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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.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.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.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.https://clinicaltrials.gov/ct2/show/NCT03877770.

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.

The funny current, I f, was first recorded in the heart 40 or more years ago by Dario DiFrancesco and others. Since then, we have learnt that I f 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 I f 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 I f 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.

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.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.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).- 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.

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.

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.

Rationale: Athletes present with atrioventricular node dysfunction manifesting as atrioventricular block. This can necessitate electronic pacemaker implantation, known to be more frequent in athletes with a long training history. Objective: Atrioventricular block in athletes is attributed to high vagal tone. Here, we investigated the alternative hypothesis that electrical remodeling of the atrioventricular node is responsible. Methods and Results: Radiotelemetry ECG data and atrioventricular node biopsies were collected in sedentary and trained Standardbred racehorses, a large-animal model of the athlete’s heart. Trained horses presented with longer PR intervals (that persisted under complete autonomic block) versus sedentary horses, concomitant with reduced expression of key ion channels involved in atrioventricular node conduction: L-type Ca 2+ channel subunit Ca V 1.2 and HCN4 (hyperpolarization-activated cyclic nucleotide-gated channel 4). Atrioventricular node electrophysiology was explored further in mice; prolongation of the PR interval (in vivo and ex vivo), Wenckebach cycle length, and atrioventricular node refractory period were observed in mice trained by swimming versus sedentary mice. Transcriptional profiling in laser-capture microdissected atrioventricular node revealed striking reduction in pacemaking ion channels in trained mice, translating into protein downregulation of Ca V 1.2 and HCN4. Correspondingly, patch-clamp recordings in isolated atrioventricular node myocytes demonstrated a training-induced reduction in I Ca, L and I f density that likely contributed to the observed lower frequency of action potential firing in trained cohorts. MicroRNA (miR) profiling and in vitro studies revealed miR-211-5p and miR-432 as direct regulators of Ca V 1.2 and HCN4. In vivo miRs suppression or detraining restored training-induced PR prolongation and ion channel remodeling. Conclusions: Training-induced atrioventricular node dysfunction is underscored by likely miR-mediated transcriptional remodeling that translates into reduced current density of key ionic currents involved in impulse generation and conduction. We conclude that electrical remodeling is a key mechanism underlying atrioventricular block in athletes.

Introduction Multiple contact-based ablation technologies have been developed to allow real-time judgement of lesion effectiveness; local impedance (LI) guided ablation and the role of ultra-high density (UHD) mapping have not yet been evaluated for cavotricuspid isthmus dependent atrial flutter (CTI-AFL). Methods This non-randomised 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 was evaluated. Results 30 patients were included, 10 in each 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). 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 5 LI patients, including epicardial-endocardial breakthrough (EEB) away from the line. Conclusion The use of LI for real-time assessment of lesion formation resulted in significantly less ablation requirement. UHD mapping rapidly identified breakthrough, including EEB, which would likely have been difficult to identify otherwise and possibly require extensive ablation, contributing towards shortening of time to CTI block with LI.

Background . Radiofrequency ablation (RFA) of CTI dependent atrial flutter (CTI-AFL) is conventionally performed under fluoroscopic guidance, or alternatively with 3D mapping and contact force (CF) catheters. Ultra-high density mapping (UHDm) and local impedance (LI) guided ablation have not yet been evaluated for this indication. Methods . An observational study comparing conventional, CF and LI-guided ablation of CTI-AFL to understand whether LI offers superior ablation metrics and UHDm allows accurate identification of breakthrough after initial RFA. Retrospective analysis of consecutive CTI-AFL cases was performed. Irrigated RFA was used in all groups. Contact was determined in the CF group with target >9 g and in the LI group with patient-specific LI. Target LI drop of -20 ohms was used to determine effective lesion formation. Standard generator impedance was used for the conventional group. Power was limited to 40-50W in all groups. In the LI group, if the CTI was not blocked after initial ablation, UHDm was used to identify breakthrough. Mean RFA time, time to CTI block, number of lesions required to achieve block, acute procedural success and complications were analysed with ANOVA. Breakthrough points were manually assessed. Results . Data is presented for 27 patients; 7 conventional, 10 CF and 10 LI. Mean RFA time was 6, 5.8, 3.2min respectively (p=0.0227). Significant differences also seen with LI vs Fluo (p=0.0194), LI vs CF (p=0.0164). Time from first application of RF to block was 22.8, 20.4, 14.2 min (p=ns). No significant difference was seen in the number of lesions required to achieve block. Acute procedural success was 100% in all groups, and there were no acute complications. Breakthrough was identified in 50% of CF and LI cases (5 patients in each group). With LI, there was one case of epicardial-endocardial breakthrough (EEB) 11mm from the CTI (figures A, B), three posterior, and one anterior aspect of the CTI, identified with UHDm. Subsequent LI-guided RFA resulted in block, on average six minutes quicker vs CF. Discussion This data illustrates that UHDm and LI-guided RFA significantly reduces the amount of ablation required (by 47% and 45% versus conventional and CF respectively; p=sig) by shortening lesion duration guided by LI change. A reduction from first RFA to block is also seen (47% and 30% respectively; p=ns). Many patients require further ablation following the initial RFA line, resulting in longer procedures. UHD mapping quickly and accurately identifies breakthrough for further focused RFA, including EEB away from the CTI which may otherwise be difficult to identify and treat using the conventional or standard 3D mapping, and result in prolonged procedure time and/or increased radiation exposure. LI also resulted in more predictable procedure times. We could not directly compare overall procedure times as many in the CF group had CTI combined with left atrial ablation. Conclusion . LI-guided ablation is safe and effective, and has shown favourable ablation metrics when compared with conventional and CF-guided ablation for CTI dependent AFL. Ultra-high density mapping more rapidly and effectively identifies sites of breakthrough after initial RFA application. A larger study is planned to provide more insight. Conflict of Interest None

Funding Acknowledgements Bristol-Myers Squibb Background Right sided cardiac catheter ablation has become an indispensable tool to treat supraventricular cardiac dysrhythmias, with ablation of certain arrhythmias having cure rates over 90%. Due to this the frequency of these procedures is increasing annually and it is imperative we understand the incidence of all complication. One lesser studied complication is that of deep vein thrombosis (DVT), for which catheter ablation demonstrates all elements of Virchow"s triad. As right sided ablations are carried out to treat troublesome palpitations, not to reduce mortality, it is important all risks are identified, especially those which are themselves potentially life threatening and can be modified. Purpose To determine the incidence of DVT after right sided cardiac catheter ablation. Methods We undertook a prospective multi-center study recruiting adult patients undergoing clinically indicated cardiac ablation for atrioventricular nodal re-entrant tachycardia and atrioventricular re-entrant tachycardia with right sided accessory pathway. Important exclusion criteria included patients on anticoagulation or antiplatelet therapy. Participants underwent bilateral compression venous duplex ultrasonography from the inferior vena cava to the popliteal vein to access for DVT at 24 hours and between 10 to 14 days post-procedure. The uncannulated contralateral leg acted as a control. Result At interim analysis 71 participants had completed the study with average age 47 year (+/- 14), procedure duration 67 minutes, and with a female predominance. Seven patients developed acute DVT in either the femoral or internal iliac vein in the access leg. No thrombus was seen in the control leg. This gives an incidence of 10% (95% CI 4-19%) with p value of 0.023 on Chi-square testing. Conclusion We found a statistically significant proportion of patients undergoing right sided cardiac catheter ablation developed acute proximal DVT on ultrasound. All patients were treated with 3 to 6 months of anticoagulation therapy in accordance with NICE guidelines. These results suggest that DVT may occur at a high frequency then previously thought in this cohort and supports the consideration of peri-procedural prophylactic anticoagulation. Abstract Figure. Acute thrombus in the femoral vein

INTRODUCTION. Radiofrequency ablation (RFA) of cavotricuspid isthmus dependent atrial flutter (CTI-AFL) can be performed with fluoroscopy (Fluo) or 3-dimensional (3D) electroanatomic mapping and contact force (CF) catheters. Local impedance (LI) is an alternative but no comparisons have yet been made. METHODS. An observational study comparing Fluo, CF- and LI-guided RFA for CTI-AFL. In the LI group, if CTI block was not obtained after initial ablation, ultra-high density mapping (UHDm) was used to identify breakthrough sites. Contact was determined using patient specific LI; RF delivered until 20 ohm LI drop seen, or LI drop plateaued >2 secs. In the CF group 10-40g force was used. Power was limited to 40-50W in all groups. Total RFA time, time from RFA start to CTI block, no. of lesions required to achieve block, acute success, complications and re-ablation during follow-up were analysed using ANOVA. RESULTS. Data presented for 24 patients (7 Fluo, 7 CF, 10 LI). Mean RFA time: 6.6, 5.9, 3.2 min respectively (p = 0.0478). Statistically significant differences also seen with LI vs Fluo (p = 0.0451) and LI vs CF (p = 0.0313). Time from first RFA to block: 25.5, 19.8, 14.2 min (p = 0.5688); number of lesions to achieve block: 8.5, 10.3, 8 (p = 0.3909). 100% success and no complications in all groups. 0% need for re-ablation (16.3 ± 7, 12.6 ± 8, 6.5 ± 4.4 months follow-up). DISCUSSION. This data illustrates that UHDm and LI-guidance significantly reduces the amount of CTI RFA, by 52% and 47% vs Fluo and CF respectively (p = sig, fig. 1). A reduction from first RFA to block is also seen (43% and 37%; p = ns, fig. 2). Given no difference in the no. of lesions, LI-guided RFA during lesion formation shortens the duration of each lesion. Many patients require further RFA (+/- mapping) if they do not achieve block following the initial ablation line, resulting in longer procedures. Several patients without block in the LI group underwent repeat UHDm, which quickly identified CTI or epicardial-endocardial breakthrough (fig. 3 & 4), allowing rapid targeting for re-ablation. In the fluo group, these procedures would often be significantly prolonged, meaning extensive RFA and radiation exposure. Fig. 1 shows smaller error bars with LI compared to the others, resulting in more predictable total ablation times; this could potentially benefit procedure scheduling (more procedures per unit time). We could not directly compare overall procedure time as many in the CF group had CTI RFA combined with left atrial RFA. Multiple LI cases were performed fluo-free with only magnetic tracking. This may allow case scheduling without a radiographer, with potential cost savings. CONCLUSION. LI-guided CTI-AFL RFA is safe and effective and has shown favourable ablation metrics compared to Fluo or CF-RFA. LI-RFA with UHDm more quickly and accurately identifies breakthrough and with fluoro-free technique could possibly reduce procedure time and cost. A larger study is planned to provide more insight. Abstract Figures

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.

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.

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.

Sinus node disease is the commonest bradyarrhythmia, often presenting as syncope or exercise limitation and is an important reason for pacemaker implantation. It is usually idiopathic and a disease of ageing with a peak incidence in the seventh decade of life, but may develop secondary to other conditions including heart failure and chronic endurance exercise. The detailed pathophysiology of sinus node disease remains unknown, studies have found evidence of widespread atrial electrical remodelling, and contemporary research suggests that cellular electrical and fibrotic changes may be important mediators of this remodelling. There is an important association between sinus node disease and atrial fibrillation, and the two arrhythmias often coexist, but the nature of this interaction remains a source of debate. This chapter will summarize the current understanding of the natural history and pathophysiology of sinus node disease, with a focus on remodelling and including discussion of theories that may explain the development of coexistent atrial arrhythmia in these patients.

Objectives This study aimed to determine the spatiotemporal stability of rotors and other atrial activation patterns over 10 min in longstanding, persistent AF, along with the relationship of rotors to short cycle-length (CL) activity. Background The prevalence, stability, and mechanistic importance of rotors in human atrial fibrillation (AF) remain unclear. Methods Epicardial mapping was performed in 10 patients undergoing cardiac surgery, with bipolar electrograms recorded over 10 min using a triangular plaque (area: 6.75 cm 2 ; 117 bipoles; spacing: 2.5 mm) applied to the left atrial posterior wall (n = 9) and the right atrial free wall (n = 4). Activations were identified throughout 6 discrete 10-s segments of AF spanning 10 min, and dynamic activation mapping was performed. The distributions of 4,557 generated activation patterns within each mapped region were compared between the 6 segments. Results The dominant activation pattern was the simultaneous presence of multiple narrow wave fronts (26%). Twelve percent of activations represented transient rotors, seen in 85% of mapped regions with a median duration of 3 rotations. A total of 87% were centered on an area of short CL activity ( Conclusions In patients with longstanding, persistent AF, activation patterns are spatiotemporally stable over 10 min. Transient rotors can be demonstrated in the majority of mapped regions, are spatiotemporally associated with short CL activity, and, when recurrent, demonstrate anatomical determinism.

OBJECTIVE Implantation of biventricular devices (BiV) with a transvenous left ventricular lead is complex requiring a significant fluoroscopy time and radiation dose. In the United Kingdom, the Health Protection Agency (HPA) collects data regarding radiographic procedures and sets national diagnostic reference levels (DRL) at the 75th percentile of the distribution of doses for a wide range of procedures. Insufficient data were returned to the HPA to allow them to set DRL for BiV devices at the last publication in 2010. Due to the large variation in data available and small datasets for BiV procedures we aimed to collect a large dataset to guide standards for implantation. METHODS We collected retrospective data (fluoroscopy time and radiation dose [DAP]) for new BiV devices for the three years 2009-2011 from three high volume tertiary centres in the North West of England. Databases were scrutinised to ensure the quality of the data. RESULTS From a total of 1374 implants we identified data for 1319 patients for fluoroscopy time and 1316 for DAP. The mean fluoroscopy time for all three centres combined was 18.7±0.3 min. The 75th percentile fluoroscopy time for the combined data was 24.2 min. The mean DAP for the three centres combined was 25.1±1.3 Gy cm2. The 75th percentile DAP for the combined data was 27.7 Gy cm2. CONCLUSIONS We present a large dataset of new biventricular device implants, based on the 75th percentile data we suggest a DRL of 24.2 min and 27.7 Gy cm2.

Focal atrial tachycardia (AT) is uncommon and characterized by centrifugal atrial activation from a point source. ATs are found clustering around well-defined sites of structural and electrophysiologic heterogeneity in both atria. Focal AT most often occurs in patients without structural heart disease. The P-wave morphology on the surface ECG provides a good guide to the site of origin. With electrophysiologic study, activation mapping efforts can begin in the region suggested by P-wave analysis. Catheter ablation is an effective therapy that can result in long-term cure in most patients with a low risk of complications.

The sinoatrial node (SAN) is the normal pacemaker of the heart. During a human lifetime it must initiate approximately 2 billion heartbeats and coordinate the cardiovascular response to our physiological and emotional demands. Disease of the SAN is common, and one of the leading indications for electronic pacemaker implantation. Advances in understanding the genetics and molecular mechanisms determining normal SAN function, and of the pathways controlling remodeling are revealing SAN disease to be heterogeneous. We review the contemporary concepts of SAN function, heart rate adaptation and SAN disease from the molecular level to clinical application.

Due to expanding clinical indications and an aging society there has been an increase in the use of implantable pacemakers. At the same time, due to increased diagnostic yield over other imaging modalities and the absence of ionizing radiation, there has been a surge in demand for magnetic resonance imaging (MRI) assessment, of both cardiac and noncardiac conditions. Patients with an implantable device have a 50-75% chance of having a clinical indication for MRI during the lifetime of their device. The presence of an implantable cardiac device has been seen as a relative contraindication to MRI assessment, limiting the prognostic and diagnostic utility of MRI in many patients with these devices. The introduction of MRI conditional pacemakers will enable more patients to undergo routine MRI assessment without risk of morbidity or device malfunction. This review gives a general overview of the principles and current evidence for the use of MRI conditional implantable cardiac devices. Furthermore, we appraise the differences between those pacemakers currently released to market.

it is well known that athletes have a low resting heart rate, i.e., a resting bradycardia and heart rates below 30 beats/min have been reported ([7][1]). For example, Wikipedia states that the Tour de France cyclist, Miguel Indurain, had a resting heart rate of 28 beats/min when race fit. The

It is now over 100years since the discovery of the cardiac conduction system, consisting of three main parts, the sinus node, the atrioventricular node and the His-Purkinje system. The system is vital for the initiation and coordination of the heartbeat. Over the last decade, immense strides have been made in our understanding of the cardiac conduction system and these recent developments are reviewed here. It has been shown that the system has a unique embryological origin, distinct from that of the working myocardium, and is more extensive than originally thought with additional structures: atrioventricular rings, a third node (so called retroaortic node) and pulmonary and aortic sleeves. It has been shown that the expression of ion channels, intracellular Ca(2+)-handling proteins and gap junction channels in the system is specialised (different from that in the ordinary working myocardium), but appropriate to explain the functioning of the system, although there is continued debate concerning the ionic basis of pacemaking. We are beginning to understand the mechanisms (fibrosis and remodelling of ion channels and related proteins) responsible for dysfunction of the system (bradycardia, heart block and bundle branch block) associated with atrial fibrillation and heart failure and even athletic training. Equally, we are beginning to appreciate how naturally occurring mutations in ion channels cause congenital cardiac conduction system dysfunction. Finally, current therapies, the status of a new therapeutic strategy (use of a specific heart rate lowering drug) and a potential new therapeutic strategy (biopacemaking) are reviewed.

Aims: Catheter ablation to achieve posterior left atrial wall (PW) isolation may be performed as an adjunct to pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (AF). We aimed to determine whether routine adenosine challenge for dormant posterior wall conduction improved long-term outcome. Methods and results: A total of 161 patients with persistent AF (mean age 59 +/- 9 years, AF duration 6 +/- 5 years) underwent catheter ablation involving circumferential PVI followed by PW isolation. Posterior left atrial wall isolation was performed with a roof and inferior wall line with the endpoint of bidirectional block. In 54 patients, adenosine 15 mg was sequentially administered to assess reconnection of the pulmonary veins and PW. Sites of transient reconnection were ablated and adenosine was repeated until no further reconnection was present. Holter monitoring was performed at 6 and 12 months to assess for arrhythmia recurrence. Posterior left atrial wall isolation was successfully achieved in 91% of 161 patients (procedure duration 191 +/- 49 min, mean RF time 40 +/- 19 min). Adenosine-induced reconnection of the PW was demonstrated in 17%. The single procedure freedom from recurrent atrial arrhythmia was superior in the adenosine challenge group (65%) vs. no adenosine challenge (40%, P < 0.01) at a mean follow-up of 19 +/- 8 months. After multiple procedures, there was significantly improved freedom from AF between patients with vs. without adenosine PW challenge (85 vs. 65%, P = 0.01).Conclusion Posterior left atrial wall isolation in addition to PVI is a readily achievable ablation strategy in patients with persistent AF. Routine adenosine challenge for dormant posterior wall conduction was associated with an improvement in the success of catheter ablation for persistent AF.

Background Anomalies of the origin and course of the circumflex artery are amongst the most common seen at coronary angiography. There is limited information regarding patient and procedural characteristics, technical feasibility and outcomes associated with percutaneous intervention (PCI) to these vessels. The aim of this study is to examine our experience with PCI to anomalous circumflex vessels and compare this to some aspects of percutaneous intervention on non-anomalous circumflex vessels. Methods Over a 41month period, 20 PCI procedures on anomalous circumflex vessels were identified and 1550 PCI procedures on non-anomalous circumflex arteries. Results In 9 anomalous cases, the circumflex arose from the left coronary cusp, in 7 cases from the right coronary cusp, and in the remaining 4 cases from the proximal right coronary artery. There were no differences in demographics or pattern or severity of coronary disease between the 2 groups. A higher proportion of patients with anomalous vessels presented acutely. Screening times were longer in the anomalous group. All 20 procedures were associated with immediate procedural success. There was one peri-procedural myocardial infarction unrelated to anomalous circumflex intervention. After a median follow-up period of 7.3months, the only major adverse cardiac event recorded in the anomalous group was an ischaemia-driven revascularisation to a non-target vessel branch. We describe techniques which can be used to improve support and facilitate successful PCI to anomalous circumflex vessels. Conclusion PCI to anomalous circumflex vessels may be technically challenging, but is feasible and carries favourable short and long-term clinical outcomes. Summary This single centre observational study demonstrates that percutaneous coronary intervention to anomalous circumflex coronary arteries although technically challenging can be performed with satisfactory procedural success rates and favourable short and longer-term clinical outcomes. It describes various techniques that can be employed to optimise successful intervention.

The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a "wandering pacemaker" and concomitant changes in the P-wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up-to-date summary of the current state of our appreciation of the above topics.

Bradyarrhythmias are common and may be caused by sinus node dysfunction or conduction block. Many of these conditions can be treated by the implantation of electronic cardiac pacemakers that reduce mortality and morbidity in carefully selected patient groups. Implantable electronic pacemakers are small, sophisticated and reliable but not without complication and limitation. Efforts have been made to create a de novo sinus node using gene therapy, the so-called biopacemaker. This approach has potential as permanent cure for bradyarrythmias with greater physiological responsiveness than that provided by rate-responsive electronic pacemakers. This article reviews the current approaches to the problem and gives a perspective on the challenges remaining to bring the therapy to clinical practice.

Advanced atrial remodeling predicts poor clinical outcomes in human atrial fibrillation (AF).The purpose of this study was to define the magnitude and predictors of change in left atrial (LA) structural remodeling over 12 months of AF.Thirty-eight patients with paroxysmal AF managed medically (group 1), 20 undergoing AF ablation (group 2), and 25 control patients with no AF history (group 3) prospectively underwent echocardiographic assessment of strain variables of LA reservoir function at baseline and at 4, 8, and 12 months. In addition, P-wave duration (Pmax,, Pmean) and dispersion (Pdis) were measured. AF burden was quantified by implanted recorders. Twenty patients undergoing ablation underwent electroanatomic mapping (mean 333 ± 40 points) for correlation with LA strain.Group 1 demonstrated significant deterioration in total LA strain (26.3% ± 1.2% to 21.7% ± 1.2%, P.05) and increases in Pmax (132 ± 3 ms to 138 ± 3 ms, P.05) and Pdis (37 ± 2 ms to 42 ± 2 ms, P.05). AF burden ≥10% was specifically associated with decline in strain and with P-wave prolongation. Conversely, group 2 manifest improvement in total LA strain (21.3% ± 1.7% to 28.6% ± 1.7%, P.05) and reductions in Pmax (136 ± 4 ms to 119 ± 4 ms, P.05) and Pdis (47 ± 3 ms to 32 ± 3 ms, P.05). Change was not significant in group 3. LA mean voltage (r = 0.71, P = .0005), percent low voltage electrograms (r = -0.59, P = .006), percent complex electrograms (r = -0.68, P = .0009), and LA activation time (r = -0.69, P = .001) correlated with total strain as a measure of LA reservoir function.High-burden AF is associated with progressive LA structural remodeling. In contrast, AF ablation results in significant reverse remodeling. These data may have implications for timing of ablative intervention.

The sinoatrial node (SAN) is the normal pacemaker of the heart and SAN dysfunction (SND) is common, but until recently the pathophysiology was incompletely understood. It was usually attributed to idiopathic age-related fibrosis and cell atrophy or ischaemia. It is now evident that changes in the electrophysiology of the SAN, known as electrical remodelling, is an important process that has been demonstrated in SND associated with heart failure, ageing, diabetes, atrial fibrillation and endurance exercise. Furthermore, familial SND has been identified and mutations have been characterised in key pacemaker genes of the SAN. This review summarises the current evidence regarding SAN function and the pathophysiology of SND.

Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, If. Block of If abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training. This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/

We read with great interest the article by Grundvold et al1 describing low heart rate on exercise as a predictor of atrial fibrillation (AF) in healthy middle-aged men. The article makes an important contribution to the emerging body of evidence that exercise can lead to cardiovascular remodeling, increasing the risk of AF in later life. Although the authors concede that conclusions regarding the pathophysiological mechanisms underlying these observations are difficult, they argue that a predominance of parasympathetic tone may account for both low heart rate and …

Aims Although the right atrium (RA contains subsidiary atrial pacemaker (SAP) tissue that can take over from the sinoatrial node (SAN) in sick sinus syndrome (SSS), SAP tissue is bradycardic. Little is known about SAP tissue and one aim of the study was to characterize ion channel expression to obtain insight into SAP pacemaker mechanisms. A second aim was to determine whether HCN over-expression (a ‘biopacemaker’-like strategy) can accelerate the pacemaker rate producing a pacemaker that is similar in nature to the SAN. Methods and results SAP tissue was isolated from the rat and the leading pacemaker site was characterized. Cell size at the leading pacemaker site in the SAP was smaller than in the RA and comparable to that in the SAN. mRNA levels showed the SAP to be similar to, but distinct from, the SAN. For example, in the SAN and SAP, expression of Tbx3 and HCN1 was higher and Nav1.5 and Cx43 lower than in the RA. Organ-cultured SAP tissue beat spontaneously, but at a slower rate than the SAN. Adenovirus-mediated gene transfer of HCN2 and the chimeric protein HCN212 significantly increased the pacemaker rate of the SAP close to that of the native SAN, but HCN4 was ineffective. Conclusion SAP tissue near the inferior vena cava is bradycardic, but shares characteristics with the SAN. Pacing can be accelerated by the over-expression of HCN2 or HCN212. This provides proof of concept for the use of SAP tissue as a substrate for biopacemaking in the treatment of SSS.

Due to expanding clinical indications and an aging society there has been an increase in the use of implantable pacemakers. At the same time, due to increased diagnostic yield over other imaging modalities and the absence of ionizing radiation, there has been a surge in demand for magnetic resonance imaging (MRI) assessment, of both cardiac and noncardiac conditions. Patients with an implantable device have a 50-75% chance of having a clinical indication for MRI during the lifetime of their device. The presence of an implantable cardiac device has been seen as a relative contraindication to MRI assessment, limiting the prognostic and diagnostic utility of MRI in many patients with these devices. The introduction of MRI conditional pacemakers will enable more patients to undergo routine MRI assessment without risk of morbidity or device malfunction. This review gives a general overview of the principles and current evidence for the use of MRI conditional implantable cardiac devices. Furthermore, we appraise the differences between those pacemakers currently released to market.

The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a "wandering pacemaker" and concomitant changes in the P-wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up-to-date summary of the current state of our appreciation of the above topics.

Aortic stenosis (AS) is thought to be caused by calcific degeneration of the aortic valve. Clinical observations suggest an association between a left dominant coronary circulation and AS, a situation previously investigated at necropsy and with small observational studies. Mitral regurgitation (MR) and aortic regurgitation (AR) are both disorders with multiple etiologies, but neither has any known association with coronary artery dominance.The coronary angiogram database of a tertiary referral centre was reviewed for consecutive left heart catheter data acquired over a six-year period. The severity of AS was classified by measured pressure gradient (in mmHg) as none (0), mild (30), moderate (30-49), or severe (49). Both, MR and AR were assessed visually by the operator.A total of 1,891 patients was included. In the AS group there was a significant association with a left dominant coronary circulation (p0.0001), and the proportion of patients with left dominance increased with the severity of AS (p0.005). There was no significant association of AR with coronary artery dominance (p = 0.84). MR was associated with a reduced prevalence of left dominance (p0.005).AS was associated with a left dominant coronary circulation, and the incidence of left dominance was increased with the severity of AS, but the opposite situation was true for MR. The reasons for these observations remain unclear.

Since the 1950s, technological advances have forged molecular biology into one of the most powerful fields of science. The primary molecular specializations of the cardiac conduction system are a lower expression of the fast Na+ channel (Nav1.5), the background K+ channel (Kir2.1), and the high conductance connexin (Cx43), but with a higher expression of the pacemaker channel (HCN4) and the alternative L-type Ca2+ channel (Cav1.3). Therefore, it is possible to investigate gene transcription and protein expression for these channels. This chapter describes the use of in situ hybridization, qPCR, and immunohistochemistry to study cardiac ion channel expression.

Introduction Biopacemaker research aims to faithfully recapitulate robust pacemaking seen from the heart's natural pacemaker, the sinoatrial node (SAN). The transcription factor Tbx18, involved in the development of the SAN core, has previously been used to reprogramme adult ventricular myocytes into SAN-like myocytes. Subsidiary atrial pacemaker (SAP) tissue in the infero-posterior wall of the right atrium has been shown to share molecular characteristics with the SAN but is bradycardic functionally. We therefore used this SAP tissue as a model for SAN dysfunction and hypothesised that overexpressing Tbx18 in this region ectopically would increase beating rate and alter key pacemaker genes. Methods We isolated beating SAN and SAP tissues from rat right atria in vitro . We compared SAN tissue (n = 6), uninfected SAP tissue (n = 8) and SAP tissue infected with the recombinant adenovirus Ad-Tbx18 (n = 7). Beating rates were monitored during 48 h of tissue culture. We then measured mRNA levels of 14 key genes using qPCR in Ad-Tbx18 infected (n = 8) and uninfected (n = 8) SAP tissue. Data were analysed using one-way ANOVA. Results After 48 h, the mean beating rate of Ad-Tbx18 infected SAP tissue was significantly higher than uninfected SAP tissue (Ad-Tbx18: 194 ± 15.6 bpm, uninfected SAP: 142 ± 8.2 bpm; p 0.05). qPCR showed a 99.7-fold increase in Tbx18 mRNA as a result of Ad-Tbx18 infection (p < 0.001). HCN1, HCN2, RYR2, and Kv1.5 levels were significantly higher in Ad-Tbx18 infected SAP tissue than uninfected SAP tissue (p < 0.01), however HCN4 was significantly lower (p < 0.01). No significant changes were seen with Cx43, Cx45, Kir2.1, Nav1.5, NCX1, Cav1.2, Cav3.1 or Tbx3. Implications Ad-Tbx18 infection overexpressed Tbx18 in SAP tissue and increased beating rate in vitro . This led to HCN4 downregulation, but HCN1, HCN2 and RYR2 were all upregulated and this could explain the observed increase in rate. Our data raises interesting questions about a potential application of Tbx18 upregulation to the dysfunctional SAN as a biopacemaking strategy in sick sinus syndrome. ![Abstract YIA1 Figure 1][1] Abstract YIA1 Figure 1 Beating rates (mean ±SEM) were monitored between 20 and 48 h of tissue culture for isolatedsinoatrial node tissue (n = 6), uninfected inferior subsidiary pacemaker tissue(n = 8) and inferior subsidiary pacemaker tissue infected with the adenovirusAd-Tbx18 (n = 7). Rates at 48 h were significantly higher in Ad-Tbx18 infectedpreparations than uninfected preparations (p < 0.01). RT-qPCR was used toquantify mRNA for key pacemaker genes isolated after 48 h of tissue culturefrom uninfected subsidiary pacemaker tissue (n = 8) and subsidiary pacemakertissue infected with Ad-Tbx18 (n = 8). HCN1, HCN2, RYR2 and Kv1.5 were upregulatedbut HCN4 was downregulated (p < 0.05) [1]: pending:yes