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Background--Celivarone is a new antiarrhythmic agent developed for the treatment of ventricular arrhythmias. This study investigated the efficacy and safety of celivarone in preventing implantable cardioverter-defibrillator (ICD) interventions or death. Methods and Results--Celivarone (50, 100, or 300 mg/d) was assessed compared with placebo in this randomized, double-blind, placebo-controlled, parallel-group study. Amiodarone (200 mg/d after loading dose of 600 mg/d for 10 days) was used as a calibrator. A total of 486 patients with a left ventricular ejection fraction ≤40% and at least 1 ICD intervention for ventricular tachycardia or ventricular fibrillation in the previous month or ICD implantation in the previous month for documented ventricular tachycardia/ventricular fibrillation were randomized. Median treatment duration was 9 months. The primary efficacy end point was occurrence of ventricular tachycardia/ventricular fibrillation-triggered ICD interventions (shocks or antitachycardia pacing) or sudden death. The proportion of patients experiencing an appropriate ICD intervention or sudden death was 61.5% in the placebo group; 67.0%, 58.8%, and 54.9% in the celivarone 50-, 100-, and 300-mg groups, respectively; and 45.3% in the amiodarone group. Hazard ratios versus placebo for the primary end point ranged from 0.860 for celivarone 300 mg to 1.199 for celivarone 50 mg. None of the comparisons versus placebo were statistically significant. Celivarone had an acceptable safety profile. Conclusions--Celivarone was not effective for the prevention of ICD interventions or sudden death. [ABSTRACT FROM AUTHOR]

Background: Sex differences in atrial fibrillation (AF) phenotype are well known, but knowledge on prognosis and its predictors is limited. This study sought to investigate sex differences in phenotype, outcome and its predictors in patients with permanent AF. Methods: In RACE II 614 permanent AF patients, 211 women and 403 men, were randomized to lenient or strict rate control. Patient characteristics, cardiovascular outcome (composite of cardiovascular death, heart failure (HF) hospitalization, stroke, systemic embolism, and life-threatening arrhythmic events) and its predictors were compared between the sexes. Results: Baseline differences exist between women and men (Table). Incidence of cardiovascular events at 3 years was relatively low, 13%; 15% for women and 11% for men (P=0.09) with no difference in individual endpoint components (Table). In multivariable analysis, AF duration (1.01 [1.00-1.01], P<0.001), NT-proBNP (1.03 [1.02-1.05], P<0.001), Hs-TroponineT (1.02 [1.01-1.04), P=0.007) and previous HF hospitalization (2.30 [1.19-4.43], P=0.013) were endpoint predictors for all patients. In women LAVI (1.05 [1.02-1.09], P=0.002), AF duration (1.02 [1.01-1.03], P<0.001) and NT-proBNP (1.06 [1.02-1.10], P=0.003) were predictors; for men AF duration (1.01 [1.00-1.01], P=0.04), NT-proBNP (1.03 [1.01-1.05], P=0.002) and hsTroponine-T (1.03 [1.01-1.05], P=0.005). In women LAVI was an important predictor. After adjustment for age, NT-proBNP, AF duration, and CHADS2 the highest tertile remained associated with a worse outcome in women but not in men (2.60 [1.00-6.78], P=0.0049). Conclusions: Women in RACE II were older, had higher CHADS2scores, more hypertension, and less CAD. Event-rate was low, there were no sex differences. Predictors for outcome in all patients were longer AF and higher NT-proBNP. In women, but not men, LAVI was associated with a worse outcome. This association likely reflects a sex specific cardiovascular disease burden. [ABSTRACT FROM AUTHOR]

Background: The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known., Methods: These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA 2 DS 2 -VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA 2 DS 2 -VA score)., Results: EAST-AFNET4 randomized 1093 patients with CHA 2 DS 2 -VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA 2 DS 2 -VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA 2 DS 2 -VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA 2 DS 2 -VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P =0.56, P interaction =0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA 2 DS 2 -VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P =0.175), but occurred more often in patients with CHA 2 DS 2 -VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P =0.019, P interaction =0.008). Life-threatening events or death were not different between groups (CHA 2 DS 2 -VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA 2 DS 2 -VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA 2 DS 2 -VA score), the P interaction was not significant for the primary efficacy outcome ( P =0.25), but remained significant ( P =0.044) for the primary safety outcome., Conclusions: Patients with recently diagnosed atrial fibrillation and CHA 2 DS 2 -VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01288352. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20. URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680.

Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.

Background: Many patients with atrial fibrillation are at high risk for stroke and require antithrombotic therapy. Antiarrhythmic drugs have not previously been shown to reduce the risk of stroke in atrial fibrillation. The effect of dronedarone, a new multichannel-blocking antiarrhythmic drug, on stroke has been evaluated in a randomized, double-blind clinical trial, ATHENA (A placebo-controlled, double-blind, parallel-arm Trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter)., Methods and Results: Patients with persistent or paroxysmal atrial fibrillation and at least 1 risk factor for cardiovascular hospitalization were randomized to receive dronedarone (400 mg BID) or double-blind matching placebo and followed up for a minimum of 1 year to a common termination at 30 months. All strokes that occurred during the study were included in the present post hoc analysis. There were 4628 patients randomized to placebo or dronedarone. The baseline risk factors for stroke were well balanced between the 2 groups, and the baseline mean CHADS(2) score was 2. The baseline use of either oral anticoagulant therapy or antiplatelet agent alone was 60%. Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (hazard ratio 0.66, 95% confidence interval 0.46 to 0.96, P=0.027). The effect of dronedarone was similar whether or not patients were receiving oral anticoagulant therapy, and there was a significantly greater effect of dronedarone in patients with higher CHADS(2) scores., Conclusions: In this post hoc analysis, a reduction in stroke was observed in patients with atrial fibrillation who were receiving usual care, which included antithrombotic therapy and heart rate control, who were randomized to dronedarone. Further studies to investigate the effect of dronedarone and other antiarrhythmic agents on stroke are indicated.

Background: Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF., Methods and Results: In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction., Conclusions: This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.

Background: Cryoablation (cryo) has a high success rate in the short-term treatment of atrial flutter (AFL), but evidence of long-term efficacy is lacking. The present study reports the long-term effect of cryo of the cavotricuspid isthmus (CTI) in patients with common AFL., Methods and Results: Thirty-five consecutive patients (28 men; mean age, 53 years) underwent cryo of the CTI. In 34 patients, the AFL had a counterclockwise rotation (cycle length, 242+/-43 ms). Eleven patients had structural heart disease. Cryo was performed with a 10F catheter with a 6-mm-tip electrode (CryoCor). Applications (3 to 5 minutes each) were delivered by use of a point-by-point technique to create the ablation line. The acute end point of the procedure was creation of bidirectional isthmus conduction block and noninducibility of AFL. A median of 14 applications (range, 4 to 30) at 10 sites (range, 4 to 19) was given along the CTI with a mean temperature of -80.0+/-5.0 degrees C. Mean fluoroscopy and procedure times were 40+/-26 minutes and 3.2+/-1.3 hours, respectively. Of the 35 patients, 34 were acutely successfully ablated (97%). After a mean follow-up of 17.6+/-6.2 months (range, 9.6 to 26.1 months), 31 patients (89%) did not have recurrence of AFL. Three of the 4 patients with recurrence had a second successful procedure. One patient had transient ST elevation in the inferior leads during cryoapplication., Conclusions: Cryo produces permanent bidirectional isthmus conduction block of the CTI. Short- and long-term success rates are comparable to those for radiofrequency ablation.

Background: Idiopathic left bundle-branch block (LBBB)-like ventricular tachycardia (VT) is considered to originate in the right ventricular outflow tract (RVOT) or from the aortic root. Both regions are derived from the embryonic outflow tract. We now report that also the pulmonary trunk can give rise to VT, suggesting a common etiology of these tachycardias., Methods and Results: We studied 6 patients with symptomatic idiopathic LBBB-VT using electrophysiological mapping techniques. The VT origin was determined by analyzing the electrograms and the angiographic location of the catheter tip at the successful ablation site or the earliest activation site. Eight VTs were induced. Two VTs, with a mean earliest endocardial activation time of -5 and -20 ms and optimal pace mapping, were successfully ablated in the RVOT. In the remaining 6 VTs, the earliest activation site was found in the pulmonary artery, and, at this site, a sharp potential was present -38+/-12 ms before the QRS in 5 VTs. The mean earliest endocardial activation time in the RVOT was -1+/-2 ms. Ablation was attempted in 5 of 6 VTs and resulted in an acutely successful procedure. After a mean follow-up of 10+/-4 months, 1 of 5 patients had a recurrence., Conclusions: The site of origin of idiopathic LBBB-VT can be in the root of the pulmonary artery, suggesting a myocardial connection from this site to the RVOT. If no good criteria for ablation in the RVOT are found, detailed mapping of the pulmonary artery should be performed.