Efficacy and safety of supraclavicular and pectoralis nerve blocks as primary peri-procedural analgesia for cardiac electronic device implantation: A pilot study.

BACKGROUND: Cardiac implantable electronic devices (CIEDs) are routinely implanted using intravenous drugs for sedation. However, some patients are poor candidates for intravenous sedation. OBJECTIVE: We present a case series demonstrating the safety and efficacy of a novel, ultrasound-guided nerve block technique that allows for pre-pectoral CIED implantation. The targets are the supraclavicular nerve (SCN) and pectoral nerve (PECS1). METHODS: We enrolled 20 patients who were planned for new CIED implantation. Following US-localization of the SCN and PECS1, local anesthetic (LA) was instilled at least 30-60 min pre-procedure. Successful nerve block was determined if < 5 mL of intraprocedural LA was used, along with lack of sensation with skin and deep tissue pinprick. Optional sedation was offered to patients' pre-procedure if discomfort was reported. RESULTS: Seventeen patients (85%) had a successful periprocedural nerve block, with only three patients exceeding 5 mL of LA. SCN and PECS1 success occurred in 19 (95%) and 18 (90%) patients, respectively. The overall success of nerve block by fulfilling all the criteria was demonstrated in 17 out of 20 patients (85%). Patients who reported no pain (VAS score = 0) were distributed as follows: 13 patients (65%) in the immediate post-procedure interval, 18 patients (90%) at the 1 h post-implant interval, and 14 patients (70%) at the 24 h post- implant interval. The median cumulative VAS score was 0 (IQR = 0 - 1). There were no reported significant adverse effects. CONCLUSION: SCN and PECS1 nerve blocks are safe and effective for patients undergoing CIED implantation to minimize or eliminate the use of intravenous sedation.

Assessment of left atrial fibrosis progression in canines following rapid ventricular pacing using 3D late gadolinium enhanced CMR images.

BACKGROUND: Atrial fibrillation (AF) is associated with extracellular matrix (ECM) remodelling and often coexists with myocardial fibrosis (MF); however, the causality of these conditions is not well established. OBJECTIVE: We aim to corroborate AF to MF causality by quantifying left atrial (LA) fibrosis in cardiac magnetic resonance (CMR) images after persistent rapid ventricular pacing and subsequent AF using a canine model and histopathological validation. METHODS: Twelve canines (9 experimental, 3 control) underwent baseline 3D LGE-CMR imaging at 3T followed by insertion of a pacing device and 5 weeks of rapid ventricular pacing to induce AF (experimental) or no pacing (control). Following the 5 weeks, pacing devices were removed to permit CMR imaging followed by excision of the hearts and histopathological imaging. LA myocardial segmentation was performed manually at baseline and post-pacing to permit volumetric %MF quantification using the image intensity ratio (IIR) technique, wherein fibrosis was defined as pixels > mean LA myocardium intensity + 2SD. RESULTS: Volumetric %MF increased by an average of 2.11 ± 0.88% post-pacing in 7 of 9 experimental dogs. While there was a significant difference between paired %MF measurements from baseline to post-pacing in experimental dogs (P = 0.019), there was no significant change in control dogs (P = 0.019 and P = 0.5, Wilcoxon signed rank tests). The median %MF for paced animals was significantly greater than that of non-paced dogs at the 5-week post-insertion time point (P = 0.009, Mann Whitney U test). Histopathological imaging yielded an average %MF of 19.42 ± 4.80% (mean ± SD) for paced dogs compared to 1.85% in one control dog. CONCLUSION: Persistent rapid ventricular pacing and subsequent AF leads to an increase in LA fibrosis volumes measured by the IIR technique; however, quantification is limited by inherent image acquisition parameters and observer variability.

Hemodynamically Tolerated Ventricular Tachycardia With Mildly Impaired Ejection Fraction: Do These Patients Have VT/VF Recurrence and ICD Therapies?

BACKGROUND: Patients with hemodynamically tolerated ventricular tachycardia (VT) and minimally reduced left ventricular ejection fraction (LVEF) remain a group that presents a prognostic and therapeutic dilemma. METHODS: We studied patients from our implanted cardioverter-defibrillator (ICD) database who received ICDs for hemodynamically tolerated VT and mildly reduced LVEF (36%-49%) at time of implant between May 2015 and December 2019. Time to appropriate ICD therapy was assessed. Clinical features associated with recurrent VT/ventricular fibrillation (VF) with ICD therapies were explored using binary logistic regression. RESULTS: Among 2037 ICDs placed between May 2015 and December 2019, 64 subjects met the inclusion criteria. The mean age of the study group was 68 ± 12 years, and 58 (90.6%) subjects were male. Average ejection fraction was 40% ± 4.4 (range 36%-49%). Twenty-two (34%) subjects received antitachycardia pacing (ATP) for VT at 229 ± 265 days after ICD placement. Fifteen (23%) subjects received appropriate ICD shocks 305 ± 321 days after implant. The rate of recurrent VT/VF among the 37 patients with ICD therapy was 195 ± 39 beats per minute (bpm). This was significantly more rapid than initial presenting VT rates before ICD placement (183 ± 27 bpm) (P = 0.048). Multivariate analysis showed no factors independently associated with recurrent VT/VF. CONCLUSIONS: Patients with mildly impaired LV function and hemodynamically tolerated VT receive appropriate ICD therapies over the 3 years following implant. This patient group warrants further investigation, as their recurrent VT/VF rates can be much more rapid, and 23% go on to receive appropriate ICD shocks.

Epigenetic Age and the Risk of Incident Atrial Fibrillation.

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; P<0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; P<0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

Evaluating Polygenic Risk Scores in "Lone" Atrial Fibrillation.

BACKGROUND: Polygenic scores incorporating varying numbers of single nucleotide polymorphisms (SNPs) have been demonstrated to exert a prominent role in atrial fibrillation (AF). We sought to compare the relative discriminatory capacities of 2 previously validated polygenic scores in "lone" AF. METHODS: A total of 186 lone AF cases of European ancestry underwent SNP genotyping. A genome-wide polygenic score (GPS) and polygenic risk score (PRS) involving 6,730,541 and 1168 SNPs, respectively, were calculated for 186 cases and 423 controls of European ancestry from the 1000 Genomes (1KG) Project. The distribution of the polygenic scores was compared between the cases and controls and their discriminatory capacities were evaluated using receiver operating characteristic (ROC) curves. RESULTS: A total of 34.4% of patients with lone AF had GPS scores greater than the top 10th percentile of 1KG controls, corresponding to a 4.64-fold increased odds (95% confidence interval [CI], 2.99-7.18; P < 0.001) for AF. A PRS score in the top 10th percentile of 1KG controls was observed in 26.3% of cases, which equated to a 3.16-fold increased odds (95% CI, 2.01-4.98; P < 0.001) for AF. Comparison of C-statistics from ROC curves indicated improved discriminatory capacity of the GPS (0.76) relative to the PRS (0.70) (P = 0.002). CONCLUSIONS: Our study evaluating 2 polygenic scores for AF suggests that the GPS, containing more than 6.7 million SNPs, exhibits an improved discriminatory capacity in lone AF compared with a PRS possessing 1168 SNPs. Our findings suggest that genetic risk scores for AF that maximally leverage genomic data may provide improved predictive power.

CONTEXTE: Il a été démontré que des scores polygéniques intégrant un nombre variable de polymorphismes mononucléotidiques (PMN) jouent un rôle important en ce qui concerne la fibrillation auriculaire (FA). Nous avons comparé le potentiel discriminatoire relatif de deux scores polygéniques déjà validés dans la FA idiopathique. MÉTHODOLOGIE: Au total, 186 sujets d'ascendance européenne atteints de FA idiopathique ont été soumis à un génotypage des PMN. Un score polygénique génomique (SPG) et un score de risque polygénique (SRP) comprenant respectivement 6 730 541 et 1 168 PMN ont été calculés pour les 186 sujets et pour 423 témoins d'ascendance européenne dont les données sont tirées du projet 1000 Genomes (1KG). Les distributions des scores polygéniques des sujets et des témoins ont été comparées, et leur potentiel discriminatoire a été évalué au moyen des courbes caractéristiques de la performance d'un test (courbes ROC, de l'anglais Receiver Operating Characteristic). RÉSULTATS: Au total, 34,4 % des patients atteints de FA idiopathique avaient un SPG supérieur à celui des témoins du 10e centile supérieur du projet 1KG, ce qui représente une probabilité de FA 4,64 fois plus élevée (intervalle de confiance [IC] à 95 % : 2,99 à 7,18; p < 0,001). Un SRP situé dans le 10e centile supérieur des témoins du projet 1KG a été observé chez 26,3 % des patients atteints de FA, soit une probabilité de FA 3,16 fois plus élevée (IC à 95 % : 2,01 à 4,98; p < 0,001). Les résultats de la comparaison des statistiques C des courbes ROC indiquent que le SPG (0,76) a un potentiel discriminatoire supérieur à celui du SRP (0,70) (p = 0,002). CONCLUSIONS: Les résultats de notre étude de deux scores polygéniques relatifs à la FA indiquent que le potentiel discriminatoire du SPG, qui comprend plus de 6,7 millions de PMN, pour prédire une FA idiopathique est supérieur à celui du SRP, qui comprend 1 168 PMN. Ces résultats indiquent que les scores de risque génétique de FA qui exploitent pleinement les données génomiques pourraient avoir un pouvoir prédictif supérieur.

Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in 'lone' atrial fibrillation.

AIMS: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF. METHODS AND RESULTS: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF. CONCLUSION: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.

Thromboembolic events following cardioversion of acute atrial fibrillation and flutter: a systematic review and meta-analysis.

BACKGROUND: Recent studies have presented concerning data on the safety of cardioversion for acute atrial fibrillation and flutter. We conducted this meta-analysis to evaluate the effect of oral anticoagulation use on thromboembolic events post-cardioversion of low-risk acute atrial fibrillation and flutter patients of < 48 h in duration. METHODS: We searched MEDLINE, Embase, and Cochrane from inception through February 6, 2020 for studies reporting thromboembolic events post-cardioversion of acute atrial fibrillation and flutter. Main outcome was thromboembolic events within 30 days post-cardioversion. Primary analysis compared thromboembolic events based on oral anticoagulation use versus no oral anticoagulation use. Secondary analysis was based on baseline thromboembolic risk. We performed meta-analyses where 2 or more studies were available, by applying the DerSimonian-Laird random-effects model. Risk of bias was assessed with the Quality in Prognostic Studies tool. RESULTS: Of 717 titles screened, 20 studies met inclusion criteria. Primary analysis of seven studies with low risk of bias demonstrated insufficient evidence regarding the risk of thromboembolic events associated with oral anticoagulation use (RR = 0.82 where RR < 1 suggests decreased risk with oral anticoagulation use; 95% CI 0.27 to 2.47; I2 = 0%). Secondary analysis of 13 studies revealed increased risk of thromboembolic events with high baseline thromboembolic risk (RR = 2.25 where RR > 1 indicates increased risk with higher CHADS2 or CHA2DS2-VASc scores; 95% CI 1.25 to 4.04; I2 = 0%). CONCLUSION: Primary analysis revealed insufficient evidence regarding the effect of oral anticoagulation use on thromboembolic events post-cardioversion of low-risk acute atrial fibrillation and flutter, though the event rate is low in contemporary practice. Our findings can better inform patient-centered decision-making when considering 4-week oral anticoagulation use for acute atrial fibrillation and flutter patients.

RéSUMé: CONTEXTE: Des études récentes ont présenté des données sur la sécurité de la cardioversion pour la fibrillation auriculaire aiguë et le flutter. Nous avons mené cette méta-analyse pour évaluer l'effet de l'utilisation de l'anticoagulation orale sur les événements thromboemboliques post-cardioversion de patients atteints de fibrillation auriculaire aiguë à faible risque et de flutter de moins de 48 heures. LES MéTHODES: Nous avons recherché dans MEDLINE, Embase et Cochrane depuis le début jusqu'au 6 février 2020 des études faisant état d'événements thromboemboliques après une cardioversion de la fibrillation auriculaire aiguë et du flutter. Le principal résultat a été des événements thromboemboliques dans les 30 jours suivant la cardioversion. L'analyse primaire a comparé les événements thromboemboliques basés sur l'utilisation de l'anticoagulation orale par rapport à l'absence d'anticoagulation orale. L'analyse secondaire était basée sur le risque thromboembolique de base. Nous avons effectué des méta-analyses lorsque deux études ou plus étaient disponibles, en appliquant le modèle à effets aléatoires DerSimonian-Laird. Le risque de biais a été évalué avec l'outil Quality in Prognostic Studies. RéSULTATS: Sur les 717 titres examinés, 20 études ont répondu aux critères d'inclusion. L'analyse primaire de sept études présentant un faible risque de biais a démontré l'insuffisance des preuves concernant le risque d'événements thromboemboliques associés à l'utilisation d'anticoagulation orale (RR = 0,82 où RR < 1 suggère une diminution du risque avec l'utilisation d'anticoagulation orale ; IC 95 % 0,27 à 2,47 ; I2 = 0 %). L'analyse secondaire de 13 études a révélé un risque accru d'événements thromboemboliques avec un risque thromboembolique de base élevé (RR = 2,25 où RR > 1 indique un risque accru avec des scores CHADS2 ou CHA2DS2-VASc plus élevés ; 95 % CI 1,25 à 4,04 ; I2 = 0 %). CONCLUSIONS: L'analyse primaire a révélé des preuves insuffisantes concernant l'effet de l'utilisation de l'anticoagulation orale sur les événements thromboemboliques après une cardioversion de fibrillation auriculaire aiguë à faible risque et de flutter, bien que le taux d'événements soit faible dans la pratique contemporaine. Nos conclusions peuvent mieux éclairer la prise de décision centrée sur le patient lorsqu'il s'agit d'envisager l'utilisation de l'anticoagulation orale pendant 4 semaines pour les patients souffrant de fibrillation auriculaire aiguë et de flutter.

Differences in Healthcare Use Between Patients With Persistent and Paroxysmal Atrial Fibrillation Undergoing Catheter-Based Atrial Fibrillation Ablation: A Population-Based Cohort Study From Ontario, Canada.

Background Patients with persistent atrial fibrillation (AF) undergoing catheter-based AF ablation have lower success rates than those with paroxysmal AF. We compared healthcare use and clinical outcomes between patients according to their AF subtypes. Methods and Results Consecutive patients undergoing AF ablation were prospectively identified from a population-based registry in Ontario, Canada. Via linkage with administrative databases, we performed a retrospective analysis comparing the following outcomes between patients with persistent and paroxysmal AF: healthcare use (defined as AF-related hospitalizations/emergency room visits), periprocedural complications, and mortality. Multivariable Poisson modeling was performed to compare the rates of AF-related and all-cause hospitalizations/emergency room visits in the year before versus after ablation. Between April 2012 and March 2016, there were 3768 consecutive patients who underwent first-time AF ablation, of whom 1040 (27.6%) had persistent AF. The mean follow-up was 1329 days. Patients with persistent AF had higher risk of AF-related hospitalization/emergency room visits (hazard ratio [HR], 1.21; 95% CI, 1.09-1.34), mortality (HR, 1.74; 95% CI, 1.15-2.63), and periprocedural complications (odds ratio, 1.36; 95% CI, 1.02-1.75) than those with paroxysmal AF. In the overall cohort, there was a 48% reduction in the rate of AF-related hospitalization/emergency room visits in the year after versus before ablation (rate ratio [RR], 0.52; 95% CI, 0.48-0.56). This reduction was observed for patients with paroxysmal (RR, 0.45; 95% CI, 0.41-0.50) and persistent (RR, 0.74; 95% CI, 0.63-0.87) AF. Conclusions Although patients with persistent AF had higher risk of adverse outcomes than those with paroxysmal AF, ablation was associated with a favorable reduction in downstream AF-related healthcare use, irrespective of AF type.

The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation.

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

Para-Hisian Pacing During Sinus Rhythm: Establishing Threshold Values to Distinguish Nodal From Septal Pathway Conduction.

OBJECTIVES: This study sought to identify minimum threshold values below which conduction over the atrioventricular (AV) node would be unexpected. BACKGROUND: Para-Hisian pacing is used to evaluate for the presence of a septal accessory pathway (AP); however, threshold values to differentiate nodal from AP conduction are unknown. METHODS: The authors performed high- and low-output para-Hisian pacing during sinus rhythm to capture the His and para-Hisian ventricular myocardium (H+V) and para-Hisian ventricular myocardium (V) alone, respectively. The change in stimulation (stim)-to-atrial electrogram interval after loss of His bundle capture in patients with (AP+) and without (AP-) a septal AP was evaluated. Stim-to-proximal coronary sinus (PCS) and stim-to-high right atrium (HRA) intervals were measured and within-patient differences (△) for V and H+V capture were calculated. RESULTS: A total of 23 AP+ and 45 AP- patients were evaluated. The difference in stimulus to earliest atrial signal in the high right atrial catheter seen with the loss of His bundle capture (△-stim-HRA) (21 ms; interquartile range [IQR]: 3 to 43 ms vs. 64 ms; IQR: 56 to 73 ms; p < 0.001) and difference in stimulus to earliest atrial signal in the proximal coronary sinus catheter seen with the loss of His Bundle capture (△-stim-PCS) (11 ms; IQR: 0 to 30 ms vs. 61 ms; IQR: 52 to 72 ms; p < 0.001) were shorter in AP+ patients. The shortest △-stim-PCS and △-stim-HRA in AP- patients were 37 ms and 32 ms, respectively, whereas the longest corresponding intervals in AP+ patients were 51 ms and 75 ms, respectively. CONCLUSIONS: A △-stim-PCS <37 ms or △-stim-HRA <32 ms confirmed the presence of a septal AP, whereas a value >51 ms for △-stim-PCS or >75 ms for △-stim-HRA excluded it. Alternatively, the minimum △-stim-PCS with loss of His capture compatible with AV nodal conduction in isolation was 37 ms, and a △-stim-PCS >51 ms effectively ruled out the presence of a septal AP.

A simple maneuver to determine if septal accessory pathway ablation requires a left atrial approach.

INTRODUCTION: Septal accessory pathway (AP) ablation can be challenging due to the complex anatomy of the septal region. The decision to access the left atrium (LA) is often made after failure of ablation from the right. We sought to establish whether the difference between ventriculo-atrial (VA) time during right ventricular (RV) apical pacing versus the VA during tachycardia would help establish the successful site for ablation of septal APs. METHODS: Intracardiac electrograms of patients with orthodromic reciprocating tachycardia (ORT) using a septal AP with successful catheter ablation were reviewed. The ∆VA was the difference between the VA interval during RV apical pacing and the VA interval during ORT. The difference in the VA interval during right ventricular entrainment and ORT (StimA-VA) was also measured. RESULTS: The median ∆VA time was significantly less in patients with a septal AP ablated on the right side compared with patients with a septal AP ablated on the left side (12 ± 19 vs. 56 ± 10 ms, p < .001). The StimA-VA was significantly different between the two groups (22 ± 14 vs. 53 ± 9 ms, p < .001). The ∆VA and StimA-VA were always ≤ 40 ms in patients with non-decremental septal APs ablated from the right side and always greater than 40 ms in those with septal APs ablated from the left. CONCLUSION: ΔVA and StimA-VA values identified with RV apical pacing in the setting of ORT involving a septal AP predict when left atrial access will be necessary for successful ablation.

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration. METHODS: Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS: This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

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 ß-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and ß-catenin. A pharmacological activator of the WNT/ß-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 ß-catenin, and evidence for targeted activation of the WNT/ß-catenin pathway as a potential treatment for this disease.

Eliminating the effects of motion during radiofrequency lesion delivery using a novel contact-force controller.

INTRODUCTION: Catheter-tissue contact force is a determinant of radiofrequency (RF) ablation lesion effectiveness. However, ablation on a beating heart is subject to force variability, making it difficult to optimally deliver consistently durable and transmural lesions. This work evaluates improvements in contact force stability and lesion reproducibility by using a catheter contact-force controller (CFC) during lesion delivery in vitro and in vivo. METHODS AND RESULTS: Using a sheath and force-sensing catheter, an experienced operator attempted to maintain a constant force of 20 g at targets within the atria and left ventricle of a pig manually and using the CFC; the average force and contact-force variation (CFV) achieved using each approach were compared. Ablation lesions (20 W, 30 seconds, 17 mL/min irrigation) were created in bovine tissue samples mounted on a platform programmed to reproduce clinically relevant motion. CFC-assisted lesions were delivered to stationary and moving tissue with forces of 5 to 35 g. Mimicking manual intervention, lesions were also delivered to moving tissue while the CFC was disabled. Resultant lesion volumes were compared using two-way analysis of variance. When using the CFC, the average force was within 1 g of the set level, with a CFV less than 5 g, during both in vitro and in vivo experiments. Reproducible and statistically identical (P = .82) lesion volumes proportional to the set force were achieved in both stationary and moving tissue when the CFC was used. CONCLUSIONS: CFC assistance maintains constant force in vivo and removes effect of motion on lesion volume during RF lesion delivery.

Atrial Fibrillation and Heart Failure: Untangling a Modern Gordian Knot.

Heart failure (HF) and atrial fibrillation (AF) share common risk factors and frequently coexist. Both are highly prevalent in our aging population, and mortality associated with the combination is significantly higher than for each alone. An intricate link exists between AF and HF, including interrelated mechanisms and pathophysiology. Asymptomatic left ventricular systolic or diastolic dysfunction can exacerbate or be exacerbated by AF, resulting in HF with reduced ejection fraction or preserved ejection fraction. A number of treatment strategies have improved symptoms, exercise tolerance, and quality of life for patients with HF, but few have resulted in alteration in prognosis. Sinus rhythm, achieved pharmacologically, has not altered important outcomes, including cardiovascular or total mortality in patients with HF. In recent studies, catheter ablation to achieve sinus rhythm seems to have a significant impact on symptoms, heart function, and possibly mortality. Until future studies can confirm or clarify the impact of catheter ablation on outcomes, the field remains cautious but optimistic that better treatment strategies for patients with HF with reduced ejection fraction or preserved ejection fraction are within reach.