Cardiac GR Mediates the Diurnal Rhythm in Ventricular Arrhythmia Susceptibility.

BACKGROUND: Ventricular arrhythmias (VAs) demonstrate a prominent day-night rhythm, commonly presenting in the morning. Transcriptional rhythms in cardiac ion channels accompany this phenomenon, but their role in the morning vulnerability to VAs and the underlying mechanisms are not understood. We investigated the recruitment of transcription factors that underpins transcriptional rhythms in ion channels and assessed whether this mechanism was pertinent to the heart's intrinsic diurnal susceptibility to VA. METHODS AND RESULTS: Assay for transposase-accessible chromatin with sequencing performed in mouse ventricular myocyte nuclei at the beginning of the animals' inactive (ZT0) and active (ZT12) periods revealed differentially accessible chromatin sites annotating to rhythmically transcribed ion channels and distinct transcription factor binding motifs in these regions. Notably, motif enrichment for the glucocorticoid receptor (GR; transcriptional effector of corticosteroid signaling) in open chromatin profiles at ZT12 was observed, in line with the well-recognized ZT12 peak in circulating corticosteroids. Molecular, electrophysiological, and in silico biophysically-detailed modeling approaches demonstrated GR-mediated transcriptional control of ion channels (including Scn5a underlying the cardiac Na+ current, Kcnh2 underlying the rapid delayed rectifier K+ current, and Gja1 responsible for electrical coupling) and their contribution to the day-night rhythm in the vulnerability to VA. Strikingly, both pharmacological block of GR and cardiomyocyte-specific genetic knockout of GR blunted or abolished ion channel expression rhythms and abolished the ZT12 susceptibility to pacing-induced VA in isolated hearts. CONCLUSIONS: Our study registers a day-night rhythm in chromatin accessibility that accompanies diurnal cycles in ventricular myocytes. Our approaches directly implicate the cardiac GR in the myocyte excitability rhythm and mechanistically link the ZT12 surge in glucocorticoids to intrinsic VA propensity at this time.

Symptomatic bradyarrhythmias in the athlete-Underlying mechanisms and treatments.

Bradyarrhythmias including sinus bradycardia and atrioventricular (AV) block are frequently encountered in endurance athletes especially at night. While these are well tolerated by the young athlete, there is evidence that generally from the fifth decade of life onward, such arrhythmias can degenerate into pathological symptomatic bradycardia requiring pacemaker therapy. For many years, athletic bradycardia and AV block have been attributed to high vagal tone, but work from our group has questioned this widely held assumption and demonstrated a role for intrinsic electrophysiological remodeling of the sinus node and the AV node. In this article, we argue that bradyarrhythmias in the veteran athlete arise from the cumulative effects of exercise training, the circadian rhythm and aging on the electrical activity of the nodes. We consider contemporary strategies for the treatment of symptomatic bradyarrhythmias in athletes and highlight potential therapies resulting from our evolving mechanistic understanding of this phenomenon.

Intra-Abdominal Hemorrhage Triggering Inappropriate Therapy From a Subcutaneous Defibrillator.

The SMART Pass filter (Boston Scientific) aims to reduce inappropriate shocks (IASs) from subcutaneous implantable cardioverter-defibrillators by filtering out low-frequency signals such as T waves. However, this filter is deactivated in the presence of diminished R-wave sensing. We describe a case of IAS in the setting of extensive intra-abdominal hemorrhage.

Decrement Evoked Potential (DEEP) Mapping of the Atria: Unmasking Atrial Fibrillation Substrate.

BACKGROUND: Atrial myopathy may underlie the progression of atrial fibrillation (AF) from a treatable disease to an irreversible condition with poor ablation outcomes. Electrophysiological methods to unmask areas prone to re-entry initiation could be key to defining latent atrial myopathy. METHODS: Consecutive patients referred for AF ablation were prospectively included at four institutions. Decrement evoked potential mapping (DEEP) was performed in eight left atrial sites and five right atrial sites, from two different pacing locations (endocardially from the left atrial appendage, epicardially from the proximal coronary sinus). The electrograms (EGMs) during S1 600 ms drive and after an extra stimulus (S2 at +30 ms above atrial refractoriness) were studied at each location and assessed for decremental properties. Follow-up was 12 months. RESULTS: Seventy-four patients were included and 85% had persistent AF. A total of 17,614 EGMs were individually analysed and measured. Nine percent of the EGMs showed DEEP properties (local delay of >10 ms after S2) with a mean decrement of 33±26 ms. DEEPs were more frequent in the left atrium than the right atrium (9.4% vs 8.0%; p<0.001) and more prevalent in persistent AF patients than paroxysmal AF patients (9.8% vs 4.6% p=0.001). Atrial DEEPs were more frequently unmasked in normal bipolar voltage areas and by epicardial pacing than endocardial pacing (9.6% vs 8.4%, respectively; p=0.004). Within the left atrium, the roof had the highest prevalence of DEEP EGMs. CONCLUSIONS: DEEP mapping of both atria is useful for highlighting areas with a tendency for unidirectional block and re-entry initiation. Those areas are more easily unmasked by epicardial pacing from the coronary sinus and more prevalent in persistent AF patients than in paroxysmal AF patients.

A U.K. Multicenter Retrospective Study of the Learning Curve and Relative Impact on Success Rates and Procedural Metrics of the RHYTHMIA HDx™ Mapping System.

The learning curve for the novel RHYTHMIA HDx™ 3-dimensional electroanatomic system is unknown. Retrospective data collection was carried out at 3 U.K. centers from the introduction of RHYTHMIA HDx™ (Boston Scientific, Marlborough, MA, USA) and associated mapping and ablation catheters. Patients were matched with controls using the CARTO® 3 mapping system (Biosense Webster Inc., Diamond Bar, CA, USA). Fluoroscopy, radiofrequency ablation, and procedure times; acute and long-term success; and complications were assessed. A total of 253 study patients along with 253 controls were included. Significant correlations existed between procedural efficiency metrics and center experience for de novo atrial fibrillation (AF) ablation (procedure time, Spearman's ρ = -0.624; ablation time, ρ = -0.795; both P < .0005) and de novo atrial flutter (AFL) ablation (ablation time, ρ = -0.566; fluoroscopy time, ρ = -0.520; both P = .001). No correlations existed for other assessed atrial arrhythmias. For de novo AF and AFL, metrics significantly improved after 10 procedures in each center (procedure time [AF only, P = .001], ablation time [AF, P < .0005; AFL, P < .0005], and fluoroscopy time [AFL only, P = .0022]) and became comparable to those of controls. Acute success and long-term success did not experience significant improvements with experience, but they were comparable to the control group throughout. Complications with RHYTHMIA HDx™ were comparable to those associated with CARTO® 3. In conclusion, a short learning curve exists with the use of RHYTHMIA HDx™ for standardized procedures (de novo AF/AFL). Procedural performance improved and became comparable to that seen with CARTO® 3 following 10 cases at each center. Clinical outcomes at 6 and 12 months and complications were no different from those observed in controls.

Left Atrial Appendage Closure: What the Evidence Does and Does Not Reveal-A View from the Outside.

This review summarizes the evidence for left atrial appendage closure (LAAC) as an alternative to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation. LAAC reduces hemorrhagic stroke and mortality versus warfarin, but is inferior for ischemic stroke reduction based on randomized data. Whilst a feasible treatment in OAC-ineligible patients, questions remain over procedural safety, and the improvement in complications observed in nonrandomized registries is uncorroborated by contemporary randomized trials. Management of device-related thrombus and peridevice leak remain unclear, and robust randomized data versus direct OACs are required before recommendations can be made for widespread adoption in OAC-eligible populations.

Left Atrial Appendage Closure: What the Evidence Does and Does Not Reveal-A View from the Outside.

This review summarizes the evidence for left atrial appendage closure (LAAC) as an alternative to oral anticoagulation (OAC) for stroke prevention in atrial fibrillation. LAAC reduces hemorrhagic stroke and mortality versus warfarin, but is inferior for ischemic stroke reduction based on randomized data. Whilst a feasible treatment in OAC-ineligible patients, questions remain over procedural safety, and the improvement in complications observed in nonrandomized registries is uncorroborated by contemporary randomized trials. Management of device-related thrombus and peridevice leak remain unclear, and robust randomized data versus direct OACs are required before recommendations can be made for widespread adoption in OAC-eligible populations.

Local impedance-guided ablation and ultra-high density mapping versus conventional or contact force-guided ablation with mapping for treatment of cavotricuspid isthmus dependent atrial flutter.

INTRODUCTION: - Local impedance (LI) guided ablation as a method of judging lesion effectiveness for cavotricuspid isthmus dependent atrial flutter (CTI-AFL), and ultra-high density (UHD) mapping when breakthrough occurred across an ablation line has not previously been assessed. METHODS: This retrospective observational study evaluated patients undergoing CTI-AFL ablation using conventional, contact force (CF) and LI guided strategies. Ablation metrics were collected, and in the LI cohort, the use of UHD mapping for breakthrough evaluated. RESULTS: 30 patients were included, 10 per group. Mean total ablation time was significantly shorter with LI (3.2 ± 1.3min) vs conventional (5.6 ± 2.7min) and CF (5.7 ± 2.0min, p = 0.0042). Time from start of ablation to CTI block was numerically shorter with LI (14.2 ± 8.0min) vs conventional and CF (19.7 ± 14.1 and 22.5 ± 19.1min, p = 0.4408). Mean lesion duration was significantly shorter with LI, but there were no differences in the number of lesions required to achieve block, procedural success, complication rates or recurrence. 15/30 patients did not achieve block following first-pass ablation. UHD mapping rapidly identified breakthrough in the five LI patients, including epicardial-endocardial breakthrough (EEB). CONCLUSION: - The use of LI during ablation for real-time lesion assessment was as efficacious as the conventional and CF methods. UHD mapping rapidly identified breakthrough, including EEB.

Deep Vein Thrombosis is Common After Cardiac Ablation and Pre-Procedural D-Dimer Could Predict Risk.

PURPOSE: Cardiac catheter ablations are an established treatment for supraventricular tachycardia (SVT) involving prolonged cannulation of the common femoral vein with multiple catheters. This study aimed to identify the risk of deep vein thrombosis (DVT) by studying the frequency of this complication after catheter ablation. METHODS: This was a prospective multi-centre cohort study of patients undergoing cardiac ablation for atrioventricular nodal re-entry tachycardia or right-sided accessory atrioventricular connection. Those taking anticoagulation or antiplatelet therapy prior to the procedure were excluded. Following the procedure, bilateral venous duplex ultrasonography from the popliteal vein to the inferior vena cava for DVT was undertaken at 24 hours and between 10 to 14 days. RESULTS: Eighty (80) patients (mean age 47.6 yrs [SD 13.4] with 67% female) underwent cardiac ablation (median duration 70 mins). Seven (7) patients developed acute DVT in either the femoral or external iliac vein of the intervention leg, giving a frequency of 8.8% (95% CI 3.6-17.2%). No thrombus was seen in the contralateral leg (p=0.023). An elevated D-dimer prior to the procedure was significantly more frequent in patients developing DVT (42.9% vs 4.1%, p=0.0081; OR 17.0). No other patient or procedural characteristics significantly influenced the risk of DVT. CONCLUSION: In patients without peri-procedural anticoagulation catheter ablation precipitated DVT in the catheterised femoral or iliac veins in 8.8% of patients. Peri-procedure prophylactic anticoagulation may be considered for all patients undergoing catheter ablation for SVT. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03877770.

Endothelial function and atrial fibrillation: A missing piece of the puzzle?

Endothelial dysfunction, a term used to describe both the physical damage and dysregulated physiology of this endothelial lining, is an increasingly recognized pathophysiological state shared by many cardiovascular diseases. Historically, the role of endothelial dysfunction in atrial fibrillation (AF) was thought to be limited to mediating atrial thromboembolism. However, there is emerging evidence that endothelial dysfunction both promotes and maintains atrial arrhythmic substrate, predicts adverse outcomes, and identifies patients at high risk of recurrence following cardioversion and ablation therapy. Treatments targeted at improving endothelial function also represent a promising new therapeutic paradigm in AF. This review summarizes the current understanding of endothelial function in AF.

Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease.

The funny current, If, was first recorded in the heart 40 or more years ago by Dario DiFrancesco and others. Since then, we have learnt that If plays an important role in pacemaking in the sinus node, the innate pacemaker of the heart, and more recently evidence has accumulated to show that If may play an important role in action potential conduction through the atrioventricular (AV) node. Evidence has also accumulated to show that regulation of the transcription and translation of the underlying Hcn genes plays an important role in the regulation of sinus node pacemaking and AV node conduction under normal physiological conditions - in athletes, during the circadian rhythm, in pregnancy, and during postnatal development - as well as pathological states - ageing, heart failure, pulmonary hypertension, diabetes and atrial fibrillation. There may be yet more pathological conditions involving changes in the expression of the Hcn genes. Here, we review the role of If and the underlying HCN channels in physiological and pathological changes of the sinus and AV nodes and we begin to explore the signalling pathways (microRNAs, transcription factors, GIRK4, the autonomic nervous system and inflammation) involved in this regulation. This review is dedicated to Dario DiFrancesco on his retirement.

Intrinsic Electrical Remodeling Underlies Atrioventricular Block in Athletes.

[Figure: see text].

Structural and Functional Properties of Subsidiary Atrial Pacemakers in a Goat Model of Sinus Node Disease.

BACKGROUND: The sinoatrial/sinus node (SAN) is the primary pacemaker of the heart. In humans, SAN is surrounded by the paranodal area (PNA). Although the PNA function remains debated, it is thought to act as a subsidiary atrial pacemaker (SAP) tissue and become the dominant pacemaker in the setting of sinus node disease (SND). Large animal models of SND allow characterization of SAP, which might be a target for novel treatment strategies for SAN diseases. METHODS: A goat model of SND was developed (n = 10) by epicardially ablating the SAN and validated by mapping of emergent SAP locations through an ablation catheter and surface electrocardiogram (ECG). Structural characterization of the goat SAN and SAP was assessed by histology and immunofluorescence techniques. RESULTS: When the SAN was ablated, SAPs featured a shortened atrioventricular conduction, consistent with the location in proximity of atrioventricular junction. SAP recovery time showed significant prolongation compared to the SAN recovery time, followed by a decrease over a follow-up of 4 weeks. Like the SAN tissue, the SAP expressed the main isoform of pacemaker hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) and Na+/Ca2+ exchanger 1 (NCX1) and no high conductance connexin 43 (Cx43). Structural characterization of the right atrium (RA) revealed that the SAN was located at the earliest activation [i.e., at the junction of the superior vena cava (SVC) with the RA] and was surrounded by the paranodal-like tissue, extending down to the inferior vena cava (IVC). Emerged SAPs were localized close to the IVC and within the thick band of the atrial muscle known as the crista terminalis (CT). CONCLUSIONS: SAN ablation resulted in the generation of chronic SAP activity in 60% of treated animals. SAP displayed development over time and was located within the previously discovered PNA in humans, suggesting its role as dominant pacemaker in SND. Therefore, SAP in goat constitutes a promising stable target for electrophysiological modification to construct a fully functioning pacemaker.

Simultaneous epicardial-endocardial mapping of the sinus node in humans with structural heart disease: Impact of overdrive suppression on sinoatrial exits.

BACKGROUND: The 3-dimensional (3D) nature of sinoatrial node (SAN) function has not been characterized in the intact human heart. OBJECTIVE: The purpose of this study was to characterize the 3D nature of SAN function in patients with structural heart disease (SHD) using simultaneous endocardial-epicardial (endo-epi) phase mapping. METHODS: Simultaneous intraoperative endo-epi SAN mapping was performed during sinus rhythm at baseline (SRbaseline) and postoverdrive suppression at 600 ms (SRpost-pace600) and 400 ms (SRpost-pace400) using 2 Abbott Advisor HD Grid Mapping Catheters. Unipolar and bipolar electrograms (EGMs) were exported for phase analysis to determine (1) activation exits; (2) wavefront propagation sequence; (3) endo-epi dissociation; and (4) fractionation. Comparison of these variables was made among the 3 rhythms from an endo-epi perspective. RESULTS: Sixteen patients with SHD were included. SRbaseline activations were unicentric and predominantly exited cranially (87.5%) with endo-epi synchrony. However, with overdrive suppression, a tendency for caudal exit shift and endo-epi asynchrony was observed: SRpost-pace600 vs SRbaseline: cranial endo 75% vs 87.5% (P = .046); cranial epi 68.8% vs 87.5% (P = 0.002); caudal endo 12.5% vs 6.2% (P = 0.215); caudal epi 25% vs 6.2% (P = .0003); and SRpost-pace400 vs SRbaseline: cranial endo 81.3% vs 87.5% (P = 0.335); cranial epi 68.7% vs 87.5% (P = 0.0034; caudal endo 12.5% vs 6.2% (P = .148); caudal epi 31.2% vs 6.2% (P = 0.0017), consistent with multicentricity. EGM fractionation was more prevalent with overdrive suppression. CONCLUSION: During mapping of the intact human heart, SAN demonstrated redundancy of sinoatrial exits with postoverdrive shift in sites of earliest activation and epi-endo dissociation of sinoatrial exits.

Supraventricular Arrhythmias in Athletes: Basic Mechanisms and New Directions.

Athletes are prone to supraventricular rhythm disturbances including sinus bradycardia, heart block, and atrial fibrillation. Mechanistically, this is attributed to high vagal tone and cardiac electrical and structural remodeling. Here, we consider the supporting evidence for these three pro-arrhythmic mechanisms in athletic human cohorts and animal models, featuring current controversies, emerging data, and future directions of relevance to the translational research agenda.

Embryology of the Cardiac Conduction System Relevant to Arrhythmias.

Embryogenesis of the heart involves the complex cellular differentiation of slow-conducting primary myocardium into the rapidly conducting chamber myocardium of the adult. However, small areas of relatively undifferentiated cells remain to form components of the adult cardiac conduction system (CCS) and nodal tissues. Further investigation has revealed additional areas of nodal-like tissues outside of the established CCS. The embryologic origins of these areas are similar to those of the adult CCS. Under pathologic conditions, these areas can give rise to important clinical arrhythmias. Here, we review the embryologic basis for these proarrhythmic structures within the heart.

Atrial Tachycardia Arising From the Crista Terminalis, Detailed Electrophysiological Features and Long-Term Ablation Outcomes.

OBJECTIVES: The goal of this study was to characterize, in detail, focal atrial tachycardia (AT) arising from the crista terminalis to investigate associations with other atrial arrhythmia and to define long-term ablation outcomes. BACKGROUND: The crista terminalis is known to be the most common site of origin for focal AT, but it is not well characterized. METHODS: This study retrospectively identified a total of 548 ablation procedures for AT performed at a single center over a 16-year period, of which 171 were arising from the crista terminalis. RESULTS: Compared with patients with other AT sites of origin, crista terminalis AT patients were older (57.3 vs. 47.3 years), more commonly female (72.9% vs. 59.1%), were more commonly associated with coexistent atrioventricular nodal re-entry tachycardia (17.1% vs. 9.7%), and were more likely to be inducible with programmed stimulation (81.5% vs. 58.9%). There was preferential conduction in the superior-inferior axis along the crista terminalis. Acute ablation success rate was high (92.2%) and improved significantly when three-dimensional mapping was used (98.5%). Recurrence in the first 12 months after a successful ablation was 9.7%. Only 2 patients developed atrial fibrillation over the long-term follow-up of >7 years. CONCLUSIONS: This large series characterized the clinical and electrophysiological features and immediate and long-term ablation outcomes for AT originating from the crista terminalis. Features of the tachycardia suggest that age-related localized remodeling of the crista terminalis causes a superficial endocardial zone of conduction slowing leading to re-entry. Ablation outcomes were good, with long-term freedom from atrial arrhythmia.

Circadian rhythm of cardiac electrophysiology, arrhythmogenesis, and the underlying mechanisms.

Cardiac arrhythmias are a leading cause of cardiovascular death. It has long been accepted that life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, and sudden cardiac death) are more likely to occur in the morning after waking. It is perhaps less well recognized that there is a circadian rhythm in cardiac pacemaking and other electrophysiological properties of the heart. In addition, there is a circadian rhythm in other arrhythmias, for example, bradyarrhythmias and supraventricular arrhythmias. Two mechanisms may underlie this finding: (1) a central circadian clock in the suprachiasmatic nucleus in the hypothalamus may directly affect the electrophysiology of the heart and arrhythmogenesis via various neurohumoral factors, particularly the autonomic nervous system; or (2) a local circadian clock in the heart itself (albeit under the control of the central clock) may drive a circadian rhythm in the expression of ion channels in the heart, which in turn varies arrhythmic substrate. This review summarizes the current understanding of the circadian rhythm in cardiac electrophysiology, arrhythmogenesis, and the underlying molecular mechanisms.

Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia.

RATIONALE: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, If, 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 If. 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.