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Background: Confirming the presence and participation of concealed nodo-ventricular (cNV) or concealed His-ventricular (cHV) pathways in tachyarrhythmias is challenging. We describe novel observations to aid in diagnosing cNV or cHV pathways. Methods: We present 7 cases of cNV and cHV pathway-mediated arrhythmias and focus on several laboratory observations: (1) differential ventricular overdrive pacing (VOD) from the base versus apex, (2) response to His refractory premature ventricular complexes, (3) paradoxical atriohisian response (shorter atriohisian interval during tachycardia than that during sinus rhythm) in long RP tachycardia, and (4) the role of adenosine to aid in the diagnosis. Results: Three cases underwent differential VOD during tachycardia. All demonstrated a shorter postpacing interval minus tachycardia cycle length during basal pacing than apical pacing with one case exhibiting apical VOD results compatible with atrioventricular nodal reentrant tachycardia. Basal VOD was useful for localizing the ventricular connection in a case with cHV pathway. In 3 cases, His refractory premature ventricular complexes reset the tachycardia without conduction to the atrium, which excluded the involvement of an atrioventricular pathway or atrial tachycardia, or atrioventricular nodal reentrant tachycardia alone. One case had His refractory premature ventricular complexes followed by subsequent constant AA interval and then tachycardia termination, suggesting a bystander cNV pathway involvement. Two cNV pathway cases presented with long RP tachycardia had paradoxical atriohisian shortening of >15 ms, suggesting parallel activation of the atrium and the atrioventricular node. Adenosine terminated the tachycardia with retrograde block in 2 cases with cNV pathways but had no response on a cHV pathway. Conclusions: cNV and cHV pathways mediated tachyarrhythmias can present with variable clinical presentations. We emphasize the important role of differential VOD sites, His refractory premature ventricular complexes that reset or terminate the tachycardia without conduction to the atrium, paradoxical atriohisian response in long RP tachycardia, and the use of adenosine for diagnosing cNV and cHV pathways.

Objectives This study sought to describe the electrophysiologic characteristics, diagnostic maneuvers, and treatment of a series of arrhythmias using concealed nodoventricular (cNV) or His-ventricular (cHV) pathways. Background Confirming the presence and participation of cNV or cHV pathways in tachyarrhythmias is challenging. Methods We present 4 cases of tachycardias with a participatory cNV or cHV pathway. Results The first patient had a narrow complex tachycardia with ventriculoatrial dissociation. Findings of an entrainment pacing from the right ventricle and fused premature ventricular complexes suggested cNV pathway involvement. The second patient had nonsustained narrow complex tachycardia with more ventricular than atrial complexes. The tachycardia exhibited an anterograde His-right bundle (RB) activation sequence and normal His-ventricular (HV) interval and consistently terminated with fused ventricular extra stimuli, suggesting cNV pathway participation. The third patient had a wide complex tachycardia (WCT) with either a right or left bundle branch block pattern. The WCT showed an eccentric His-RB activation sequence and short HV interval and terminated with fused premature ventricular complexes, suggesting a cHV (or concealed fasciculoventricular) pathway involvement. The fourth patient had a WCT with alternating bundle branch block morphologies with a short HV interval. Entrainment from the basal right ventricle demonstrated fusion and a short postpacing interval, suggesting cHV (or fasciculoventricular) pathway involvement. Ablation at the proximal RB rendered the tachycardia noninducible. Conclusions A structured approach can help diagnose and treat cNV or cHV pathways. We emphasize the importance of evaluating both the His-RB activation pattern and HV interval during sinus rhythm and tachycardia as well as the ventricular pacing study.

BACKGROUND Patients' self-reports suggest that acute alcohol consumption may trigger a discrete atrial fibrillation (AF) event. OBJECTIVE To objectively ascertain whether alcohol consumption heightens risk for an AF episode. DESIGN A prospective, case-crossover analysis. SETTING Ambulatory persons in their natural environments. PARTICIPANTS Consenting patients with paroxysmal AF. MEASUREMENTS Participants were fitted with a continuous electrocardiogram (ECG) monitor and an ankle-worn transdermal ethanol sensor for 4 weeks. Real-time documentation of each alcoholic drink consumed was self-recorded using a button on the ECG recording device. Fingerstick blood tests for phosphatidylethanol (PEth) were used to corroborate ascertainments of drinking events. RESULTS Of 100 participants (mean age, 64 years [SD, 15]; 79% male; 85% White), 56 had at least 1 episode of AF. Results of PEth testing correlated with the number of real-time recorded drinks and with events detected by the transdermal alcohol sensor. An AF episode was associated with 2-fold higher odds of 1 alcoholic drink (odds ratio [OR], 2.02 [95% CI, 1.38 to 3.17]) and greater than 3-fold higher odds of at least 2 drinks (OR, 3.58 [CI, 1.63 to 7.89]) in the preceding 4 hours. Episodes of AF were also associated with higher odds of peak blood alcohol concentration (OR, 1.38 [CI, 1.04 to 1.83] per 0.1% increase in blood alcohol concentration) and the total area under the curve of alcohol exposure (OR, 1.14 [CI, 1.06 to 1.22] per 4.7% increase in alcohol exposure) inferred from the transdermal ethanol sensor in the preceding 12 hours. LIMITATION Confounding by other time-varying exposures that may accompany alcohol consumption cannot be excluded, and the findings from the current study of patients with AF consuming alcohol may not apply to the general population. CONCLUSION Individual AF episodes were associated with higher odds of recent alcohol consumption, providing objective evidence that a modifiable behavior may influence the probability that a discrete AF event will occur. PRIMARY FUNDING SOURCE National Institute on Alcohol Abuse and Alcoholism.

The incidence of atrial flutter following radiofrequency ablation of supraventricular tachycardias is poorly understood. Ablation of atrioventricular nodal reentry tachycardia may place patients at risk of flutter because ablation of the slow pathway is in close proximity to the cavotricuspid isthmus. This study aims to evaluate the risk of atrial flutter following ablation of atrioventricular nodal reentry tachycardia relative to ablation of other supraventricular tachycardias. A single-center retrospective analysis was completed for all supraventricular tachycardia ablations performed between July 2006 and July 2016. Patient and procedural details were collected for 544 patients who underwent atrioventricular nodal reentry tachycardia ablation (n = 342), atrioventricular reentry tachycardia ablation (n = 125), or atrial tachycardia ablation (n = 60). Follow-up for flutter after ablation of their incident arrhythmia was assessed. Patients who underwent atrioventricular nodal reentry tachycardia ablation were more likely to develop CTI-dependent flutter than patients who underwent ablation of other supraventricular tachycardias (4.97% vs. 0%; p = 0.002). Compared with patients who did not develop flutter, patients who developed flutter after atrioventricular nodal reentry tachycardia ablation were more likely to have undergone ablation of atypical atrioventricular nodal reentry tachycardia (11.8% vs. 2.15%; p = 0.016). We identified an association between atrioventricular nodal reentry tachycardia ablation and development of CTI-dependent atrial flutter. This finding may have implications for the management and follow-up after atrioventricular nodal reentry tachycardia ablation.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death in young people and athletes. To date, no treatment has proven to slow the progression of the disease. Preload reducing agents such as nitrates and diuretics have shown promising results in preventing training-induced development of ARVC in a murine model. Objective The purpose of this study was to describe our experience with preload reducing therapy in patients with ARVC and symptomatic right ventricular (RV) dysfunction. Methods We performed retrospective chart review of prospectively collected registry data and included 20 patients with definite ARVC who had serial echocardiographic measurements and an implantable cardioverter-defibrillator. Six of the 20 patients with RV end-diastolic area (RVEDA) above median (>25 cm2) and New York Heart Association functional class II–IV symptoms were successfully treated with long-term isosorbide dinitrate 5–40 mg tid (at maximum tolerated dose) and hydrochlorothiazide-spironolactone 25–25 mg daily. The main outcomes of interest were RVEDA, RV fractional area change (FAC), and RV outflow tract measurements. Generalized estimating equations with repeated measures were used to identify the association between preload reducing agents and echocardiographic structural progression. Results Patients who received preload reducing agents (n = 6) were older and had larger RVs with lower FAC at baseline. However, treatment with preload reducing agents was associated with less RVEDA enlargement during mean 3.3 (range 1–6.7) years of treatment in multivariate analysis (% change in RVEDA associated with treatment –7.71; 95% confidence interval –13.29 to –2.13; P = .007). Conclusion Preload reducing agents show promising results in slowing RV enlargement in patients with ARVC and show possible disease-modifying potential.

Objectives This study describes a series of cases best explained by invoking the left septal fascicle (LSF) as a critical component of the arrhythmia circuit. Background Numerous anatomic studies have shown evidence of the LSF, but its precise role in the onset of arrhythmia is unclear. Methods This paper presents 5 cases that implicated the LSF as a critical component of arrhythmogenesis. Results The first case had ventricular fibrillation repeatedly documented after a single premature atrial complex, produced left-sided conduction delay and simultaneous earliest activation of the left anterior fascicle (LAF) and left posterior fascicle (LPF). The LSF was ablated, resulting in an arrhythmia cure. The second case showed narrow QRS morphology during fascicular re-entrant tachycardia. The earliest mid-septal diastolic potentials had distal-to-proximal activation suggesting an LSF as a retrograde common pathway. The third case, with multiple ectopic Purkinje-related premature complexes exhibited earliest Purkinje potentials in the mid-septum, with subsequent anterograde activation of the LAF and LPF. Ablation of the LSF eliminated the premature ventricular complexes (PVCs). The fourth case demonstrated LPF and LAF PVCs. The His-left bundle activation showed earliest potentials at the proximal insertion of the left bundle during LPF PVCs, as well as a distal-to-proximal activation pattern during LAF PVC, suggestive of LSF involvement. The fifth case had focal non–re-entrant fascicular beats successfully ablated over the LSF. Conclusions Involvement of the LSF is suspected with presentation of multiform fascicular and narrow QRS complex ventricular episodes of arrhythmia. Diagnoses and ablation require detailed mapping of the entire left sided conduction system.

INTRODUCTION Some patients have late recurrence after acutely successful radiofrequency catheter ablation (RFCA) of premature ventricular complexes (PVCs). The aim of this study was to evaluate predictors of long-term success following acutely successful PVC RFCA. METHODS We identified consecutive patients at our institution with frequent PVCs undergoing RFCA and reviewed procedural data and medical records. Acute success was defined as elimination of targeted PVCs for at least 30-min after RFCA. Long-term success was defined as absence of targeted PVCs during all follow-up visits and PVC-burden

Background The short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping. Methods and results We retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up. Conclusion 3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm. Graphic abstract

Objectives This study sought to characterize the presentations, electrophysiological features and diagnostic maneuvers for a series of unique arrhythmias involving the HPS. Background By v...

Background No independently validated score currently exists for risk stratification of patients with frequent premature ventricular complexes (PVCs). Objectives The purpose of this study was to develop a risk score to predict adverse events in patients with frequent PVCs. Methods We analyzed consecutive patients between 2012 and 2017 undergoing 14-day continuous monitoring with frequent PVCs (>5%) and concurrent echocardiography. We performed binary logistic regression to determine multivariate predictors of adverse left ventricular remodeling (left ventricular ejection fraction [LVEF] 75 mL/m2). A risk score was created using the log(odds ratio (OR)) of these predictors and validated prospectively to determine the risk of future adverse events in those with baseline LVEF >45%. An adverse event was defined as LVEF decline by 10%, heart failure hospitalization, or cardiovascular mortality. Two validation cohorts were used: follow-up from the original derivation cohort (cohort 1) and an independent Korean PVC registry (cohort 2). Results The derivation cohort comprised 206 patients with a mean PVC burden of 11.6% ± 6.2% and considerable daily fluctuation (minimum burden 7.3% ± 6.2% vs maximum 17.9% ± 8.0%). Independent predictors of adverse remodeling were as follows: superiorly directed PVC axis (OR 2.7; 1 point), PVC burden 10%–20% (OR 3.5; 2 points) and >20% (OR 4.4; 3 points), PVC coupling interval >500 ms (OR 4.7; 4 points), nonsustained ventricular tachycardia (OR 5.3; 4 points), which form the ABC-VT risk score. This score predicted future adverse events in both validation cohorts: cohort 1, hazard ratio 1.43; 95% confidence interval 1.19–1.73; P Conclusion The ABC-VT score is a simple tool that predicts adverse left ventricular remodeling and future clinical deterioration in patients with frequent PVCs.

Background The slow delayed rectifier potassium current IKs is crucial for the repolarization of the cardiac action potential. It is conducted by the voltage-gated channel KV 7.1 encoded by KCNQ1, together with its β-subunit KCNE1. Loss-of-function (LOF) mutations in KCNQ1 have been associated with heritable cardiac arrhythmias such as Long QT syndrome (LQTS). This disease is characterized by prolonged ventricular repolarization and propensity to ventricular tachyarrhythmia that may lead to syncope, cardiac arrest, and sudden death. We aimed to functionally characterize two KV 7.1 mutations (p.A150T and p.L374H) identified in two independent LQTS patients with different severity of disease phenotype, family history, and co-segregation of LQTS. Methods We performed whole-cell patch clamp recordings in CHO-K1 cells, and confocal imaging in Madin-Darby Canine Kidney (MDCK) cells. Results IKs -A150T showed significantly decreased current amplitudes from above +20 mV (approximately 52% decrease at +40 mV), but demonstrated cell membrane localization similar to wild-type (WT). IKs -L374H, however, exhibited a complete LOF compared to WT channels. Confocal imaging showed endoplasmic reticulum retention of the channel in MDCK cells. Mimicking the heterozygous state of the patients by co-expressing WT and mutant subunits resulted in an approximately 22% decrease in current at +40 mV for A150T. The L374H mutation showed a more pronounced effect (62% reduction at +40 mV compared to WT channel). Conclusion Both mutations, KV 7.1 A150T and L374H, led to loss of channel function. The degree of LOF may mirror the disease phenotype observed in the patients.

Introduction: The surface EKG of typical atrioventricular nodal reentrant tachycardia (AVNRT) shows simultaneous ventricular-atrial (RP) activation with pseudo R’ in V1 and typical heart rates ranging from 150-220/min. Slower rates are suspicious for junctional tachycardia (JT). However, occasionally we encounter typical AVNRT with slow ventricular rates. We describe a series of typical AVNRT cases with heart rates under 110/min. Methods: A total of 1972 patients with AVNRT who underwent slow pathway ablation were analyzed. Typical AVNRT was diagnosed when; 1) evidence of dual atrioventricular nodal conduction, 2) tachycardia initiation by atrial drive train with A-H-A response, 3) septal ventriculoatrial (VA) time < 70 ms, and 4) ventricular-atrial-ventricular (V-A-V) response to ventricular overdrive (VOD) pacing with post pacing interval-tachycardia cycle length (PPI-TCL) > 115ms. JT was excluded by either termination or advancement of tachycardia by atrial extrastimuli (AES) or atrial overdrive (AOD) pacing. Results: We found 11 patients (Age 20-78 years old, 6 female) who met the above-mentioned criteria. The TCL ranged from 560ms to 782ms. Except for one patient showing tachycardia termination, all patients demonstrated a V-A-V response and PPI-TCL over 115ms with VOD. AES or AOD pacing successfully excluded JT by either advancing the tachycardia in 10 patients or by tachycardia termination in one patient. Slow pathway was successfully ablated, and tachycardia was not inducible in all patients. Conclusions: This case series describes patients with typical AVNRT with slow ventricular rate (less than 110/min) who may mimic JT. We emphasize the importance of using pacing maneuvers to exclude JT.

In this review, we emphasize the unique value of recording the activation sequence of the His bundle or right bundle branch (RB) for diagnoses of various supraventricular and fascicular tachycardias. A close analysis of the His to RB (H-RB) activation sequence can help differentiate various forms of supraventricular tachycardias, namely atrioventricular nodal reentry tachycardia from concealed nodofascicular tachycardia, a common clinical dilemma. Furthermore, bundle branch reentry tachycardia and fascicular tachycardias often are included in the differential diagnosis of supraventricular tachycardia with aberrancy, and the use of this technique can help the operator make the distinction between supraventricular tachycardias and these other forms of ventricular tachycardias using the His-Purkinje system. We show that this technique is enhanced by the use of multipolar catheters placed to span the proximal His to RB position to record the activation sequence between proximal His potential to the distal RB potential. This allows the operator to fully analyze the activation sequence in sinus rhythm as compared to that during tachycardia and may help target ablation of these arrhythmias. We argue that 3 patterns of H-RB activation are commonly identified—the anterograde H-RB pattern, the retrograde H-RB (right bundle to His bundle) pattern, and the chevron H-RB pattern (simultaneous proximal His and proximal RB activation)—and specific arrhythmias tend to be associated with specific H-RB activation sequences. We show that being able to record and categorize this H-RB relationship can be instrumental to the operator, along with standard pacing maneuvers, to make an arrhythmia diagnosis in complex tachycardia circuits. We highlight the importance of H-RB activation patterns in these complex tachycardias by means of case illustrations from our groups as well as from prior reports.

The His-Purkinje system is a network of bundles and fibres comprised of specialised cells that allow for coordinated, synchronous activation of the ventricles. Although the histology and physiology of the His-Purkinje system have been studied for more than a century, its role in ventricular arrhythmias has recently been discovered with the ongoing elucidation of the mechanisms leading to both benign and life-threatening arrhythmias. Studies of Purkinje-cell electrophysiology show multiple mechanisms responsible for ventricular arrhythmias, including enhanced automaticity, triggered activity and reentry. The variation in functional properties of Purkinje cells in different areas of the His-Purkinje system underlie the propensity for reentry within Purkinje fibres in structurally normal and abnormal hearts. Catheter ablation is an effective therapy in nearly all forms of reentrant arrhythmias involving Purkinje tissue. However, identifying those at risk of developing fascicular arrhythmias is not yet possible. Future research is needed to understand the precise molecular and functional changes resulting in these arrhythmias.

Background: Prior studies of structural and electrocardiographic changes in arrhythmogenic right ventricular (RV) cardiomyopathy and their role in predicting ventricular arrhythmias (ventricular tachycardia) have shown conflicting results. Methods: We reviewed 405 ECGs, 315 transthoracic echocardiographies, and 441 implantable cardioverter defibrillator interrogations in 64 arrhythmogenic RV cardiomyopathy patients (56% men, mean age [SD], 44.2 [14.6] years) over a mean follow-up of 10 (range, 2.3–19) years. Generalized estimating equations were used to identify the association between ECG abnormalities, clinical variables, and transthoracic echocardiographic measurements (>mild degree of tricuspid regurgitation, RV outflow tract diameter in parasternal long axis and short axis, RV end-diastolic area, fractional area change). Results: There was a 4.65 (95% CI, 0.51%–8.8%) increase in RV end-diastolic area, a 3.75 (95% CI, 1.17%–6.34%) decrease in fractional area change, and 1.9 (95% CI, 1.3–2.8) higher odds (odds ratio) of RV wall motion abnormality with every 5-year increase in age after patients’ first transthoracic echocardiography. >Mild tricuspid regurgitation was an independent predictor of RV enlargement and dysfunction (hazard ratio of >10% drop in fractional area change from baseline [95% CI], 3.51 [1.77–6.95] and hazard ratio of >10% increase in RV end-diastolic area from baseline [95% CI], 4.90 [2.52–9.52]). Patients with implantable cardioverter defibrillator were more likely to develop >mild tricuspid regurgitation and larger structural and functional disease progression. More pronounced increase in RV end-diastolic area was translated into higher rates of any ventricular tachycardia. Inferior T-wave inversions and sum of R waves (mm) in V1 to V3 were predictors of RV enlargement and dysfunction with the former also predicting risk of any ventricular tachycardia. Conclusions: Arrhythmogenic RV cardiomyopathy is a progressive disease. Tricuspid regurgitation is an independent predictor of structural disease progression, which may be exacerbated by use of a transvenous implantable cardioverter defibrillator lead.

Dysregulated protein degradative pathways are increasingly recognized as mediators of human cardiac disease. This pathway may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication. Genetic mutations in desmosomal genes resulting in the destabilization/breakdown of the desmosomal proteome are a central hallmark of all genetic-based desmosomal-targeted diseases, including the cardiac disease arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here we identified a desmosomal resident regulatory complex, composed of subunit 6 of the COP9 signalosome (CSN6), enzymatically restricted neddylation and targets desmosomal proteome. Pharmacological restoration of CSN enzymatic function (via neddylation inhibitors) could rescue desmosomal protein loss in CSN6 deficient cardiomyocytes. Through the generation of two novel mouse models, we showed that cardiomyocyte-restricted CSN6 loss in mice selectively accelerated desmosomal destruction to trigger classic disease features associated with ARVD/C. We further showed that disruption of CSN6-mediated (neddylation) pathways underlined ARVD/C as CSN6 binding, localization, levels and function were impacted in hearts of classic ARVD/C mouse models and ARVD/C patients impacted by desmosomal loss and mutations, respectively. We anticipate our findings have broad implications towards understanding mechanisms driving desmosome degradation in other desmosomal-based diseases, such as cancers.

Limited efforts have been focused on the interventions which could therapeutically alter arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), a fatal cardiac disease of the desmosomal (mechanical) cell-cell junction. The desmosome is a critical target for intervention as mutations in desmosomal genes underlie 40-50% of ARVD/C populations and its dysregulation is associated with severe cardiac electrical and structural alterations, which facilitate myocardial failure, arrhythmias and premature death in these populations. Cardiomyocyte reduction of the predominant ventricular gap junction protein connexin43 is a molecular alteration that underlies desmosomal deficits and arrhythmias in ARVD/C. However, the role of connexin43 in structural alterations associated with ARVD/C remains unclear. We intervened with connexin43 reduction in human and mouse models of ARVD/C via connexin43 restoration strategies, which revealed beneficial effects in both ARVD/C models. We show ARVD/C human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes that recapitulate desmosomal structural defects and reveal connexin43 diminution alterations that are reflective of disease found in donor ARVD/C hearts. Connexin43 restoration was sufficient to rescue cardiac physiological deficits and increase desmosomal gene expressions in ARVD/C hiPSC derived cardiomyocytes, encompassing structural alterations. In vivo studies exploiting a mouse model of ARVD/C harboring severe desmosomal structural alterations revealed that cardiac connexin43 restoration was sufficient to prolong lifespan and restore cardiac desmosomal proteins. Herein, we provide evidence for non-canonical functions for connexin43, classically associated with electrical function, in the mechanical modulation of junctions. Our findings have broad implications in exploiting connexin43 as a therapeutic in advanced diseases associated with cardiac structural defects.

Introduction The clinical role of atrial arrhythmias (AA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) and the echocardiographic variables that predict them are not well defined. We describe the prevalence, types, echocardiographic predictors, and management of AA in patients with ARVC. Methods We retrospectively evaluated medical records of 117 patients with definite ARVC (2010 Task Force Criteria) from two tertiary care centers. We identified those patients with sustained AA (>30 seconds), including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT). We collected demographic, genetic, and clinical data. The median follow-up was 3.4 years (interquartile range = 2.0-5.7). Results Total 26 patients (22%) had one or more types of AA: AF (n = 19), AFL (n = 9), and AT (n = 8). We performed genetic testing on 84 patients with ARVC (71.8%). Two patients with AA (8%) had peripheral emboli, and one patient (4%) suffered inappropriate implantable cardioverter-defibrillator shock. We performed catheter ablation of AA in eight patients (31%), with no procedural complications. Right atrial area and left atrial volume index were independently associated with increased odds of AA; odds ratio (OR), 1.1 (95% confidence interval [CI]:1.02-1.16) (P = .01) and OR, 1.1 (95% CI:1.03-1.15) (P = .003), respectively. An increase in tricuspid annular plane peak systolic excursion was independently associated with reduced odds; OR, 0.3 (95% CI: 0.1-0.94) (P = .003). Conclusions Atrial arrhythmias (AA) are common in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Inappropriate shocks and systemic emboli may be associated with AA. Atrial size and right ventricular dysfunction may help identify patients with ARVC at increased odds of AA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project