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Ventricular arrhythmias in cardiac channelopathies are linked to autonomic triggers, which are sub-optimally targeted in current management strategies. Improved molecular understanding of cardiac channelopathies and cellular autonomic signalling could refine autonomic therapies to target the specific signalling pathways relevant to the specific aetiologies as well as the central nervous system centres involved in the cardiac autonomic regulation. This review summarizes key anatomical and physiological aspects of the cardiac autonomic nervous system and its impact on ventricular arrhythmias in primary inherited arrhythmia syndromes. Proarrhythmogenic autonomic effects and potential therapeutic targets in defined conditions including the Brugada syndrome, early repolarization syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia will be examined. Pharmacological and interventional neuromodulation options for these cardiac channelopathies are discussed. Promising new targets for cardiac neuromodulation include inhibitory and excitatory G-protein coupled receptors, neuropeptides, chemorepellents/attractants as well as the vagal and sympathetic nuclei in the central nervous system. Novel therapeutic strategies utilizing invasive and non-invasive deep brain/brain stem stimulation as well as the rapidly growing field of chemo-, opto-, or sonogenetics allowing cell-specific targeting to reduce ventricular arrhythmias are presented. [ABSTRACT FROM AUTHOR]

This article provides an overview of the top 10 papers in arrhythmias published in 2023, focusing on advancements in the understanding and treatment of atrial fibrillation (AF) and long QT syndrome (LQTS). The article discusses the use of the HARMS2-AF score for screening high-risk individuals for AF and the cost-effectiveness of AF screening. It also examines the clinical implications of oral anticoagulation in subclinical AF and the role of catheter ablation in treating AF. Additionally, the article explores a new threshold for defining AF recurrences and the potential for epicardial arrhythmogenic substrate ablation in LQTS. [Extracted from the article]

Aims Utilizing real-world UK data, we aimed to understand: (i) whether anti-arrhythmic drugs and catheter ablation are effective in improving the survival of atrial fibrillation (AF) patients and (ii) which rhythm control option produces better results for the whole AF population and for specific groups of patients, stratified by age, sex, and history of heart failure. Methods and results We identified 199 433 individuals (mean age at diagnosis 75.7 ± 12.7 years; 50.2% women) with new-onset AF diagnosis in nationwide electronic health records linking primary care consultation with hospital data and death registry data from 1998 to 2016. We investigated the survival and causes of death of new-onset AF patients receiving vs. not-receiving rhythm control therapies. During a median follow-up of 2.7 (0.7–6.0) years, we observed a significantly lower mortality in patients receiving rhythm control [multivariate-adjusted hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.84–0.88]. Pulmonary vein isolation was associated with a two-third significant mortality reduction compared with no rhythm control (HR = 0.36, 95% CI 0.28–0.48), flecainide with 50% reduction (HR = 0.52, 95% CI 0.48–0.57), and propafenone and sotalol with reduction by a third (HR = 0.63, 95% CI 0.50–0.81, 0.71, 95% CI 0.68–0.74, respectively). Amiodarone showed no survival benefit in individuals <70 years (HR = 0.99, 95% CI 0.97–1.02). Otherwise, the effect of rhythm control on survival did not differ by age, sex, nor history of heart failure. Conclusion Among individuals with new-onset AF, favourable survival was observed for patients receiving rhythm control treatment. Among different rhythm control strategies, pulmonary vein isolation showed the most pronounced survival benefit. [ABSTRACT FROM AUTHOR]

This document is a response by Lambiase and van Duijvenboden to a letter regarding their article titled "Prognostic Significance of Different Ventricular Ectopic Burdens During Submaximal Exercise in Asymptomatic UK Biobank Subjects." The authors appreciate the interest in their publication and acknowledge the limitation of not having continuous blood pressure measurements during exercise in the UK Biobank. However, they did explore the associations between resting blood pressure and PVC burden in more detail. They found that higher resting systolic blood pressure and pulse pressure were associated with an increased risk of high PVC burden. The authors also discuss the potential link between hypertension, autonomic dysfunction, impaired vagal reactivation, and increased PVC burden during recovery. They suggest that future studies with simultaneous measurements of blood pressure and cardiac rhythm during exercise would be of great interest. [Extracted from the article]

The article presents the discussion on societal impact arrhythmia papers reporting on important public health issues. Topics include foods and food supplements, health behaviours, work and sleep environment, and life events increasing the incidence of AF; and daily alcohol consumption of one standard drink being protective in myocardial infarction, heart failure, and stroke.

Graph: Graphical Abstract (A) Comprehensive clinical, electrocardiographic, and genetic overview of the various diseases associated with VA or SCD as reported in the 2022 ESC Guidelines for VA and SCD.[1] The VA/SCD Guidelines provide many updated recommendations for the management of patients with congenital heart disease, idiopathic VF, acquired Long QT, Brugada and early repolarization syndrome, as well as catecholaminergic polymorphic VT, and short QT syndrome. Effect of MRI-guided fibrosis ablation vs conventional catheter ablation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: the DECAAF II randomized clinical trial. In these patients, rhythm control is generally not considered whilst RAFAS suggests early ablation may be beneficial.[10] Larger well-controlled clinical trials on catheter ablation in patients with AF detected early after acute ischaemic stroke are definitely needed to settle the issue. [Extracted from the article]

Strong recent clinical evidence links the presence of prominent oscillations of ventricular repolarization in the low-frequency range (0.04-0.15 Hz) to the incidence of ventricular arrhythmia and sudden death in post-MI patients and patients with ischaemic and non-ischaemic cardiomyopathy. It has been proposed that these oscillations reflect oscillations of ventricular action potential duration at the sympathetic nerve frequency. Here we review emerging evidence to support that contention and provide insight into possible underlying mechanisms for this association. [ABSTRACT FROM AUTHOR]

Background: Inhomogeneity of ventricular contraction is associated with sudden cardiac death, but the underlying mechanisms are unclear. Alterations in cardiac contraction impact electrophysiological parameters through mechanoelectric feedback. This has been shown to promote arrhythmias in experimental studies, but its effect in the in vivo human heart is unclear.Objective: The purpose of this study was to quantify the impact of regional myocardial deformation provoked by a sudden increase in ventricular loading (aortic occlusion) on human cardiac electrophysiology.Methods: In 10 patients undergoing open heart cardiac surgery, left ventricular (LV) afterload was modified by transient aortic occlusion. Simultaneous assessment of whole-heart electrophysiology and LV deformation was performed using an epicardial sock (240 electrodes) and speckle-tracking transesophageal echocardiography. Parameters were matched to 6 American Heart Association LV model segments. The association between changes in regional myocardial segment length and activation-recovery interval (ARI; a conventional surrogate for action potential duration) was studied using mixed-effect models.Results: Increased ventricular loading reduced longitudinal shortening (P = .01) and shortened ARI (P = .02), but changes were heterogeneous between cardiac segments. Increased regional longitudinal shortening was associated with ARI shortening (effect size 0.20 [0.01-0.38] ms/%; P = .04) and increased local ARI dispersion (effect size -0.13 [-0.23 to -0.03] ms/%; P = .04). At the whole organ level, increased mechanical dispersion translated into increased dispersion of repolarization (correlation coefficient r = 0.81; P = .01).Conclusion: Mechanoelectric feedback can establish a potentially proarrhythmic substrate in the human heart and should be considered to advance our understanding and prevention of cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Summary of the progress in arrhythmias in 2020. RACE4 and ALL-IN indicated that integrated nurse-led care improves outcomes in AF patients. 3,4 The same was reported for early rhythm control therapy 15 and cryoablation as initial AF treatment. 25,26 Subcutaneous ICD was non-inferior to classical transvenous ICD therapy in PRAETORIAN. 54 One mechanistic study showed that autoantibodies against misexpressed actin, keratin, and connexin-43 proteins create a blood-borne biomarker profile enhancing diagnosis of Brugada syndrome. 50 Another mechanistic study indicated that transseptal LV pacing yields similar improvement in contractility as His bundle pacing whilst being more easy to execute. 44 In PRE-DETERMINE a simple-to-use ECG risk score improved risk prediction in patients with ischemic heart disease possibly enhancing appropriate ICD therapy in high risk patients. 58 [ABSTRACT FROM AUTHOR]

Background: The subcutaneous (S) implantable cardioverter-defibrillator (ICD) is safe and effective for sudden cardiac death prevention. However, patients in previous S-ICD studies had fewer comorbidities, had less left ventricular dysfunction, and received more inappropriate shocks (IAS) than in typical transvenous ICD trials. The UNTOUCHED trial (Understanding Outcomes With the S-ICD in Primary Prevention Patients With Low Ejection Fraction) was designed to evaluate the IAS rate in a more typical, contemporary ICD patient population implanted with the S-ICD using standardized programming and enhanced discrimination algorithms.Methods: Primary prevention patients with left ventricular ejection fraction ≤35% and no pacing indications were included. Generation 2 or 3 S-ICD devices were implanted and programmed with rate-based therapy delivery for rates ≥250 beats per minute and morphology discrimination for rates ≥200 and <250 beats per minute. Patients were followed for 18 months. The primary end point was the IAS-free rate compared with a 91.6% performance goal, derived from the results for the ICD-only patients in the MADIT-RIT study (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy). Kaplan-Meier analyses were performed to evaluate event-free rates for IAS, all-cause shock, and complications. Multivariable proportional hazard analysis was performed to determine predictors of end points.Results: S-ICD implant was attempted in 1116 patients, and 1111 patients were included in postimplant follow-up analysis. The cohort had a mean age of 55.8±12.4 years, 25.6% were women, 23.4% were Black, 53.5% had ischemic heart disease, 87.7% had symptomatic heart failure, and the mean left ventricular ejection fraction was 26.4±5.8%. Eighteen-month freedom from IAS was 95.9% (lower confidence limit, 94.8%). Predictors of reduced incidence of IAS were implanting the most recent generation of device, using the 3-incision technique, no history of atrial fibrillation, and ischemic cause. The 18-month all-cause shock-free rate was 90.6% (lower confidence limit, 89.0%), meeting the prespecified performance goal of 85.8%. Conversion success rate for appropriate, discrete episodes was 98.4%. Complication-free rate at 18 months was 92.7%.Conclusions: This study demonstrates high efficacy and safety with contemporary S-ICD devices and programming despite the relatively high incidence of comorbidities in comparison with earlier S-ICD trials. The inappropriate shock rate (3.1% at 1 year) is the lowest reported for the S-ICD and lower than many transvenous ICD studies using contemporary programming to reduce IAS. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02433379. [ABSTRACT FROM AUTHOR]

Brugada syndrome is an inherited cardiac condition characterized by a typical electrocardiogram signature of coved-type ST-segment elevation in the right precordial leads and ventricular arrhythmias leading to sudden cardiac death, in the absence of unequivocal structural heart disease. Brugada syndrome specifically affects the right ventricle, which predisposes to cardiac arrest. Besides medical management with quinidine, emerging data indicate that catheter ablation can help reduce the ventricular arrhythmia burden in these patients. This review explores the mechanisms of ventricular arrhythmia, current approaches and evidence for ablating the epicardial arrhythmogenic substrate in this condition. [ABSTRACT FROM AUTHOR]

Introduction: Implantable loop recorders (ILR) are predominantly implanted by cardiologists in the catheter laboratory. We developed a nurse‐delivered service for the implantation of LINQ (Medtronic; Minnesota) ILRs in the outpatient setting. This study compared the safety and cost‐effectiveness of the introduction of this nurse‐delivered ILR service with contemporaneous physician‐led procedures. Methods: Consecutive patients undergoing an ILR at our institution between 1st July 2016 and 4th June 2018 were included. Data were prospectively entered into a computerized database, which was retrospectively analyzed. Results: A total of 475 patients underwent ILR implantation, 271 (57%) of these were implanted by physicians in the catheter laboratory and 204 (43%) by nurses in the outpatient setting. Six complications occurred in physician‐implants and two in nurse‐implants (P = .3). Procedural time for physician‐implants (13.4 ± 8.0 minutes) and nurse‐implants (14.2 ± 10.1 minutes) were comparable (P = .98). The procedural cost was estimated as £576.02 for physician‐implants against £279.95 with nurse‐implants, equating to a 57.3% cost reduction. In our center, the total cost of ILR implantation in the catheter laboratory by physicians was £10 513.13 p.a. vs £6661.55 p.a. with a nurse‐delivered model. When overheads for running, cleaning, and maintaining were accounted for, we estimated a saving of £68 685.75 was performed by moving to a nurse‐delivered model for ILR implants. Over 133 catheter laboratory and implanting physician hours were saved and utilized for other more complex procedures. Conclusion: ILR implantation in the outpatient setting by suitably trained nurses is safe and leads to significant financial savings. [ABSTRACT FROM AUTHOR]

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has shown favorable outcomes in large registries with broad inclusion criteria. The cohorts reported had less heart disease and fewer comorbidities than standard ICD populations.Objective: The purpose of this study is to characterize acute performance for primary prevention patients with a left ventricular ejection fraction (LVEF) ≤35% (primary prevention ≤35%).Methods: Primary prevention ≤35% patients with no prior documented sustained ventricular tachycardia (VT), pacing indication, end-stage heart failure, or advanced renal failure were prospectively enrolled. Analyses included descriptive statistics, Kaplan-Meier time to event, and multivariable linear and logistic regression.Results: In 1112 of 1116 patients, an S-ICD was successfully implanted (99.6%). Predictors for longer procedure time included 3-incision technique, higher body mass index (BMI), performing defibrillation testing (DFT), imaging, younger age, black race, and European vs North American centers. Patients undergoing DFT (82%) were successfully converted (99.2%; 93.5% converting at ≤65 J). Higher BMI was predictive of failing DFT at ≤65 J. The rate of 30-day freedom from complications was 95.8%. Most complications involved postoperative healing (45%) or interventions after DFT or impedance check (19%).Conclusion: The procedural outcome data of UNTOUCHED reinforce that S-ICD therapy has low perioperative complication rates and high conversion efficacy of induced ventricular fibrillation, even in a higher-risk cohort with low LVEF and more comorbidities than previous S-ICD studies. Higher BMI warrants more careful attention to implant technique. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a clinically heterogeneous arrhythmia that is currently classified according to the variety of temporal rhythm based manifestations observed clinically, including 'first detected episode', 'paroxysmal', 'persistent', or 'permanent' AF. Despite being widely adopted by the most recent consensus guidelines, the utility of this classification system to stratify patients into distinct and clinically useful groups that have different outcomes including mortality, morbidity, specific cardiovascular outcomes, and quality of life (QoL), remains questionable. This is particularly true regarding the distinction between paroxysmal and persistent AF. Here, we demonstrate there is limited and conflicting evidence that this distinction is useful in predicting mortality, morbidity (including stroke and heart failure), symptom burden and QoL, although there is convincing evidence that patients with paroxysmal AF have favourable outcomes following electrical cardioversion and have better ablation procedural outcomes. Risk stratification schemes including the CHA2DS2VASc score are widely used to help clinicians stratify patients at high risk of stroke, whilst a number of newer, potentially superior, competitors have also recently been developed. A range of parameters including left atrial (LA) size, LA morphology, LA fibrosis [assessed by magnetic resonance imaging (MRI)] LA appendage morphology and LA function (assessed by echo) have all been recently suggested to identify higher risk patients and may, perhaps in combination with validated risk stratification scores and emerging genetic data, provide clinicians with the information necessary to more accurately stratify patients to ensure better outcomes of specific AF treatments and prevent adverse events. [ABSTRACT FROM AUTHOR]

Athletes with cardiac disorders frequently pose an ethical and medical dilemma to physicians assessing their eligibility to participate in sport. In recent decades, patient empowerment has been gaining increasing recognition in clinical decision-making. Empowerment is a process through which people are involved over the decisions and actions that affect their own lives. In the context of a cardiac disorder, empowerment means giving an athlete the chance to participate in the decision about whether or not to remain active in competition. Three models of treatment decision-making are described in this article, with progressive levels of empowerment: the paternalistic model (the athlete has a passive role), the shared-decision making model (both athlete and physician participate in the decision), and the informed-decision making (the decision is made by the athlete while the role of the physician is solely to provide information). This article critically discusses the issues involved in disqualification of athletes with cardiovascular disorders and suggests possible ways of incorporating patient empowerment in potentially career-ending decisions. The authors propose a model of empowerment, which gives patients the opportunity to choose how much, and if, they would like to be involved in the decision-making process. [ABSTRACT FROM AUTHOR]

Background: The features of the hypertrophic cardiomyopathy (HCM) ECG make it a challenge for subcutaneous implantable cardioverter-defibrillator (S-ICD) screening. We aimed to investigate the causes of screening failure at rest and on exercise to inform optimal S-ICD ECG vector development.Methods and Results: One hundred and thirty-one HCM patients (age, 50±16 years; 92 males and 39 females) with ≥1 HCM risk factor for sudden death underwent S-ICD ECG screening at rest and on exercise. Fifty patients (38%) were ineligible for S-ICD because of screening failure in every lead vector: 33 (66%) failed in the supine position, 12 (24%) failed in the standing position, and 5 (10%) failed on exercise. In patients who could exercise and passed screening at rest, 31 (44%) had 1 vector safety, 16 (23%) had 2 vector safety, and 24 (33%) had 3 vector safety. Increased R:T wave ratio in the S-ICD screening ECG (odds ratio, 4.0; confidence interval, 3.0-5.3; P<0.001) was associated with screening failure, while R/T ratio <3 in aVF (odds ratio, 0.3; confidence interval, 0.12-0.69; P=0.006) and increasing age (odds ratio, 0.97; confidence interval, 0.95-0.99; P=0.03) was associated with reduced screening failure. European Society of Cardiology risk score was higher in those failing screening (risk score 5.5% [interquartile range, 3.2-8.7] in failed versus 4.5% [interquartile range, 2.9-7.4] in passed; P=0.04).Conclusions: HCM patients have a significant incidence of screening failure, which is determined primarily by the increased R:T ratio on the screening ECG and lead aVF. High-risk patients have an increased screening failure rate. Optimization of sensing algorithms is required to ensure that the highest risk HCM patients can benefit from S-ICD implantation. [ABSTRACT FROM AUTHOR]

Aim: Cryoballoon ablation (Cryoballoon) has emerged as a new alternative for the treatment of symptomatic drug-refractory atrial fibrillation (AF). Whether the results of Cryoballoon are more reproducible than those of radiofrequency (RF) ablation remains to be proved.Methods and Results: A total of 860 consecutive patients undergoing a first ablation procedure for paroxysmal AF (467 treated with RF and 393 treated with Cryoballoon) were selected from a prospective multicentre survey of AF ablation (FrenchAF). Radiofrequency and Cryoballoon were compared regarding mid-term efficacy and safety. During a median follow-up of 14 months (interquartile range 8-23), patients treated with Cryoballoon displayed similar rates of freedom from atrial arrhythmia relapse in centres performing this technique (68-80% at 18 months). However, in centres performing RF, a greater heterogeneity in procedural results was observed (46-79% were free from atrial arrhythmia relapse at 18 months). On multivariate analysis, Cryoballoon (HR = 0.47, 95% CI 0.35-0.65, P < 0.001) and annual AF ablation caseload (HR = 0.87 per every 100 AF ablation procedures per year; 95% CI 0.80-0.96, P = 0.003) were independent predictors of procedural success. However, on sensitivity analysis, according to the ablation method, annual AF ablation caseload predicted only sinus rhythm maintenance in the subgroup of patients treated with RF. Analysis of interoperator results with Cryoballoon and RF confirmed lower reproducibility of RF, but suggested that besides caseload, other operator-related factors may play a role.Conclusion: Cryoballoon seems to be less operator-dependent and more reproducible than RF in the setting of paroxysmal AF ablation. [ABSTRACT FROM AUTHOR]

Background: The restitution of the action potential duration (APDR) and conduction velocity (CVR) are mechanisms whereby cardiac excitation and repolarization adapt to changes in heart rate. They modulate the vulnerability to dangerous arrhythmia, but the mechanistic link between restitution and arrhythmogenesis remains only partially understood. Methods: This paper provides an experimental and theoretical study of repolarization and excitation restitution properties and their interactions in the intact human epicardium. The interdependence between excitation and repolarization dynamic is studied in 8 patients (14 restitution protocols, 1722 restitution curves) undergoing global epicardial mapping with multi-electrode socks before open heart surgery. A mathematical description of the contribution of both repolarization and conduction dynamics to the steepness of the APDR slope is proposed. Results: This study demonstrates that the APDR slope is a function of both activation and repolarization dynamics. At short cycle length, conduction delay significantly increases the APDR slope by interacting with the diastolic interval. As predicted by the proposed mathematical formulation, the APDR slope was more sensitive to activation time prolongation than to the simultaneous shortening of repolarization time. A steep APDR slope was frequently identified, with 61% of all cardiac sites exhibiting an APDR slope > 1, suggesting that a slope > 1 may not necessarily promote electrical instability in the human epicardium. APDR slope did not change for different activation or repolarization times, and it was not a function of local baseline APD. However, it was affected by the spatial organization of electrical excitation, suggesting that in tissue APDR is not a unique function of local electrophysiological properties. Spatial heterogeneity in both activation and repolarization restitution contributed to the increase in the modulated dispersion of repolarization, which for short cycle length was as high as 250 ms. Heterogeneity in conduction velocity restitution can translate into both activation and repolarization dispersion and increase cardiac instability. The proposed mathematical formulation shows an excellent agreement with the experimental data (correlation coefficient r = 0.94) and provides a useful tool for the understanding of the complex interactions between activation and repolarization restitution properties as well as between their measurements. [ABSTRACT FROM AUTHOR]

Background: Striking temporal associations exist between ventricular arrhythmia and acute mental stress, for example, during natural disasters, or defibrillator shocks associated with stressful events. We hypothesized that electrophysiological changes in response to mental stress may be exaggerated at short coupling intervals and hence relevant to arrhythmia initiation.Objective: The aim of this study was to determine the dynamic response in human electrophysiology during mental stress.Methods: Patients with normal hearts and supraventricular tachycardia underwent electrophysiological studies avoiding sedation. Conditions of relaxation and stress were induced with standardized psychometric protocols (mental arithmetic and anger recall) during decremental S1S2 right ventricular (RV) pacing. Unipolar electrograms were acquired simultaneously from the RV endocardium, left ventricular (LV) endocardium (LV endo), and epicardium (LV epi), and activation-recovery intervals (ARIs) computed.Results: Twelve patients ( 9 women; median age 34 years) were studied. During stress, effective refractory period (ERP) reduced from 228 ± 23 to 221 ± 21 ms (P < .001). ARIs reduced during mental stress (P < .001), with greater reductions in LV endocardium than in the epicardium or RV endocardium (LV endo -8 ms; LV epi -5 ms; RV endo -4 ms; P < .001). Mental stress depressed the entire electrical restitution curve, with minimal effect on slope. A substantial reduction in minimal ARIs on the restitution curve in LV endo occurred, commensurate with the reduction in ERP (LV endo ARI 195 ± 31 ms at rest to 182 ± 32 ms during mental stress; P < .001). Dispersion of repolarization increased sharply at coupling intervals approaching ERP during stress but not at rest.Conclusion: Mental stress induces significant electrophysiological changes. The increase in dispersion of repolarization at short coupling intervals may be relevant to observed phenomena of arousal-associated arrhythmia. [ABSTRACT FROM AUTHOR]

Aim and Hypothesis: Despite the proven symptomatic and mortality benefit of cardiac resynchronization therapy (CRT), there is anecdotal evidence it may be pro-arrhythmic in some patients. We aimed to identify if there were significant differences in the incidence of ventricular arrhythmias (VAs) in patients undergoing CRT-D and implantable cardioverter-defibrillators (ICD) implantation for primary prevention indication. We hypothesized that CRT is unlikely to be pro-arrhythmic based on the positive mortality and morbidity data from large randomized trials. Methods and Results: A retrospective analysis of device therapies for VA in a primary prevention device cohort was performed. Patients with ischemic (IHD) and non-ischemic (DCM) cardiomyopathy and ICD or CRT+ICD devices (CRT-D) implanted between 2005 and 2007 without prior history of sustained VA were included for analysis. VA episodes were identified from stored electrograms and defined as sustained (VT/VF) if therapy [anti-tachycardia pacing (ATP) or shocks] was delivered or non-sustained (NSVT) if not. Of a total of 180 patients, 117 (68% male) were in the CRT-D group, 42% IHD, ejection fraction (EF) 24.5 ± 8.2% and mean follow-up 23.9 ± 9.8 months. 63 patients (84% male) were in the ICD group, 60% IHD, EF 27.7 ± 7.2% and mean follow-up 24.6 ± 10.8 months. Overall, there was no significant difference in the incidence of VA (35.0 vs. 38.1%, p = 0.74), sustained VT (21.3 vs. 28.5%, p = 0.36) or NSVT (12.8 vs. 9.5%, p = 0.63) and no significant difference in type of therapy received for VT/VF: ATP (68 vs. 66.6%, p = 0.73) and shocks (32 vs. 33.3%, p = 0.71) between the CRT-D and ICD groups, respectively. Conclusion: In patients with cardiomyopathy receiving CRT-D and ICDs for primary prophylaxis, there was no significant difference in the incidence of VA. From this single center retrospective analysis, there is no evidence to support cardiac resynchronization causing pro-arrhythmia. [ABSTRACT FROM AUTHOR]

The KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene encodes the Kv7.1 potassium channel which forms a complex with KCNE1 (potassium voltage-gated channel Isk-related family member 1) in the human heart to produce the repolarizing IKs (slow delayed rectifier potassium current). Mutations in KCNQ1 can perturb IKs function and cause LQT1 (long QT syndrome type 1). In LQT1, compound mutations are relatively common and are associated with increased disease severity. LQT1 compound mutations have been shown to increase channel dysfunction, but whether other disease mechanisms, such as defective channel trafficking, contribute to the increase in arrhythmic risk has not been determined. Using an imaging-based assay we investigated the effects of four compound heterozygous mutations (V310I/R594Q, A341V/P127T, T391I/Q530X and A525T/R518X), one homozygous mutation (W248F) and one novel compound heterozygous mutation (A178T/K422fs39X) (where fs denotes frameshift) on channel trafficking. By analysing the effects in the equivalent of a homozygous, heterozygous and compound heterozygous condition, we identify three different types of behaviour. A341V/P127T and W248F/W248F had no effect, whereas V310I/R594Q had a moderate, but not compound, effect on channel trafficking. In contrast, T391I/Q530X, A525T/R518X and A178T/K422fs39X severely disrupted channel trafficking when expressed in compound form. In conclusion, we have characterized the disease mechanisms for six LQT1 compound mutations and report that, for four of these, defective channel trafficking underlies the severe clinical phenotype. [ABSTRACT FROM AUTHOR]

Computerized simulations of cardiac activity have significantly contributed to our understanding of cardiac electrophysiology, but techniques of simulations based on patient-acquired data remain in their infancy. We sought to integrate data acquired from human electrophysiological studies into patient-specific models, and validated this approach by testing whether electrophysiological responses to sequential premature stimuli could be predicted in a quantitatively accurate manner. Methods: Eleven patients with structurally normal hearts underwent electrophysiological studies. Semi-automated analysis was used to reconstruct activation and repolarization dynamics for each electrode. This S2 extrastimuli data was used to inform individualized models of cardiac conduction, including a novel derivation of conduction velocity restitution. Activation dynamics of multiple premature extrastimuli were then predicted from this model and compared against measured patient data as well as data derived from the ten-Tusscher cell-ionic model. Results: Activation dynamics following a premature S3 were significantly different from those after an S2. Patient specific models demonstrated accurate prediction of the S3 activation wave, (Pearson's R2 = 0.90, median error 4%). Examination of the modeled conduction dynamics allowed inferences into the spatial dispersion of activation delay. Further validation was performed against data from the ten-Tusscher cell-ionicmodel, with our model accurately recapitulating predictions of repolarization times (R2 = 0.99). Conclusions: Simulations based on clinically acquired data can be used to successfully predict complex activation patterns following sequential extrastimuli. Such modeling techniques may be useful as a method of incorporation of clinical data into predictive models. [ABSTRACT FROM AUTHOR]

Aims Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. Methods and results Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. Conclusion Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification. [ABSTRACT FROM PUBLISHER]

Background The use of fluoroscopic screening involves exposure to ionising radiation for both patients and operators. Objective To assess the effects of radiation dose reduction manoeuvres (DRM) during radiofrequency ablation (RFA) procedures. Design Prospective study of DRM. Setting Tertiary cardiac centre. Interventions Two DRM were combined: removal of the secondary radiation grid and programming an ultra-low pulsed fluoroscopy rate. These methods were assessed using an anthropomorphic phantom model to measure skin entrance dose rates. Procedures were classified as complex (ablation of atrial fibrillation, ventricular tachycardia or complex congenital heart disease arrhythmias) or simple (all other RFA). Main outcome measures Dose area product and screening times were compared for ablations performed before and after DRM. Equivalent doses to organs and malignancy risk were determined by computer modelling. Results Over a 39-month period, 1007 ablation procedures were performed (631 simple, 376 complex). Radiation dose was significantly reduced after DRM for both simple (20.4±26.9 Gycm² vs 8.0±10.3 Gycm², p<0.00001) and complex ablations (63.3±50.1 Gycm² vs 32.8±31.7 Gycm², p<0.00001) with no difference in screening times. The mean lifetime risk of fatal cancer attributable to radiation exposure per million procedures was reduced from 182 to 68 for simple ablations and from 440 to 155 for complex ablations. Conclusions Significant reductions in radiation exposure during RFA were achieved using simple DRM, corresponding to a two-thirds reduction of the risk of excess fatal malignancy. [ABSTRACT FROM AUTHOR]

• Inaccuracies of QRS and T-wave markers significantly impact QRS-Ta estimation. • These errors influence the classification of clinically relevant abnormal values. • Our algorithm provides robust measurements in the presence of inaccurate VCG markers. • We present for the first time, the distribution of the QRS-Ta in a large cohort. The spatial QRS-T angle (QRS-Ta) derived from the vectorcardiogram (VCG) is a strong risk predictor for ventricular arrhythmia and sudden cardiac death with potential use for mass screening. Accurate QRS-Ta estimation in the presence of ECG delineation errors is crucial for its deployment as a prognostic test. Our study assessed the effect of inaccurate QRS and T-wave marker placement on QRS-Ta estimation and proposes a robust method for its calculation. Reference QRS-Ta measurements were derived from 1,512 VCGs manually annotated by three expert reviewers. We systematically changed onset and offset timings of QRS and T-wave markers to simulate inaccurate placement. The QRS-Ta was recalculated using a standard approach and our proposed algorithm, which limits the impact of VCG marker inaccuracies by defining the vector origin as an interval preceding QRS-onset and redefines the beginning and end of QRS and T-wave loops. Using the standard approach, mean absolute errors (MAE) in peak QRS-Ta were >40% and sensitivity and precision in the detection of abnormality (>105°) were <80% and <65% respectively, when QRS-onset was delayed or QRS-offset anticipated >15 ms. Using our proposed algorithm, MAE for peak QRS-Ta were reduced to <4% and sensitivity and precision of abnormality were >94% for inaccuracies up to ±15 ms. Similar results were obtained for mean QRS-Ta. In conclusion, inaccuracies of QRS and T-wave markers can significantly influence the QRS-Ta. Our proposed algorithm provides robust QRS-Ta measurements in the presence of inaccurate VCG annotation, enabling its use in large datasets. [ABSTRACT FROM AUTHOR]

A 58-year-old woman with symptomatic multiple monomorphic premature ventricular beats of a right ventricular outflow tract origin was referred for ablation. An inferior vena cava interruption with azygos continuation was discovered during catheter placement. This case describes positioning of the noncontact mapping array and successful radiofrequency ablation in this challenging anatomy. (PACE 2013; 36:e129-e131) [ABSTRACT FROM AUTHOR]

Aims: Comparison of outcomes between subcutaneous and transvenous implantable cardioverter-defibrillator (S-ICD and TV-ICD) therapy is hampered by varying patient characteristics and complication definitions. The aim of this analysis is to compare clinical outcomes of S-ICD and TV-ICD therapy in a matched cohort.Methods and results: Patients implanted with de novo implantable cardioverter-defibrillators without need for pacing were selected from two studies: SIMPLE (n = 1091 single and n = 553 dual chamber TV-ICDs) and EFFORTLESS (n = 798 S-ICDs). Subcutaneous implantable cardioverter-defibrillator patients were 1:1 matched on propensity score to TV-ICD patients. Propensity scores were calculated using 15 baseline characteristics including diagnosis. The Kaplan-Meier estimates for complications requiring invasive intervention, appropriate shocks, and inappropriate shocks were calculated at 3 years follow-up. The primary analysis yielded 391 patients pairs with balanced baseline characteristics, with mean age 55 ± 14 years, 49% ischaemic cardiomyopathy, mean left ventricular ejection fraction 40%, 71% primary prevention, and 89% of TV-ICDs were single chamber. Follow-up was mean 2.9 years in the S-ICD arm vs. 3.3 in the TV-ICD arm. All-cause complications occurred in 9.0% of S-ICD vs. 6.5% of TV-ICD patients, P = 0.29. Appropriate shocks occurred in 9.9% of S-ICD vs. 13.8% in TV-ICD patients, P = 0.03 and inappropriate shocks in 11.9% in S-ICD vs. 8.9% in TV-ICD patients (P = 0.07). Total shock burden (20 vs. 31, P = 0.05) and appropriate shock burden per 100 patients years (9 vs. 18, P = 0.02) were lower for S-ICD patients, while inappropriate shock burden was equal (11 vs. 13, P = 0.56).Conclusion: The earliest experience of the S-ICD demonstrates similar outcomes as contemporary TV-ICD therapy in a matched comparison with predominately single-chamber devices at 3 years follow-up. [ABSTRACT FROM AUTHOR]

BACKGROUND: The consequences of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals remain unclear. This study aimed to assess the association between PVC burdens during submaximal exercise and major adverse cardiovascular events (MI/HF/LTVA: myocardial infarction [MI], heart failure [HF], and life-threatening ventricular arrhythmia [LTVA]), and all-cause mortality. Additional end points were MI, LTVA, HF, and cardiovascular mortality. METHODS: A neural network was developed to count PVCs from ECGs recorded during exercise (6 minutes) and recovery (1 minute) in 48 315 asymptomatic participants from UK Biobank. Associations were estimated using multivariable Cox proportional hazard models. Explorative studies were conducted in subgroups with cardiovascular magnetic resonance imaging data (n=6290) and NT-proBNP (N-terminal Pro-B-type natriuretic peptide) levels (n=4607) to examine whether PVC burden was associated with subclinical cardiomyopathy. RESULTS: Mean age was 56.8±8.2 years; 51.1% of the participants were female; and median follow-up was 12.6 years. Low PVC counts during exercise and recovery were both associated with MI/HF/LTVA risk, independently of clinical factors: adjusted hazard ratio (HR), 1.2 (1–5 exercise PVCs, P <0.001) and HR, 1.3 (1–5 recovery PVCs, P <0.001). Risks were higher with increasing PVC count: HR, 1.8 (>20 exercise PVCs, P <0.001) and HR, 1.6 (>5 recovery PVCs, P <0.001). A similar trend was observed for all-cause mortality, although associations were only significant for high PVC burdens: HRs, 1.6 (>20 exercise PVCs, P <0.001) and 1.5 (>5 recovery PVCs, P <0.001). Complex PVC rhythms were associated with higher risk compared with PVC count alone. PVCs were also associated with incident HF, LTVA, and cardiovascular mortality, but not MI. In the explorative studies, high PVC burden was associated with larger left ventricular volumes, lower ejection fraction, and higher levels of NT-proBNP compared with participants without PVCs. CONCLUSIONS: In this cohort of middle-aged and older adults, PVC count during submaximal exercise and recovery were both associated with MI/HF/LTVA, all-cause mortality, HF, LTVAs, and cardiovascular mortality, independent of clinical and exercise test factors, indicating an incremental increase in risk as PVC count rises. Complex PVC rhythms were associated with higher risk compared with PVC count alone. Underlying mechanisms may include the presence of subclinical cardiomyopathy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Arrhythmic mitral valve prolapse and sudden cardiac death," by Cristina Basso and colleagues in the 2015 issue.

Background: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) showed noninferiority of subcutaneous implantable cardioverter defibrillator (S-ICD) compared with transvenous implantable cardioverter defibrillator (TV-ICD) with regard to inappropriate shocks and complications. In contrast to TV-ICD, S-ICD cannot provide antitachycardia pacing for monomorphic ventricular tachycardia. This prespecified secondary analysis evaluates appropriate therapy and whether antitachycardia pacing reduces the number of appropriate shocks.Methods: The PRAETORIAN trial was an international, investigator-initiated randomized trial that included patients with an indication for implantable cardioverter defibrillator (ICD) therapy. Patients with previous ventricular tachycardia <170 bpm or refractory recurrent monomorphic ventricular tachycardia were excluded. In 39 centers, 849 patients were randomized to receive an S-ICD (n=426) or TV-ICD (n=423) and were followed for a median of 49.1 months. ICD programming was mandated by protocol. Appropriate ICD therapy was defined as therapy for ventricular arrhythmias. Arrhythmias were classified as discrete episodes and storm episodes (≥3 episodes within 24 hours). Analyses were performed in the modified intention-to-treat population.Results: In the S-ICD group, 86 of 426 patients received appropriate therapy, versus 78 of 423 patients in the TV-ICD group, during a median follow-up of 52 months (48-month Kaplan-Meier estimates 19.4% and 17.5%; P=0.45). In the S-ICD group, 83 patients received at least 1 shock, versus 57 patients in the TV-ICD group (48-month Kaplan-Meier estimates 19.2% and 11.5%; P=0.02). Patients in the S-ICD group had a total of 254 shocks, compared with 228 shocks in the TV-ICD group (P=0.68). First shock efficacy was 93.8% in the S-ICD group and 91.6% in the TV-ICD group (P=0.40). The first antitachycardia pacing attempt successfully terminated 46% of all monomorphic ventricular tachycardias, but accelerated the arrhythmia in 9.4%. Ten patients with S-ICD experienced 13 electrical storms, versus 18 patients with TV-ICD with 19 electrical storms. Patients with appropriate therapy had an almost 2-fold increased relative risk of electrical storms in the TV-ICD group compared with the S-ICD group (P=0.05).Conclusions: In this trial, no difference was observed in shock efficacy of S-ICD compared with TV-ICD. Although patients in the S-ICD group were more likely to receive an ICD shock, the total number of appropriate shocks was not different between the 2 groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022. [ABSTRACT FROM AUTHOR]

Background Recurrent atrial fibrillation episodes following pulmonary vein isolation (PVI) are frequently due to reconnection of PVs. Adenosine can unmask dormant conduction, leading to additional ablation to improve AF-free survival. We performed a meta-analysis of the literature to assess the role of adenosine testing in patients undergoing atrial fibrillation (AF) ablation. Methods PubMed, EMBASE, and Cochrane databases were searched through until December 2015 for studies reporting on the role of adenosine guided-PVI versus conventional PVI in AF ablation. Results Eleven studies including 4099 patients undergoing AF ablation were identified to assess the impact of adenosine testing. Mean age of the population was 61 ± 3 years: 25% female, 70% with paroxysmal AF. Follow up period of 12.5 ± 5.1 months. A significant benefit was observed in the studies published before 2013 (OR = 1.75; 95%CI 1.32–2.33, p < 0.001, I 2 = 11%), retrospective (OR = 2.05; 95%CI 1.47–2.86, p < 0.001, I 2 = 0%) and single-centre studies (OR = 1.58; 95%CI 1.19–2.10, p = 0.002, I 2 = 30%). However, analysis of studies published since 2013 (OR = 1.41; 95% CI 0.87–2.29, p = 0.17, I 2 = 75%) does not support any benefit from an adenosine-guided strategy. Similar findings were observed by pooling prospective case-control (OR = 1.39; 95%CI 0.93–2.07, p = 0.11, I 2 = 75%), and prospective randomized controlled studies (OR = 1.62; 95%CI 0.81–3.24, p = 0.17, I 2 = 86%). Part of the observed high heterogeneity can be explained by parameters such as dormant PVs percentage, use of new technology, improvement of center/operator experience, patients' characteristics including gender, age, and AF type. Conclusions Pooling of contemporary data from high quality prospective case–control & prospective randomized controlled studies fails to show the benefit of adenosine-guided strategy to improve AF ablation outcomes. [ABSTRACT FROM AUTHOR]

Advances in investigative techniques have led to an increasing awareness and understanding of the role of central neural control in the autonomic nervous system regulation of the heart. Substantial evidence exists for a role of the higher centres in neuro-cardiac control including the effect of focal brain stimulation and acute brain lesions on cardiac electrophysiology, blood pressure, contractile function and the development of arrhythmias. Mental stress and strong emotions have long been associated with sudden cardiac death. There is an emerging literature relating the gene-environment interactions in determining the neural patterning responsible for the stress response itself. The role of the higher brain centres in determining myocardial behaviour has become accessible through the utilisation of optogenetic techniques to modulate activity in specific brainstem nuclei, enabling the dissection of specific vagal and sympathetic inputs on cardiac electrophysiology and arrhythmogenesis. Central cardiac control mechanisms are modulated by afferent signals from the heart. Ascending interoceptive pathways from heart to several forebrain regions influence the behavioural response and autonomic output to the heart. These processes are expressed as control loops at multiple levels of the neuraxis and are assumed to converge in part at the level of the baroreflex to shape the efferent drive to the heart and vasculature. [ABSTRACT FROM AUTHOR]

Inherited primary arrhythmia syndromes are a clinically heterogeneous group of relatively uncommon but important inherited cardiac conditions that are associated with an increased risk of sudden cardiac death (SCD) in the setting of a structurally normal heart. These include long-QT syndrome (LQTS), Short-QT syndrome (SQTS), Brugada syndrome (BrS) and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). The cardiomyopathies represent the other major group of inherited cardiac conditions associated with SCD, of which hypertrophic cardiomyopathy (HCM) is the most common. Exercise is a known trigger of ventricular arrhythmias in many of these conditions, however marked genetic and clinical heterogeneity within individual diseases means that certain patients are at a much greater risk of lethal ventricular arrhythmias during exercise than others. For instance, LQTS type 1 (LQT1) and CPVT patients are at particular risk during exertion, whilst in patients with other genetic variants of LQTS, BrS and SQTS, alternative triggers are more significant precipitants. Many channelopathy (principally Brugada, CPVT) & cardiomyopathy (mainly HCM) patients receive primary or secondary prevention therapy with an implantable cardiac defibrillator (ICD). Exercising with an ICD in situ carries a range of additional risks including inappropriate shocks and lead complications. This review will focus on the risk of exercise-induced SCD in patients with inherited cardiac conditions, the current clinical guidelines in this area and the special consideration of patients with an ICD. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to assess the prevalence of J-point elevation among the relatives of sudden arrhythmic death syndrome (SADS) probands. Background: J-point elevation is now known to be associated with idiopathic ventricular fibrillation. We hypothesized that this early repolarization phenomenon is an inherited trait responsible for a proportion of otherwise unexplained SADS cases. Methods: Families of SADS probands were evaluated in an inherited arrhythmia clinic. Twelve-lead electrocardiograms were analyzed for J-point elevation defined as >0.1 mV from baseline present in 2 or more of the inferior (II, III, and aVF) or lateral (1, aVL, V4 to V6) leads. Electrocardiographic data were compared with those of 359 controls of a similar age, sex, and ethnic distribution. Results: A total of 363 first-degree relatives from 144 families were evaluated. J-point elevation in the inferolateral leads was present in 23% of relatives and 11% of control subjects (odds ratio: 2.54, 95% confidence interval: 1.66 to 3.90; p < 0.001). Conclusions: J-point elevation is more prevalent in the relatives of SADS probands than in controls. This indicates that early repolarization is an important potentially inheritable pro-arrhythmic trait or marker of pro-arrhythmia in SADS. [Copyright &y& Elsevier]