Assessment of patient characteristics influencing the complexity of leadless pacemaker implantation.

Background: The complexity of leadless pacemaker (LP) implantation varies widely. However, the predictive factors determining this difficulty are poorly understood. Objective: The purpose of this study was to evaluate the factors influencing LP implantation difficulty, specifically procedural time during right atrial (RA) and right ventricular (RV) manipulation, based on patient background, cardiac function, and anatomic characteristics. Methods: Analysis included LP implantation cases between 2017 and 2023, excluding the initial 3 implants performed by each operator. The relevance of patient background, cardiac function, and anatomic features on procedural and fluoroscopy times was evaluated. Results: Fifty-four patients (mean age 82.2 ± 10.0 years; 57.4% male) were included in the study. Median procedural and fluoroscopy time was 45.8 minutes and 16.0 minutes, respectively, with an average of 2.0 ± 1.4 device deployments. Univariate analysis showed associations between procedural time and older age, RA and RV diameter, and severity of tricuspid regurgitation (TR). After adjustment for physician and potential contributing factors, RV dilation (midventricular diameter ≥35 mm) and severe TR were identified as independent predictors of prolonged procedural time. Medical history exhibited no association with procedural time. Consistent results were observed in analyses using fluoroscopy time as the outcome. Conclusion: RV dilation and severe TR were associated with prolonged procedural time for LP implantation. Anatomic features obtained from preprocedural echocardiography could provide valuable insights into both the safety and efficiency of LP implantation, thereby enhancing tailored treatment strategies for patients undergoing pacemaker implantation.

Single-swap editing for the correction of common Duchenne muscular dystrophy mutations.

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disease of progressive muscle weakness and wasting caused by the absence of dystrophin protein. Current gene therapy approaches using antisense oligonucleotides require lifelong dosing and have limited efficacy in restoring dystrophin production. A gene editing approach could permanently correct the genome and restore dystrophin protein expression. Here, we describe single-swap editing, in which an adenine base editor edits a single base pair at a splice donor site or splice acceptor site to enable exon skipping or reframing. In human induced pluripotent stem cell-derived cardiomyocytes, we demonstrate that single-swap editing can enable beneficial exon skipping or reframing for the three most therapeutically relevant exons-DMD exons 45, 51, and 53-which could be beneficial for 30% of all DMD patients. Furthermore, an adeno-associated virus delivery method for base editing components can efficiently restore dystrophin production locally and systemically in skeletal and cardiac muscles of a DMD mouse model containing a deletion of Dmd exon 44. Our studies demonstrate single-swap editing as a potential gene editing therapy for common DMD mutations.

Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy.

Mutations in RNA binding motif protein 20 (RBM20) are a common cause of familial dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine-rich (RS-rich) domain, which mediates nuclear localization. These mutations induce RBM20 mis-localization to form aberrant ribonucleoprotein (RNP) granules in the cytoplasm of cardiomyocytes and abnormal alternative splicing of cardiac genes, contributing to DCM. We used adenine base editing (ABE) and prime editing (PE) to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Using ABE to correct RBM20R634Q human iPSCs, we achieved 92% efficiency of A-to-G editing, which normalized alternative splicing of cardiac genes, restored nuclear localization of RBM20, and eliminated RNP granule formation. In addition, we developed a PE strategy to correct the RBM20R636S mutation in iPSCs and observed A-to-C editing at 40% efficiency. To evaluate the potential of ABE for DCM treatment, we also created Rbm20R636Q mutant mice. Homozygous (R636Q/R636Q) mice developed severe cardiac dysfunction, heart failure, and premature death. Systemic delivery of ABE components containing ABEmax-VRQR-SpCas9 and single-guide RNA by adeno-associated virus serotype 9 in these mice restored cardiac function as assessed by echocardiography and extended life span. As seen by RNA sequencing analysis, ABE correction rescued the cardiac transcriptional profile of treated R636Q/R636Q mice, compared to the abnormal gene expression seen in untreated mice. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.

A humanized knockin mouse model of Duchenne muscular dystrophy and its correction by CRISPR-Cas9 therapeutic gene editing.

Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disease caused by mutations in the X-linked dystrophin (DMD) gene. Exon deletions flanking exon 51, which disrupt the dystrophin open reading frame (ORF), represent one of the most common types of human DMD mutations. Previously, we used clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) gene editing to restore the reading frame of exon 51 in mice and dogs with exon 50 deletions. Due to genomic sequence variations between species, the single guide RNAs (sgRNAs) used for DMD gene editing are often not conserved, impeding direct clinical translation of CRISPR-Cas therapeutic gene-editing strategies. To circumvent this potential obstacle, we generated a humanized DMD mouse model by replacing mouse exon 51 with human exon 51, followed by deletion of mouse exon 50, which disrupted the dystrophin ORF. Systemic CRISPR-Cas9 gene editing using an sgRNA that targets human exon 51 efficiently restored dystrophin expression and ameliorated pathologic hallmarks of DMD, including histopathology and grip strength in this mouse model. This unique DMD mouse model with the human genomic sequence allows in vivo assessment of clinically relevant gene editing strategies as well as other therapeutic approaches and represents a significant step toward therapeutic translation of CRISPR-Cas9 gene editing for correction of DMD.

A consolidated AAV system for single-cut CRISPR correction of a common Duchenne muscular dystrophy mutation.

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene, is a lethal neuromuscular disease. Correction of DMD mutations in animal models has been achieved by CRISPR/Cas9 genome editing using Streptococcus pyogenes Cas9 (SpCas9) delivered by adeno-associated virus (AAV). However, due to the limited viral packaging capacity of AAV, two AAV vectors are required to deliver the SpCas9 nuclease and its single guide RNA (sgRNA), impeding its therapeutic application. We devised an efficient single-cut gene-editing method using a compact Staphylococcus aureus Cas9 (SaCas9) to restore the open reading frame of exon 51, the most commonly affected out-of-frame exon in DMD. Editing of exon 51 in cardiomyocytes derived from human induced pluripotent stem cells revealed a strong preference for exon reframing via a two-nucleotide deletion. We adapted this system to express SaCas9 and sgRNA from a single AAV9 vector. Systemic delivery of this All-In-One AAV9 system restored dystrophin expression and improved muscle contractility in a mouse model of DMD with exon 50 deletion. These findings demonstrate the effectiveness of CRISPR/SaCas9 delivered by a consolidated AAV delivery system in the correction of DMD in vivo, representing a promising therapeutic approach to correct the genetic causes of DMD.

CRISPR/Cas correction of muscular dystrophies.

Muscular dystrophies are a heterogeneous group of monogenic neuromuscular disorders which lead to progressive muscle loss and degeneration of the musculoskeletal system. The genetic causes of muscular dystrophies are well characterized, but no effective treatments have been developed so far. The discovery and application of the CRISPR/Cas system for genome editing offers a new path for disease treatment with the potential to permanently correct genetic mutations. The post-mitotic and multinucleated features of skeletal muscle provide an ideal target for CRISPR/Cas therapeutic genome editing because correction of a subpopulation of nuclei can provide benefit to the whole myofiber. In this review, we provide an overview of the CRISPR/Cas system and its derivatives in genome editing, proposing potential CRISPR/Cas-based therapies to correct diverse muscular dystrophies, and we discuss challenges for translating CRISPR/Cas genome editing to a viable therapy for permanent correction of muscular dystrophies.

Cardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular Dystrophy.

[Figure: see text].

Symptom burden and treatment perception in patients with atrial fibrillation, with and without a family history of atrial fibrillation.

Atrial fibrillation (AF) is known to aggregate within family and might be associated with a lower quality-of-life (QoL). We evaluated the association between a family history (FHx) of AF and patient-reported symptom burden and perception towards treatment. We performed a retrospective analysis in a cohort of 1285 newly diagnosed patients with AF. Patients completed the atrial fibrillation effect on quality of life (AFEQT) questionnaire at the time of registration and at the 1-year follow-up. Patients who had a first-degree relative with AF were classified into the FHx group. Baseline characteristics and AFEQT scores were compared between groups, and a multivariate analysis was used to evaluate the independent association between FHx and QoL. Overall, 15.9% of patients (n = 204) had a positive AF FHx. Compared to the non-FHx group, the FHx group had an earlier onset of AF (60.2 ± 12.0 years vs. 64.5 ± 12.1 years; P < 0.05) and lower AFEQT overall summary (AFEQT-OS) score at baseline (73.9 ± 17.8 vs. 77.0 ± 16.8; P < 0.05). After adjustment for clinical background, a positive FHx was independently associated with a worse QoL (changes in AFEQT-OS score = - 3.18; 95% confidence interval: - 5.67 to - 0.69; P = 0.012). No between-group difference in AFEQT-OS scores was noted at the 1-year follow-up. An FHx of AF was associated with a lower QoL, which could be improved by therapeutic intervention in patients with AF. Recognizing the presence of an FHx of AF is important to predict patient's symptom load and treatment acceptance.

Electrical Isolation of the Marshall Bundle by Radiofrequency Catheter Ablation: In Patients With Atrial Fibrillation.

OBJECTIVES: This study sought to isolate arrhythmogenic Marshall bundles (MBs) by radiofrequency (RF) catheter ablation. BACKGROUND: The vein of Marshall (VOM) is surrounded by a muscular bundle called the MB. The MB is 1 of the arrhythmogenic sources of atrial fibrillation (AF) and electrically connects to either the left atrial (LA) myocardium or coronary sinus (CS) musculature. By eliminating such electric connections using RF catheter ablation, the MB might be electrically isolated. METHODS: This retrospective study included 20 patients (64 ± 10 years old, 5 women) who underwent an MB isolation for nonparoxysmal AF. After pulmonary vein isolation, we performed venography of the VOM and inserted a 2-F electrode catheter into the VOM. RF applications were delivered to eliminate the MB electrograms from both the LA and CS when the MB was considered arrhythmogenic. RESULTS: MB isolation was achieved in 14 patients (70%). Of them, complete or partial MB isolation was accomplished in 7 patients (35%) each. The average number of RF applications in the LA (35 W, 30 s) and CS (25 W, 30 s) was 15 ± 14 and 4 ± 3, respectively. No severe adverse events were observed. During a follow-up of 23 ± 11 months, 18 patients (90%) maintained sinus rhythm. CONCLUSIONS: RF applications targeting recordings from an electrode catheter in the VOM were feasible, and the MB could be electrically isolated. Elimination of the MB potentials would be a clear endpoint for patients with an arrhythmogenic MB.

Discrepancy in recognition of symptom burden among patients with atrial fibrillation.

Our aim was to investigate the variability in physician recognition of atrial fibrillation (AF)-related symptoms, which greatly contributes to the management of AF patients. METHODS AND RESULTS: A total of 1493 newly-referredAF patients (67 ±â€¯11 y/o, 1057 men) consecutively registered in an outpatient-based Japanese multicenter database (KiCS-AF) from September 2012 to December 2016 were analyzed. Self-reportedAF symptom burden was assessed via symptom and daily activities domains within the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. Physician symptom under-recognition (UR) was defined as no subjective complaints recorded in the medical records despite AFEQT score of <80; and physician's apparent over-recognition (OvR) was defined as documentation of subjective complaints despite total AFEQT score of ≥80. There was poor agreement between patient-reported and physicians-estimated symptom burden (kappa 0.28, 95% CI 0.23 to 0.33). In the logistic regression analysis, age> 75 (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.13-2.62), male sex (OR, 1.82; 95% CI, 1.22-2.74), and persistent/permanent AF (OR 2.54/3.36; CI, 1.63-3.99/1.91-5.89, respectively) were predictors of UR. Conversely, heart failure (OR, 2.46; 95% CI, 1.44-4.25) and treatment in an ablation facility (OR, 1.43; 95% CI, 1.02-2.02) were associated with greater odds of OvR in addition to age, sex, and type of AF. CONCLUSIONS: Discordance in recognition of AF symptom burden by physicians was frequent in AF patients seen in outpatient management and involved both patient- and physician-related factors.

A high BNP level predicts an improvement in exercise tolerance after a successful catheter ablation of persistent atrial fibrillation.

INTRODUCTION: Restoration of sinus rhythm (SR) by catheter ablation (CA) of atrial fibrillation (AF) improves exercise tolerance. However, it is still unclear what characteristics of patients are contributing to an improvement in exercise tolerance after CA of AF without heart failure. METHODS AND RESULTS: This study consisted of 51 consecutive patients with persistent or long-standing persistent AF without heart failure who were restored to SR for over 6 months by a successful CA. Exercise tolerance was evaluated by cardiopulmonary exercise testing before and 3 and 6 months after CA. The clinical characteristics contributing to an improvement in exercise tolerance was elucidated. The peak oxygen uptake (VO2 )% significantly increased from 101.4 ± 20.3% to 110.9 ± 19.9% 3 months after the CA (P < .001). The improvement rate in the peak VO2 % exhibited a positive correlation to the baseline brain natriuretic peptide (BNP; ρ = 0.39, P < .01), but not to the age, AF duration, left ventricular ejection fraction, or left atrial size. The linear regression analysis revealed that the baseline BNP was an independent predictor of an improvement in the peak VO2 % (coefficients = 0.32; 95% confidence interval = 0.08, 0.54; P = .01). The peak VO2 % improved significantly in the patients whose baseline BNP level was greater than 100 pg/mL, compared to the others (P < .01). These favorable findings were also observed 6 months after the CA. CONCLUSION: Elimination of persistent AF by CA was associated with an improvement in exercise tolerance. This was particularly true in patients with high BNP values at baseline.

The Durability of Atrial Fibrillation Ablation Using an Oesophageal Temperature Cut-Off of 38°C.

BACKGROUND: A lower cut-off of the oesophageal temperature (ET) during catheter ablation of atrial fibrillation (AF) should be safer, but its durability may become in question. We evaluated an ET cut-off of 38°C with an output of 25W on the posterior wall. METHODS: In 636 consecutive patients (age: 60±10years, male: 542, paroxysmal AF: 405, CHADS2 score: 0.7±0.9), an ET probe was utilised in 303 patients (259 pulmonary vein isolations [PVIs] and 44 simultaneous isolations of the posterior wall and all PVs box isolations [BOXIs]). When the ET increased to >38°C, the radiofrequency delivery was switched off and the ablation point was tagged as an "EsoTag" by the CARTO™ system (Biosense Webster, Irvine, CA, USA). We analysed the characteristics of the ablation lesions at the EsoTags with respect to the dormant conduction, gaps in the redo-session, and ablation outcome. RESULTS: EsoTags were identified in 94.6% of the left PVIs and all BOXIs, and dormant conduction at the EsoTags was identified in 12.0% and 6.8%, respectively. In 10,796 ablation points, the ablation at the EsoTags that were associated with dormant conduction had a significantly shorter duration, smaller force-time integral, and smaller Δimpedance. The duration of an ET of >38°C was significantly and positively correlated with the body mass index and negatively with the left atrial appendage flow velocity. During the redo-sessions in a 10.5±6.0months of follow-up (PVI: 14.7%, BOXI: 11.4%), reconnections at the EsoTags with dormant conduction were observed only in two patients after the PVI. The AF survival rate did not significantly differ in the presence of dormant conduction at the EsoTags (83.1% vs. 75.0%, p=0.696). There were no patients hospitalised for gastroparesis. CONCLUSIONS: Atrial fibrillation ablation utilising an oesophageal temperature cut-off of 38°C might be safe and durable.

Assessment of Sex Differences in the Initial Symptom Burden, Applied Treatment Strategy, and Quality of Life in Japanese Patients With Atrial Fibrillation.

Importance: The clinical characteristics and outcomes of women and men with atrial fibrillation (AF) are reported to be different. However, whether sex-related differences extend to patients' symptom burden and perceived quality of life (QOL) or the management pattern of AF has been rarely studied, particularly in Asian countries. Objective: To assess the differences in symptoms, treatment, and QOL between Japanese female and male patients with AF. Design, Setting, and Participants: Retrospective cohort study using data from the multicenter outpatient registry Keio Interhospital Cardiovascular Studies-Atrial Fibrillation (KiCS-AF), which collects information regarding health status and the treatment of patients with newly diagnosed or referred AF. One-year follow-up data were available for 1534 patients at 11 referral centers in the Tokyo, Japan, area who were enrolled between September 2012 and December 2015. All data available up to the 1-year follow-up examination through July 31, 2017, were included. Main Outcomes and Measures: Sex, symptoms, AF treatment, and QOL as determined by Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaires at their initial visit and 1 year later. Results: Of 1534 patients, 1076 (70.1%) were men. Compared with men, women were more likely to be older (median age, 73 years [interquartile range {IQR}, 65-78 years] vs 65 years [IQR, 57-73 years], P < .001) and have higher median brain-type natriuretic peptide levels (102.8 pg/mL [IQR, 47.3-235.5 pg/mL] vs 74.1 pg/mL [IQR, 28.5-150.5 pg/mL], P < .001). Women also had lower median AFEQT overall summary scores than men (75 [IQR, 61-85] vs 80 [IQR, 69-90]; P < .001) but similar treatment satisfaction at baseline. During follow-up, women were less likely to be treated with a rhythm control strategy (48.1% [n = 214] vs 58.0% [n = 621], P < .001), including catheter ablation of AF (adjusted hazard ratio, 0.77 [95% CI, 0.62-0.95]; P = .02). At 1-year follow-up, women and men had improved QOL scores, regardless of their baseline characteristics (eg, age or brain-type natriuretic peptide levels) or treatment strategies, yet the sex gap persisted and grew (adjusted change in AFEQT overall summary score during 12 months, 5.89 [95% CI, 2.24-9.54] in women vs 8.94 [95% CI, 5.59-12.30] in men; P = .02). Conclusions and Relevance: In contemporary Japanese clinical practice among unselected patients with AF, women were initially seen with greater QOL impairment, and the sex gap grew 1 year after presentation. The present study underscores the need for focused efforts to better understand and close this observed sex gap over the initial year of treatment for patients with AF.

Importance of the vein of Marshall involvement in mitral isthmus ablation.

BACKGROUND: Epicardiac conduction via the vein of Marshall (VOM) can bypass the mitral isthmus (MI) line, making MI ablation difficult. This study aimed to assess the contribution of the VOM in achieving MI conduction block. METHODS: This study included 143 consecutive patients with nonparoxysmal atrial fibrillation who underwent initial MI ablation. They were retrospectively classified into two groups, a VOM-guided group (n = 28) and a conventional group (n = 115), according to the use of a 2-Fr electrode catheter inserted in the VOM. The acute success rate of achieving MI block and the ablation data were assessed. When the bidirectional block was verified exclusively in the VOM or coronary sinus (CS) electrodes, we defined it as a pseudo MI block. In the VOM-guided group, we ascertained the complete MI block, verified both in the VOM and CS electrodes. RESULTS: In the VOM-guided group, the pseudoblock was observed in 33.3% of the patients during MI ablation. With significantly less radiofrequency energy (19 322.6 ± 11 352.8 vs 25 389.3 ± 19 951.9, P = 0.04), we achieved a similar level of success rate in MI ablation in the VOM-guided group (96.4% vs 91.3%, P = 0.36). Notably, after achieving complete MI block, atrial burst pacing induced two perimitral flutters in the VOM-guided group, which were successfully terminated by the additional radiofrequency application. CONCLUSIONS: Assessment of electrical conduction through the VOM could clarify the existence of a pseudo MI conduction block. However, the existence of a slow conduction through the MI could be detected only after induction of perimitral atrial tachycardia with atrial programmed stimulation.

A Homozygous CASQ2 Mutation in a Japanese Patient with Catecholaminergic Polymorphic Ventricular Tachycardia.

A 62-year-old female had suffered from recurrent syncopal episodes triggered by physical and emotional stress since childhood. She had no family history of sudden death. An intensive examination could not detect any structural disease, and exercise stress testing provoked polymorphic ventricular ectopy followed by polymorphic ventricular tachycardia accompanied with syncope leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). A genetic analysis with a next generation sequencer identified a homozygous W361X mutation in the CASQ2 gene. Careful history taking disclosed that her parents had a consanguineous marriage. Here we present a Japanese patient with a recessive form of CPVT.

Incidence, Clinical Characteristics, and Long-term Outcome of the Dilated Phase of Hypertrophic Cardiomyopathy.

Some patients with hypertrophic cardiomyopathy (HCM) develop systolic dysfunction, called the dilated phase of HCM (d-HCM), which is associated with increased morbidity and mortality. We conducted a retrospective study using an HCM database to clarify the incidence, clinical characteristics, and long-term outcomes of d-HCM. We analyzed an HCM cohort consisting of 434 patients (273 with apical HCM and 161 with non-apical HCM; 18 had obstructive HCM, 16 had dilated HCM, and 127 had other HCM) diagnosed by echocardiography in our hospital between 1991 and 2010. The follow-up period was 8.4 ± 6.7 years. The mean age at final follow-up was 67 ± 14 years, and 304 patients (70%) were men. The mean age of the 16 d-HCM patients at the initial visit was 45 ± 17 years, the age at final follow-up was 59 ± 18 years, and 13 were men. Thirteen d-HCM patients developed atrial fibrillation and six patients developed ischemic stroke. Twelve d-HCM patients were implanted with cardiac devices: one pacemaker, nine implantable cardioverter-defibrillators, and two cardiac resynchronization therapy with defibrillator. Five patients died of progressive heart failure at the age of 61 ± 23 years. The age at the initial visit and final follow-up were lower and the NYHA class, brain natriuretic peptide levels, and left ventricular function at initial evaluation were worse in the d-HCM group. Univariate analysis demonstrated that a lower age at the initial visit was associated with d-HCM (hazard ratio 0.955/1 year increase; 95% CI 0.920-0.991, P = 0.015). In our HCM cohort, the incidence of d-HCM was 4%. A high prevalence of atrial fibrillation and cerebral infarction and poor prognosis were noted in this group, despite patients undergoing medication and device implantation.

A tale of two sisters with hypertrophic cardiomyopathy and recurrent embolism: When is the optimal timing of the intervention for left atrial appendage?

Hypertrophic cardiomyopathy (HCM) is an extremely heterogeneous genetic disease that affects the left ventricle (LV) and has a varied clinical course and phenotypic expression. Here, we report a case of two sisters with HCM who developed a massive refractory left atrial appendage (LAA) thrombus and recurrent embolism. The older sister, who was at a high surgical risk due to progressive LV systolic dysfunction with an ejection fraction of 19%, underwent LAA plication in combination with implantation of an LV assist device after progression to treatment-refractory heart failure at the age of 49. The younger sister underwent surgical thrombectomy, LAA plication, and Maze surgery before deterioration of heart failure at the age of 47. She was free from embolism and atrial fibrillation for 2years after surgery. Individualized therapeutic approaches targeting the LAA at a relatively early stage are required in the subgroups of HCM patients with left atrial dysfunction.

Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation: Comparing Uninterrupted Rivaroxaban and Warfarin (ASCERTAIN).

OBJECTIVES: This randomized study compared uninterrupted rivaroxaban therapy with warfarin therapy as prophylaxis against catheter ablation (CA)-induced asymptomatic cerebral infarction (ACI) and identified the risk factors of rivaroxaban. BACKGROUND: The reported incidence of ACI during CA for atrial fibrillation (AF) remains at 10% to 30%, and periprocedural oral anticoagulation could affect this incidence. METHODS: Patients with nonvalvular AF undergoing radiofrequency CA were randomly assigned to receive either uninterrupted rivaroxaban or warfarin as periprocedural anticoagulation therapy. CA was performed after at least 1 month of adequate anticoagulation. Cerebral magnetic resonance imaging (MRI) was performed within 2 weeks before and 1 day after CA to detect ACI. RESULTS: A total 132 patients were enrolled; 127 (median: 60.0 years of age; 83.5% males; 64.6% incidence of paroxysmal AF) complied with the study protocol and were analyzed; 64 patients received rivaroxaban, and 63 patients received warfarin. The rates of CA-induced ACI in the rivaroxaban group (15.6% [10 of 64 patients]) were similar to those in the warfarin group (15.9% [10 of 63 patients]; p = 1.000). No thromboembolic events developed; no differences in major or nonmajor bleeding rates were observed between the 2 drug groups (3.1% vs. 1.6%, respectively, or 18.8% vs. 19.0%, respectively). Multiple regression analysis indicated that the presence of deep and subcortical white matter hyperintensity (p = 0.002; odds ratio [OR]: 5.323) and the frequency of cardioversions (p = 0.016; OR: 1.250) were associated with the incidence of ACI. CONCLUSIONS: No notable differences were found between the incidence of CA-induced ACI in the rivaroxaban group and that in the warfarin group in this randomized study.

Sex-Dependent Phenotypic Variability of an SCN5A Mutation: Brugada Syndrome and Sick Sinus Syndrome.

Background Brugada syndrome ( BS ) is known to be 9 times more prevalent in males than females. However, little is known about the development of sick sinus syndrome in female members with familial BS . Methods and Results Familial BS patients and family members, both from our institutions and collaborating sites that specialize in clinical care of BS , participated in this study. We collected information on their clinical and genetic background, along with the inheritance patterns of BS . Detailed information on each case with familial BS is described. A total of 7 families, including 25 BS patients (12 females and 13 males), were included. Seven were probands and 18 were family members. Ten out of the 12 female patients and none of the 13 male patients developed sick sinus syndrome. Sudden death or spontaneous ventricular fibrillation occurred in 7 out of 13 male patients and 2 out of 12 female patients. Conclusions Familial BS existed in which female patients developed sick sinus syndrome but male patients did not. Some of those female patients with sick sinus syndrome had unrecognized BS . Information should be collected not only regarding a family history of sudden death or BS , but also whether a pacemaker was implanted in female members.