A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation.

AIMS: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial. METHODS: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. RESULTS: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h. CONCLUSION: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the IKr channel.

Development and Validation of the AFImpact: An Atrial Fibrillation-Specific Measure of Patient-Reported Health-Related Quality of Life.

BACKGROUND: Improvement in health-related quality of life is a key therapeutic goal of disease management in atrial fibrillation (AF). OBJECTIVES: To describe the development of the AFImpact, an AF-specific health-related quality-of-life patient-reported outcome measure. METHODS: Development and validation of the AFImpact comprised a qualitative stage, consisting of a literature review and concept elicitation interviews (91 patients with AF), item generation, and cognitive debriefing (30 patients with AF), and a quantitative stage, consisting of evaluation of the instrument's psychometric properties (313 patients with AF). Preliminary responsiveness to change was assessed in 118 patients undergoing cardioversion. RESULTS: On the basis of the literature review and concept elicitation interviews, 75 items were generated. Factor analyses guided a reduction to 18 items. Three domains were confirmed: vitality (7 items), emotional distress (8 items), and sleep (3 items). The 18-item AFImpact demonstrated high item convergent and discriminant validity. Cronbach α coefficients showed high internal consistency reliability. Test-retest reliability of individual items in stable patients (n = 33) was satisfactory, with intraclass correlation coefficients ranging from 0.61 to 0.86. All three AFImpact domain scores differentiated patients who reported different levels of overall health, thereby supporting known-groups validity. Scores for each item improved after cardioversion, with effect sizes ranging from -0.19 to -0.65. CONCLUSIONS: Psychometric evaluations support the reliability and validity of the AFImpact as a patient-reported outcome instrument to measure the impact of AF, with preliminary results in patients undergoing cardioversion supporting responsiveness to change.

Rhythm Control and Its Relation to Symptoms during the First Two Years after Radiofrequency Ablation for Atrial Fibrillation.

CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique Identifier: NCT00697359. OBJECTIVES: To evaluate rhythm control up to two years after atrial fibrillation (AF) ablation and its relation to reported symptoms. BACKGROUND: The implantable loop recorder (ILR) continuously records the electrocardiogram (ECG), has an automatic AF detection algorithm, and has a possibility for patients to activate an ECG recording during symptoms. METHODS: Fifty-seven patients (mean age 57 ± 9 years, 60% male, 88% paroxysmal AF) underwent AF ablation following ILR implantation. Device data were downloaded at the ablation and three, six, 12, 18, and 24 months after ablation. RESULTS: Fifty-four patients completed the two-year follow-up. Thirteen (24%) patients had no AF episodes detected by ILR during follow-up. Ten of 41 patients (24%) with AF recurrence were only detected by ILR and AF recurrences were detected earlier by ILR (P < 0.001). The median AF burden in patients with AF recurrence was 5.7% (interquartile range 0.4-14.4) and was even lower in patients with AF only detected by ILR (P = 0.001). Forty-eight % of the patients indicated symptoms via the patient activator but 33% of those recordings were not due to AF. Early AF recurrence (within 3 months) was highly associated with later AF recurrence (P < 0.001). AF burden >0.5% and longest AF episode >6 hours before the ablation were independent predictors of AF recurrence during intermittent but not continuous monitoring. CONCLUSIONS: After AF ablation, the AF burden was low throughout the 24 months follow-up. Nevertheless, symptoms were commonly indicated but one-third of patient-activated recordings did not show AF. Continuous monitoring was superior to intermittent follow-up in detecting AF episodes and assessing the AF burden.

Inverse Correlation between the Atrial Fibrillatory Rate and the Ventricular Repolarization Time: Observations at Baseline and after an Intravenous Infusion of a Combined Potassium and Sodium Current Blocker.

BACKGROUND: The atrial fibrillatory rate (AFR) and the ventricular rate and repolarization (QTcF) were studied at baseline and under the influence of the combined potassium and sodium current blocker AZD7009. METHODS: Ninety-two patients with atrial fibrillation (AF) were randomized to an intravenous infusion of AZD7009 or placebo. The atrial fibrillatory activity in lead V1 was extracted using spatiotemporal QRST cancellation. The exponential decay (ED) characterized the degree of atrial signal organization. RESULTS: The mean (SD) AFR at baseline was 396  ±  57 (range 253-584) and 410 ± 33 (range 363-469) bpm in patients randomized to AZD7009 and placebo, respectively. The AFR decreased within the first minutes of the AZD7009 infusion and reached its minimum of 235 ± 34 bpm after 18 minutes. On placebo, the AFR was unchanged. On AZD7009, the ED decreased from 1.2 ± 0.3 to reach its lowest level at 0.7 ± 0.2 after 14 minutes. The ventricular rate did not change significantly over time. The AFR was statistically significantly related to the ventricular repolarization at baseline, the QTcF being longer at lower AFR values, and this relationship remained during and after AZD7009. In the full multivariate linear regression model, including age, sex, left ventricular ejection fraction, QRS duration, heart rate, QTcF, AF episode duration, AF history duration, and right atrial or left atrial size, only QTcF and age were statistically significantly correlated with the AFR. The correlation remained when the uncorrected QT interval was used. CONCLUSIONS: The QTcF was inversely correlated with AFR, both at baseline and during administration of AZD7009. The AFR was not correlated with the ventricular rate.

Costs of unstructured investigation of unexplained syncope: insights from a micro-costing analysis of the observational PICTURE registry.

AIMS: The observational PICTURE (Place of Reveal In the Care pathway and Treatment of patients with Unexplained Recurrent Syncope) registry enrolled 570 patients with unexplained syncope, documented their care pathway and the various tests they underwent before the insertion of an implantable loop recorder (ILR). The aims were to describe the extent and cost of diagnostic tests performed before the implant. METHODS AND RESULTS: Actual costs of 17 predefined diagnostic tests were characterized based on a combination of data from PICTURE and a micro-costing study performed at a medium-sized UK university hospital in the UK. The median cost of diagnostic tests per patient was £1114 (95% CI £995-£1233). As many patients received more than the median number of tests, the mean expenditure per patient was higher with £1613 (95% CI £1494-£1732), and for 10% of the patients the cost exceeded £3539. Tests were frequently repeated, and early use of specific and expensive tests was common. In the 12% of patients with types of tests entirely within the recommendations for an initial evaluation before ILR implant, the mean cost was £710. CONCLUSION: Important opportunities to reduce test-related costs before an ILR implant were identified, e.g. by more appropriate use of tests recommended in the initial evaluation, by decreasing repetition of tests, and by avoiding early use of specialized and expensive tests. A structured multidisciplinary approach would be the best model to achieve an optimal outcome.

Changes in medication preceding out-of-hospital cardiac arrest where resuscitation was attempted.

OBJECTIVE: To describe recent changes in medication preceding out-of-hospital cardiac arrest (OHCA) where resuscitation was attempted. METHODS: OHCA victims were identified by the Swedish Cardiac Arrest Register and linked by means of their unique 10-digit personal identification numbers to the Prescribed Drug Register. We identified new claimed prescriptions during a 6-month period before the OHCA compared with those claimed in the period 12 to 18 months before. The 7-digit Anatomical Therapeutical Chemical codes of individual drugs were used. The study period was November 2007-January 2011. RESULTS: OHCA victims with drugs were (1) older than those who did not claim any drugs in any period (70 ± 16 years vs. 54 ± 22 years, P < 0.001), (2) more often women (34% vs. 20%, P < 0.001), and (3) had more often a presumed cardiac etiology (67% vs. 54%, P < 0.001). The OHCA victims were less likely to have ventricular tachycardia/ventricular fibrillation as the first recorded rhythm (26% vs. 33%, P < 0.001) or to survive 1 month (9% vs. 17%, P < 0.0001). New prescriptions were claimed by 5122 (71%) of 7243 OHCA victims. The most frequently claimed new drugs were paracetamol (acetaminophen) 10.3%, furosemide 7.8%, and omeprazole 7.6%. Of drugs known or supposed to cause QT prolongation, ciprofloxacin was the most frequent (3.4%) altogether; 16% had a new claimed prescription of a drug included in the "qtdrugs.org" lists. CONCLUSIONS: Most OHCA victims had new drugs prescribed within 6 months before the event but most often intended for diseases other than cardiac. No claims can be made as to the causality.

Predictors of hospitalization for heart failure and of all-cause mortality after atrioventricular nodal ablation and right ventricular pacing for atrial fibrillation.

AIMS: Atrioventricular junction ablation (AVJA) is a highly effective treatment in patients with therapy refractory atrial fibrillation (AF) but renders the patient pacemaker dependent. We aimed to analyse the long-term incidence of hospitalization for heart failure (HF) and all-cause mortality in patients who underwent AVJA because of AF and to determine predictors for HF and mortality. METHODS AND RESULTS: We retrospectively enrolled 162 consecutive patients, mean age 67 ± 9 years, 48% women, who underwent AVJA because of symptomatic AF refractory to pharmacological treatment (n = 117) or unsuccessful repeated pulmonary vein isolation (n = 45). Hospitalization for HF occurred in 32 (20%) patients and 35 (22%) patients died, representing a cumulative incidence for hospitalization for HF and mortality over the first 2 years after AVJA of 9.1 and 5.2%, respectively. Hospitalization for HF occurred to the same extent in patients who failed pharmacological treatment as in patients with repeated pulmonary vein isolation (PVI), although the mortality was slightly higher in the former group. QRS prolongation ≥120 ms and left atrial diameter were independent predictors of hospitalization for HF, while hypertension and previous HF were independent predictors of death. CONCLUSION: The long-term hospitalization rate for HF and all-cause mortality was low, which implies that long-term ventricular pacing was not harmful in this patient population, including patients with unsuccessful repeated PVI.

Low mortality and low rate of perceived and documented arrhythmias after Cox maze III surgery for atrial fibrillation.

BACKGROUND: To report a long-term single-site experience of the cut-and-sew Cox maze III procedure for atrial fibrillation (AF). METHODS: A total of 232 consecutive patients underwent the Cox maze III procedure for symptomatic therapy-refractory AF, with concomitant surgery in 34 patients. Follow-up data were obtained from electrocardiograms, patient visits, questionnaires, and medical files. RESULTS: There were 103 patients (44%) with paroxysmal AF during 8.8 ± 6.5 years and 129 patients (56%) with nonparoxysmal AF for 7.3 ± 6.7 years. The preoperative New York Heart Association class was better in patients with paroxysmal AF (P < 0.0001); the left ventricular ejection fraction was 59 ± 7% versus 56 ± 8%, P = 0.003, and the left atrial area 24 ± 6 versus 27 ± 6 cm(2) , P = 0.01. Early and late postoperative adverse events occurred at similar rates. Four patients from each group died of reasons unrelated to surgery. The mean follow-up was 66 ± 42 (5-155) months. In total, 184/229 (80%) patients were free of documented AF/atrial flutter/atrial tachycardia (AF/AFl/AT) off antiarrhythmic drugs (AA) and 189/229 (83%) on or off AA. The hazard ratio (HR) for paroxysmal versus nonparoxysmal AF patients regarding documented AF/AFl/AT was 0.8 (95% confidence interval [CI] 0.4-1.4; P = 0.40). For patients without versus with concomitant surgery, the corresponding HR was 0.4 (95% CI 0.2-0.8; P = 0.008). Of 197 patients (89%) responding to the questionnaire, 41 had sought care for symptoms of arrhythmia, 29 of whom had documented AF/AFl/AT, whereas another six had other arrhythmias. CONCLUSION: Cut-and-sew Cox maze III surgery provided long-lasting high efficacy, also in patients with nonparoxysmal AF of long duration and/or concomitant surgery, and was associated with low rates of subsequent adverse events.

Rapid slowing of the atrial fibrillatory rate after administration of AZD7009 predicts conversion of atrial fibrillation.

BACKGROUND: Effects on the atrial fibrillatory rate (AFR) were studied during infusion with the combined potassium and sodium channel blocker AZD7009. METHODS AND RESULTS: Patients with persistent atrial fibrillation (AF) were randomized to AZD7009 or placebo. Thirty-five patients converted to sinus rhythm (SR) and were matched to 35 non-converters. The mean AFR before conversion was 231 fibrillations per minute (fpm), having decreased by 41%; in non-converters, it was 296 fpm at the end of infusion, having decreased by 26%. The rate of decrease was greater in converters at 5 min, -88 vs. -66 fpm (p=0.02), and at 10 min, -133 vs. -111 fpm (p=0.048). The AFR-SD and the exponential decay decreased. A small left atrial area was the only baseline predictor of conversion to SR. CONCLUSIONS: AZD7009 produced a significantly more rapid decrease of the AFR in converters than in non-converters, but the AFR at baseline was not predictive of conversion.

All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide long-term case-control study.

AIMS: To evaluate long-term all-cause risk of mortality in women and men hospitalized for the first time with atrial fibrillation (AF) compared with matched controls. METHODS AND RESULTS: A total of 272 186 patients (44% women) ≤ 85 years at the time of hospitalization with incidental AF 1995-2008 and 544 344 matched controls free of in-hospital diagnosis of AF were identified. Patients were followed via record linkage of the Swedish National Patient Registry and the Cause of Death Registry. Using Cox regression models, the long-term relative all-cause mortality risk, adjusted for concomitant diseases, in women vs. controls was 2.15, 1.72, and 1.44 (P < 0.001) in the age categories ≤ 65, 65-74, and 75-85 years, respectively. The corresponding figures for men were 1.76, 1.36, and 1.24 (P < 0.001). Among concomitant diseases, neoplasm, chronic renal failure, and chronic obstructive pulmonary disease contributed most to the increased all-cause mortality vs. controls. In patients with AF as the primary diagnosis, the relative risk of mortality was 1.63, 1.46, and 1.28 (P < 0.001) in women and 1.45, 1.17, and 1.10 (P < 0.001) in men. CONCLUSION: Atrial fibrillation was an independent risk factor of all-cause mortality in patients with incident AF. The concomitant diseases that contributed most were found outside the thromboembolic risk scores. The highest relative risk of mortality was seen in women and in the youngest patients compared with controls, and the differences between genders in each age category were statistically significant.

Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial.

Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg-1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg-1 AP30663, 5 mg kg-1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg-1 and 5 mg kg-1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg-1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .

Sinus bradycardia and sinus pauses immediately after electrical cardioversion of persistent atrial fibrillation--what do they mean?

BACKGROUND: To determine the role of sinus bradyarrhythmia (SB) immediately after electrical cardioversion of persistent atrial fibrillation (AF) on the short-term recurrence rate and long-term pacemaker need and all-cause mortality. METHODS: SB defined as sinus bradycardia (sinus rate <40 bpm for ≥2 consecutive cycles) and/or sinus pauses (>2 s), were recorded during 5 minutes immediately after successful DC cardioversion in 140 consecutive patients with persistent AF. RESULTS: SB was observed during the first minute of SR in 31 patients (22%). Sinus bradycardia was present in 27 patients, sinus pauses in 16 (>3 s in 10) patients, and both in 12 patients. Compared to patients without SB, the mean heart rate during the first minute after cardioversion was lower, 57 ± 13 versus 63 ± 11 bpm; P < 0.05, while the mean heart rates during the subsequent 4 minutes were not statistically significantly different. The AF recurrence rates were not significantly different at 1 week (45% vs. 40%), or at 3 months (68% vs. 53%) in patients with or without SB. After a mean follow-up of 86 ± 6 months the pacemaker implantation rate was 10% versus 11% (NS) and an all-cause mortality of 26 versus 18% (NS). CONCLUSIONS: SB immediately after electrical cardioversion of persistent AF had no significant impact on the 3-month AF recurrence rate, the long-term need for pacemaker or all-cause mortality.

Assessment of ventricular repolarization variability with the DeltaT50 method improves identification of patients with congenital long QT syndromes.

BACKGROUND: We analyzed ventricular repolarization variability in genotyped long QT syndrome (LQTS) patients and in healthy volunteers (HV). METHOD: The deltaT50, that is, the temporal variability of ventricular repolarization at 50% of the T-wave downslope, was analyzed every 15th minute on 175 and 390 Holter electrocardiogram (ECG) recordings from HV and genotyped LQTS patients, respectively. The average deltaT50 and QTcF were calculated in each subject. RESULTS: DeltaT50 was 2.26 ± 0.71 ms (mean ± SD) in the HV and 5.74 ± 2.30 ms in the LQTS population (P < 0.0001). The sensitivity and specificity of QTcF (cutoff value 450 ms) to discriminate between the LQTS patients and the HV were 51.5% and 98.9%, and for deltaT50 (cutoff value 3 ms) 93.9% and 88.6%, respectively. The combination of both variables improved the diagnosis of the LQTS patients even further. Subgroups of LQTS patients at higher risk of cardiac events (with LQTS3, JLN, QTc > 500 ms or symptoms) had higher deltaT50 than subgroups at lower risk (with LQTS1, QTc < 450 ms or without symptoms). The variation in deltaT50 between day and night was concordant with the risk of symptoms; patients with LQTS1 had higher deltaT50 in the daytime and patients with LQTS3 had higher deltaT50 during the night. CONCLUSION: DeltaT50 more accurately distinguished between LQTS patients and HV than QTcF and was higher in LQTS patients with a higher risk of cardiac events. DeltaT50 can be used together with QTcF to improve the diagnosis in patients with the LQTS phenotype and tentatively also be of value for risk assessment in such patients.

Decrease of the atrial fibrillatory rate, increased organization of the atrial rhythm and termination of atrial fibrillation by AZD7009.

BACKGROUND: The atrial fibrillatory rate (AFR), on AZD7009 as compared to placebo, was investigated as a potential biomarker for electrophysiological effect in early antiarrhythmic drug development. METHODS: Patients with permanent AF received infusions of AZD7009 and placebo in an exploratory two-way, single-blind, randomized cross-over study. The ECG was continuously recorded, and following QRST cancellation the AFR, its standard deviation (SD), the exponential decay and the atrial electrogram amplitude were determined as 3-min averages. RESULTS: The mean AFR rapidly decreased by 43% from baseline (394 ± 38 to 225 ± 61 fibrillations/min, p=0.0003) on AZD7009, but not on placebo. The SD of the AFR and the exponential decay decreased in parallel. In 2 of 8 patients, termination of AF occurred after the AFR had decreased by 58% and 53%, respectively. CONCLUSIONS: The AFR may potentially serve as a biomarker of electrophysiological effects in early evaluation of rhythm control agents.

Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference.

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF.

All-cause mortality trends in patients hospitalized for atrial fibrillation in Sweden: Role of age, stroke risk, and education.

Background: The incidence of atrial fibrillation (AF) has long been increasing, and AF is associated with increased mortality. Over time, mortality trends may differ between subgroups depending on their underlying risk patterns and treatments. Aim: To explore all-cause-mortality trends over time in patients hospitalized for incident AF, and the effects of age, stroke risk, and education level. Methods and results: Patients hospitalized for incident AF between January 1995 and December 2003 were selected from Swedish national registries. Based on date of index admission, patients were divided into four cohorts and followed for five years. Age- and sex-matched controls were selected. Kaplan-Meier estimates and Cox regressions with trend analysis were used for statistical evaluation. There were 64,489 patients (mean age 72 ± 10.1 years) and 116,893 controls. There was a significantly decreasing trend in the relative risk of all-cause mortality in AF patients over time, with a trend hazard ratio of 0.94 (95 % confidence interval [CI] 0.92-0.96, p < 0.001) in women and 0.91 (95 % CI 0.89-0.93, p < 0.001) in men. The mortality trends did not differ significantly between AF patients and controls. The mortality risk remained unchanged in women aged 18-64 years, in patients with low stroke risk, and in patients with post-secondary education. Conclusion: The all-cause mortality risk decreased over time in both patients and controls, but subgroup analysis revealed an unchanged mortality trend in women aged 18-64 years, in patients with low stroke risk, and in patients with post-secondary education.

Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: results from the PICTURE registry.

AIMS: To collect information on the use of the Reveal implantable loop recorder (ILR) in the patient care pathway and to investigate its effectiveness in the diagnosis of unexplained recurrent syncope in everyday clinical practice. METHODS AND RESULTS: Prospective, multicentre, observational study conducted in 2006-2009 in 10 European countries and Israel. Eligible patients had recurrent unexplained syncope or pre-syncope. Subjects received a Reveal Plus, DX or XT. Follow up was until the first recurrence of a syncopal event leading to a diagnosis or for ≥1 year. In the course of the study, patients were evaluated by an average of three different specialists for management of their syncope and underwent a median of 13 tests (range 9-20). Significant physical trauma had been experienced in association with a syncopal episode by 36% of patients. Average follow-up time after ILR implant was 10±6 months. Follow-up visit data were available for 570 subjects. The percentages of patients with recurrence of syncope were 19, 26, and 36% after 3, 6, and 12 months, respectively. Of 218 events within the study, ILR-guided diagnosis was obtained in 170 cases (78%), of which 128 (75%) were cardiac. CONCLUSION: A large number of diagnostic tests were undertaken in patients with unexplained syncope without providing conclusive data. In contrast, the ILR revealed or contributed to establishing the mechanism of syncope in the vast majority of patients. The findings support the recommendation in current guidelines that an ILR should be implanted early rather than late in the evaluation of unexplained syncope.

Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously.

AIM: AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR). METHODS AND RESULTS: Patients with AF episodes of duration 3 h to 3 months were randomized in a 3:1 ratio to receive a maximum 30 min intravenous infusion of AZD1305 or matching placebo. The primary efficacy endpoint was the proportion of patients converting within 90 min of the start of infusion, after which patients who had not converted were to undergo direct current (DC) cardioversion. Four ascending AZD1305 dose groups were assigned sequentially, with dose rates of 50, 100, 130, and 180 mg/h. A total of 171 patients were randomized. Pharmacological conversion was achieved in 0 of 43 patients (0%) in the placebo group, and in 2 of 26 (8%; P= 0.14 vs. placebo), 8 of 45 (18%; P= 0.006), 17 of 45 (38%; P< 0.001), and 6 of 12 patients (50%; P< 0.001) in AZD1305 dose groups 1-4, respectively. Maximum QTcF (QT interval corrected according to Fridericia's formula) generally increased dose-dependently up to a plateau, although there was wide variation between patients. Two patients experienced torsade de pointes (TdP): one patient without symptoms in dose group 3, and one patient requiring DC defibrillation in dose group 4. Both patients recovered without sequelae. CONCLUSIONS: AZD1305 was effective in converting AF to SR, but was associated with QT prolongation and TdP. The benefit-risk profile was judged as unfavourable and the AZD1305 development programme was discontinued. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov identifier NCT00915356.

Cardiac function in relation to rhythm outcome after intraoperative epicardial left atrial cryoablation.

OBJECTIVES: To assess the effects of intraoperative left atrial epicardial cryoablation on rhythm and atrial and ventricular function. DESIGN: Thirty five patients with coronary artery disease and documented atrial fibrillation underwent coronary artery bypass surgery and concomitant cryoablation. An age and gender matched control group of 35 patients with atrial fibrillation underwent bypass surgery alone. Echocardiography was performed 9 ? 32 days before and 22 ? 6 months after surgery. RESULTS: The proportion of patients in sinus rhythm at follow-up was 63% and 34% (p = 0.04) in the cryoablation and control groups, respectively. In patients with sinus rhythm both before surgery and at follow-up, the left atrial area increased (p = 0.002) and the mitral annular excursion during atrial contraction decreased (p = 0.01) after cryoablation. The mitral flow velocity during atrial systole decreased after cryoablation (p = 0.002). The LV diameter increased (p = 0.03) and the left ventricular ejection fraction (LVEF) decreased (p = 0.03) in cryoablated but not in control patients. Continued deterioration was seen in patients with atrial fibrillation both pre- and postoperatively. CONCLUSIONS: At long-term follow-up, a significantly higher proportion of patients was in sinus rhythm in the cryoablation than in the control group. The atrial and ventricular function had decreased at follow-up two years after surgery. This decrease was small and occurred within or close to the reference values in patients with sinus rhythm at follow-up, while patients remaining in atrial fibrillation showed a significant continued deterioration. Some subgroups were small, and the findings, although statistically significant, should be interpreted with caution.

The signal-averaged electrocardiogram before and after electrical cardioversion of persistent atrial fibrillation-implications of the sudden change in rhythm.

BACKGROUND: Atrial fibrillation (AF), electrical cardioversion (direct current, or DC) shock energy, and a sudden change to sinus rhythm (SR) might all influence the interpretation of the signal-averaged electrocardiogram (SAECG) as risk markers of ventricular tachyarrhythmia. METHODS: The SAECG was recorded in 82 patients with persistent AF before and 2 hours after DC and analyzed for ventricular late potentials (LPs) and spectral turbulence. RESULTS: Sixty-nine patients (84%) obtained SR. Their mean (SD) heart rate decreased by 22 (20) beats/min, and the QTcF interval was significantly prolonged, 17 (38) milliseconds, as was the filtered QRS duration, 1.1 (4.7) milliseconds (40 Hz). The proportion of LP positivity (20%) did not change with the change in rhythm. Eight of 60 spectral turbulence-negative patients before DC became positive after DC (P = .01). The change in SAECG variables did not correlate significantly with the amount of energy delivered at DC. CONCLUSION: The LP analysis provided similar results in AF and SR, whereas the spectral turbulence analysis was more abnormal in SR. The electrical shock itself did not seem to explain this phenomenon.