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Aims  Atrial fibrillation (AF) is a commonly occurring arrhythmia after cardiac surgery (postoperative AF, poAF) and is associated with poorer outcomes. Considering that reduced atrial contractile function is a predictor of poAF and that Ca2+ plays an important role in both excitation–contraction coupling and atrial arrhythmogenesis, this study aims to test whether alterations of intracellular Ca2+ handling contribute to impaired atrial contractility and to the arrhythmogenic substrate predisposing patients to poAF. Methods and results  Right atrial appendages were obtained from patients in sinus rhythm undergoing open-heart surgery. Cardiomyocytes were investigated by simultaneous measurement of [Ca2+]i and action potentials (APs, patch-clamp). Patients were followed-up for 6 days to identify those with and without poAF. Speckle-tracking analysis of preoperative echocardiography revealed reduced left atrial contraction strain in poAF patients. At the time of surgery, cellular Ca2+ transients (CaTs) and the sarcoplasmic reticulum (SR) Ca2+ content were smaller in the poAF group. CaT decay was slower in poAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting preserved sodium-calcium exchanger function. In agreement, western blots revealed reduced SERCA2a expression in poAF patients but unaltered phospholamban expression/phosphorylation. Computational modelling indicated that reduced SERCA activity promotes occurrence of CaT and AP alternans. Indeed, alternans of CaT and AP occurred more often and at lower stimulation frequencies in atrial myocytes from poAF patients. Resting membrane potential and AP duration were comparable between both groups at various pacing frequencies (0.25–8 Hz). Conclusions  Biochemical, functional, and modelling data implicate reduced SERCA-mediated Ca2+ reuptake into the SR as a major contributor to impaired preoperative atrial contractile function and to the pre-existing arrhythmogenic substrate in patients developing poAF. [ABSTRACT FROM AUTHOR]

Background: A large number of SCN5A variants have been reported to underlie Brugada syndrome (BrS). However, the evidence supporting individual variants is highly heterogeneous. Objective: We systematically re‐evaluated all SCN5A variants reported in BrS using the 2015 American college of medical genetics and genomics and the association for molecular pathology (ACMG‐AMP) guidelines. Methods: A PubMed/Embase search was performed to identify all reported SCN5A variants in BrS. Standardized bioinformatic re‐analysis (SIFT, PolyPhen, Mutation Taster, Mutation assessor, FATHMM, GERP, PhyloP, and SiPhy) and re‐evaluation of frequency in the gnomAD database were performed. Fourteen ACMG‐AMP rules were deemed applicable for SCN5A variant analysis. Results: Four hundred and eighty unique SCN5A variants were identified, the majority of which 425 (88%) were coding variants. One hundred and fifty‐six of 425 (37%) variants were classified as pathogenic/likely pathogenic. Two hundred and fifty‐eight (60%) were classified as variants of uncertain significance, while a further 11 (3%) were classified as benign/likely benign. When considering the subset of variants that were considered "null" variants separately, 95% fulfilled criteria for pathogenicity/likely pathogenicity. In contrast, only 17% of missense variants fulfilled criteria for pathogenicity/likely pathogenicity. Importantly, however, only 25% of missense variants had available functional data, which was a major score driver for pathogenic classification. Conclusion: Based on contemporary ACMG‐AMP guidelines, only a minority of SCN5A variants implicated in BrS fulfill the criteria for pathogenicity or likely pathogenicity. [ABSTRACT FROM AUTHOR]

Key points Ageing is associated with an increased risk of cardiovascular disease and arrhythmias, with the most common arrhythmia being found in the atria of the heart., Little is known about how the normal atria of the heart remodel with age and thus why dysfunction might occur., We report alterations to the atrial systolic Ca2+ transient that have implications for the function of the atrial in the elderly., We describe a novel mechanism by which increased Ca buffering can account for changes to systolic Ca2+ in the old atria., The present study helps us to understand how the processes regulating atrial contraction are remodelled during ageing and provides a basis for future work aiming to understand why dysfunction develops., Abstract Many cardiovascular diseases, including those affecting the atria, are associated with advancing age. Arrhythmias, including those in the atria, can arise as a result of electrical remodelling or alterations in Ca2+ homeostasis. In the atria, age-associated changes in the action potential have been documented. However, little is known about remodelling of intracellular Ca2+ homeostasis in the healthy aged atria. Using single atrial myocytes from young and old Welsh Mountain sheep, we show the free Ca2+ transient amplitude and rate of decay of systolic Ca2+ decrease with age, whereas sarcoplasmic reticulum (SR) Ca content increases. An increase in intracellular Ca buffering explains both the decrease in Ca2+ transient amplitude and decay kinetics in the absence of any change in sarcoendoplasmic reticulum calcium transport ATPase function. Ageing maintained the integrated Ca2+ influx via ICa-L but decreased peak ICa-L. Decreased peak ICa-L was found to be responsible for the age-associated increase in SR Ca content but not the decrease in Ca2+ transient amplitude. Instead, decreased peak ICa-L offsets increased SR load such that Ca2+ release from the SR was maintained during ageing. The results of the present study highlight a novel mechanism by which increased Ca buffering decreases systolic Ca2+ in old atria. Furthermore, for the first time, we have shown that SR Ca content is increased in old atrial myocytes. [ABSTRACT FROM AUTHOR]

Cardiac implantable electronic device (CIED) infection is a potentially devastating complication of CIED procedures, causing significant morbidity and mortality for patients. Of all CIED complications, infection has the greatest impact on mortality, requirement for re-intervention and additional hospital treatment days. Based on large prospective studies, the infection rate at 12-months after a CIED procedure is approximately 1%. The risk of CIED infection may be related to several factors which should be considered with regards to risk minimization. These include technical factors, patient factors, and periprocedural factors. Technical factors include the number of leads and size of generator, the absolute number of interventions which have been performed for the patient, and the operative approach. Patient factors include various non-modifiable underlying comorbidities and potentially modifiable transient conditions. Procedural factors include both peri-operative and post-operative factors. The contemporary PADIT score, derived from a large cohort of CIED patients, is useful for the prediction of infection risk. In this review, we summarize the key information regarding epidemiology, incidence and risk factors for CIED infection., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Video-assisted thoracoscopic surgery (VATS) ablation has been advocated as a treatment option for non-paroxysmal atrial fibrillation (AF) in recent guidelines. Real-life data on its safety and efficacy during a centre's early experience are sparse., Methods and Results: Thirty patients (28 persistent/longstanding persistent AF) underwent standalone VATS ablation for AF by an experienced thoracoscopic surgeon, with the first 20 cases proctored by external surgeons. Procedural and follow-up outcomes were collected prospectively, and compared with 90 propensity-matched patients undergoing contemporaneous catheter ablation (CA). Six (20.0%) patients undergoing VATS ablation experienced ≥1 major complication (death n = 1, stroke n = 2, conversion to sternotomy n = 3, and phrenic nerve injury n = 2). This was significantly higher than the 1.1% major complication rate (tamponade requiring drainage n = 1) seen with CA (P < 0.001). Twelve-month single procedure arrhythmia-free survival rates without antiarrhythmic drugs were 56% in the VATS and 57% in the CA cohorts (P = 0.22), and 78% and 80%, respectively given an additional CA and antiarrhythmic drugs (P = 0.32)., Conclusion: During a centre's early experience, VATS ablation may have similar success rates to those from an established CA service, but carry a greater risk of major complications. Those embarking on a programme of VATS AF ablation should be aware that complication and success rates may differ from those reported by selected high-volume centres., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Maintaining sinus rhythm in patients with non-paroxysmal AF is an elusive goal. Some suggest that hybrid ablation, combining minimally invasive epicardial surgical ablation with endocardial catheter ablation, may be more effective than either modality alone. However, randomised trials are lacking. We investigated whether hybrid ablation is more effective than epicardial ablation alone at preventing recurrent AF by performing a systematic review and meta-analysis. The review was prospectively registered with PROSPERO (CRD42016043389). MEDLINE and EMBASE were searched for studies of standalone minimally invasive epicardial ablation of AF and/or hybrid ablation, identifying 41 non-overlapping studies comprising 2737 patients. A random-effects meta-analysis, meta-regression and sensitivity analysis were performed. Single-procedure survival free from atrial arrhythmias without antiarrhythmic drugs was similar between epicardial-alone and hybrid approaches at 12 months (epicardial alone 71.5 %; [95 % CI 66.1-76.9], hybrid 63.2 %; [95 % CI 51.5-75.0]) and 24 months (epicardial alone 68.5 %; [95 % CI 57.7-79.3], hybrid 57.0 %; [95 % CI 33.6-80.4]). Freedom from atrial arrhythmias with AADs and rates of unplanned additional catheter ablations were also similar between groups. Major complications occurred more often with hybrid ablation (epicardial alone 2.9 %; [95 % CI 1.9-3.9], hybrid 7.3 %; [95 % CI 4.2-10.5]). Meta-regression suggested that bipolar radiofrequency energy and thoracoscopic access were associated with greater efficacy, but adjusting for these factors did not unmask any difference between epicardial-alone and hybrid ablation. Hybrid and epicardial ablation alone appear to be equally effective treatments for AF, although hybrid ablation may be associated with higher complication rates. These data derived from observational studies should be verified with randomised data., Competing Interests: Disclosure: Charles Pearman was supported by a clinical lectureship from the National Institute for Health Research. Laura Bonnett was supported by a post-doctoral research fellowship (PDF-2015-08-044) from the National Institute for Health Research. Shouvik Haldar, Tom Wong and Dhiraj Gupta were supported by the National Institute of Health Research grant EME 12/127/127.

Rationale: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, I f , underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes., Objective: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4., Methods and Results: As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3'-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-423-5p reversed training-induced bradycardia via rescue of HCN4 and I f . Further experiments showed that in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5., Conclusions: HCN remodeling likely occurs in human athletes, as well as in rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes., (© 2017 The Authors.)

Key Points: Ageing is associated with an increased risk of cardiovascular disease and arrhythmias, with the most common arrhythmia being found in the atria of the heart. Little is known about how the normal atria of the heart remodel with age and thus why dysfunction might occur. We report alterations to the atrial systolic Ca 2+ transient that have implications for the function of the atrial in the elderly. We describe a novel mechanism by which increased Ca buffering can account for changes to systolic Ca 2+ in the old atria. The present study helps us to understand how the processes regulating atrial contraction are remodelled during ageing and provides a basis for future work aiming to understand why dysfunction develops., Abstract: Many cardiovascular diseases, including those affecting the atria, are associated with advancing age. Arrhythmias, including those in the atria, can arise as a result of electrical remodelling or alterations in Ca 2+ homeostasis. In the atria, age-associated changes in the action potential have been documented. However, little is known about remodelling of intracellular Ca 2+ homeostasis in the healthy aged atria. Using single atrial myocytes from young and old Welsh Mountain sheep, we show the free Ca 2+ transient amplitude and rate of decay of systolic Ca 2+ decrease with age, whereas sarcoplasmic reticulum (SR) Ca content increases. An increase in intracellular Ca buffering explains both the decrease in Ca 2+ transient amplitude and decay kinetics in the absence of any change in sarcoendoplasmic reticulum calcium transport ATPase function. Ageing maintained the integrated Ca 2+ influx via I Ca-L but decreased peak I Ca-L . Decreased peak I Ca-L was found to be responsible for the age-associated increase in SR Ca content but not the decrease in Ca 2+ transient amplitude. Instead, decreased peak I Ca-L offsets increased SR load such that Ca 2+ release from the SR was maintained during ageing. The results of the present study highlight a novel mechanism by which increased Ca buffering decreases systolic Ca 2+ in old atria. Furthermore, for the first time, we have shown that SR Ca content is increased in old atrial myocytes., (© 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)