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Radiofrequency (RF) ablation for the treatment of atrial fibrillation has gained widespread acceptance since the concept was introduced by Haissaguerre et al a quarter of a century ago. High power short duration ablation has been widely adopted in the management of atrial fibrillation. Evidence for combining lesion size index and high power short duration ablation is lacking. In this issue of the journal, Cai et al evaluated the combination of HPSD with LSI with a focus on long-term efficacy.

Background There are limited data on the comparative analyses of TightRailTM rotating dilator sheath (Philips) and laser sheath for lead extraction. Objective To evaluate the effectiveness and safety of the TightRailTM sheath as a primary or secondary tool for TLE. Methods Retrospective cohort analysis of 202 consecutive patients who underwent TLE using either TightRailTM sheath and/or GlideLightTM laser sheath (Philips) in our hospital. The study population was divided into three groups: Group A underwent TLE with laser sheath only (N = 157), Group B with TightRailTM sheath only (N = 22), and Group C with both sheaths (N = 23). Results During this period, 375 leads in 202 patients were extracted, including 297 leads extracted by laser sheath alone, 45 leads by TightRailTM sheath alone, and 33 by both TightRailTM sheath and laser sheaths. The most common indications included device infection (44.6%) and lead-related complications (44.1%). The median age of leads was 8.9 years. TightRailTM sheath (Group B) achieved similar efficacy as a primary extraction tool compared with laser sheath (Group A), with complete procedure success rate of 93.3% (vs. 96.6%, P = 0.263) and clinical success rate of 100.0% (vs. 98.1%, P = 0.513). Among 32 leads in which TightrailTM was used after laser had failed (Group C), the complete procedure success rate was 75.8%. No significant difference in procedural adverse events were observed. Conclusion Our single-center experience confirms that the TightRailTM system is an effective first-line and second-line method for TLE. Further investigation is required to guide the selection of mechanical and laser sheaths in lead extraction cases. This article is protected by copyright. All rights reserved.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3–8.7; P Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215.

Background Interrupted inferior vena cava (IVC) is a rare venous anomaly that complicates the treatment of patients who require electrophysiology (EP) procedures. Methods We describe five consecutive cases of patients with interrupted IVC who presented to the EP laboratory requiring interventional procedures including catheter ablation for atrial fibrillation and supraventricular tachycardia and left atrial appendage closure. All cases were successfully completed utilizing a variety of approaches to vascular access including transseptal puncture via transhepatic and internal jugular approaches. Conclusion Procedures in the EP lab can be performed successfully in patients with interrupted IVC.

Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment. In this review, we summarize the available published data on gene therapy and discuss the challenges, opportunities, and limitations of this approach.

Several clinical trials have established the role of cardiac resynchronization therapy in patients with heart failure, impaired left ventricular function and dyssynchrony. Challenges to traditional therapy include coronary sinus anatomy and failure to respond. Left ventricular endocardial pacing could overcome anatomic constraints, provide more flexibility, and allow for more physiologic activation. Cases and case series have demonstrated the promise of the approach. Preclinical studies support the superior hemodynamic effects of left ventricular endocardial pacing. Leadless left ventricular endocardial pacing is a recent innovation that is undergoing prospective testing. Successful delivery may be associated with clinical response and positive cardiac structural remodeling.

Background Atrial fibrillation (AF) is the most common clinical arrhythmia, although the pathophysiology remains poorly understood. Population-based genetic studies have identified a susceptibility locus for AF at the gene ZFHX3. Hypothesis We hypothesized that a cardiac-restricted knockout of the transcription factor ZFHX3 in a mammalian model organism would perturb normal cardiac development and function, and illuminate the role of ZFHX3 in AF. Methods and results We generated a murine cardiac-restricted knockdown of ZFHX3 using cre-lox recombination. Knockdown was confirmed by organ specific genotyping. Among knockdown mice, increased inducibility of atrial arrhythmias was observed at in vivo electrophysiology testing at 3 months of age (% arrhythmia induction maneuvers 10 vs 0, p Conclusion We have uncovered a role for ZFHX3 in the left-right patterning of cardiac atria. Disruption of this developmental process predisposes to atrial cardiomyopathy, affects atrial electrophysiology properties, changes which may increase the susceptibility to AF.

Background: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. Methods: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. Results: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction ( P −6 ), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 ( P =5.9×10 −11 ) and SCN5A ( P =1.1×10 −7 ) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. Conclusions: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

Stress is associated with increased susceptibility to infection. We investigated if the mechanism involves immunomodulation of dendritic cells and whether this can be inhibited by a polyphenol-rich diet. Blood samples were taken from a total of 100 male endurance athletes at 5 time points around a marathon run: 4 weeks before; 1 week before; and immediately, 24 h, and 72 h after. Participants were randomized into 2 double-blinded groups. One group received a polyphenol-rich beverage during a 3-week training phase before marathon while the other group received a placebo beverage. Flow cytometric analysis of dendritic cell (DC) counts and subpopulation counts (myeloid, plasmocytoid DCs) was performed. Levels of viral antigen presenting toll-like receptor (TLR) 7 messenger RNA was measured by real-time polymerase chain reaction. Marathon running induced a significant increase of circulating myeloid DCs (0.2% vs. 0.33% of whole-blood leukocytes (wbl); p < 0.01) and a significant decrease of plasmozytoid DCs (0.12% vs. 0.03% of wbl; p < 0.01) and TLR7 expression (decline of 60%; p < 0.01). Polyphenol supplementation did not significantly affect mobilization of dendritic cells but showed beneficial effects on regeneration of TLR7 expression in wbl at 3 days postmarathon (decline of 40% vs. increase of 1000%; p < 0.05). In conclusion, physical stress affects circulating DCs, with an increase of myeloid and a decrease of plasmozytoid DCs. This may partially explain the susceptibility to viral infections after strenuous exercise. These detrimental effects are not attenuated by polyphenol supplementation. However, polyphenols support regeneration of viral antigen presenting TLR7 after strenuous exercise.

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11b(DTR) mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Both physiologic stress and chronic heart disease are associated with increased systemic levels of chromogranin A (CGA) and NT-proBNP. Marathon running causes physiological stress and imposes a significant cardiac burden. Polyphenol-rich Mediterranean and Asian diets have been demonstrated to exert beneficial effects on the cardiovascular system. In this study we investigated whether pretreatment with a polyphenol beverage could attenuate the physiological and cardiac stress associated with a marathon. In the BeMaGIC trial, 277 athletes were randomized into 2 groups in a double-blinded fashion, receiving 1–1.5 L/day of the same beverages either with (study beverage) or without (placebo) polyphenol enrichment (approximately 400 mg of gallic acid equivalents per day of a complex mixture of polyphenols). Blood samples were taken 3 weeks and 1 day before, and immediately, 24 h, and 72 h after running a marathon. In our current substudy, CGA and NT-proBNP levels were analyzed by ELISA in the fastest 18 and the slowest 22 runners. CGA and NT-proBNP levels increased significantly immediately after the marathon and returned to baseline at 72 h after the marathon. Neither CGA nor NT-proBNP differed significantly between athletes receiving study beverage versus placebo. Separating our cohort into fast and slow runners did not reveal any significant difference regarding CGA or NT-proBNP levels between groups. Our study provides no evidence that polyphenol supplementation attenuates marathon running-induced physiological stress and cardiac burden in fast or slow runners.

Atrial fibrillation (AF) is an all-too-common and often challenging reality of clinical care. AF leads to significant morbidity and mortality; however, currently available treatments for AF have modest efficacy and high recurrence rates. In recent years, genetic therapy approaches have been explored in preclinical models of AF, and offer potential as a treatment modality with targeted delivery, tissue specificity, and therapy tailored to address mechanisms underlying the arrhythmia. However, many challenges remain before gene therapy can advance to a clinically relevant AF treatment. In this review, we will summarize the available published data on gene therapy and discuss the challenges, opportunities, and limitations of this approach.

It has been conclusively proven that physical activity exerts beneficial effects on individual health. However, endurance activities in susceptible individuals can increase the risk of concerning cardiovascular conditions such as ventricular hypertrophy or arrhythmia. This increased risk can be attributed to a cardiac remodeling process specifically associated with endurance sports. In recent years, microRNAs (miRNAs) have been postulated to play many roles in health and disease. In the heart miRNAs regulate electrical remodeling, cardiac dilatation, fibrosis, calcium handling, heart failure, atrial fibrillation and autonomic tone in myocardial infarction. A growing body of evidence suggests that miRNAs also regulate endurance sports induced remodeling of the heart. Since miRNAs circulate in the blood they have a potential role as biomarkers in athletes indicating the degree of remodeling and predicting the risk of progression to an overt disease state.

Background The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood. Objective We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects. Methods We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early-onset AF was prominent in the family, we then screened individuals with early-onset AF, defined as an age of onset GATA6 . Variants were functionally characterized using reporter assays in a mammalian cell line. Results Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6 . In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 ± 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity. Conclusion Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early-onset AF.

Introduction Physical activity is beneficial for individual health, but endurance sport is associated with the development of arrhythmias like atrial fibrillation. The underlying mechanisms leading to this increased risk are still not fully understood. MicroRNAs are important mediators of proarrhythmogenic remodeling and have potential value as biomarkers in cardiovascular diseases. Therefore, the objective of our study was to determine the value of circulating microRNAs as potential biomarkers for atrial remodeling in marathon runners (miRathon study). Methods 30 marathon runners were recruited into our study and were divided into two age-matched groups depending on the training status: elite (ER, ≥55 km/week, n = 15) and non-elite runners (NER, ≤40 km/week, n = 15). All runners participated in a 10 week training program before the marathon. MiRNA plasma levels were measured at 4 time points: at baseline (V1), after a 10 week training period (V2), immediately after the marathon (V3) and 24h later (V4). Additionally, we obtained clinical data including serum chemistry and echocardiography at each time point. Results MiRNA plasma levels were similar in both groups over time with more pronounced changes in ER. After the marathon miR-30a plasma levels increased significantly in both groups. MiR-1 and miR-133a plasma levels also increased but showed significant changes in ER only. 24h after the marathon plasma levels returned to baseline. MiR-26a decreased significantly after the marathon in elite runners only and miR-29b showed a non-significant decrease over time in both groups. In ER miRNA plasma levels showed a significant correlation with LA diameter, in NER miRNA plasma levels did not correlate with echocardiographic parameters. Conclusion MiRNAs were differentially expressed in the plasma of marathon runners with more pronounced changes in ER. Plasma levels in ER correlate with left atrial diameter suggesting that circulating miRNAs could potentially serve as biomarkers of atrial remodeling in athletes.