Patients with atrial fibrillation (AF) are increasingly referred to cardiac electrophysiologists for specialist management ranging from cardioversion to ablation and insertion of left atrial appendage devices and implantable cardiac monitors. The arrhythmia is associated with a fivefold risk of thromboembolic events and this risk is accentuated with interventions such as cardioversion or ablation. Vitamin K antagonist (VKA) therapy, for example with warfarin, is generally advised for patient with an annual or procedure related risk of more than 1 or 2%. This therapy is intuitive and validated by clinical experience, specifically large registry databases but it has often not been extensively investigated by controlled randomised trials, except in one setting: long-term thromboembolic management. Compared to placebo warfarin reduces stroke by 64% and mortality by 26% whereas result with aspirin are disappointing.

Recently four NOACS (Non-VKA Oral Anticoagulants) have been compared with warfarin for the prevention of stroke and systemic embolism in patients with AF at risk of thromboembolism. All have demonstrated favorable results (meta-analysis showed a further reduction of stroke by 18%, mortality by 10% and intracranial hemorrhage by 50%), and three of these agents have been introduced into clinical practice. International guidelines all recommend that the approved NOACS can be used instead of VKAs and some express a definite preference for the newer drugs.

However, the clinical development of NOACs is incomplete; specifically large formal comparative trials in the setting of ablation and cardioversion are missing. Small, single and multi-centre trials and subgroup analyses from large randomised trials have suggested that dabigatran is an appropriate agent to protect against thromboembolism associated with cardioversion and ablation. There are fewer data with apixaban and rivaroxaban but they also seem to be similarly protective. Recent international guidelines recommend all three for cardioversion, but as yet none recommend NOACs be used for peri-ablation management. For cardioversion it is stipulated that NOACS should be used similarly to VKA drugs but ongoing investigations will not only enrich the database about this method of administration, but in some cases shorter pre- and post-cardioversion strategies are being investigated. The fast acting NOACs have been proposed as “pill-in-the-pocket” therapies for stroke prevention if taken when an episode of AF occurs, but it must be emphasised that no evidence presently exists to support this approach.

The cardiac electrophysiologist has a special interest in the potential value of left atrial ablation in preventing AF-related stroke. Several studies, some large, but none as yet randomised and prospective, strongly suggest that reduction of AF burden is associated with a marked decrease of stroke (and non-stroke related dementia). For this reason implantable devices are needed to continuously monitor the cardiac rhythm such that anticoagulant can be resumed if AF recurs. As an alternative to NOACs left atrial appendage occlusion may be adopted for stroke prevention, especially in AF patients at high risk of stroke who are unable or unwilling to take anticoagulants, or in whom anticoagulation is ineffective. Multiple new strategies now exist for AF-related stroke prevention but they need careful evaluation before we can exploit them in order to manage almost all patients very effectively.

Cardiac arrhythmias associated with Brugada syndrome (BrS) or an early repolarization (ER) pattern in the inferior or infero-lateral ECG leads are mechanistically linked to accentuation of transient outward current (I_to)-mediated J waves. Although BrS and ER syndrome (ERS) differ with respect to magnitude and lead location of abnormal J waves, they are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. ERS is divided into three subtypes with the most severe, Type 3, displaying an ER pattern globally in the inferior, lateral and right precordial leads. BrS has been linked to mutations in 18 different genes, whereas ERS has been associated with mutations in 7 different genes. In both ERS and BrS, ion channel gene mutations cause an outward shift in the balance of current, thus accentuating the action potential notch in ventricular epicardium and leading to the development of phase 2 reentry and polymorphic VT. These repolarization defects give rise to fractionated electrogram activity and high frequency late potentials in epicardial bipolar electrograms nearly identical to those recorded from the right ventricular outflow tract of patients with BrS. Hypothermia as well as ischemia potentiate the development of both ERS and BrS. Therapy in both congenital and acquired syndromes is geared toward producing an inward shift in the balance of current active during the early phases of the ventricular epicardial action potential. This is accomplished by inhibition of Ito using quinidine or augmentation of calcium channel current (I_Ca) together with inhibition of Ito using cilostazol or milrinone.

Catheter ablation of persistent AF remains challenging. Various ablation strategies have been proposed including predetermined lesion sets (like the stepwise approach) or ablation targets tailored to the patient. A more tailored based approach using body surface mapping and phase mapping has been used for the last 150 pts with persistent AF and allowed for AF termination with a 50% reduction in energy delivery when compared to stepwise approach. Variable end points have been used but, in our experience, AF termination during the index procedure remains associated to a much better outcome. This complex ablation procedure frequently requires more than one ablation session to finally achieve the maintenance of a durable sinus rhythm. However, patients’ selection can certainly identify good responders to ablation. Atrial tachycardia is extremely common in this context and interestingly, some of these AT may be participating in AF maintenance.

Ventricular tachycardia is a life-threatening condition. It is amenable to catheter ablation using different strategies. There has been a lot of interest around substrate guided strategies that overcome some of the limitations of the conventional approach. Amongst these strategies, LAVA elimination has been described, where the abnormal potentials are targeted by ablation (as reported before) and the acute end point of the procedure in addition to non inducibility (when relevant) is their elimination. LAVA complete elimination is associated with better clinical outcome and reduced mortality as compared to persistence of LAVA at the end of the ablation procedure. The use of high resolution image integration and epicardial approach plays also an important role and will be described.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disorder characterized by adrenergic-induced bidirectional and polymorphic VT. It is mostly the result of mutations in genes encoding the cardiac ryanodine receptor Ca²⁺ release channel (RyR2) or infrequently cardiac calsequestrin (CASQ2), which cause spontaneous RyR2 channel openings. These mutations are identified in approximately 60% of the patients. The cytosolic calcium overload generates delayed afterdepolarizations, triggered activity, and ventricular arrhythmias.

Key features include repetitive polymorphic VPBs or VTs reproducibly induced during exercise tests, isoproterenol infusion, or emotion. CPVT occurs in children and adolescents and causes syncope and sudden cardiac death at a young age, in the absence of structural heart disease.

Recently a HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes was published including new recommendations for CPVT.

The optimal medical management includes not only betablockers that are still the cornerstone therapy. The necessity of faultless compliance to the s-blocking therapy is crucial. Flecainide is a class IIa recommendation in addition to beta-blockers. Left cardiac sympathetic denervation is a class IIb recommendation in resistant patients. ICD as a class I recommendation in patients experiencing severe arrhythmias despite optimal medical management.

There is clearly a need for additional research in terms of new therapeutic targets, risk stratification, role of genetic and environmental modifiers of the CPVT phenotype, and genetic background of current genotype negative cases.

Many clinical and preclinical studies showed that the autonomic nervous system activation can change atrial electrophysiology and induce atrial tachyarrhythmias, including atrial fibrillation (AF). Therefore, modulation of the autonomic tone may be helpful in AF control. Direct recording in ambulatory canine models of AF showed that simultaneous discharges of the stellate ganglion and vagal nerve precede AF in a majority of the episodes. In comparison, the intrinsic cardiac nerve activity was invariably recorded before the onset of AF. Surgical methods, such as the cryoablation of the stellate ganglion, have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias. However, that method requires an invasive procedure and is unlikely to be widely practices for AF control. A number of less invasive methods have been developed to modulate autonomic nerve activity. Randomized trials showed that catheter ablation of the ganglionated plexi may reduce the AF recurrence after ablation. Canine studies suggest that vagal nerve stimulation may reduce the sympathetic tone and thereby decrease the episodes of AF. Renal sympathetic denervation may be helpful in AF control among patients with hypertension. A number of other neuromodulation methods, including acupuncture and tragus stimulation, have been shown to be beneficial in AF control both in humans and in animal models. We will discuss the relationship between the autonomic nervous system and the pathophysiology of AF, and the potential benefit and limitations of neuromodulation in the management of this arrhythmia.

Heart failure is associated with significant neural and ionic channel remodeling, which may benefit cardiac contraction but may also be proarrhythmic. Studies in humans and animal models show that abnormally prolonged or shortened action potential duration (APD) is in part responsible for the induction of ventricular fibrillation (VF). The APD is controlled by multiple different factors, including the sarcolemmal ion currents, the intracellular calcium handling and the autonomic tone. Sympathetic nerve activation may increase intracellular calcium, prolongs APD, cause early afterdepolarization (EAD) and triggered activity. However, we also observed that after VF and defibrillation episodes, the failing ventricles may exhibit extremely shortened APD which promote late phase 3 EAD and recurrent VF. The latter finding led to the discovery that the small conductance calcium activated K (SK) channel is upregulated in heart failure. The conductance of SK channel is sensitive to the intracellular calcium concentration, thus is active during rapid heart rate. Excessive activation of this channel accounts for postshock APD shortening while insufficient activation (or blocking) of this channel contributes to APD prolongation at slow rates. Recent works in our laboratory showed that apamin is a highly specific blocker of the SK current. When given to transmural wedge preparation of failing human ventricles, apamin significantly prolongs the APD transmurally. The magnitude of APD prolongation is positively correlated with the pacing cycle length (PCL), but negatively correlated with the APD when PCL is fixed. In rabbit ventricles with complete heart block, apamin may induce torsades de pointes ventricular arrhythmia and VF. In another study using canine models, we showed that SK channel is specifically co-localized with the sympathetic nerve fibers in the stellate ganglion. These findings support the hypothesis that the SK channel is involved in the ionic and neural remodeling in heart failure. The SK channel may be a new target for heart failure treatment.

Recent research into the molecular pathophysiology of atrial fibrillation (AF) has provided new mechanistic insights and possibilities for clinical translation. This presentation will focus on recent advances in our understanding of the fundamental molecular determinants of AF-occurrence: arrhythmia initiation, persistence and progression. AF is initiated by spontaneous ectopic firing. Recent work with human atrial cardiomyocytes has revealed the central role of Ca²⁺-handling abnormalities and DADs. A central feature is dysfunction of the SR ryanodine-receptor (RyR) Ca²⁺-release channel. The mechanisms underlying abnormal RyR2-release are different in different clinical forms of AF, which must be considered in developing new therapies. AF-persistence is related to remodeling that stabilizes reentry circuits, primarily by reducing the refractory period (RP). Rapid atrial activation-rates during AF increase cell-Ca²⁺, which signals through calcineurin/ NFAT to decrease expression of I_CaL and increase expression of IK1, causing APD-abbreviation and reduced RP. In addition to RP reductions, changes in autonomic tone and conduction properties related to fibrosis and/or connexin-remodeling can be important in acquired persistent-AF substrates, such as those related to excess endurance training or obstructive sleep apnea. Finally, AF progression to more long-lasting and therapeutically-resistant forms is a major clinical problem. Progression appears to be related to tissue fibrosis and structural remodeling, with Ca²⁺ signaling appearing to play a major causative role. In addition, metabolic factors are emerging as potentially important determinants of resistance to AF-progression. These new mechanistic insights have the potential to lead to new therapies that will improve AF-management.

Atrial fibrillation (AF) is the most common arrhythmia, but its treatment is inadequate largely because of our limited knowledge of AF mechanisms. Traditionally, AF is attributed to multiple reentry circuits due to conduction and refractoriness abnormalities. Electrical and structural remodeling paradigms have emerged as key elements in AF-substrate development, but there are crucial intermediate, presently-unidentified factors in AF perpetuation. Lines of evidence point to the importance of focal mechanisms and of abnormalities in intracellular Ca²⁺ handling as missing links in AF-initiating focal activity and in perpetuation by rapidly-firing foci and reentry. Experimental atrial tachycardia promotes AF induction and maintenance by abbreviation of atrial refractoriness, primarily by I_Ca,L-downregulation and increased inward rectifier potassium currents, which partly result from abnormalities in kinase/phosphatase signalling. In contrast, AF development in heart failure models is maintained by fibrosis-related reentry (without refractoriness abbreviation) and focal-driver mechanisms likely resulting from cardiomyocyte Ca²⁺-overload with subsequent delayed afterdepolarisations (DADs) and triggered activity. In AF-patients, atrial tachycardia and heart disease-based remodeling coexist, resulting in highly complex changes of atrial function involving reentry and Ca²⁺-related triggered activity-based focal sources. At the molecular level, dysfunctional ryanodine receptor channels and abnormal Ca²⁺-ATPase function in the sarcoplasmic reticulum (SR), the principal Ca²⁺-store organelle, predispose to spontaneous SR Ca²⁺-release events, DADs and triggered activity, promoting AF induction and its ability to sustain. Thus, Ca²⁺-related triggered activity may be a novel critical mechanism in the initiation, progression and maintenance of clinical AF.

A large data set of a clinical study was used to examine the extent to which are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between sexes. Day-time drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female and 176 male healthy subjects aged 32.7±9.1 years. Individual subject data were used to fit the regression equations QT=χ+(δ/ξ)(1-RR^γ)+ε where QT and RR are in seconds, ε are normally distributed zero centred errors, and the value of parameter ξ leads to the lowest regression residual. In this model, parameters δ and ξ represent QT/RR slope and curvature, respectively. In females and males, the QT/RR curvatures were 0.544±0.661 and 0.797±0.706, respectively (p=0.0006). The corresponding QT/RR slopes were 0.158±0.030 and 0.139±0.023, respectively (p<0.0001). There are substantial sex differences in QT/RR patterns. Females have the QT/RR pattern not only steeper than males but also more curved.

The individual heart rate correction formula derived from the curvilinear regression provided significantly lower intra-subject variability of QTc interval than other individual heart rate corrections. Moreover, using drug-influenced data of the study, the curvilinear correction formula was compared to the modified Holter bin method. The comparisons between the Holter Bin and curvilinear heart rate correction reproduced closely each other. Compared to the individual correction, the Holter bin method led to slight increases in the standard deviations of ΔΔQT values but these were on average below 0.25 ms.

The net value of ICD therapy is in part intrinsic to the termination of spontaneous arrhythmias by shocks and through anti tachycardia pacing, but is also largely dependent upon the specific programmed parameters specified by the physician. In fact choice of 1) Bradycardia mode and rate 2) Tachycardia detection rates, duration and other options and 3) Tachycardia therapy including both shock and pacing options change both the survival benefit and the morbidity experienced by the patient. For most patients who receive an ICD, the arrhythmias to be experienced by the patient have never previously occurred or were without symptoms, thus the choices must be selected strategically on the basis of other factors that are already understood. Unfortunately most ICDs have not been programmed to take advantage of options that are available and therefore the patients neither receive the morbidity or survival benefits. The first consensus document to represent all of the continental Heart Rhythm Societies will provide guidance for programming ICDs to be published in the Spring of 2015. This will include HRS, APHRS, EHRA and SOLAECE and include guidance from Heart Rhythm Community members all across the globe.

Background. Catheter-based ablation for atrial fibrillation (AF) performed percutaneously is shown to be limited in patients with nonparoxysmal AF (non-PAF). The full Cox-Maze surgical procedure demonstrated good success with non-PAF, but concerns were raised regarding increased morbidity eliminating the beneficial effect of the success rate. This study assessed the safety and efficacy of a stand alone on-pump Cox-Maze procedure for non-PAF.

Methods. Since 2005, 138 stand alone Cox-Maze procedures for non-PAF were performed through a right minithoracotomy (6 cm) with femoral cannulation. Patients were monitored prospectively through our AF registry. Rhythm was verified by electrocardiogram and 24-hour Holter monitoring. Health-related quality of life (SF-12 Health Survey) and AF symptoms were assessed.

Results. Data on 117 patients was available for analyses. Patients were a mean age of 56.5 ± 8.9 years and 79% had long-standing persistent AF. Patient outcomes included no operative deaths (<30 days) or renal failure, 1 pacemaker, and 1 transient ischemic attack. The return to sinus rhythm at 6, 12, 24, 36 months was 94%, 94%, 93%, 91%, and off antiarrhythmic drugs was 93%, 93%, 92%, 90%, respectively. The success rate at 6 months after the initial 20 patients improved from 89% to 95%. Multivariate analysis found longer duration of AF was associated with greater odds for AF at 6 months (OR=1.18; 95% CI = 1.01-1.38; p=0.04). Significant improvement was noted for health-related quality of life (physical and mental composite scores) and decreased AF symptom frequency and severity at 1 year.

Conclusions. The early morbidity as well as long-term success rate after the Cox-Maze III/IV procedure in a challenging group of non-PAF patients are acceptable. Our experience suggests the development of educational strategies to overcome the initial learning curve and patient selection criteria for AF surgical ablation.

The full Cox-Maze IV procedure performed on cardiopulmonary bypass (CPB) and off pump procedure centred on bilateral pulmonary vein isolation, with or without additional lesions. The full Cox-Maze IV device set can provide a 2 year freedom for AF of 80-90% when performed via sternotomy and with a combination of bipolar radiofrequency and cryotherapy or alternatively using a right thoracotomy approach which can yield quite similar result. However, such approach on CPB is considered too invasive. An alternative approach to stand-alone therapy is based on off-pump bilateral pulmonary vein isolation with a bipolar radiofrequency clamp and access is via either bilateral mini thoracotomy or bilateral thoracoscopy and with excision of the left atrial appendage (LAA). Additional lines can be added. Single centre studies success rate can exceed 80% but in the Atrial Fibrillation Catheter Ablation vs Surgical Ablation Treatment (FAST) randomised controlled trial, the 12 month freedom for AF off anti-arrthymic drug was 66% only for minimally invasive surgical ablation. Lately several experience centres are currently studying hybrid approach that combine both minimally invasive surgical ablation and percutaneous catheter ablation and, if fully developed may offer a more complete stand-alone procedure of AF, surgically located linear, transmural lesions, catheter-based connections and ‘touch-up’ lesions and management of LAA. The pros and cons will be discussed.

Abstract: The reason for multiple atrial fibrillation ablation failure is variable. Assuming PVs stay isoltated the presence of foci outside the PVs or the posterior wall should always be considered. Therefore, to maximize success it appears important to assess the presence of additional site responsible for firing and re-initiation of AF since the first procedure using a high dose of isoproterenol. In patients with long standing persistent atrial fibrillation, and in some patients with paroxysmal or persistent atrial fibrillation associated with severe LA scarring, isolation of the left atrial appendage and the coronary sinus should be considered to achieve long term freedom freedom from atrial fibrillation.

Abstract: Suboptimal catheter tip-to-tissue contact force (CF) during ablation of atrial fibrillation might a represent reason for failure. Whether a better catheter contact force during radiofrequency irrigated tip catheter ablation for AF improves the outcomes at follow up while minimizing complications is the topic of this presentation. All current randomized trials and non randomized studies will be discussed and analyzed.