Association Between Atrial Fibrillation and Diabetes-Related Complications: A Nationwide Cohort Study.

OBJECTIVE: This study aimed to investigate the associations between concurrent atrial fibrillation and diabetes-related complications among patients with diabetes. RESEARCH DESIGN AND METHODS: This nationwide observational cohort study used the health checkup database from the Korean National Health Insurance Service. Patients diagnosed with diabetes who underwent health checkups between 2009 and 2012 were investigated. The patients with atrial fibrillation were matched in a 1:5 ratio with those without atrial fibrillation using propensity scores. Study outcomes included macrovascular, microvascular (diabetic retinopathy and diabetic nephropathy), and diabetic foot complications. The risks of clinical outcomes were measured using hazard ratios (HRs) with 95% CIs. RESULTS: A total of 65,760 patients with diabetes were analyzed (54,800 without atrial fibrillation and 10,960 with atrial fibrillation). After well-balanced propensity score matching, atrial fibrillation was associated with significantly higher risks of macrovascular complications (HR 1.12, 95% CI 1.09-1.16), diabetic nephropathy (HR 1.23, 95% CI 1.16-1.30), and diabetic foot complications (HR 1.13, 95% CI 1.09-1.17) compared with no atrial fibrillation, while the risk of diabetic retinopathy was comparable (HR 0.99, 95% CI 0.96-1.03). Patients with atrial fibrillation had a significantly higher risk of diabetic foot amputation (HR 4.12, 95% CI 1.98-8.56). CONCLUSIONS: Among patients with diabetes, concurrent atrial fibrillation was associated with increased risks for diabetes-related macrovascular complications, diabetic nephropathy, and diabetic foot. Such patients require holistic management to reduce the risk of adverse outcomes.

Improved prognosis with integrated care management including early rhythm control and healthy lifestyle modification in patients with concurrent atrial fibrillation and diabetes mellitus: a nationwide cohort study.

BACKGROUND: Patients with concurrent atrial fibrillation (AF) and diabetes mellitus (DM) [AF-DM] have a high risk of cardiovascular and diabetes-related complications, but are less engaged in a comprehensive treatment approach. We evaluated the association of early rhythm control (ERC), lifestyle modification (LSM), and a combination of ERC and LSM with cardiovascular or diabetes-related complication risk in patients with AF-DM (type 2). METHODS: From the National Health Information Database, 47,940 patients diagnosed with AF-DM in 2009-2016 were included. We defined ERC as rhythm control therapy within two years of AF diagnosis and LSM as adherence to ≥ 2 of the healthy behaviors among non-current smoking, non-drinking, and regular exercise. We compared the primary (ischemic stroke) and secondary (macro- and microvascular complications, glycemic emergency, and all-cause death) outcomes in four groups: non-ERC and non-LSM (group 1), LSM only (group 2), ERC only (group 3), and both ERC and LSM (group 4). RESULTS: Of total, 10,617 (22%), 26,730 (55.8%), 2,903 (6.1%), and 7,690 (16.0%) were classified into groups 1 to 4, in sequence. The mean duration from AF diagnosis to ERC was 25.6 ± 75.5 days. During 4.0 (interquartile range: 2.5-6.2) years' follow-up, groups 2 and 3 were associated with 23% and 33% lower risks of stroke than group 1, respectively. Group 4 was associated with the lowest risk of stroke: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.51-0.67, p < 0.001. Regarding secondary outcomes, the lowest risks were also observed in group 4; macro- and microvascular complications, glycemic emergency, and all-cause death had HRs (95% CIs) of 0.63 (0.56-0.70), 0.88 (0.82-0.94), 0.72 (0.62-0.84), and 0.80 (0.73-0.87), respectively, all p < 0.001. CONCLUSIONS: For AF-DM patients, ERC and LSM exert a synergistic effect in preventing cardiovascular and diabetes-related complications with the greatest lowered risk of stroke. A comprehensive treatment approach should be pursued in AF-DM patients.

XaMINA: A Real-World, Prospective, Observational Study of Treatment-Naïve Patients Treated with Rivaroxaban for Stroke Prevention in Atrial Fibrillation in Asia.

INTRODUCTION: The efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism have been demonstrated in Asian and non-Asian patients with non-valvular atrial fibrillation (NVAF) in multiple studies. However, limited published data exist on its use specifically in treatment-naïve patients from the Asia region. Patients in South Korea and Taiwan can now receive rivaroxaban as first-line therapy, allowing for data generation in this patient group. METHODS: XaMINA was a prospective, real-world, multicenter, single-arm, observational cohort study of patients with NVAF in South Korea and Taiwan naïve to anticoagulation and initiating rivaroxaban. The primary outcome was major bleeding; secondary outcomes included all-cause mortality, symptomatic thromboembolic events, and treatment persistence. RESULTS: In total, 1094 patients were included and the follow-up was 1 year. The baseline mean CHADS2 score was 1.63 ± 0.98, mean CHA2DS2-VASc score was 2.92 ± 1.42, and mean HAS-BLED score was 1.00 ± 0.75. The primary outcome occurred in 20 (1.8%) patients [incidence rate 2.1 events per 100 patient-years (95% CI 1.35-3.25)]. Thromboembolic events occurred in 9 (0.8%) patients, of whom 5 (0.5%) had stroke, 3 (0.3%) myocardial infarction, and 1 (0.1%) a transient ischemic attack. There were no cases of non-central nervous system systemic embolism, and 735 (67.2%) patients persisted with rivaroxaban treatment for 1 year. CONCLUSION: XaMINA demonstrated low incidence rates of major bleeding events and thromboembolic events in patients with NVAF newly initiating rivaroxaban in South Korea and Taiwan, consistent with previous real-world studies reconfirming the results of the ROCKET AF study. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (identifier NCT03284762) on 15 September 2017.

2021 Focused Update Consensus Guidelines of the Asia Pacific Heart Rhythm Society on Stroke Prevention in Atrial Fibrillation: Executive Summary.

The consensus of the Asia Pacific Heart Rhythm Society (APHRS) on stroke prevention in atrial fibrillation (AF) has been published in 2017 which provided useful clinical guidance for cardiologists, neurologists, geriatricians, and general practitioners in the Asia-Pacific region. In these years, many important new data regarding stroke prevention in AF were reported. The practice guidelines subcommittee members comprehensively reviewed updated information on stroke prevention in AF, and summarized them in this 2021 focused update of the 2017 consensus guidelines of the APHRS on stroke prevention in AF. We highlighted and focused on several issues, including the importance of the AF Better Care pathway, the advantages of non-vitamin K antagonist oral anticoagulants (NOACs) for Asians, the considerations of use of NOACs for Asian AF patients with single one stroke risk factor beyond gender, the role of lifestyle factors on stroke risk, the use of oral anticoagulants during the "coronavirus disease 2019" pandemic, etc. We fully realize that there are gaps, unaddressed questions, and many areas of uncertainty and debate in the current knowledge of AF, and the physician's decision remains the most important factor in the management of AF.

Proton Pump Inhibitor Co-Therapy in Patients with Atrial Fibrillation Treated with Oral Anticoagulants and a Prior History of Upper Gastrointestinal Tract Bleeding.

PURPOSE: The risk of gastrointestinal bleeding (GIB) can be mitigated by proton pump inhibitor (PPI) co-therapy in patients with atrial fibrillation (AF) treated with anticoagulants. We aimed to evaluate the effect of PPIs on the risk of GIB in Asian patients with AF, treated with oral anticoagulants (OACs), and with a prior history of upper GIB. METHODS: Using a nationwide claims database, OAC-naïve patients with AF and a history of upper GIB before initiating OAC treatment between January 2010 and April 2018 were included. Patients were categorized into 10 groups according to the index OAC (warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban) and whether or not they received PPI co-therapy, and were followed up for incidence of major GIB. RESULTS: Among a total of 42,048 patients, 40% were prescribed PPIs as co-therapy with OACs. Over a median 0.6 years (interquartile ranges 0.2-1.7 years) of follow-up, rivaroxaban use without PPIs showed the highest crude incidence of major GIB (2.62 per 100 person-years), followed by the use of warfarin without a PPI (2.20 per 100 person-years). Compared to the patients without PPI use, PPI co-therapy was associated with a significantly lower risk of major GIB, by 40% and 36%, in the rivaroxaban and warfarin groups, respectively. In dabigatran, apixaban, and edoxaban users, PPI co-therapy did not show a significant reduction in the risk of major GIB. CONCLUSION: Among patients with AF receiving anticoagulant treatment and with a prior history of upper GIB, PPI co-therapy was associated with a significant reduction in the risk of major GIB in patients treated with rivaroxaban and warfarin.

Effectiveness and Safety of Contemporary Oral Anticoagulants Among Asians With Nonvalvular Atrial Fibrillation.

Background and Purpose- Limited evidence exists on the effectiveness and safety of warfarin and all 4 available non-vitamin K antagonist oral anticoagulants (NOACs) from current clinical practice in the Asian population with nonvalvular atrial fibrillation. We aimed to evaluate the comparative effectiveness and safety of warfarin and 4 NOACs. Methods- We studied a retrospective nonrandomized observational cohort of oral anticoagulant naïve nonvalvular patients with atrial fibrillation treated with warfarin or NOACs (rivaroxaban, dabigatran, apixaban, or edoxaban) from January 2015 to December 2017, based on the Korean Health Insurance Review and Assessment database. For the comparisons, warfarin to 4 NOACs and NOAC to NOAC comparison cohorts were balanced using the inverse probability of treatment weighting. Ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding, and a composite clinical outcome were evaluated. Results- A total of 116 804 patients were included (25 420 with warfarin, 35 965 with rivaroxaban, 17 745 with dabigatran, 22 177 with apixaban, and 15 496 with edoxaban). Compared with warfarin, all NOACs were associated with lower risks of ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding, and composite outcome. Apixaban and edoxaban showed a lower rate of ischemic stroke compared with rivaroxaban and dabigatran. Apixaban, dabigatran, and edoxaban had a lower rate of gastrointestinal bleeding and major bleeding compared with rivaroxaban. The composite clinical outcome was nonsignificantly different for apixaban versus edoxaban. Conclusions- In this large contemporary nonrandomized Asian cohort, all 4 NOACs were associated with lower rates of ischemic stroke and major bleeding compared with warfarin. Differences in clinical outcomes between NOACs may give useful guidance for physicians to choose drugs to fit their particular patient clinical profile.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in octogenarian patients with non-valvular atrial fibrillation.

BACKGROUND AND OBJECTIVE: Elderly patients with atrial fibrillation (AF) are known to have a high risk of stroke and bleeding. We investigated the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in octogenarian patients with non-valvular AF compared with warfarin. METHODS: A total of 687 octogenarian patients with AF who were administered NOACs (n = 403) or warfarin (n = 284) for stroke prevention between 2012 and 2016 were included. Thromboembolic (TE) events (stroke or systemic embolism), major bleeding events, and all-cause death were analyzed. RESULTS: The NOACs group (age 83.4±3.2 years, women 52.4%, CHA2DS2-VASc score 5.0±1.8) comprised 141 dabigatran, 158 rivaroxaban, and 104 apixaban users. Most patients from the NOACs group had been prescribed a reduced dose of medication (85.6%). During 14±18 months of follow-up periods, there were 19 TE events and 18 major bleeding events. Patients with NOAC showed a lower risk of TE (1.84 vs. 2.71 per 100 person-years, hazard ration [HR] 0.134, 95% confidence interval [CI] 0.038-0.479, P = 0.002), major bleeding (1.48 vs. 2.72 per 100 person-years, HR 0.110, 95% CI 0.024-0.493, P = 0.001), and all-cause death (2.57 vs. 3.50 per 100 person-years, HR 0.298, 95% CI 0.108-0.824, P = 0.020). CONCLUSION: In octogenarian Asian patients with AF, NOACs might be associated with lower risks of thromboembolic events, major bleeding, and all-cause death than warfarin. Although most patients had received reduced doses, on-label use of NOACs was effective and safe.

Label Adherence for Non-Vitamin K Antagonist Oral Anticoagulants in a Prospective Cohort of Asian Patients with Atrial Fibrillation.

PURPOSE: Label adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs. MATERIALS AND METHODS: In this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations. RESULTS: We evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA2DS2-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use. CONCLUSION: In real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.

Edoxaban in Asian Patients With Atrial Fibrillation: Effectiveness and Safety.

BACKGROUND: It is unclear whether edoxaban shows better risk reduction of ischemic stroke, bleeding, and all-cause mortality than warfarin in Asian patients with nonvalvular atrial fibrillation (AF). OBJECTIVES: This study compared the effectiveness and safety of edoxaban with those of warfarin in a Korean population with AF. METHODS: Using the Korean National Health Insurance Service database, we included new users of edoxaban and warfarin in patients with AF from January 2014 to December 2016 (n = 4,200 on edoxaban, and n = 31,565 on warfarin) and analyzed the risk of ischemic stroke, intracranial hemorrhage (ICH), hospitalization for gastrointestinal (GI) bleeding, hospitalization for major bleeding, and all-cause death. The propensity score matching method was used to balance covariates across edoxaban and warfarin users. RESULTS: We compared a 1:3 propensity score-matched cohort of patients with AF who were new users of edoxaban and warfarin (n = 4,061 and n = 12,183, respectively). Baseline characteristics were balanced between the 2 groups (median age 72 years; median CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65-74 years, sex category (female)] score 3). Edoxaban users had a significantly lower risk of ischemic stroke (hazard ratio [HR]: 0.693; 95% confidence interval [CI]: 0.487 to 0.959), ICH (HR: 0.407; 95% CI: 0.182 to 0.785), hospitalization for GI bleeding (HR: 0.597; 95% CI: 0.363 to 0.930), hospitalization for major bleeding (HR: 0.532; 95% CI: 0.352 to 0.773), and all-cause death (HR: 0.716; 95% CI: 0.549 to 0.918) than warfarin users. All subgroups (age, sex, CHA2DS2-VASc score, renal function, edoxaban dose) showed better clinical outcomes with edoxaban than with warfarin. CONCLUSIONS: In this real-world Asian population with AF, edoxaban might be associated with reduced risk of ischemic stroke, major bleeding, and all-cause death compared with warfarin. These benefits were consistent across various high-risk subgroups.

Proteinuria Detected by Urine Dipstick Test as a Risk Factor for Atrial Fibrillation: A Nationwide Population-Based Study.

Proteinuria is one of the well-known risk factors for cardiovascular disease. However the impact of proteinuria on the incidence of atrial fibrillation (AF) is unclear. In this study, we investigated the association between proteinuria detected using urine dipstick test and the risk of AF. A total of 18,201,275 individuals were analyzed, who had no prior AF and had received biennial health checkups provided by the National Health Insurance Service between 2005 and 2008 in Korea. Incidences of AF were ascertained through the end of 2015. During a mean follow-up of 9.6 years, a total of 324,764 (1.8%) developed AF (1.86 per 1,000 person-years). In Cox regression models, proteinuria was associated with an increased risk of AF: adjusted HR and 95% CI of AF occurrence were 1.13 (1.10-1.16), 1.34 (1.31-1.38), 1.53 (1.48-1.58), 1.82 (1.71-1.94), and 1.86 (1.61-2.16) in individuals with trace, 1+, 2+, 3+, and 4+ proteinuria, respectively, compared with those without proteinuria. The result was consistent even after additional adjustment for estimated glomerular filtration rate. In addition, the risk of AF further increased or decreased according to the follow-up dipstick test results. Thus, proteinuria measured with a dipstick test might be considered a potent risk factor for AF development.

Electrogram analysis and pacing are complimentary for recognition of abnormal conduction and far-field potentials during substrate mapping of infarct-related ventricular tachycardia.

BACKGROUND: Mapping to identify scar-related ventricular tachycardia re-entry circuits during sinus rhythm focuses on sites with abnormal electrograms or pace-mapping findings of QRS morphology and long stimulus to QRS intervals. We hypothesized that (1) these methods do not necessarily identify the same sites and (2) some electrograms are far-field potentials that can be recognized by pacing. METHODS AND RESULTS: From 12 patients with coronary disease and recurrent ventricular tachycardia undergoing catheter ablation, we retrospectively analyzed electrograms and pacing at 546 separate low bipolar voltage (<1.5 mV) sites. Electrograms were characterized as showing evidence of slow conduction if late potentials (56%) or fractionated potentials (76%) were present. Neither was present at (13%) sites. Pacing from the ablation catheter captured 70% of all electrograms. Higher bipolar voltage and fractionation were independent predictors for pace capture. There was a linear correlation between the stimulus to QRS duration during pacing and the lateness of a capturing electrogram (P<0.001), but electrogram and pacing markers of slow conduction were discordant at 40% of sites. Sites with far-field potentials, defined as those that remained visible and not captured by pacing stimuli, were identified at 48% of all pacing sites, especially in areas of low bipolar voltage and late potentials. Initial radiofrequency energy application rendered 74% of targeted sites electrically unexcitable. CONCLUSIONS: Far-field potentials are common in scar areas. Combining analysis of electrogram characteristics and assessment of pace capture may refine identification of substrate targets for radiofrequency ablation.

Ventricular tachycardia in cardiac sarcoidosis: characterization of ventricular substrate and outcomes of catheter ablation.

BACKGROUND: Cardiac sarcoid-related ventricular tachycardia (VT) is a rare disorder; the underlying substrate and response to ablation are poorly understood. We sought to examine the ventricular substrate and outcomes of catheter ablation in this population. METHODS AND RESULTS: Of 435 patients with nonischemic cardiomyopathy referred for VT ablation, 21 patients (5%) had cardiac sarcoidosis. Multiple inducible VTs were observed with mechanism consistent with scar-mediated re-entry in all VTs. Voltage maps showed widespread and confluent right ventricular scarring. Left ventricular scarring was patchy with a predilection for the basal septum, anterior wall, and perivalvular regions. Epicardial right ventricular scar overlay and exceeded the region of corresponding endocardial scar. After ≥1 procedures, ablation abolished ≥1 inducible VT in 90% and eliminated VT storm in 78% of patients; however, multiple residual VTs remained inducible. Failure to abolish all inducible VTs was because of septal intramural circuits or extensive right ventricular scarring. Multiple procedure VT-free survival was 37% at 1 year, but VT control was achievable in the majority of patients with fewer antiarrhythmic drugs compared with preablation (2.1±0.8 versus 1.1±0.8; P<0.001). CONCLUSIONS: Patients with cardiac sarcoidosis and VT exhibit ventricular substrate characterized by confluent right ventricular scarring and patchy left ventricular scarring capable of sustaining a large number of re-entrant circuits. Catheter ablation is effective in terminating VT storm and eliminating ≥1 inducible VT in the majority of patients, but recurrences are common. Ablation in conjunction with antiarrhythmic drugs can help palliate VT in this high-risk population.

Ventricular arrhythmias near the distal great cardiac vein: challenging arrhythmia for ablation.

BACKGROUND: Catheter ablation for ventricular arrhythmia (VA) near the distal great cardiac vein (GCV) is often challenging, and data are limited. METHODS AND RESULTS: Analysis was performed in 30 patients (19 men; age, 52.8±15.5 years) who underwent catheter ablation for focal VA (11 ventricular tachycardia and 19 premature contractions) with early activation in the GCV (36.7±8.0 ms pre-QRS). Angiography in 27 patients showed earliest GCV site within 5 mm of a coronary artery in 20 (74%). Ablation was performed in the GCV in 15 patients and abolished VA in 8. Ablation was attempted at adjacent non-GCV sites in 19 patients and abolished VA in 5 patients (4 from the left ventricular endocardium and 1 from the left coronary cusp); all success had VA with an initial r wave in lead I and activation ≤7 ms after the GCV (GCV-non-GCV interval). In 13 patients, percutaneous epicardial mapping was performed, but because of adjacent coronaries only 2 received radiofrequency application with VA elimination in 1. Surgical cryoablation was performed in 3 patients and abolished VA in 2. Overall acute success was achieved in 16 (53%) patients. After a median of 2.8 months, 13 patients remained free of VA. Major complications occurred in 4 patients, including coronary injury requiring stenting. CONCLUSIONS: Ablation for this arrhythmia is challenging and often limited by the adjacent coronary vessels. Success of anatomically guided endocardial ablation may be identified by a short GCV-non-GCV interval and r wave in lead I.

Left ventricular dyssynchrony in pre-excitation syndrome: effect of accessory pathway location and reversibility after ablation therapy.

We sought to evaluate the effects and reversibility of different locations of accessory pathways (AP) on left ventricular dyssynchrony (LVdys). The acute and chronic effects of AP were evaluated in a canine model (n = 11) and in patients with pre-excitation syndrome (n = 25). Pre-excitation was simulated in the canine model by applying VDD-type epicardial ventricular pacing near the atrioventricular (AV) groove with 50-ms AV interval after median thoracotomy, at five different sites in each animal. For the simulation of pre-excitation through the septal accessory pathway, right basal septal pacing was performed using a transvenous lead. Left ventricular dyssynchrony was measured by a two-dimensional speckle-tracking technique: before and during pacing in the canine model, and before and within 24 h after the ablation in patients with Wolff-Parkinson-White (WPW) syndrome. In the canine model, the most prominent intraventricular LVdys was observed in left lateral pre-excitation (P < 0.001). In patients with pre-excitation syndrome, LVdys was greatest in patients with left free wall accessory pathways before the ablation (P = 0.013). After catheter ablation, such a difference diminished (P = 0.619). The degree of LVdys was different according to the site of AP in both the acute model and chronic patients, and the most significant LVdys associated with pre-excitation was observed in left lateral AP. Left ventricular dyssynchrony was reversible in patients with WPW syndrome. Left ventricular dyssynchrony observed in patients with pre-excitation syndrome might be a different entity from that observed in patients with heart failure.

Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-ß1.

BACKGROUND: Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Ca(i)) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor ß1 (TGF-ß1). METHODS AND RESULTS: MHC-TGFcys(33)ser Tx mice develop atrial fibrosis because of elevated levels of TGF-ß1. We studied membrane potential and Ca(i)transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Ca(i) transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca(2+)-ATPase 2a. CONCLUSIONS: Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Ca(i) transient, EAD and triggered activity. Inhibition of Ca(2+) release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-ß1 Tx atria.

Circadian and seasonal variations of ventricular tachyarrhythmias in patients with early repolarization syndrome and Brugada syndrome: analysis of patients with implantable cardioverter defibrillator.

INTRODUCTION: The circadian and seasonal patterns of ventricular tachyarrhythmia (VTA) in patients with early repolarization syndrome (ERS) have not been determined. We compared the timing of VTAs in patients with ERS and Brugada syndrome (BS). METHODS AND RESULTS: We enrolled patients with ERS (n = 14) and BS (n = 53) who underwent implantable cardioverter defibrillator (ICD) implantation. The timing of VTAs, including cardiac arrest and appropriate shocks, was determined. During follow up of 6.4 ± 3.6 years in the ERS group and 5.0 ± 3.3 years in the BS group, 5 of 14 (36%) ERS and 10 of 53 (19%) BS patients experienced appropriate shocks (P = 0.37). Cardiac arrest showed a trend of nocturnal distribution peaking from midnight to early morning (P = 0.14 in ERS, P = 0.16 in BS). Circadian distribution of appropriate shocks showed a significant nocturnal peak in patients with ERS (P < 0.0001) but a trend toward a nocturnal peak in patients with BS (P = 0.08). There were no seasonal differences in cardiac arrest in patients with ERS and BS. However, patients with ERS showed a seasonal peak in appropriate shocks from spring to summer (P < 0.0001). There was no significant seasonal peak in patients with BS. The timing of VTAs (cardiac arrest plus appropriate shock) showed significant nocturnal distributions in patients with ERS and BS (P < 0.01, respectively). A significant clustering of VTAs was noted from spring to summer (P < 0.01) in patients with ERS, but not in patients with BS (P = 0.42). CONCLUSIONS: Incidence of VTAs showed marked circadian variations with night-time peaks in patients with ERS and BS.

Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation.

BACKGROUND: Autonomic denervation may suppress atrial fibrillation (AF) vulnerability. This study was designed to assess the short- to mid-term effects of botulinum toxin, a cholinergic neurotransmission blocker, on AF inducibility. METHODS AND RESULTS: A total of 23 mongrel dogs were studied. The sinus node and atrioventricular node epicardial fat pads were exposed through a right lateral thoracotomy. Botulinum toxin (Botox, 50 U per fat pad) or 0.9% normal saline (control) was injected into the center of each of the 2 fat pads. The electrophysiological effects were evaluated at 1, 2, and 3 weeks (7 to 8 animals at each time point) with and without cervical vagal stimulation. The vagal stimulation effects on the sinus and atrioventricular nodes were inhibited, and dispersion of atrial effective refractory period was lower at 1 week in the Botox group. Significant suppression of AF inducibility was observed at 1 week but disappeared at 2 and 3 weeks. These changes were not observed in the control group. CONCLUSIONS: Temporary suppression of vagally mediated AF, for at least 1 week, was achieved with botulinum toxin injection in this canine model. This effect might be associated with reduced dispersion of effective refractory period. A temporary autonomic block using botulinum toxin might be a novel therapeutic option for several clinical conditions such as post-cardiac surgery AF.