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Pulmonary vein (PV) isolation using radiofrequency (RF) ablation can induce PV stenosis. Cryoablation may offer a safer alternative energy source for PV isolation. PV isolation with cryoablation was attempted in 31 patients with paroxysmal atrial fibrillation (AF). Event monitors were used to measure the AF episode burden. Serial spiral CT scans were obtained to monitor PV stenosis pre- and postcryoablation. Cryoablation was immediately successful for PV isolation in 29 of 31 patients (94%), with 5.9 +/- 1.2 months of follow-up. Additional RF ablation was performed for AF recurrences in seven patients. The remaining 22 patients with a single cryoablation procedure demonstrated a time-dependent, long-term reduction in the frequency of AF episodes. At 6 months of follow-up, 18 of 22 of cryo-treated only patients (82%) were free of symptomatic AF episodes, and antiarrhythmic drugs were discontinued in 12 of 22 patients. Serial spiral CT scans demonstrated no change in the cryo-treated PV ostial diameter. PV cryoablation was effective to control paroxysmal AF in most patients. Early recurrences of AF postcryoablation were common, though tended to resolve within 6 months postablation, consistent with a process of reverse atrial remodeling. Cryoablation of the PVs did not cause PV stenosis or other serious adverse events. [ABSTRACT FROM AUTHOR]

Increased attention is now being focused on developing new technologies to cure atrial fibrillation using catheter ablation techniques. The performance of a MAZE-type procedure using standard catheter ablation technologies is arduous and is associated with an unacceptable risk of complications. The Guidant Heart Rhythm Technologies Linear Ablation System was developed to create long transmural linear lesions. Unique features of this system include the availability of different preshaped multi-electrode steerable ablation catheters, the use of phased radiofrequency (RF) energy, and the control of RF output by varying the duty cycle. A prospective multicenter clinical trial to evaluate the safety and efficacy of a right atrial ablation procedure using this technology to treat atrial fibrillation is currently underway. To date, 15 patients have been enrolled and the procedure was acutely effective in 14 of 15 patients with no complications. Atrial fibrillation has recurred during short-term follow-up in 12 of 15 patients, a not surprising result, because this initial phase of testing involved only right-sided ablation. The early results of the phase I clinical trial confirm the findings of others that successful ablation of chronic atrial fibrillation is likely to require a left atrial approach. This clinical trial, as well as others that are currently underway, will be invaluable in the continuing development of catheter ablation of atrial fibrillation and, ultimately, in determining if the routine use of this therapeutic tool can become a reality. [ABSTRACT FROM AUTHOR]

Objectives: The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.Background: ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test.Methods: Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database.Results: The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2.Conclusions: This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to determine the extent of left ventricular (LV) involvement in individuals predisposed to developing arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and to investigate novel morphologic variants of ARVD/C.Background: The discovery of desmosomal mutations associated with ARVD/C has led researchers to hypothesize equal right ventricular (RV) and LV affliction in the disease process.Methods: Thirty-eight (age 30 +/- 17 years; 18 males) family members of 12 desmosomal mutation-carrying ARVD/C probands underwent genotyping and cardiac magnetic resonance imaging (CMR). The CMR investigators were blinded to clinical and genetic data.Results: Twenty-five individuals had mutations in PKP2, DSP, and/or DSG2 genes. RV abnormalities were associated with the presence of mutation(s) and with disease severity determined by criteria (minor = 1; major = 2) points for ARVD/C diagnosis. The only LV abnormality detected, the presence of intramyocardial fat, was present in 4 individuals. Each of these individuals was a mutation carrier, whereas 1 had no previously described ARVD/C-related abnormality. On detailed CMR, a focal "crinkling" of the RV outflow tract and subtricuspid regions ("accordion sign") was observed in 60% of the mutation carriers and none of the noncarriers (p < 0.001). The sign was present in 0%, 37%, 71%, and 75% of individuals who met 1, 2, 3, and 4+ criteria points, respectively (p < 0.01).Conclusions: Despite a possible LV involvement in ARVD/C, the overall LV structure and function are well preserved. Independent LV involvement is of rare occurrence. The accordion sign is a promising tool for early diagnosis of ARVD/C. Its diagnostic utility should be confirmed in larger cohorts. [ABSTRACT FROM AUTHOR]

Neurocardiogenic syncope is the most common cause of acute loss of consciousness in adults. The present study attempted to identify neuroendocrine and hemodynamic changes before syncope that could therefore play a pathophysiologic role. Twenty-five patients referred for chronic orthostatic intolerance had plasma catecholamines measured serially; 21 patients during tilt-table testing (evoking syncope in 13) and 4 others with spontaneous syncope while supine. Forearm blood flow was measured by impedance plethysmography. All 12 patients with blood sampled before tilt-induced syncope had progressive, marked increases in plasma epinephrine levels (mean 11 times baseline, p <0.0001) before syncope. Simultaneously obtained norepinephrine levels increased to a much smaller extent than did epinephrine levels ("sympathoadrenal imbalance"). In the same patients, forearm vascular resistance decreased by 21% before syncope. Proportionate changes in forearm vascular resistance before syncope correlated negatively with those in the epinephrine:norepinephrine ratio (r = -0.75, p = 0.005). Patients without syncope had forearm vasoconstriction and no sympathoadrenal imbalance during tilt. Patients with syncope while supine also had sympathoadrenal imbalance before loss of consciousness. Sympathoadrenal imbalance precedes tilt-evoked and spontaneous neurocardiogenic syncope and correlates with concurrent skeletal muscle vasodilation. Sympathoadrenal imbalance may contribute to hemodynamic derangements precipitating neurocardiogenic syncope. [ABSTRACT FROM AUTHOR]

The consensus process that culminated in this symposium established an algorithm to guide the diagnosis and treatment of patients with vasovagal syncope and related disorders. In some patients, the hemodynamic response to standing may identify an abnormality-postural orthostatic tachycardia syndrome or orthostatic hypotension-that can often be treated without further testing. When the response to standing is normal, tilt-table testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment. In some patients, however, the diagnosis is clear from the history, and tilt-table testing may not be necessary. Not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt. In evaluating the results of tilt-table testing, an important consideration is the distinction between vasovagal syncope and the dysautonomic response to tilt characterized by a gradual and progressive decrease in blood pressure that leads to syncope. Current practice patterns suggest that beta blockers, fludrocortisone, and midodrine, are commonly used to treat patients with vasovagal syncope, and patients with the dysautonomic response are generally treated with fludrocortisone and midodrine. Permanent pacing with specialized pacing algorithms should be considered for patients with frequent vasovagal syncope that is refractory to medical therapy. The guidelines proposed here are an amalgam of clinical experience, expert opinion, and research evidence; however, they do not suggest a standard of care for all patients. [ABSTRACT FROM AUTHOR]

The objective of this study was to identify factors that predict fluoroscopy duration and radiation exposure during catheter ablation procedures. The patient population included 859 patients who participated in the Atakr Ablation System clinical trial at 1 of 9 centers (398 male and 461 female patients, aged 36 +/- 21 years). Each patient underwent catheter ablation of an accessory pathway, the atrioventricular junction, or atrioventricular nodal reentrant tachycardia using standard techniques. The duration of fluoroscopy was 53 +/- 50 minutes. Factors identified as independent predictors of fluoroscopy duration included patient age and sex, the success or failure of the ablation procedure, and the institution at which the ablation was performed. Catheter ablation in adults required longer fluoroscopy exposure than it did in children. Men required longer durations of fluoroscopy exposure than did women. The mean estimated "entrance" radiation dose was 1.3 +/- 1.3 Sv. The dose needed to cause radiation skin injury was exceeded during 22% of procedures. The overall mean effective absorbed dose from catheter ablation procedures was 0.025 Sv for female patients and 0.017 Sv for male patients. This degree of radiation exposure would result in an estimated 1,400 excess fatal malignancies in female patients and 2,600 excess fatal malignancies in male patients per 1 million patients. [ABSTRACT FROM AUTHOR]

Background: While there are several completed clinical trials that address treatment strategies in patients with symptomatic and recurrent atrial fibrillation (AF), there are no randomized clinical trials that address first-line rhythm control of new-onset AF. Recent data suggest that early initiation of rhythm control within 1 year can improve outcomes., Methods: In this open-label pragmatic clinical trial nested within the Get with The Guidelines Atrial Fibrillation registry, approximately 3,000 patients with first-detected AF will be enrolled at approximately 200 sites. Participants will be randomized (1:1) to treatment with dronedarone in addition to usual care versus usual care alone. The primary endpoint will be time to first cardiovascular (CV) hospitalization or death from any cause through 12 months from randomization. Secondary endpoints will include a WIN ratio (all-cause death, ischemic stroke or systemic embolism, heart failure hospitalization, acute coronary hospitalization), CV hospitalization, and all-cause mortality. Patient reported outcomes will be analyzed based on change in Atrial Fibrillation Effect on Quality of Life (AFEQT) and change in Mayo AF-Specific Symptom Inventory (MAFSI) from baseline to 12 months., Conclusion: CHANGE AFIB will determine if treatment with dronedarone in addition to usual care is superior to usual care alone for the prevention of CV hospitalization or death from any cause in patients with first-detected AF. The trial will also determine whether initiation of rhythm control at the time of first-detected AF affects CV events or improves patient reported outcomes., Trial Registration: - NCT05130268., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Desmoplakin (DSP) variants are associated with left-predominant or biventricular arrhythmogenic cardiomyopathy. Exercise promotes penetrance and sustained ventricular arrhythmias (VA) in right-sided arrhythmogenic right ventricular cardiomyopathy, but its effect is unknown in DSP variant carriers., Objectives: To assess whether exercise is associated with clinical outcomes among individuals with a pathogenic or likely pathogenic (P/LP) DSP variant., Methods: Adults with P/LP DSP variants were interviewed about physical activity from age 10. Endurance athletes were defined based on a mean exercise dose >24 metabolic equivalent hours/week (METhr/wk) of moderate to vigorous intensity exercise. Lifetime survival free from VA (ventricular tachycardia/fibrillation or appropriate ICD therapy), clinical heart failure (HF) (presentation to the emergency department or hospitalization with HF), and myocardial injury events characteristic of DSP-cardiomyopathy (symptoms, elevated troponin, imaging with non-obstructive coronaries) were examined with the Kaplan-Meier method and Cox regression models., Results: Participants (N=100, 66% female, age 36 ± 15 years) were active with a median 28.4 METhr/wk (IQR 14.8-46) of pre-baseline evaluation exercise, and just 8 individuals continued athlete level exercise post-baseline evaluation. In multivariable analyses, endurance athletes (60%) had no worse survival free from VA [HR 1.00 (95% CI 0.5-1.98)] or clinical HF [HR 0.86 (95% CI 0.36-2.05)] but their risk for myocardial injury was elevated [HR 2.37 (95% CI 1.11-5.05)]. Furthermore, myocardial injury episodes were strongly associated with an elevated risk of both VA [HR 7.86 (95% CI 3.56-17.33)] and clinical HF [HR 10.28 (95% CI 2.95-35.83)] thereafter., Conclusions: Endurance exercise may promote progression of DSP-cardiomyopathy by increasing risk of myocardial injury episodes, but the effect on VA and clinical HF is less clear. This study informs shared decision-making exercise and sports participation discussions., (Copyright © 2024. Published by Elsevier Inc.)

Pediatric neurological injury and disease is a critical public health issue due to increasing rates of survival from primary injuries (e.g., cardiac arrest, traumatic brain injury) and a lack of monitoring technologies and therapeutics for treatment of secondary neurological injury. Translational, preclinical research facilitates the development of solutions to address this growing issue but is hindered by a lack of available data frameworks and standards for the management, processing, and analysis of multimodal datasets. Here, we present a generalizable data framework that was implemented for large animal research at the Children's Hospital of Philadelphia to address this technological gap. The presented framework culminates in a custom, interactive dashboard for exploratory analysis and filtered dataset download. Compared with existing clinical and preclinical data management solutions, the presented framework better enables management of various data types (single measure, repeated measures, time series, and imaging), integration of datasets for comparison across experimental models, cohorts, and groups, and facilitation of predictive modeling from integrated datasets. Further, a predictive model development use case demonstrated utilization and value of the data framework. The general outline of a preclinical data framework presented here can serve as a template for other translational research labs that generate heterogeneous datasets and require a dynamic platform that can easily evolve alongside their research., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: The safety and efficacy of paroxysmal atrial fibrillation (PAF) ablation with the HELIOSTAR multielectrode radiofrequency (RF) balloon catheter have been demonstrated in European studies; data from elsewhere are lacking. This prospective, multicenter study conducted in the United States, Italy, and China investigated the safety and efficacy of pulmonary vein isolation (PVI) using HELIOSTAR in drug-refractory symptomatic PAF., Methods: The primary effectiveness endpoint (PEE) was 12-month freedom from documented atrial fibrillation/atrial flutter/atrial tachycardia plus freedom from acute procedural failure, nonstudy catheter failure, repeat ablation failure, direct current cardioversion (DCCV), and Class I/III antiarrhythmic drug (AAD) failure. The primary safety endpoint was the occurrence of early-onset primary adverse events (PAEs). Cerebral magnetic resonance imaging (MRI) and cardiac computed tomography were performed in a patient subset to assess silent cerebral lesions (SCLs) and severe pulmonary vein (PV) stenosis, respectively., Results: Across 36 centers, 257 eligible subjects in the main phase had the study catheter inserted. Acute PVI was achieved in all subjects, with the majority (94.1%) using the balloon catheter only. In 67.7% and 92.2% of subjects, respectively, PEE and freedom from repeat ablation were met; clinical success rate was 77.7%. The PAE rate was 5.1%. One of 15 (6.7%) subjects with MRI showed a new SCL at 1 month postablation, which resolved at 3 months. Clinically meaningful improvements in Atrial Fibrillation Effect on QualiTy-of-life scores were seen at 3 months and were sustained to 12 months postablation, and accompanied with reduction of Class I/III AAD use and DCCV., Conclusion: STELLAR confirmed the safety and efficacy of the HELIOSTAR catheter for PVI, with clinically meaningful improvements in quality of life in patients with drug-refractory symptomatic PAF. Most PVIs were achieved without focal touch-up, and > 90% of patients were free from repeat ablation at 12 months., Trial Registration: ClinicalTrials.gov Identifier: NCT03683030., (© 2024 The Author(s). Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms. Likewise, risk factors for SCD vary by genetic subtype, indicating that genotype-specific guidelines for management are also warranted. Of particular importance, genotype-specific therapeutic approaches are being developed. Results from a randomized controlled trial for flecainide use in ARVC patients are currently pending. Research in a plakophilin-2-deficient mouse model suggests this antiarrhythmic drug may be particularly useful for patients with likely pathogenic or pathogenic (LP/P) PKP2 variants. Additionally, the first gene therapy clinical trials in ARVC patients harboring LP/P PKP2 variants are currently underway. This review aims to provide clinicians caring for ACM patients with an up-to-date overview of the current literature in genotype-specific natural history of disease and management of ACM patients and describe scientific advances that have led to upcoming clinical trials., (© 2024 The Author(s). Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Background: No disease-specific therapy currently exists for arrhythmogenic right ventricular cardiomyopathy (ARVC), a progressive cardiogenetic condition conferring elevated risk for ventricular arrhythmias, heart failure, and sudden cardiac death. Emerging gene therapies have the potential to fill this gap. However, little is known about how adults with ARVC, or any other inherited cardiomyopathy or arrhythmia syndrome, appraise the risks and benefits of gene therapy research and which considerations may influence their decisions about clinical trial participation., Methods: Twenty adults with clinically diagnosed and gene-positive ARVC participated in semi-structured interviews that explored perceptions of gene therapy and hypothetical decision-making for gene therapy clinical trial participation. Interview transcripts were qualitatively coded and analyzed., Results: Participants expressed enthusiasm for gene therapy with varied levels of personal interest in trial participation. Although clinical severity appeared to be associated with an elevated interest in early trial participation, participants anticipated weighing both personal and trial-specific factors including life stage, trial stage, risks, benefits, participation burden, study leadership, and anticipated cost of future gene therapy. Adaptation to living with ARVC and involvement in the ARVC patient community were also relevant to decision-making about trial participation. Potential ethical concerns included unquestioning trust in clinical teams collaborating on industry-led trials and vulnerability of those recently diagnosed or with high perceived severity of ARVC symptoms., Conclusions: Several characteristics of the individual and trial warrant consideration during the informed consent process. Insights from this study may affect trial planning and communication with participants who have inherited cardiac conditions., Competing Interests: Dr James performs modest consulting for Lexeo Therapeutics and Pfizer. Dr Calkins is a consultant for Medtronic, Inc, Biosense Webster, Pfizer, StrideBio, Rocket, and Abbott. B. Murray is a consultant for MyGeneCounsel. C. Tichnell is a consultant for StrideBio Inc. Dr Barth is a consultant for Solid Biosciences. Dr James receives research funding from Lexeo Therapeutics; Tenaya Therapeutics, Arvada Therapeutics, StrideBio Inc, EicOsis. C. Tichnell receives salary support on these grants. L. Okwara receives salary support on a grant from Lexeo Therapeutics. Dr Calkins receives research support from Boston Scientific Corp. C. Tichnell and Dr James receive salary support from this grant. Dr Calkins receives research support from Tenaya Inc. C. Tichnell, L. Okwara, and C. James receive salary support on this grant. Dr Calkins receives research support from Medtronic, Biosense Webster, Farapulse, and Adagio. E.M. Schopp, Dr Jamal, and A. Turiff are funded by the Intramural Research Program of the National Institutes of Health. The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) increases the risk of heart failure (HF) and arrhythmias. Speckle-tracking echocardiography (STE) detects myocardial dysfunction, but its predictive role for HF in this population remains unclear., Methods: Seventy-one patients with ARVC (age 43.7 ± 14.8 years, 53.5% male) without prevalent HF at baseline who were enrolled in the Johns Hopkins ARVC Registry were retrospectively included. Global strain (GS) and strain rate (SR) of the left ventricle (LV), right ventricle free wall (RVFW), left atrium (LA), and right atrium (RA) were measured by a blinded operator. Cox regression models assessed their association with incident HF., Results: Incident HF developed in 23 patients (age 49.3 ± 12.5 years, 52.2% male) during a median follow-up of 2.7 years. Decreases in strain were significantly associated with HF: LV peak global longitudinal systolic strain (GLS; hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.06-1.35; P = 0.003), RVFW strain (HR 1.11, 95% CI 1.04-1.18; P = 0.003), LA GS (HR 1.05, 95% CI 1.00-1.09; P = 0.030), and RA GS (HR 1.07, 95% CI 1.03-1.12; P < 0.001). Associations for LV GLS, RVFW strain, and RA GS remained significant after adjusting for age and sex. Strain values frequently fell below established reference ranges. Any strain value (LV GLS, RVFW strain, LA GS, or RA GS) below the normal limit was associated with an 8-fold increase in HF (HR 8.43, 95% CI 1.97-36.02; P = 0.004), and each individual component below the normal threshold doubled the risk (HR 2.35, 95% CI 1.60-3.45; P < 0.001)., Conclusions: STE deformation abnormalities are associated with incident HF in ARVC patients. Echocardiographic strain may aid in identifying patients at risk of HF for closer follow-up and management., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Although targeting atrial fibrillation (AF) drivers and substrates has been used as an effective adjunctive ablation strategy for patients with persistent AF (PsAF), it can result in iatrogenic scar-related atrial tachycardia (iAT) requiring additional ablation. Personalized atrial digital twins (DTs) have been used preprocedurally to devise ablation targeting that eliminate the fibrotic substrate arrhythmogenic propensity and could potentially be used to predict and prevent postablation iAT., Objectives: In this study, the authors sought to explore possible alternative configurations of ablation lesions that could prevent iAT occurrence with the use of biatrial DTs of prospectively enrolled PsAF patients., Methods: Biatrial DTs were generated from late gadolinium enhancement-magnetic resonance images of 37 consecutive PsAF patients, and the fibrotic substrate locations in the DT capable of sustaining reentries were determined. These locations were ablated in DTs by representing a single compound region of ablation with normal power (SSA), and postablation iAT occurrence was determined. At locations of iAT, ablation at the same DT target was repeated, but applying multiple lesions of reduced-strength (MRA) instead of SSA., Results: Eighty-three locations in the fibrotic substrates of 28 personalized biatrial DTs were capable of sustaining reentries and were thus targeted for SSA ablation. Of these ablations, 45 resulted in iAT. Repeating the ablation at these targets with MRA instead of SSA resulted in the prevention of iAT occurrence at 15 locations (18% reduction in the rate of iAT occurrence)., Conclusions: Personalized atrial DTs enable preprocedure prediction of iAT occurrence after ablation in the fibrotic substrate. It also suggests MRA could be a potential strategy for preventing postablation AT., Competing Interests: Funding Support and Author Disclosures This work was supported by funding from National Institutes of Health grants U01-HL141074 (Dr Trayanova), R01HL166759 (Drs Trayanova., Kholmovski, and Spragg), and R01HL142496 (Dr Trayanova). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In atrial fibrillation (AF) management, understanding left atrial (LA) substrate is crucial. While both electroanatomic mapping (EAM) and late gadolinium enhancement magnetic resonance imaging (LGE-MRI) are accepted methods for assessing the atrial substrate and are associated with ablation outcome, recent findings have highlighted discrepancies between low-voltage areas (LVAs) in EAM and LGE areas., Objective: The purpose of this study was to explore the relationship between LGE regions and unipolar and bipolar LVAs using multipolar high-density mapping., Methods: Twenty patients scheduled for AF ablation underwent preablation LGE-MRI. LA segmentation was conducted using a deep learning approach, which subsequently generated a 3-dimensional mesh integrating the LGE data. High-density EAM was performed in sinus rhythm for each patient. The electroanatomic map and LGE-MRI mesh were coregistered. LVAs were defined using cutoffs of 0.5 mV for bipolar voltage and 2.5 mV for unipolar voltage. The correspondence between LGE areas and LVAs in the LA was analyzed using confusion matrices and performance metrics., Results: A considerable 87.3% of LGE regions overlapped with unipolar LVAs, compared with only 16.2% overlap observed with bipolar LVAs. Across all performance metrics, unipolar LVAs outperformed bipolar LVAs in identifying LGE areas (precision: 78.6% vs 61.1%; sensitivity: 87.3% vs 16.2%; F 1 score: 81.3% vs 26.0%; accuracy: 74.0% vs 35.3%)., Conclusion: Our findings demonstrate that unipolar LVAs strongly correlate with LGE regions. These findings support the integration of unipolar mapping alongside bipolar mapping into clinical practice. This would offer a nuanced approach to diagnose and manage AF by revealing critical insights into the complex architecture of the atrial substrate., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Evidence from clinical trials of early pulsed field ablation (PFA) systems in treating atrial fibrillation has demonstrated their promising potential to reduce complications associated with conventional thermal modalities while maintaining efficacy. However, the lack of a fully integrated mapping system, a staple technology of most modern electrophysiology procedures, poses limitations in lesion creation and workflow options. A novel variable-loop PFA catheter integrated with an electroanatomic mapping system has been developed that allows for real-time nonfluoroscopic procedural guidance and lesion indexing as well as feedback of tissue-to-catheter proximity. AdmIRE (Assessment of Safety and Effectiveness in Treatment Management of Atrial Fibrillation With the Bosense-Webster Irreversible Electroporation Ablation System), a multicenter, single-arm, Food and Drug Administration investigational device exemption study, evaluated the long-term safety and effectiveness of this integrated PFA system in a large United States-based drug-refractory symptomatic paroxysmal atrial fibrillation patient population., Methods: Using the PFA catheter with a compatible electroanatomic mapping system, patients with drug-refractory symptomatic paroxysmal atrial fibrillation underwent pulmonary vein isolation. The primary safety end point was primary adverse event within 7 days of ablation. The primary effectiveness end point was a composite end point that included 12-month freedom from documented atrial tachyarrhythmia (ie, atrial fibrillation, atrial tachycardia, atrial flutter) episodes, failure to achieve pulmonary vein isolation, use of a nonstudy catheter for pulmonary vein isolation, repeat procedure (except for one redo during blanking), taking a new or previously failed class I or III antiarrhythmic drug at higher dose after blanking, or direct current cardioversion after blanking., Results: At 30 centers, 277 patients with paroxysmal atrial fibrillation (61.5±10.3 years of age; 64.3% male) in the pivotal cohort underwent PFA. More than 25% of the procedures were performed without fluoroscopy. Median (Q1, Q3) pulmonary vein isolation procedure, fluoroscopy, and transpired PFA application times were 81.0 (61.0, 112.0), 7.1 (0.00, 14.3), and 31.0 (24.8, 40.9) minutes, respectively. The primary adverse event rate was 2.9% (8 of 272), with the most common complication being pericardial tamponade. The 12-month primary effectiveness end point was 74.6%. The 1-year freedom from atrial fibrillation, atrial tachycardia, or atrial flutter recurrence rate after blanking was 75.4%. Substantial improvements in quality of life were observed as early as 3 months after the procedure, concurrent with a reduction in multiple health care use measures., Conclusions: AdmIRE confirmed the safety and effectiveness of the variable-loop PFA catheter, with short procedure and PFA application times and low fluoroscopy exposure., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05293639., Competing Interests: Dr Reddy reports receiving consulting fees and grant support from Biosense-Webster; unrelated to this article, serves as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Anumana, Apama Medical-Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, Cardiofocus, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, Laminar Medical, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; unrelated to this work, has served as a consultant for Abbott, Adagio Medical, Append Medical, AtriAN, BioTel Heart, Biotronik, Boston Scientific, Cairdac, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Philips, and Pulse Biosciences; and unrelated to this work, has equity in Atraverse, DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Soundcath, Surecor, and Vizaramed. Dr Calkins receives consulting fees from Biosense Webster and Boston Scientific and payment for honoraria from Boston Scientific and Medtronic. Dr Mansour reports grants from Biosense Webster, Inc, and Boston Scientific; consulting fees from Biosense Webster, Inc, Boston Scientific, Philips, and Medtronic; support for attending meetings/travel from Biosense Webster, Inc, and Boston Scientific; and stock/stock options from NewPace Limited and EPD Solutions. Dr Wazni serves as a consultant for Biosense Webster. Dr Di Biase is a consultant for Biosense Webster, Stereoataxis, and Rhythm Management, and has received speaker honoraria/travel from Biosense Webster, St. Jude Medical (now Abbott), Boston Scientific, Medtronic, Biotronik, Atricure, Baylis, and Zoll. Drs Bahu and Liu have nothing to disclose. Dr Newton serves as a consultant for Biosense Webster. Dr Sauer receives grants from Biosense Webster and Medtronic and consulting fees from Boston Scientific, Biosense Webster, and Abbott. Dr Goyal receives consulting fees from Biosense Webster and Medtronic. Dr Iyer receives consulting fees from Biosense Webster. Dr Nair serves as a consultant for and receives research grants from Abbott, Boston Scientific, Medtronic, Biosense Webster, and Adagio, and receives research grants from Laminar. Dr Athill receives consulting fees from Boston Scientific, Abbott, and Biosense Webster, and payment/honoraria from Zoll and Janssen. Dr Hussein receives research grants from Boston Scientific and serves on steering committees for Biosense Webster. Dr Whalen serves on the advisory board for Biosense Webster. Dr Melby serves as a consultant for and receives research grants from Biosense Webster. Dr Natale serves as a consultant for Abbott, Biosense Webster, Biotronik, Boston Scientific, and iRhythm.

In the last three decades, ablation of atrial fibrillation (AF) has become an evidence-based safe and efficacious treatment for managing the most common cardiac arrhythmia. In 2007, the first joint expert consensus document was issued, guiding healthcare professionals involved in catheter or surgical AF ablation. Mounting research evidence and technological advances have resulted in a rapidly changing landscape in the field of catheter and surgical AF ablation, thus stressing the need for regularly updated versions of this partnership which were issued in 2012 and 2017. Seven years after the last consensus, an updated document was considered necessary to define a contemporary framework for selection and management of patients considered for or undergoing catheter or surgical AF ablation. This consensus is a joint effort from collaborating cardiac electrophysiology societies, namely the European Heart Rhythm Association, the Heart Rhythm Society, the Asia Pacific Heart Rhythm Society, and the Latin American Heart Rhythm Society., Competing Interests: All members provided disclosure statements to assess potential conflicts of interest. Details are available in the Supplementary material., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background and Aims: Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown., Methods: All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes., Results: Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively)., Conclusions: Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy (ACM). Among ACM, pathogenic desmoplakin ( DSP ) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remain unknown., Methods: Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including hearts. We first used unbiased genome-wide analyses to generate cardiac fibroblasts-like, induced pluripotent stem cell-derived MSCs from normal donors and ACM patients with DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to transforming growth factor beta-1 (TGF-β1) using Western/Co-IP, autophagy assay, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR., Results: TGFβ1 induced excessive accumulations of vimentin (VIM)/fibrillar collagens, and over-activated fibrotic genes in DSP- mutant MSCs when compared to normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP- mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered beclin-1 (BECN1) from activating autophagy and caveolin-1 (CAV1)-mediated endocytosis. Decreased autophagy caused collagen accumulations and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes [ COL1A1, COL3A1, and fibronectin ( FN )] via heightened p38 activities after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expressions., Conclusions: Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

Background: The Efficacy of Delayed Enhancement MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation of Atrial Fibrillation randomized trial showed no difference in atrial fibrillation (AF) recurrence with additional delayed enhancement magnetic resonance imaging (DE-MRI) fibrosis-targeted ablation to pulmonary vein isolation (PVI) in persistent AF., Objective: We evaluated the effect of lesion delivery on ablation-induced scarring and AF recurrence., Methods: Lesions delivered, targeting fibrotic and nonfibrotic areas identified from preablation DE-MRI, were studied in relation to ablation-induced scarring on 3-month DE-MRI, including their association with arrhythmia recurrence., Results: A total of 593 patients treated with radiofrequency were analyzed: 293 (49.4%) underwent PVI and 300 (50.6%) underwent additional fibrosis-guided ablation. Lesion analysis showed that 80.9% in the MRI fibrosis-guided group vs 16.5% in the PVI group (P < .001) had ≥40% of baseline fibrosis targeted. MRI assessment of ablation-induced scar showed that 44.8% of fibrosis-guided ablation and 15.5% of PVI had ≥40% of their fibrosis covered by scar (P < .001), demonstrating significant attenuation from lesions delivered to scar formed. In the overall population, fibrosis coverage with scar was not associated with recurrence (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.80-1.01; P = .08 per 20% increase). In patients with baseline fibrosis < 20%, fibrosis coverage with scar was associated with lower recurrence than PVI (HR 0.85; 95% CI 0.73-0.97; P = .03), whereas the association was not significant when baseline fibrosis ≥ 20% (HR 0.97; 95% CI 0.80-1.17; P = .77). Significant center variation was observed in fibrosis targeting and coverage with scarring., Conclusion: Radiofrequency ablation lesions do not uniformly result in scar formation. A post hoc analysis suggests reduced arrhythmia recurrence when ablation-induced scarring covers fibrotic regions in patients with low baseline fibrosis., Competing Interests: Disclosures Dr Marrouche reported other from Marrek (founder) and from ECG Check (previous shareholder) outside the submitted work and a patent issued for MRI fibrosis imaging. Dr Wazni reported personal fees (for consulting services) from Biosense Webster and Boston Scientific during the conduct of the study. Dr Greene reported personal fees from DURECT Corporation, Janssen Pharmaceuticals, and Pfizer and grants from Boehringer Ingelheim, AstraZeneca, and CSL outside the submitted work. Dr Dean reported grants from Boston Scientific, Medtronic, Siemens, Biosense Webster, and Abbott during the conduct of the study and grants from the National Institutes of Health outside the submitted work. Dr Kholmovski reported personal fees and other (share ownership) from Marrek during the conduct of the study and outside the submitted work, grants from Medtronic outside the submitted work, and a patent issued for US 9713436 licensed to Marrek, US 10004425 licensed to Marrek, and US 10726545 licensed to Marrek. Dr Mansour reported personal fees (for consulting services) from Biosense Webster, Boston Scientific, and Medtronic and personal fees (holding equity) from EPD Solutions and New Pace Ltd outside the submitted work. Dr Marchlinski reported personal fees (scientific advisory board) from Abbott Medical, Biosense Webster, and Medtronic outside the submitted work. Dr Wilber reported other (executive committee for the clinical trial) from Abbott and Boston Scientific; other (coprimary investigator, clinical trial) from AtriCure; grants from Abbott, AtriCure, and Biosense Webster; and personal fees from the American College of Cardiology Foundation (Editor-in-Chief of the Journal of the American College of Cardiology editor’s page), Biosense Webster (consulting), and Medtronic (lectures for fellows) outside the submitted work. Dr Jaïs reported grants from Biosense Webster and Boston Scientific during the conduct of the study and grants from Acutus and Medtronic outside the submitted work. Dr Sanders reported other (advisory board and research grants to his institution) from Medtronic, Abbott Medical, and Boston Scientific; other (advisory board) from CathRx and PaceMate outside the submitted work; and support by a practitioner fellowship from the National Health and Medical Research Council of Australia. Dr Brachmann reported grants from Medtronic and Biotronik during the conduct of the study and personal fees from Medtronic outside the submitted work. Dr Bax reported departmental unrestricted research grants from Abbott, Edwards Lifesciences, Medtronic, Biotronik, Boston Scientific, GE Healthcare, Novartis, and Bayer outside the submitted work. Dr Deneke reported grants (education) from Biotronik and personal fees (speaker) from Abbott and Boston Scientific (scientific committee) outside the submitted work. Dr Calkins reported personal fees from Biosense Webster, Abbott, and Boston Scientific outside the submitted work. No other disclosures were reported., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Although the differential diagnosis for cardiac masses is broad and includes both benign and malignant primary cardiac tumors, metastases of noncardiac primary malignancies to the heart are an important etiology. We present an unusual case of a rapidly progressive right atrial mass caused by metastatic hepatocellular carcinoma., Competing Interests: Dr Carrick is funded by the National Institutes of Health (T32HL007227, L30HL165535) and is a recipient of the Semyon and Janna Friedman Fellowship award. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Pathogenic/likely pathogenic (P/LP) desmin ( DES ) variants cause heterogeneous cardiomyopathy and/or skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACE), including cardiac conduction disease (CCD), sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, LVAD/cardiac transplant, HF-related death), in patients with P/LP DES variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization., Objectives: We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with P/LP DES variants through a systematic review and individual patient data meta-analysis using published reports., Methods: We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with P/LP DES variants. Cardiomyopathy diagnosis or occurrence of MACE were considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from CCD, sustained VA, HF events, and composite MACE was assessed., Results: Out of 4,212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% male, 52.2% probands, median age: 31 years [22.0; 42.8] at first evaluation, median follow-up: 3 years [0; 11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 [41.7%] having CCD, 36 [15.7%] sustained VA, and 43 [18.7%] HF events. Familial penetrance of cardiac disease was 63.6% among relatives with P/LP DES variants. Male sex was associated with increased risk of sustained VA (HR 2.28, p=0.02) and HF events (HR 2.45, p=0.008)., Conclusions: DES cardiomyopathy exhibits heterogeneous phenotypes and distinct natural history, characterized by high familial penetrance and substantial MACE burden. Male patients face higher risk of sustained VA events.