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Background: Exercise-based cardiac rehabilitation may benefit adults with atrial fibrillation or those who had been treated for atrial fibrillation. Atrial fibrillation is caused by multiple micro re-entry circuits within the atrial tissue, which result in chaotic rapid activity in the atria. Objectives: To assess the benefits and harms of exercise-based rehabilitation programmes, alone or with another intervention, compared with no-exercise training controls in adults who currently have AF, or have been treated for AF. Search methods: We searched the following electronic databases; CENTRAL and the Database of Abstracts of Reviews of Effectiveness (DARE) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, PsycINFO Ovid, Web of Science Core Collection Thomson Reuters, CINAHL EBSCO, LILACS Bireme, and three clinical trial registers on 14 July 2016. We also checked the bibliographies of relevant systematic reviews identified by the searches. We imposed no language restrictions. Selection criteria: We included randomised controlled trials (RCT) that investigated exercise-based interventions compared with any type of no-exercise control. We included trials that included adults aged 18 years or older with atrial fibrillation, or post-treatment for atrial fibrillation. Data collection and analysis: Two authors independently extracted data. We assessed the risk of bias using the domains outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed clinical and statistical heterogeneity by visual inspection of the forest plots, and by using standard Chi 2 and I 2 statistics. We performed meta-analyses using fixed-effect and random-effects models; we used standardised mean differences where different scales were used for the same outcome. We assessed the risk of random errors with trial sequential analysis (TSA) and used the GRADE methodology to rate the quality of evidence, reporting it in the 'Summary of findings' table. Main results: We included six RCTs with a total of 421 patients with various types of atrial fibrillation. All trials were conducted between 2006 and 2016, and had short follow-up (eight weeks to six months). Risks of bias ranged from high risk to low risk.The exercise-based programmes in four trials consisted of both aerobic exercise and resistance training, in one trial consisted of Qi-gong (slow and graceful movements), and in another trial, consisted of inspiratory muscle training. For mortality, very low-quality evidence from six trials suggested no clear difference in deaths between the exercise and no-exercise groups (relative risk (RR) 1.00, 95% confidence interval (CI) 0.06 to 15.78; participants = 421; I 2 = 0%; deaths = 2). Very low-quality evidence from five trials suggested no clear difference between groups for serious adverse events (RR 1.01, 95% CI 0.98 to 1.05; participants = 381; I 2 = 0%; events = 8). Low-quality evidence from two trials suggested no clear difference in health-related quality of life for the Short Form-36 (SF-36) physical component summary measure (mean difference (MD) 1.96, 95% CI -2.50 to 6.42; participants = 224; I 2 = 69%), or the SF-36 mental component summary measure (MD 1.99, 95% CI -0.48 to 4.46; participants = 224; I 2 = 0%). Exercise capacity was assessed by cumulated work, or maximal power (Watt), obtained by cycle ergometer, or by six minute walking test, or ergospirometry testing measuring VO2 peak. We found moderate-quality evidence from two studies that exercise-based rehabilitation increased exercise capacity, measured by VO2 peak, more than no exercise (MD 3.76, 95% CI 1.37 to 6.15; participants = 208; I 2 = 0%); and very low-quality evidence from four studies that exercise-based rehabilitation increased exercise capacity more than no exercise, measured by the six-minute walking test (MD 75.76, 95% CI 14.00 to 137.53; participants = 272; I 2 = 85%). When we combined the different assessment tools for exercise capacity, we found very low-quality evidence from six trials that exercise-based rehabilitation increased exercise capacity more than no exercise (standardised mean difference (SMD) 0.86, 95% CI 0.46 to 1.26; participants = 359; I 2 = 65%). Overall, the quality of the evidence for the outcomes ranged from moderate to very-low. Authors' conclusions: Due to few randomised patients and outcomes, we could not evaluate the real impact of exercise-based cardiac rehabilitation on mortality or serious adverse events. The evidence showed no clinically relevant effect on health-related quality of life. Pooled data showed a positive effect on the surrogate outcome of physical exercise capacity, but due to the low number of patients and the moderate to very low-quality of the underpinning evidence, we could not be certain of the magnitude of the effect. Future high-quality randomised trials are needed to assess the benefits and harms of exercise-based cardiac rehabilitation for adults with atrial fibrillation on patient-relevant outcomes.

Among atrial tachyarrhythmias (AT), atrial fibrillation (AF) is the most common sustained arrhythmia. Many patients with AT have no symptoms during brief or even extended periods of the arrhythmia, making detection in patients at risk for stroke challenging. Subclinical atrial tachyarrhythmia and asymptomatic or silent atrial tachyarrhythmia often precede the development of clinical AF. Clinical AF and subclinical atrial fibrillation (SCAF) are associated with an increased risk of thromboembolism. Indeed, in many cases, SCAF is discovered only after complications such as ischaemic stroke or congestive heart failure have occurred

Supplemental Digital Content is available in the text., Background Evidence has emerged that small-conductance Ca2+-activated K+ (SK) channels constitute a new target for treatment of atrial fibrillation (AF). SK channels are predominantly expressed in the atria as compared with the ventricles. Various marketed antiarrhythmic drugs are limited by ventricular adverse effects and efficacy loss as AF progresses. Methods and Results A total of 43 pigs were used for the studies. AF reversion in conscious long-term tachypaced pigs: Pigs were subjected to atrial tachypacing (7 Hz) until they developed sustained AF that could not be reverted by vernakalant 4 mg/kg (18.8±3.3 days of atrial tachypacing). When the SK channel inhibitor AP14145 was tested in these animals, vernakalant-resistant AF was reverted to sinus rhythm, and reinduction of AF by burst pacing (50 Hz) was prevented in 8 of 8 pigs. Effects on refractory period and AF duration in open chest pigs: The effects of AP14145 and vernakalant on the effective refractory periods and acute burst pacing-induced AF were examined in anaesthetized open chest pigs. Both vernakalant and AP14145 significantly prolonged atrial refractoriness and reduced AF duration without affecting the ventricular refractoriness or blood pressure in pigs subjected to 7 days atrial tachypacing, as well as in sham-operated control pigs. Conclusions SK currents play a role in porcine atrial repolarization, and pharmacological inhibition of these with AP14145 demonstrates antiarrhythmic effects in a vernakalant-resistant porcine model of AF. These results suggest SK channel blockers as potentially interesting anti-AF drugs.

Background Atrial fibrillation (AF) increases the rate of stroke 5-fold, and AF-related strokes have a poorer prognosis compared with non–AF-related strokes. Atrial fibrillation and stroke constitute an intensifying challenge, and health care organizations are calling for awareness on the topic. Previous studies have demonstrated that AF is often asymptomatic and consequently undiagnosed. The implantable loop recorder (ILR) allows for continuous, long-term electrocardiographic monitoring with daily transmission of arrhythmia information, potentially leading to improvement in AF detection and stroke prevention. Methods The LOOP study is an investigator-initiated, randomized controlled trial with 6,000 participants randomized 3:1 to a control group or to receive an ILR with continuous electrocardiographic monitoring. Participants are identified from Danish registries and are eligible for inclusion if 70 years or older and previously diagnosed as having at least one of the following conditions: hypertension, diabetes mellitus, heart failure, or previous stroke. Exclusion criteria include history of AF and current oral anticoagulation treatment. When an AF episode lasting ≥6 minutes is detected, oral anticoagulation will be initiated according to guidelines. Expected follow-up is 4 years. The primary end point is time to stroke or systemic embolism, whereas secondary end points include time to AF diagnosis and death. Conclusion The LOOP study will evaluate health benefits and cost-effectiveness of ILR as a screening tool for AF to prevent stroke in patients at risk. Secondary objectives include identification of risk factors for the development of AF and characterization of arrhythmias in the population. The trial holds the potential to influence the future of stroke prevention.

Background— The majority of available data on the clinical course of patients with ventricular preexcitation in the ECG originates from tertiary centers. We aimed to investigate long-term outcomes in individuals from a primary care population with electrocardiographic preexcitation. Methods and Results— Digital ECGs from 328 638 primary care patients were collected during 2001 to 2011. We identified 310 individuals with preexcitation (age range, 8–85 years). Data on medication, comorbidity, and outcomes were collected from Danish nationwide registries. The median follow-up time was 7.4 years (quartiles, 4.6–10.3 years). Compared with the remainder of the population, patients with preexcitation had higher adjusted hazards of atrial fibrillation (hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.07–4.70) and heart failure (HR, 2.11; 95% CI, 1.27–3.50). Subgroup analysis on accessory pathway location revealed a higher adjusted hazard of heart failure for a right anteroseptal accessory pathway (HR, 5.88; 95% CI, 2.63–13.1). There was no evidence of a higher hazard of death among individuals with preexcitation when looking across all age groups (HR, 1.07; 95% CI, 0.68–1.68). However, a statistically significant ( P =0.01) interaction analysis ( Conclusions— In this large ECG study, individuals with preexcitation had higher hazards of atrial fibrillation and heart failure. The higher hazard of heart failure seemed to be driven by a right anteroseptal accessory pathway. Among elderly people, we found a statistically significant association between preexcitation and a higher hazard of death.

Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current ( I to) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K+ Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF. Methods and results Two hundred and nine unrelated early-onset lone AF patients (

Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC. These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP compared with the ones not present. In order to validate our findings, seven variants associated with cardiomyopathy were genotyped in a control population and this revealed frequencies comparable with the ones found in ESP. In conclusion, we identified genotype prevalences up to more than one thousand times higher than expected from the phenotype prevalences in the general population (HCM 1:500, DCM 1:2500, and ARVC 1:5000) and our data suggest that a high number of these variants are not monogenic causes of cardiomyopathy.

Genetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group.The coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios were calculated for different genetic models.Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles).We show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental.

Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes SCN1B-SCN4B, FHL1, and LMNA in the pathogenesis of ARVC. Methods Sixty-five unrelated patients (55 fulfilling ARVC criteria and 10 borderline cases) were screened for variants in SCN1B-4B, FHL1, and LMNA by direct sequencing and LightScanner melting curve analysis. Results A total of 28 sequence variants were identified: seven in SCN1B, three in SCN2B, two in SCN3B, two in SCN4B, four in FHL1, and ten in LMNA. Three of the variants were novel. One of the variants was non-synonymous. No disease-causing mutations were identified. Conclusions In our limited sized cohort the six studied candidate genes were not associated with ARVC., Highlights ► Arrhythmogenic right ventricular cardiomyopathy (ARVC). ► Tachyarrhythmias. ► DNA sequencing the genes SCN1B-4B, FHL1, and LMNA. ► No disease-causing mutations were identified.

Background To assess the effects of comprehensive cardiac rehabilitation compared with usual care on physical activity and mental health for patients treated with catheter ablation for atrial fibrillation. Methods The patients were randomized 1:1 stratified by paroxysmal or persistent atrial fibrillation and sex to cardiac rehabilitation consisting of 12 weeks physical exercise and four psycho-educational consultations plus usual care (cardiac rehabilitation group) versus usual care. The primary outcome was Vo 2 peak. The secondary outcome was self-rated mental health measured by the Short Form-36 questionnaire. Exploratory outcomes were collected. Results 210 patients were included (mean age: 59 years, 74% men), 72% had paroxysmal atrial fibrillation prior to ablation. Compared with usual care, the cardiac rehabilitation group had a beneficial effect on Vo 2 peak at four months (24.3mL kg −1 min −1 versus 20.7mL kg −1 min −1 , p of main effect=0.003, p of interaction between time and intervention=0.020). No significant difference between groups on Short Form-36 was found (53.8 versus 51.9 points, P =.20). Two serious adverse events (atrial fibrillation in relation to physical exercise and death unrelated to rehabilitation) occurred in the cardiac rehabilitation group versus one in the usual care group (death unrelated to intervention) ( P =.56). In the cardiac rehabilitation group 16 patients versus 7 in the usual care group reported non-serious adverse events ( P =.047). Conclusion Comprehensive cardiac rehabilitation had a positive effect on physical capacity compared with usual care, but not on mental health. Cardiac rehabilitation caused more non-serious adverse events.

Several cardiac imaging modalities are able to visualize the left atrium (LA) and, therefore, allow for quantification of both structural and functional properties of this cardiac chamber. In echocardiography, only the maximal LA volume is included in the assessment of diastolic function at the current moment. Numerous studies, however, have shown that functional measures may be superior to the maximal LA volume in several aspects and to possess clinical value even in the absence of structural abnormalities. Such functional measures could prove particularly useful in the setting of predicting atrial fibrillation, which will be a point of focus in this review. Pivotal cardiac magnetic resonance imaging studies have revealed high correlation between LA fibrosis and risk of atrial fibrillation recurrence after catheter ablation, and subsequent multimodality imaging studies have uncovered an inverse relationship between LA reservoir function and degree of LA fibrosis. This has sparked an increased interest into the application of advanced imaging modalities, including both speckle tracking echocardiography and tissue tracking by cardiac magnetic resonance imaging. Even though increasing evidence has supported the use of functional measures and proven its superiority to the maximal LA volume, they have still not been adopted in clinical guidelines. The reason for this discrepancy may rely on the fact that there is little to no agreement on how to technically perform deformation analysis of the LA. Such technical considerations, limitations, and alternate imaging prospects will be addressed in this review.

Background The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). Methods In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. Results After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). Conclusions In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Temporal development of new-onset atrial fibrillation (NOAF) after aortic valve replacement is unclear, and opportunistic screening has limited diagnostic accuracy. This is the first study to investigate the incidence and temporal development of NOAF detected by implantable loop recorder (ILR) in patients with aortic stenosis, randomized to surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR).An ILR was implanted in a subgroup of patients without pre-procedural atrial fibrillation (AF), randomized to SAVR or TAVR in the NOTION trial. Data from the ILR were transmitted in intervals of 2weeks for 12weeks post-procedurally and analyzed.The study included 25 and 27 patients who underwent SAVR and TAVR, respectively. The cumulative rate of NOAF was 100% and 81.5% for patients undergoing SAVR and TAVR, respectively (P=0.06). TAVR patients without NOAF 6weeks post-procedurally remained free from NOAF. The prevalence of AF after SAVR decreased significantly after 8weeks when compared with the first 2weeks (50.0% vs. 84.0%, respectively; P0.05). The prevalence of AF after TAVR did not change significantly during follow-up. The median AF burden (percentage of time with AF) was 2.8% and 0.04% during the first 2weeks after SAVR and TAVR, respectively (P=0.01) and it decreased significantly over time after SAVR but not after TAVR.NOAF subsided 6weeks after TAVR. AF prevalence and burden decreased significantly over time after SAVR, but remained stable after TAVR. These findings may be considered for post-procedural anti-coagulation strategy.

We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers. All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries. In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63–1.4). Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS. Genet Med advance online publication 06 October 2016

This review focuses on the genetic basis of atrial fibrillation (AF) and the role of variants in the susceptibility of developing the disease. AF is the most common cardiac arrhythmia affecting 1–2% of the general population. Studies in the last decade have demonstrated that AF, and in particular lone AF, has a substantial genetic component. A number of genome-wide association studies (GWAS) have indicated that common genetic variants, more precisely the so called single-nucleotide polymorphisms (SNPs) are associated with AF. Presently more than 10 genomic regions have been identified using this approach. Highly penetrant variants in lone AF have also been described in a number of cases. Furthermore, familial AF, although rare, have been recognized for many years. Variants associated with AF have been identified in more than 40 genes, including cardiac gap junction proteins, ion channels and beta subunits. The evidence for some of these findings is not as strong as the evidence for the common variants. All in all, it is a complex picture, as both gain- and loss of function variants have been identified in a number of the genes. This review will focus on the common variants associated with AF. The pathophysiological mechanisms responsible for AF are still far from completely understood, and it is assumed that this arrhythmia represents a complex interplay of genetic predispositions, arrhythmogenic contributors such as electrolytes and inflammatory stimuli as well as contributions from concomitant cardiac and non-cardiac diseases.

The purpose of our survey is to analyse the clinical approach used to prevent and treat cardiovascular implantable electronic device (CIED) infections in Europe. The survey involves high-volume implanting centres. According to the survey the incidence of CIED infections shows a slight decrease in most centres and is substantially under 2% in the majority of centres interviewed. However, there are still differences in terms of prophylactic antibiotic therapy: 8.9% of the centres administer oxacillin as preoperative treatment, 4.4% of them do not give any antibiotic therapy, all centres use some kind of skin antisepsis, but only 42.2% use chlorhexidine. In case of local infection, 43.5% of centres perform lead extraction as first approach. In the case of systemic infection or evidence of lead or valvular endocarditis, 95% of centres treat these conditions by extracting the leads, which indicates that the adherence to the lead extraction guidelines is quite good.

The purpose of this EP wire is to examine clinical practice in the field of out-of-hospital cardiac arrest (OHCA) management, with special focus on in-hospital diagnostic and therapeutic strategies.Fifty-three European centres, all members of the EHRA-EP Research network, completed the questions of the survey. A dedicated strategy for OHCA management is active in 85% of the centres. Shockable tachyarrhythmias such as initial OHCA rhythm are reported in70% of the patients in 64% of the centres. In-hospital therapeutic hypothermia was applied in50% of the patients in 53% of the centres and in50% in 47% of the centres. In the year 2011 90% of the centres performed10 primary percutaneous coronary angioplasties (PCI) in OHCA patients. The survival rate, when the initial documented rhythm was shockable, was30% in 42% of the centres, and conversely, was significantly lower when asystole or pulseless electrical activity was the initial rhythm. A favourable neurological recovery was reported in50% of the patients in 13 (26%) centres and in 21-50% of the patients in 21 (44%).This EP wire survey demonstrates a favourable implementation in OHCA of an invasive management strategy, including coronary angiography/PCI and implantable cardioverter defibrillator therapy, while therapeutic hypothermia appears to be underused.

Background— Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na V 1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A . Methods and Results— The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P =0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current. Conclusions— In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.

This EP Wire surveyed clinical practice with regard to the use of antithrombotic therapy in relation to device implantation (pacemakers, ICT, resynchronization therapy) and atrial fibrillation ablation in 71 centres-members of the European Heart Rhythm Association research network. The results of this survey show variation in clinical practice, but reassuringly some consistency with guidelines and consensus recommendations on the management of periprocedure (devices, ablation) antithrombotic therapy.

Background: Right precordial (V1–3) elevated electrode placement ECG (EEP-ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population. Methods: Two different populations consisting of healthy subjects were used. A total of 340 subjects were included, 80% were men, the median age was 43 year (interquartile range: 31–51) and all were of European ethnicity. Results: No type 1 ECG patterns were identified but 16 (4.7%) subjects with a type 2 ECG and 32 (9.4%) subjects with a type 3 ECG were identified in any lead placement. In total 43 (13%) subjects had any BrS ECG pattern in any lead placement. The specificity was 100% (one-sided 97.5% CI: 99%) for the use of EEP-ECG to uncover type 1 pattern. For type 2 pattern the specificity was 95% (95% CI: 92–97%) and for type 3 pattern 91% (95% CI: 88–94%). Conclusions: Elevated electrode placement ECG in the diagnosis of BrS seems to have a very high specificity with regards to the finding of a type 1 ECG pattern in a European population; conversely a finding of a type 2 or 3 pattern is of a significantly lower specificity and should perhaps be disregarded.

In dogs, manipulation of heart rate has no effect on the exercise-induced increase in cardiac output. Whether these findings apply to humans remain uncertain, because of the large differences in cardiovascular anatomy and regulation. To investigate the role of heart rate and peripheral vasodilatation in the regulation of cardiac output during steady-state exercise, we measured central and peripheral haemodynamics in 10 healthy male subjects, with and without atrial pacing (100-150beats min −1 ) during: (i) resting conditions, (ii) one-legged knee extensor exercise(24 W)and(iii)femoralarterialATPinfusionatrest.ExerciseandATPinfusionincreased cardiac output, leg blood flow and vascular conductance (P

The study aim was to evaluate patient acceptance and content with remote follow-up (FU) of their implantable cardioverter defibrillator (ICD) and to estimate patients’ wish for changes in remote follow-up routines. Four hundred seventy-four ICD patients at the device follow-up clinic at Rigshospitalet using CareLink® (Medtronic) remote follow-up, who had made ≥2 transmissions, received a questionnaire. Three hundred eighty-five patients (81.2%) answered. Mean time with ICD was 56 ± 45 months and mean age was 62 ± 13 years; 80% was male. Diagnosis related to ICD implant was: ischemic heart disease in 56% and dilated cardiomyopathy in 21%. Twenty-six percent had primary prophylactic indication. Mean time on remote FU was 16.4 ± 6.9 months. Mean time spent on in-clinic FU (two-way transport and FU) was 4 h and 36 min ± 7 h and 50 min, excluding 12 patients from Greenland and Faroe Islands. Ninety-five percent of the patients was very content or content with remote FU compared to in-clinic FU; 3% was less content and 2% was not content. For scheduled transmissions, 21% of the patients wished for a faster reply (sms or e-mail) compared to current practice with a letter. Eighty-four percent preferred more detailed information concerning ICD leads, battery status, and ICD therapies. A total of 96 patients (25%) had performed extra unscheduled remote transmissions: 20 due to shock, 20 due to alarm, 35 due to palpitations, and 18 for other or combined reasons. Ninety-five percent of the patients were content with the remote FU. Only 25% had unscheduled transmissions and most unscheduled transmissions were for appropriate reasons. Eighty-four percent of the patients wished for a more detailed response and 21% wished for a faster reply after routine transmissions.

Background Three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 have been associated with atrial fibrillation (AF) in genome-wide association studies (GWAS). Five additional loci have been associated primarily with the PR interval and subsequently with AF. We aimed to investigate if 8 single nucleotide polymorphisms (SNPs), representing the 8 genomic loci previously linked with AF in genome-wide association studies, were associated with early-onset lone AF. Methods We included 209 patients with early-onset lone AF, and a control group consisting of 534 individuals free of AF. The 8 SNPs were genotyped using TaqMan assays (Applied Biosystems, Foster City, CA). Results Three SNPs were found to be significantly associated with early-onset lone AF: rs2200733 closest to PITX2 (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.16-2.27; P = 0.004), rs3807989 near to CAV1 (OR 1.35; 95% CI, 1.06-1.72; P = 0.015), and rs11047543 near to SOX5 (OR 1.70; 95% CI, 1.18-2.44; P = 0.004). When correcting for multiple testing, rs2200733 and rs11047543 were still significantly associated with AF. Conclusions Three SNPs, rs2200733 (4q25), rs3807989 (7p31), and rs11047543 (12p12), were associated with early-onset lone AF. All 3 SNPs are positioned close to genes that in previous studies have been demonstrated to be important for cardiac morphology/development, thereby suggesting a link between these SNPs and structural heart disease. Our results however, indicate that variants in these 3 loci are associated with AF through mechanisms that do not involve major structural abnormalities in the heart.

The clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is often challenging due to phenotypic variation, reduced/age-related penetrance, and lack of a diagnostic test. A single report has suggested quantitative myocardial immunoanalysis for the desmosomal protein plakoglobin as a diagnostic test with high sensitivity and specificity. We performed immunohistochemistry for plakoglobin and a control protein on myocardial biopsies with fibrofatty replacements from 50 consecutive, unrelated patients. The clinical, genetic, and immunohistochemical data were evaluated by independent observers in a blinded manner. The immunohistochemical and clinical diagnoses were compared and the sensitivity, specificity, and predictive values calculated. Our analysis showed 37 samples (74%) with a reduced immunosignal for plakoglobin. Of the 34 patients with a clinical diagnosis of ARVC, 29 displayed a reduced plakoglobin signal. Of the 14 patients with a clinical diagnosis other than ARVC, 6 displayed a reduced signal. Two patients were excluded from further analysis. A sensitivity of 85%, a specificity of 57%, a positive predictive value of 83%, and a negative predictive value of 62% were found. In conclusion, immunohistochemical analysis for plakoglobin, applied as a diagnostic test for ARVC, seems associated with a relatively high sensitivity, but limited specificity, and although additional validation is required, we advocate caution in basing clinical decision-making on the proposed diagnostic test.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been associated with mutations in genes encoding cellular adhesion proteins. However, only about 40% of patients have mutations in known genes. We hypothesized that mutations in the genes encoding β-catenin (CTNNB1), α-T-catenin (CTNNA3), and PERP (PERP)-all important structural proteins located at the intercalated disc-were involved in the pathogenesis of ARVC. We screened 65 unrelated patients (55 fulfilling 1994 Task Force criteria and ten borderline cases) for mutations in CTNNB1, CTNNA3, and PERP by direct sequencing and LightScanner melting curve analysis. Our comprehensive mutation scanning did not identify any disease-causing mutations. Thirty-five sequence variants were found, including one rare nonsynonymous variant of unknown significance (CTNNA3 A689V). Fourteen of the variants were novel. In conclusion, in our cohort of a limited size, no mutations were identified in the three studied candidate genes despite their involvement in formation and maintenance of the intercalated disk. We recommend focus on other components of cardiomyocyte adhesion in future research into the pathogenesis of ARVC.

Objectives: The aim of this study was to screen lone atrial fibrillation (AF) patients for mutations in the genes KCNJ2, KCNJ3 and KCNJ5, all encoding potassium channels. Furthermore, we wanted to replicate the prior association of two single-nucleotide polymorphisms (SNPs) in KCNJ5, C171T (rs6590357) and G810T (rs7118824), with lone AF in Han Chinese. Methods: We sequenced the coding region and splice site of KCNJ2, KCNJ3 and KCNJ5 in 187 early-onset lone-AF patients screening for mutations and counting SNP frequencies for the two noted SNPs in KCNJ5. Results: No mutations were found in KCNJ2, KCNJ3 or KCNJ5. Both genotype distribution and allele frequencies of the SNPs rs6590357 and rs7118824 significantly differed between the AF and control group (pgenotype = 0.0067, pallele = 0.0021 and pgenotype = 0.014, pallele = 0.0101, respectively). On allele level, the OR for lone AF for rs6590357 was 1.77 (95% CI 1.16–2.73, p = 0.009) and for rs7118824 it was 1.71 (95% CI 1.13–2.57, p = 0.01) in a model adjusted for age and gender. Conclusions: Our findings indicate that rs6590357 and rs7118824 in KCNJ5 are associated with early-onset lone AF in Caucasians. No mutations were found in the exon or splice site of KCNJ2, KCNJ3 or KCNJ5.

Incidence of sudden unexpected death in infancy (SUDI) and sudden infant death syndrome (SIDS) differs among studies and non-autopsied cases are difficult to assess.To investigate causes of sudden death in infancy in a nationwide setting. Validate the use of the ICD-10 code for SIDS (R95) in the Danish Cause of Death registry.A retrospective analysis of all infant deaths (1 year of age) in Denmark in 2000-2006. All death certificates and autopsy reports were read.We identified 192 SUDI cases (10% of total deaths, 0.42 per 1000 births) with autopsy performed in 87% of cases. In total, 49% of autopsied SUDI cases were defined as SIDS (5% of all deaths, 0.22 per 1000 births); Cardiac cause of death was denoted in 24% of cases. The Danish Cause of Death Registry misclassified 30% of SIDS cases.A large proportion of infant deaths are SUDI, and the majority of these are caused by cardiac disease or SIDS. Autopsy is not always performed and valuable information is subsequently lost. Cause of Death registry data is not accurate in describing SIDS.

Background Studies on incidences of sports-related sudden cardiac death (SrSCD) are few and data are needed for the discussion of preparticipation screening for cardiac disease. Objective We sought to chart the incidence and etiology of SrSCD in the young in Denmark (population 5.4 million) and to compare this to the incidence of sudden cardiac death (SCD) in the background population. Methods All 5,662 death certificates for decedents in the period 2000 to 2006 in the age group 12 to 35 years in Denmark were read independently by 2 physicians to identify cases of SCD. Information from autopsy reports, selected hospital records, and multiple registries was used to identify cases of SCD and SrSCD. SrSCD was defined as SCD occurring during or within 1 hour after exercise in a competitive athlete. The size of the athlete population was estimated from national survey data. Results Fifteen (range 0 to 5 per year) cases of SrSCD were found, 8 of which had antecedent symptoms. The incidence rate was 1.21 (95% confidence interval [CI]: 0.68 to 2.00) per 100,000 athlete person-years. The most common autopsy findings were arrhythmogenic right ventricular cardiomyopathy (n = 4), sudden unexplained death (n = 4), and coronary artery disease (n = 2). The incidence of SCD in the general population age 12 to 35 was 3.76 (95% CI: 3.42 to 4.14) per 100,000 person-years. Conclusion In Denmark, SrSCD is a rare occurrence and the incidence rate is lower than that of SCD in the general population. This may imply a low value of preparticipation screening of athletes in Denmark.

Summary. Objective: Our objective was to provide a comprehensive description of fatal pulmonary embolism (PE) in younger persons. Specifically, we recorded information on symptoms, comorbidity, medical contact, if this had been required, and subsequent autopsy findings. Methods: We reviewed all death certificates from persons aged 0–35 years who had died between 1 January 2000 and 31 December 2006, and retrospectively identified all cases of fatal PE. Additional information was retrieved from the National Patient Registry, autopsy reports, and clinical charts. Results: Sixty-one cases of fatal PE were included; 38% of these were in males. The median age was 29 years. The predominant symptoms were dyspnea, syncope, leg pains, and chest pains. Sixty-three per cent of patients reportedly experienced symptoms for days, weeks, or months. More than half of the patients had sought medical care, and at the time of medical evaluation the majority of the patients were not hemodynamically compromised. In 21% cases, the correct diagnosis was reached before death; however, in only 5% of cases was this accomplished before clinical deterioration. Furthermore, clinical history and subsequent postmortem examinations showed that approximately half of younger persons dying from PE were otherwise healthy, and in no case was occult cancer diagnosed. Conclusions: Our data show that a substantial proportion of younger victims of fatal PE had experienced symptoms for an extended period of time. Furthermore, the correct diagnosis remained elusive in the majority of cases, even though approximately half of the subjects had sought medical evaluation for symptoms that, in retrospect, were most likely caused by a venothrombotic event.

Systemic low-grade inflammation is a prognostic risk factor of atrial fibrillation (AF). We hypothesized that genetic polymorphisms, which determine the rate of inflammatory cytokines, are associated with the risk of AF, independently of comorbidity. We included 192 patients with so-called lone AF and age 40 years or below, and 188 healthy controls. All patients were genotyped for single nucleotide polymorphisms (SNPs) in inflammatory genes using fluorescence-based real-time polymerase chain reaction (PCR). A case-control analysis of the C/C, C/T and T/T genotypes on IL1A-889 revealed a significant difference in both the frequency of genotypes (p = 0.03) and in the allelic frequency (p = 0.015). These differences were not significant after Bonferroni corrections. For IL1B-511, IL10-592, IL10-1082, IL18-137, IL18-607 and TNF-308 there were no significant differences, neither in genotype frequency, nor in allelic frequency between the lone AF patients and the controls. Our study failed to show an association between polymorphisms in inflammatory genes and early onset of lone AF. It remains to be established whether polymorphisms in inflammatory genes play a causative role in the pathophysiology of AF.

Implantable cardioverter-defibrillator (ICD) therapy is effective in primary and secondary prevention for patients who are at high risk of sudden cardiac death. However, the current risk stratification of patients who may benefit from this therapy is unsatisfactory. Single nucleotide polymorphisms (SNPs) are DNA sequence variations occurring when a single nucleotide in the genome differs among members of a species. A novel concept has emerged being that these common genetic variations might modify the susceptibility of a certain population to specific diseases. Thus, genetic factors may also modulate the risk for arrhythmias and sudden cardiac death, and identification of common variants could help to better identify patients at risk. The DISCOVERY study is an interventional, longitudinal, prospective, multi-centre diagnostic study that will enrol 1287 patients in approximately 80 European centres. In the genetic part of the DISCOVERY study, candidate gene polymorphisms involved in coding of the G-protein subunits will be correlated with the occurrence of ventricular arrhythmias in patients receiving an ICD for primary prevention. Furthermore, in order to search for additional sequence variants contributing to ventricular arrhythmias, a genome-wide association study will be conducted if sufficient a priori evidence can be gathered. In the second part of the study, associations of SNPs with ventricular arrhythmias will be sought and a search for potential new biological arrhythmic pathways will be investigated. As it is a diagnostic study, DISCOVERY will also investigate the impact of long-term device diagnostic data on the management of patients suffering from chronic cardiac disease as well as medical decisions made regarding their treatment.

Mutations in the cardiac sodium channel encoded by the gene SCN5A can result in a wide array of phenotypes. We report a case of a young male with a novel SCN5A mutation (R121W) afflicted by sick sinus syndrome, progressive cardiac conduction disorder, atrial flutter and ventricular tachycardia. His father carried the same mutation, but had a milder phenotype, presenting with progressive cardiac conduction later in life. The mutation was found to result in a loss-of-function in the sodium current. In conclusion, the same SCN5A mutation can result in a wide array of clinical phenotypes and perhaps the spectrum of SCN5A loss-of-function associated disease entities should be viewed as one syndrome.

Background: Sinus node dysfunction (SND) is a heterogeneous disorder of unknown etiology characterized by a variety of supraventricular arrhythmias with symptoms of syncope, palpitations, and dizziness. The mechanism underlying the abnormal rhythm is incompletely understood. Objective: Because vagal stimulation and acetylcholine (ACh) affect the function of pacemaker cells, we hypothesized that genetic variation in the genes encoding the ACh-activated K+ channels, the KACh channels, could be involved in the pathogenesis of SND. Methods and Results: We screened 184 patients listed in the pacemaker registry of the Copenhagen University Hospital aged KCNJ3 and KCNJ5, encoding the main subunits of the KACh channels, were re-sequenced. We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. Conclusions: Genetic variation in KCNJ3 and KCNJ5 encoding the subunits of the KACh channels is apparently not involved in the pathogenesis of SND.

To study plasma YKL-40 in patients with atrial fibrillation (AF) treated with radiofrequency (RF) catheter ablation and to assess the predictive role of plasma YKL-40 and its changes after restoration of sinus rhythm (SR). Forty-six patients (mean age 55 years, range 31–81) with paroxysmal/persistent AF were treated with RF catheter ablation; Holter monitoring for 14 days was performed before ablation and after 3 months. Recurrent symptomatic AF or atrial tachycardia >10 min was considered failure, and the patients were offered a second ablation session. YKL-40 was determined in plasma samples taken prior to ablation and at follow-up visits up to 12 months after ablation. After a maximum of two ablations, 19 patients (41%) had SR without recurrence of AF after 12 months. The patients with no recurrence of AF had significantly lower baseline plasma levels of YKL-40 prior to ablation compared to patients with recurrence of AF (31 vs. 62 μg/l, P = 0.029). Plasma YKL-40 was not an independent predictor of recurrence of AF after ablation. No significant changes in plasma YKL-40 levels were seen from baseline to follow-up at 12 months. In patients with paroxysmal or persistent AF treated with catheter ablation, high plasma YKL-40 before ablation is associated with recurrence of AF.

Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic. Methods: We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Results: Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146–2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations. Conclusions: Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2, functional characterization and large-scale sequencing to clarify normal variation in the gene.

The aim of the present study was to identify the molecular mechanism behind ventricular tachycardia in a patient with Brugada syndrome. Arrhythmias in patients with Brugada syndrome often occur during sleep. However, a 28-year-old man with no previously documented arrhythmia or syncope who experienced shortness of breath and chest pain during agitation is described. An electrocardiogram revealed monomorphic ventricular tachycardia; after he was converted to nodal rhythm, he spontaneously went into sinus rhythm, and showed classic Brugada changes with coved ST elevation in leads V(1) to V(2). Mutation analysis of SCN5A revealed a novel mutation, 3480 deletion T frame shift mutation, resulting in premature truncation of the protein. Heterologous expression of this truncated protein in human embryonic kidney 293 cells showed a markedly reduced protein expression level. By performing whole-cell patch clamp experiments using human embryonic kidney 293 cells transfected with the mutated SCN5A, no current could be recorded. Hence, the results suggest that the patient suffered from haploinsufficiency of Na(v)1.5, and that this mutation was the cause of his Brugada syndrome.

Aims The aim of this study is to investigate whether protection with rubber or plastic gloves during post-mortem explantation of an implantable cardioverter defibrillator (ICD) offers enough protection for the explanting operator during a worst-case scenario (i.e. ICD shock). Methods and results We investigated the insulating properties of rubber and plastic gloves (double layer) within the first 60 min exposure (mimicking the maximum time of an explantation procedure) to saline (simulating the effects of body fluids on the gloves). For latex gloves, we measured an increase in voltage up to 68.1 V ( P < 0.0001), for neoprene a maximum voltage of 5.3 V ( P = 0.245), and for plastic a voltage of 2.3 V within the first hour. If the exposure time to fluid did not exceed 50 min, a double pair of intact gloves made of latex, neoprene, or plastic constituted such a large resistance that the resting voltage over the operating person would not exceed 50 V. Conclusion The use of intact medical gloves made of latex, neoprene, or plastic eliminates the potential electrical risk during explantation of an ICD. Two gloves on each hand offer sufficient protection. We will recommend the use of neoprene gloves.

To investigate whether NT-proBNP before ablation treatment and after exercise testing has predictive information regarding the clinical outcome following pulmonary vein isolation in patients with atrial fibrillation (AF).NT-proBNP analysis were obtained before the ablation (before and after exercise test), and repeated at 1, 3, and 12 months after the final procedure.A total of 51 patients were included. At study entry, the median NT-proBNP concentration was 14.0 pmol/L (quartiles: 8.0 and 27.0). After the exercise test, the mean NT-proBNP value increased from 13.0 pmol/L (quartiles: 7.5 and 26.0) to 15.0 pmol/L (quartiles: 9.0 and 34.0), p0.001. Following a maximum of two ablations, 22 patients were free of AF while 29 patients experienced recurrent AF. In patients with successful ablation, the mean NT-proBNP concentration at baseline was 10.0 pmol/L (quartiles: 7.0 and 22.2) compared to 22.0 pmol/L (quartiles: 12.0 and 34.5) in patients with ablation failure, p = 0.02. With respect to exercise testing, a trend towards a higher increases during exercise were seen in patients with recurrent AF compared to patients without: 2.0 pmol/L (quartiles 1.9 and 7.0) vs. 1.5 pmol/L (quartiles 0 and 3.0), p = 0.07. A baseline NT-proBNP concentration15.0 pmol/L was found to be an independent predictor of ablation failure.A significantly lower NT-proBNP concentration at baseline and a trend towards a diminished increase during exercise was seen in patients successfully ablated for AF compared to patients with recurrent AF. A baseline NT-proBNP concentrationor=15 pmol/l independently predicts ablation success.

The aim of this study was to assess the predictive value of inflammatory markers in patients with paroxysmal/persistent atrial fibrillation (AF) treated with radiofrequency (RF) catheter ablation.Forty-six consecutive patients, mean age 55 years (range 31 - 81 yrs), with paroxysmal or persistent AF were treated with either segmental or circumferential pulmonary vein isolation ablation technique. All patients presented with sinus rhythm on inclusion. Holter monitoring lasting at least 14 days was performed before ablation and after 3 months. Recurrent symptomatic AF or atrial tachycardia10 minutes was considered failure and patients were offered a second ablation session. Interleukin-6 and high-sensitivity C-reactive protein were measured prior to ablation and at follow-up visits.After a maximum of two ablations, 19 patients (41%) had SR without recurrence of AF after 12 months. Patients in SR had significantly lower left atrium diameter (p = 0.007) and lower values of both IL-6 (p = 0.007) and hs-CRP (p = 0.018) at baseline before ablation. IL-6 concentration prior to ablation was an independent predictor of recurrent AF (p = 0.027).In patients with a history of paroxysmal or persistent AF treated with RF catheter ablation, elevated levels of IL-6 and hs-CRP before ablation are independent predictors of recurrence of AF.

— During a 21-month period, 65 consecutive patients admitted with ascites were included in a prospective study of the incidence of spontaneous bacterial peritonitis, and paracentesis was performed on admission. The ascitic fluid was cultured, ascitic leucocytes were counted and pH was measured. Bacterial growth was found in five patients with chronic liver disease, who were diagnosed as having spontaneous bacterial peritonitis (SBP), since no intra-abdominal focus could be demonstrated. Thus, the incidence of SBP in this material was 7.7% (95% confidence limits: 2.5–17%). SBP was caused by Escherichia coli (n = 3), coagulase negative staphylococcus (n = 1), and Bacteroides species (n = 1). Abdominal tenderness, abnormal intestinal sounds, fever and hepatic encephalopathy were equally frequent in the group with SBP and in patients with sterile ascites. Infection was not anticipated in any of the patients with SBP. In contrast to several previous studies, neither ascites pH nor ascites leucocyte counts were any help in obtaining a rapid diagnosis. Survival time of patients with SBP was significantly shorter than of patients without SBP.

An 11-year-old girl sitting in the kitchen suddenly complained of dizziness. Seconds later, she collapsed and had cardiac arrest. Cardiopulmonary resuscitation was initiated immediately but was unsuccessful, despite prolonged efforts. The girl was previously healthy and had never experienced any cardiac or muscular symptoms. At autopsy, the gross examination was normal. The heart weighed 230 g; the chamber sizes, wall thicknesses, and myocardial appearance were normal. Microscopic examination of the right ventricular myocardium showed marked fibrofatty replacement (Figures 1 and 2⇓). No replacements were found in the left ventricular myocardium or in the skeletal musculature. On this basis, it was concluded that the cause of death was arrhythmogenic right ventricular cardiomyopathy (ARVC). Figure 1. Biopsy from the right ventricular free wall showing fibrofatty replacement. Hematoxylin-eosin stain, magnification ×25. …

The role of atrial (ANP) and B-type (BNP) natriuretic peptide in atrial fibrillation (AF) is not clear. Our aim was to describe ANP and BNP in AF, and their changes following cardioversion in persistent AF. Furthermore, we wanted to assess the association between ANP and BNP and cardiac volume and function evaluated by magnetic resonance imaging. ANP and BNP decreased significantly following cardioversion. After 180 days of sinus rhythm, ANP and BNP were still significantly elevated. Same results were seen in patients with lone AF. Left and right atrial volumes correlated positively with ANP and BNP. Changes in left atrial volume were predictive of changes in ANP and BNP following cardioversion. AF may cause enduringly elevated ANP and BNP and atrial volume seems to be an important determinant of ANP and BNP in AF.

Background Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 β-subunit, has been shown to reduce IKs. Objective The purpose of this study was to test the hypothesis that mutations in KCNE5 are associated with AF in a large cohort of patients with AF. Methods One-hundred fifty-eight patients with AF were screened for mutations in the coding region of KCNE5. Results A missense mutation involving substitution of a phenylalanine for leucine at position 65 (L65F) was identified in one patient. This patient did not have a history of familial AF, and neither KCNQ1 nor KCNE2 mutations were found. Transient transfection of Chinese hamster ovary (CHO) cells expressing IKs(KCNQ1+KCNE1) with KCNE5 suppressed the developing and tail currents of IKs in a concentration-dependent manner. Transient transfection with KCNE5-L65F failed to suppress IKs, yielding a current indistinguishable from that recorded in the absence of KCNE5. Developing currents recorded during a test pulse to +60 mV and tail currents recorded upon repolarization to −40 mV both showed a significant concentration-dependent gain of function in IKs with expression of KCNE5-L65F vs KCNE5-WT. Conclusion The results of this study suggest that a missense mutation in KCNE5 may be associated with nonfamilial or acquired forms of AF. The arrhythmogenic mechanism most likely is a gain of function of IKs.

The purpose of this study was to explore the effect of actively constructing virtual patient (VP) cases compared with solving VP cases on knowledge gains, skills transfer and time spent on cases. Forty-five fourth-year medical students were randomized to constructing (VP-construction, n = 23) or solving (VP-solving, n = 22) four cardiopulmonary VP cases. Whereas the VP-solving group solved the cases, the VP-construction group only received the final diagnosis and had to complete the history, physical findings, and lab results. After a week, participants completed a transfer test involving two standardized patients representing cardiopulmonary cases. Performances on the transfer test were video-recorded and assessed by two blinded raters using the Reporter, Interpreter, Manager, Educator (RIME) framework. Thirty-nine participants completed the transfer test. The VP-construction group spent significantly more time on the VP cases compared with the VP-solving group, p = 0.002. There were no significant differences in RIME scores between the VP-construction group and VP-solving group, p = 0.54. In conclusion, engaging novice students in active VP case construction may be more time consuming than solving VP cases, without resulting in superior skills transfer.

Background Amiodarone is known to affect the thyroid, but little is known about thyroid recovery after short-term amiodarone treatment. Objectives We aimed to evaluate the impact of 8 weeks of amiodarone treatment on thyroid function in patients with atrial fibrillation (AF) undergoing catheter ablation in a randomised, double-blind clinical trial. Methods 212 patients referred for AF ablation at two centres were randomized to 8 weeks of oral amiodarone or placebo. Thyroid function tests (TSH, thyroid stimulating hormone; T4, thyroxine; T3, triiodothyronine; fT4, free T4; fT3, free T3) were performed at baseline and 1, 3 and 6 months. Results Study drug was discontinued due to mild thyroid dysfunction in 1 patient in the placebo vs. 3 in the amiodarone group ( p = 0.6). In linear mixed models there were significant effects of amiodarone on thyroid function tests, modified by follow-up visit ( p − 9 for both TSH, T4, T3, fT4 and fT3). The amiodarone group had higher TSH, fT4 and T4 after 1 and 3 months compared to placebo, whereas T3 and fT3 were lower. In all cases, the amiodarone-induced thyroid dysfunction was largest at 1 month, declining at 3 months, and with no differences at 6 months, compared to baseline. Conclusion We found amiodarone to have a significant impact on thyroid function after only 1 month, but with a fast recovery of thyroid function after amiodarone discontinuation. Our study indicates that short-term amiodarone can be considered safe in patients without prior thyroid dysfunction.

Heart rate (HR) at rest is a well-known marker of cardiovascular morbidity and mortality. Results on the association between HR and incident atrial fibrillation (AF) have, however, been conflicting. Using digital electrocardiograms from 281,451 primary care patients, we aimed to describe the association between HR at rest and the hazards of incident AF. Secondary end points were death from all causes and pacemaker implantation. Data on drug use, co-morbidity, and outcomes were collected from nationwide administrative health care registries. During a median follow-up time of 8.4 years, 15,666 subjects were observed to develop AF, of which 1,631 were lone AF. A HR at rest from 30 to 51 beats/min was associated with an adjusted hazard ratio of 1.16 (95% CI 1.06 to 1.27) for AF compared with the reference group (66 to 72 beats/min). From 72 beats/min and upward, the hazard ratio of AF increased in a dose-response manner, reaching an adjusted hazard ratio of 1.36 (95% CI 1.26 to 1.46) for HR between 95 and 120 beats/min. Both for low and high HR, the associations were accentuated for the outcome lone AF (adjusted hazard ratios of 1.48, 95% CI 1.19 to 1.84 and 1.84, 95% CI 1.47 to 2.30 for HR between 30 to 51 and 95 to 120 beats/min, respectively). For death from all causes, the hazard increased almost linearly with increasing HR. A HR at rest from 30 to 51 beats/min was associated with an adjusted hazard ratio of 1.80 (95% CI 1.46 to 2.21) for pacemaker implantation. In conclusion, a U-shaped association was found between HR at rest and incident AF, and this association was strongest for the outcome lone AF.

Background Revision of the Task Force diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) has increased their sensitivity for the diagnosis of early and familial forms of the disease. The epsilon wave is a major diagnostic criterion in the context of ARVC/D, which, however, remains not quantifiable and therefore may leave room for substantial subjective interpretation. Objective The purpose of this study was to assess interobserver agreement in epsilon wave definition and epsilon wave importance for ARVC/D diagnosis. Methods Electrocardiographic (ECG) tracings depicting leads V 1 , V 2 , and V 3 collected from individuals evaluated for ARVC/D (n = 30) were given to panel members who were asked to respond to the question whether ECG patterns meet epsilon wave definition outlined by the Task Force diagnostic criteria. The prevalence and importance of epsilon waves for ARVC/D diagnosis were assessed in a pooled data set of patients with definite ARVC/D from European and American registries (n = 815). Results The number of ECG patterns identified as epsilon waves varied from 5 to 18 per reviewer (median 13 per reviewer). A unanimous agreement was reached for only 10 cases (33%), 2 of which qualified as epsilon waves and 8 as non–epsilon waves by all panel members. From a pooled data set, 106 patients reportedly had epsilon waves (13%). In 105 of 106 patients with epsilon waves (99%), exclusion of epsilon waves from the diagnostic score would not affect the "definite" diagnostic category. Conclusion Interobserver variability in the assessment of epsilon waves is high; however, the impact of epsilon waves on ARVC/D diagnosis is negligibly low. The results urge to exercise caution in the assessment of epsilon waves, especially in patients who would not otherwise meet diagnostic criteria.

Background Population‐based studies suggest that genetic factors contribute to sudden cardiac death ( SCD ). Methods and Results In the first part of the present study (Diagnostic Data Influence on Disease Management and Relation of Genetic Polymorphisms to Ventricular Tachy‐arrhythmia in ICD Patients [DISCOVERY] trial) Cox regression was done to determine if 7 single‐nucleotide polymorphisms ( SNP s) in 3 genes coding G‐protein subunits ( GNB 3, GNAQ , GNAS ) were associated with ventricular tachyarrhythmia ( VT ) in 1145 patients receiving an implantable cardioverter‐defibrillator ( ICD ). In the second part of the study, SNP s significantly associated with VT were further investigated in 1335 subjects from the Oregon SUDS , a community‐based study analyzing causes of SCD . In the DISCOVERY trial, genotypes of 2 SNP s in the GNAS gene were nominally significant in the prospective screening and significantly associated with VT when viewed as recessive traits in post hoc analyses ( TT vs CC / CT in c.393C>T: HR 1.42 [ CI 1.11‐1.80], P =0.005; TT vs CC / CT in c.2273C>T: HR 1.57 [ CI 1.18‐2.09], P =0.002). TT genotype in either SNP was associated with a HR of 1.58 ( CI 1.26‐1.99) ( P =0.0001). In the Oregon SUDS cohort significant evidence for association with SCD was observed for GNAS c.393C>T under the additive ( P =0.039, OR =1.21 [ CI 1.05‐1.45]) and recessive ( P =0.01, OR =1.52 [ CI 1.10‐2.13]) genetic models. Conclusions GNAS harbors 2 SNP s that were associated with an increased risk for VT in ICD patients, of which 1 was successfully replicated in a community‐based population of SCD cases. To the best of our knowledge, this is the first example of a gene variant identified by ICD VT monitoring as a surrogate parameter for SCD and also confirmed in the general population. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00478933.