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Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off-target effects and the need for time-consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial-and-error sVNS in vivo and ex vivo micro-computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid-cervical level and they were localized on average on opposite sides of the nerve cross-section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent-related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac-related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off-target effects and potentially mitigating the need for titration. KEY POINTS: Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Aims: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB., Methods and Results: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up., Conclusion: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health grants OT2OD023848 and P01 HL164311 to Dr Shivkumar and from the UCLA Amara-Yad Project. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Assessment of origin of ventricular tachycardias (VTs) arising from epicardial vs endocardial sites are largely challenged by the available criteria and etiology of cardiomyopathy. Current electrocardiographic (ECG) criteria based on 12-lead ECG have varying sensitivity and specificity based on site of origin and etiology of cardiomyopathy., Objectives: This study sought to test the hypothesis that epicardial VT has a slower initial rate of depolarization than endocardial VT., Methods: We developed a method that takes advantage of the fact that electrical conduction is faster through the cardiac conduction system than the myocardium, and that the conduction system is primarily an endocardial structure. The technique calculated the rate of change in the initial VT depolarization from a signal-averaged 12-lead ECG. We hypothesized that the rate of change of depolarization in endocardial VT would be faster than epicardial. We assessed by applying this technique among 26 patients with VT in nonischemic cardiomyopathy patients., Results: When comparing patients with VTs ablated using epicardial and endocardial approaches, the rate of change of depolarization was found to be significantly slower in epicardial (6.3 ± 3.1 mV/s vs 11.4 ± 3.7 mV/s; P < 0.05). Statistical significance was found when averaging all 12 ECG leads and the limb leads, but not the precordial leads. Follow up analysis by calculation of a receiver-operating characteristic curve demonstrated that this analysis provides a strong prediction if a VT is epicardial in origin (AUC range 0.72-0.88). Slower rate of change of depolarization had high sensitivity and specificity for prediction of epicardial VT., Conclusions: This study demonstrates that depolarization rate analysis is a potential technique to predict if a VT is epicardial in nature., Competing Interests: Funding Support and Author Disclosures This work was supported in part by the University of Minnesota’s Medical School Academic Investment Education Program grant and the Institute for Engineering in Medicine. Dr Prisco is funded by the National Institutes of Health T32 HL144472. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Calcification of aortic valve leaflets is a growing mortality threat for the 18 million human lives claimed globally each year by heart disease. Extensive research has focused on the cellular and molecular pathophysiology associated with calcification, yet the detailed composition, structure, distribution and etiological history of mineral deposition remains unknown. Here transdisciplinary geology, biology and medicine (GeoBioMed) approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP) and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100's nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions as viable alternatives to current reliance on surgical/percutaneous valve implants., (© 2024. The Author(s).)

Background: Tetralogy of Fallot (TOF) is associated with risk for sustained monomorphic ventricular tachycardia (VT). Preemptive electrophysiology study before transcatheter pulmonary valve placement is increasing, but the value of MDCT for anatomical VT isthmus assessment is unknown., Objectives: The purpose of this study was to determine the impact of multidetector computed tomography (MDCT) in the evaluation of sustained monomorphic VT for repaired TOF., Methods: Consecutive pre-transcatheter pulmonary valve MDCT studies were identified, and anatomical isthmus dimensions were measured. For a subset of patients with preemptive electrophysiology study, MDCT features were compared with electroanatomical maps., Results: A total of 61 repaired TOFs with MDCT were identified (mean 35 ± 14 years, 58% men) with MDCT electroanatomical map pairs in 35 (57%). Calcification corresponding to patch material was present in 46 (75%) and was used to measure anatomical VT isthmuses. MDCT wall thickness correlated positively with number of ablation lesions and varied with functional isthmus properties (blocked isthmus 2.6 mm [Q1, Q3: 2.1, 4.0 mm], slow conduction 4.8 mm [Q1, Q3: 3.3, 6.0 mm], and normal conduction 5.6 mm [Q1, Q3: 3.9, 8.3 mm]; P < 0.001). A large conal branch was present in 6 (10%) and a major coronary anomaly was discovered in 3 (5%). Median ablation lesion distance was closer to the right vs the left coronary artery (10 mm vs 15 mm; P = 0.01) with lesion-to-coronary distance <5 mm in 3 patients., Conclusions: MDCT identifies anatomical structures relevant to catheter ablation for repaired TOF. Wall thickness at commonly targeted anatomical VT isthmuses is associated with functional isthmus properties and increased thermal energy delivery., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Competing Interests: Funding Support and Author Disclosures This work was made possible by support from NIH grants OT2OD023848 & P01 HL164311 to Dr Shivkumar and the UCLA Amara-Yad Project. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Cardioneuroablation has been emerging as a potential treatment alternative in appropriately selected patients with cardioinhibitory vasovagal syncope (VVS) and functional AV block (AVB). However the majority of available evidence has been derived from retrospective cohort studies performed by experienced operators., Methods: The Cardioneuroablation for the Management of Patients with Recurrent Vasovagal Syncope and Symptomatic Bradyarrhythmias (CNA-FWRD) Registry is a multicenter prospective registry with cross-over design evaluating acute and long-term outcomes of VVS and AVB patients treated by conservative therapy and CNA., Results: The study is a prospective observational registry with cross-over design for analysis of outcomes between a control group (i.e., behavioral and medical therapy only) and intervention group (Cardioneuroablation). Primary and secondary outcomes will only be assessed after enrollment in the registry. The follow-up period will be 3 years after enrollment., Conclusions: There remains a lack of prospective multicentered data for long-term outcomes comparing conservative therapy to radiofrequency CNA procedures particularly for key outcomes including recurrence of syncope, AV block, durable impact of disruption of the autonomic nervous system, and long-term complications after CNA. The CNA-FWRD registry has the potential to help fill this information gap., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The parasympathetic nervous system via the vagus nerve exerts profound influence over the heart. Together with the sympathetic nervous system, the parasympathetic nervous system is responsible for fine-tuned regulation of all aspects of cardiovascular function, including heart rate, rhythm, contractility, and blood pressure. In this review, we highlight vagal efferent and afferent innervation of the heart, with a focus on insights from comparative biology and advances in understanding the molecular and genetic diversity of vagal neurons, as well as interoception, parasympathetic dysfunction in heart disease, and the therapeutic potential of targeting the parasympathetic nervous system in cardiovascular disease., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: A growing number of patients with tetralogy of Fallot develop left ventricular systolic dysfunction and heart failure, in addition to right ventricular dysfunction. Although cardiac resynchronization therapy (CRT) is an established treatment option, the effect of CRT in this population is still not well defined. This study aimed to investigate the early and late efficacy, survival, and safety of CRT in patients with tetralogy of Fallot., Methods: Data were analyzed from an observational, retrospective, multicenter cohort, initiated jointly by the Pediatric and Congenital Electrophysiology Society and the International Society of Adult Congenital Heart Disease. Twelve centers contributed baseline and longitudinal data, including vital status, left ventricular ejection fraction (LVEF), QRS duration, and NYHA functional class. Outcomes were analyzed at early (3 months), intermediate (1 year), and late follow-up (≥2 years) after CRT implantation., Results: A total of 44 patients (40.3±19.2 years) with tetralogy of Fallot and CRT were enrolled. Twenty-nine (65.9%) patients had right ventricular pacing before CRT upgrade. The left ventricular ejection fraction improved from 32% [24%-44%] at baseline to 42% [32%-50%] at early follow-up ( P <0.001) and remained improved from baseline thereafter ( P ≤0.002). The QRS duration decreased from 180 [160-205] ms at baseline to 152 [133-182] ms at early follow-up ( P <0.001) and remained decreased at intermediate and late follow-up ( P ≤0.001). Patients with upgraded CRT had consistent improvement in left ventricular ejection fraction and QRS duration at each time point ( P ≤0.004). Patients had a significantly improved New York Heart Association functional class after CRT implantation at each time point compared with baseline ( P ≤0.002). The transplant-free survival rates at 3, 5, and 8 years after CRT implantation were 85%, 79%, and 73%., Conclusions: In patients with tetralogy of Fallot treated with CRT consistent improvement in QRS duration, left ventricular ejection fraction, New York Heart Association functional class, and reasonable long-term survival were observed. The findings from this multicenter study support the consideration of CRT in this unique population., Competing Interests: Disclosures None.

Calcitonin gene-related peptide (CGRP) is widely used as a marker for nociceptive afferent axons. However, the distribution of CGRP-IR axons has not been fully determined in the whole rat heart. Immunohistochemically labeled flat-mounts of the right and left atria and ventricles, and the interventricular septum (IVS) in rats for CGRP were assessed with a Zeiss imager to generate complete montages of the entire atria, ventricles, and septum, and a confocal microscope was used to acquire detailed images of selected regions. We found that 1) CGRP-IR axons extensively innervated all regions of the atrial walls including the sinoatrial node region, auricles, atrioventricular node region, superior/inferior vena cava, left pre-caval vein, and pulmonary veins. 2) CGRP-IR axons formed varicose terminals around individual neurons in some cardiac ganglia but passed through other ganglia without making appositions with cardiac neurons. 3) Varicose CGRP-IR axons innervated the walls of blood vessels. 4) CGRP-IR axons extensively innervated the right/left ventricular walls and IVS. Our data shows the rather ubiquitous distribution of CGRP-IR axons in the whole rat heart at single-cell/axon/varicosity resolution for the first time. This study lays the foundation for future studies to quantify the differences in CGRP-IR axon innervation between sexes, disease models, and species., Competing Interests: Declaration of competing interest No potential conflicts of interest were disclosed., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures This work was made possible by support from National Institutes of Health grant OT2OD023848 to Dr Shivkumar. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Recurrent ventricular tachycardia (VT) after prior endocardial catheter ablation(s) presents challenges in the setting of prior cardiac surgery where percutaneous epicardial access may not be feasible., Objective: The purpose of this study was to compare the outcomes of cryothermal vs radiofrequency ablation in direct surgical epicardial access procedures., Methods: We performed a retrospective study of consecutive surgical epicardial VT ablation cases. Surgical cases using cryothermal vs radiofrequency ablation were analyzed and outcomes were compared., Results: Between 2009 and 2022, 43 patients underwent either a cryothermal (n = 17) or a radiofrequency (n = 26) hybrid epicardial ablation procedure with direct surgical access. Both groups were similarly matched for age, sex, etiology of VT, and comorbidities with a high burden of refractory VT despite previous endocardial and/or percutaneous epicardial ablation procedures. The surgical access site was lateral thoracotomy (76.5%) in the cryothermal ablation group compared with lateral thoracotomy (42.3%) and subxiphoid approach (38.5%) in the radiofrequency group, with the remainder in both groups performed via median sternotomy. The ablation time was significantly shorter in those undergoing cryothermal ablation vs radiofrequency ablation (11.54 ± 15.5 minutes vs 48.48 ± 23.6 minutes; P < .001). There were no complications in the cryothermal ablation group compared with 6 patients with complications in the radiofrequency group. Recurrent VT episodes and all-cause mortality were similar in both groups., Conclusion: Hybrid surgical VT ablation with cryothermal or radiofrequency energy demonstrated similar efficacy outcomes. Cryothermal ablation was more efficient and safer than radiofrequency in a surgical setting and should be considered when surgical access is required., (Copyright © 2023 Heart Rhythm Society. All rights reserved.)

Background: Patients with repaired tetralogy of Fallot (TOF) are at risk for ventricular tachycardia (VT) related to well-described anatomical isthmuses., Objective: The purpose of this study was to explore QRS morphology as an indicator of anatomical isthmus conduction., Methods: Patients with repaired TOF and complete right bundle branch block referred for transcatheter pulmonary valve replacement (PVR) or presenting with sustained VT underwent comprehensive 3-dimensional mapping in sinus rhythm. Electrocardiographic characteristics were compared to right ventricular (RV) activation and anatomical isthmus conduction properties., Results: Twenty-two patients (19 pre-pulmonary valve replacement and 3 clinical VT) underwent comprehensive 3-dimensional mapping (median 39 years; interquartile range [IQR] 27-48 years; 12 [55%] male). Septal RV activation (median 40 ms; IQR 34-46 ms) corresponded to the nadir in lead V 1 and free wall activation (median 71 ms; IQR 64-81 ms) to the transition point in the upstroke of the R' wave. Patients with isthmus block between the pulmonary annulus and the ventricular septal defect patch and between the ventricular septal defect patch and the tricuspid annulus (when present), were more likely to demonstrate lower amplitude R' waves in lead V 1 (5.8 mV vs 9.4 mV; P = .005), QRS fragmentation in lead V 1 (15 [94%] vs 2 [13%]; P < .001), and terminal S waves in lead aVF (15 [94%] vs 6 [40%]; P < .001) than those with intact conduction. During catheter ablation, these QRS changes developed during isthmus block., Conclusion: For patients with repaired TOF, the status of septal isthmus conduction was evident from sinus rhythm QRS morphology. Low-amplitude, fragmented R' waves in lead V 1 and terminal S waves in the inferior leads were related to septal isthmus conduction abnormalities, providing a mechanistic link between RV activation and common electrocardiographic findings., (Published by Elsevier Inc.)

The field of cardiac pacing has changed rapidly in the last several years. Since the initial description of His bundle pacing targeting the conduction system, recent advances in pacing the left bundle branch and its fascicles have evolved. The field and investigators' knowledge of conduction system pacing including relevant anatomy and physiology has advanced significantly. The aim of this review is to provide a comprehensive update on recent advances in conduction system pacing., Competing Interests: Funding Support and Author Disclosures Work on anatomy was made possible by support from National Institutes of Health grants OT2OD023848 (to Dr K Shivkumar) and from the Tawara-McAlpine Festschrift (a component of the UCLA Amara-Yad Project). Dr Vijayaraman has received honoraria, consulting fees, and research and fellowship support from Medtronic; honoraria from Biotronik and Boston Scientific; and consulting fees from Abbott; and holds a patent for an HBP delivery tool. Dr Chelu has received research support from PCORI, National Institutes of Health, Abbott, and Impulse Dynamics; and honoraria from Impulse Dynamics. Dr Curila has received consulting fees and honoraria from Medtronic, Biotronik, and Abbott; has filed U.S. patent: US11,517,243B2: “Method of electrocardiographic signal processing and apparatus for performing the method”; and is a shareholder of VDI Technologies. Dr Dandamudi has received honoraria and consulting fees from Medtronic; and served on advisory boards of Medtronic, Biotronik, and Abbott. Dr Herweg has served as a speaker and consultant for Abbott; and has received speaking fees and fellowship support from Medtronic. Dr Jastrzebski has received honoraria and consulting fees from Medtronic and Abbott. Dr Sharma has received honoraria from Medtronic; and consulting fees from Medtronic, Abbott, Biotronik, and Boston Scientific. Dr Shivkumar is a cofounder of NeuCures Inc. Dr Tung has received honoraria and consulting fees from– Abbott. Dr Upadhyay has received honoraria from and served on advisory boards for Abbott, Biotronik, Boston Scientific, Medtronic, Philips BioTel, and Zoll Medical. Dr Vernooy has received consulting fees from Biosense Webster, Philips, Medtronic, and Abbott; honoraria from Microport; and research and educational grants (paid to institution) from Philips, Abbott, Medtronic, and Biosense Webster. Dr Whinnett has received honoraria from Medtronic and Boston Scientific; and consulting fees from Medtronic and Abbott. Dr Zanon has received honoraria from Abbott, Biotronik, Boston Scientific, Medtronic, and Microport. Dr Ellenbogen has received consulting fees from Medtronic, Boston Scientific, Abbott, and Biotronik; and honoraria from Medtronic, Boston Scientific, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardioneuroablation (CNA) is an attractive treatment of vasovagal syncope. Its long-term efficacy and safety remain unknown., Objective: The purpose of this study was to develop a chronic porcine model of CNA to examine the susceptibility to ventricular tachyarrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]) and cardiac autonomic function after CNA., Methods: A percutaneous CNA model was developed by ablation of left- and right-sided ganglionated plexi (n = 5), confirmed by histology. Reproducible bilateral vagal denervation was confirmed after CNA by extracardiac vagal nerve stimulation (VNS) and histology. Chronic studies included 16 pigs randomized to CNA (n = 8) and sham ablation (n = 8, Control). After 6 weeks, animals underwent hemodynamic studies, assessment of cardiac sympathetic and parasympathetic function using sympathetic chain stimulation and direct VNS, respectively, and proarrhythmic potential after left anterior descending (LAD) coronary artery ligation., Results: After CNA, extracardiac VNS responses remained abolished for 6 weeks despite ganglia remaining in ablated ganglionated plexi. In the CNA group, direct VNS resulted in paradoxical increases in blood pressure, but not in sham-ablated animals (CNA group vs sham group: 8.36% ± 7.0% vs -4.83% ± 8.7%, respectively; P = .009). Left sympathetic chain stimulation (8 Hz) induced significant corrected QT interval prolongation in the CNA group vs the sham group (11.23% ± 4.0% vs 1.49% ± 4.0%, respectively; P < .001). VT/VF after LAD ligation was more prevalent and occurred earlier in the CNA group than in the control group (61.44 ± 73.7 seconds vs 245.11 ± 104.0 seconds, respectively; P = .002)., Conclusion: Cardiac vagal denervation is maintained long-term after CNA in a porcine model. However, chronic CNA was associated with cardiovascular dysreflexia, diminished cardioprotective effects of cardiac vagal tone, and increased susceptibility to VT/VF in ischemia. These potential long-term negative effects of CNA suggest the need for rigorous clinical studies on CNA., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The supraclavicular fossa is the dominant location for human brown adipose tissue (BAT). Activation of BAT promotes non-shivering thermogenesis by utilization of glucose and free fatty acids and has been the focus of pharmacological and non-pharmacological approaches for modulation in order to improve body weight and glucose homeostasis. Sympathetic neural control of supraclavicular BAT has received much attention, but its innervation has not been extensively investigated in humans., Methods: Dissection of the cervical region in human cadavers was performed to find the distribution of sympathetic nerve branches to supraclavicular fat pad. Furthermore, proximal segments of the 4th cervical nerve were evaluated histologically to assess its sympathetic components., Results: Nerve branches terminating in supraclavicular fat pad were identified in all dissections, including those from the 3rd and 4th cervical nerves and from the cervical sympathetic plexus. Histology of the proximal segments of the 4th cervical nerves confirmed tyrosine hydroxylase positive thin nerve fibers in all fascicles with either a scattered or clustered distribution pattern. The scattered pattern was more predominant than the clustered pattern (80% vs. 20%) across cadavers. These sympathetic nerve fibers occupied only 2.48% of the nerve cross sectional area on average., Conclusions: Human sympathetic nerves use multiple pathways to innervate the supraclavicular fat pad. The present finding serves as a framework for future clinical approaches to activate human BAT in the supraclavicular region., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Patients with repaired tetralogy of Fallot are at elevated risk for ventricular arrhythmia and sudden cardiac death. Over the past decade, the pathogenesis and natural history of ventricular tachycardia has become increasingly understood, and catheter ablation has emerged as an effective treatment modality. Concurrently, there has been great progress in the development of a versatile array of transcatheter valves that can be placed in the native right ventricular outflow tract for the treatment of long-standing pulmonary regurgitation. Although such valve platforms may eliminate the need for repeat cardiac operations, they may also impede catheter access to the myocardial substrates responsible for sustained macro-reentrant ventricular tachycardia. This manuscript provides the rationale and design of a recently devised multicenter study that will examine the clinical outcomes of a uniform, preemptive strategy to eliminate ventricular tachycardia substrates before transcatheter pulmonary valve implantation in patients with tetralogy of Fallot., Competing Interests: Declaration of Competing Interest Drs. Aboulhosn and Levi report a relation with Edwards Lifesciences Corp. that includes consulting or advisory and with Medtronic Inc. that includes consulting or advisory. The remaining authors have no competing interests to declare., (Published by Elsevier Inc.)

Right ventricular perforation is a catastrophic complication of catheter-based intracardiac interventions. In this context, appreciation of 5 attachments of the right ventricle to the aortoventricular unit is essential to recognize extent of right ventricular free wall. We herein present progressive dissection and virtual and photographic endoscopic images of the hearts without distortion. Real dissection images show us how and where to avoid this complication by indicating the true muscular component of the ventricular septum. Both virtual and photographic endoscopic images, when combined with transillumination, beautifully shows the thin wall regions and trabeculations with unprecedented clarity. We believe recognition of these anatomical nuances can reduce the likelihood of right ventricular perforation., Competing Interests: Funding Support and Author Disclosures This work was made possible by support from NIH grants OT2OD023848 to Dr Shivkumar and from the UCLA Amara-Yad Project. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures None.

Competing Interests: Funding Support and Author Disclosures This work was made possible by support from National Institutes of Health grants OT2OD023848 to Dr Shivkumar and from the UCLA Amara-Yad Project. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra-operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant., Methods: We designed a prospective, multicenter, open-label, randomized-controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra-operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life., Conclusion: The primary aim of this first-ever randomized trial is to assess the efficacy of intra-operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA., (© 2023 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Introduction: Cryoablation in open-chest surgical interventions for ventricular arrhythmias has been reported with reasonable procedural outcomes. However, the characteristics of cryoablation lesions on the ventricular myocardium are not well defined. The purpose of the present study was to determine the tissue and vascular effects of a linear epicardial cryoablation probe in a porcine animal model., Methods: Five adult Yorkshire swine underwent median sternotomy and application of linear cryoablation lesions using a malleable aluminum linear cryoablation probe of varying duration (2, 3, 4, and 5 min), including one lesion placed intentionally over the left anterior descending coronary (LAD) artery. Histological analysis was performed., Results: Maximum lesion depth was approximately 1.0 cm with 3 min freezes, with no significant increase in depth achieved with longer lesions. No transmural lesions were achieved. No large vessel epicardial coronary artery injuries were seen to the LAD; however, surprisingly, remote isolated interventricular septal injury was seen in all animals, suggestive of possible compromise of smaller coronary arterial vessels., Conclusion: Single application freezes with an aluminum linear cryoablation probe can create homogeneous ablative lesions over the ventricular myocardium with a maximum depth of approximately 1.0 cm. No large vessel injury occurred with direct lesion application of the LAD; however, small coronary vessels may be at risk., (© 2023 Wiley Periodicals LLC.)

Background: Positron emission tomography computed tomography (PET-CT) is not routinely used for premature ventricular complexes (PVCs). Whether specific clinical factors are associated with abnormal PET-CT results is not clear., Methods: The treatment courses and baseline characteristics of consecutive patients in a single center between 2012 and 2021, age > 18 years old, and who received 18 F-fluorodeoxyglucose (FDG) PET-CT imaging for evaluation of PVCs were retrospectively analyzed., Results: A total of 102 patients was included. Of these, 27 patients (26.4%) had abnormal PET-CT and 61 (59.8%) had normal imaging. Abnormal PET-CT findings were associated with non-sustained ventricular tachycardia (NSVT) (95.2% vs. 52.6%, p = 0.001), higher number of PVC morphologies (2.29 ± 0.7 vs. 1.31 ± 0.6, p < 0.001), greater PVC coupling interval dispersion (72.47 ± 66.4 ms vs. 13.42 ± 17.9 ms, p < 0.001), and greater likelihood of fast heart rate dependent PVCs (78.5% vs. 38.2%, p = 0.017). Fourteen (51.8%) patients had an abnormal PET-CT and abnormal late gadolinium enhancement (LGE). Patients with abnormal PET-CT were more frequently treated with immunosuppression (81.4% vs. 3.2%, p < .0001) than with catheter ablation (11.1% vs. 45.9%, p = 0.002) compared to the normal PET-CT group. Over a median follow-up of 862 days (IQR 134, 1407), PVC burden decreased in both groups [from 23 ± 16% to 9 ± 10% (p < 0.001) in abnormal PET-CT group and from 21 ± 15% to 7 ± 10% (p < 0.001) in normal PET-CT group]., Conclusions: Abnormal PET-CT findings were more commonly associated with NSVT, multiform PVCs, greater PVC coupling interval dispersion, and fast heart rate dependent PVCs. LGE was not sensitive for detecting inflammation. Immunosuppression was effective in managing PVCs with abnormal PET-CT., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The clinical relevance and prognostic implications of ventricular parasystole are unknown., Objectives: This study sought to assess the prevalence of ventricular parasystole in patients with implantable cardioverter-defibrillators (ICDs) and ventricular parasystole's association with ventricular arrhythmias and conduction system abnormalities., Methods: This study retrospectively evaluated patients who underwent ICD interrogation at a single center between June 1, 2019, and August 31, 2020, and reviewed all available ICD and electrocardiogram data. This study identified patients with ventricular parasystole and compared the prevalence of ventricular fibrillation (VF), ventricular tachycardia (VT), and new conduction system abnormalities in those with ≥5 years of intrinsic QRS-complex electrocardiograms to those without parasystole., Results: This study included 374 patients (age 57 ± 21 years, 72% male, 45% nonischemic, 32% ischemic cardiomyopathy), of which, 104 (28%) had VT only, 39 (10%) VF only, and 10 (3%) both VT/VF. Ventricular parasystole was identified in 33 patients (9%); parasystolic foci were predominantly from the His-Purkinje system. Compared with those without parasystole, patients with parasystole had a significantly higher rate of VF (36% vs 11%; P < 0.01), but not VT (42% vs 29%; P = 0.12). Patients with parasystole, compared with those without parasystole, had a higher prevalence of new conduction abnormalities, particularly progressive intraventricular conduction delay (11 of 18 [61%] vs 12 of 83 [14%]; P < 0.01) and new right bundle branch block (4 of 18 [22%] vs 1 of 83 [1%]; P < 0.01)., Conclusions: Ventricular parasystole was strongly associated with new conduction system abnormalities and VF in patients who have cardiomyopathy with ICDs, suggesting a potential link between VF and His-Purkinje damage in this patient population., Competing Interests: Funding Support and Author Disclosures Dr Bradfield and Dr Shivkumar are supported by National Institutes of Health grant OT2OD028201. Dr Do has received research funding and speaker fees from Medtronic Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Bradyarrhythmias including sinus node dysfunction (SND) and atrioventricular block (AVB) can necessitate pacemaker (PPM) implantation in orthotopic heart transplant (OHT) recipients. Prior studies have shown conflicting findings regarding the effect of PPM implantation on survival. We evaluated the effect of PPM indication on long-term re-transplant-free survival in OHT patients., Methods: We conducted a retrospective cohort study of OHT patients at UCLA Medical Center from 1985 to 2018. Indication for PPM (SND, AVB) was identified. Cox proportional hazards model with pacemaker implantation as a time-varying covariate was used to evaluate its effect on the primary endpoint of retransplant or death. We included 1609 OHTs in 1511 adult patients with median follow-up of 12 years., Results: At transplant, patients were aged 53 ± 13 years and 1125 (74.5%) were male. Pacemakers were implanted in 109 (7.2%) patients; 65 for SND (4.3%) and 43 for AVB (2.8%). Repeat OHT was performed in 103 (6.4%) cases and 798 (52.8%) patients died during the follow-up period. The risk of the primary endpoint was significantly higher in patients requiring PPM for AVB (HR 3.0, 95% CI 2.1-4.2, p < .01) after controlling for age at OHT, gender, hypertension, diabetes, renal disease, history of repeat OHT, acute rejection, transplant coronary vasculopathy, and atrial fibrillation, but not PPM for SND (HR 1.0, 95% CI 0.70-1.4, p = 1.0)., Conclusions: Patients who required PPM for AVB, but not SND, were at significantly higher risk of death or retransplant compared to patients who did not require PPM., (© 2023 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

This study sought to evaluate the impact of chronic vagal nerve stimulation (cVNS) on cardiac and extracardiac neural structure/function after myocardial infarction (MI). Groups were control, MI, and MI + cVNS; cVNS was started 2 days post-MI. Terminal experiments were performed 6 weeks post-MI. MI impaired left ventricular mechanical function, evoked anisotropic electrical conduction, increased susceptibility to ventricular tachycardia and fibrillation, and altered neuronal and glial phenotypes in the stellate and dorsal root ganglia, including glial activation. cVNS improved cardiac mechanical function and reduced ventricular tachycardia/ventricular fibrillation post-MI, partly by stabilizing activation/repolarization in the border zone. MI-associated extracardiac neural remodeling, particularly glial activation, was mitigated with cVNS., Competing Interests: This work was supported by the National Institutes of Health through the Office of the Director Grant OT2 OD023848 (Drs Shivkumar, Ardell, Ajijola, and Hoover), the National Institute of Biomedical Imaging and Bioengineering Grant U01 EB025138 (Drs Shivkumar and Ardell), and the National Heart, Lung, and Blood Institute Grants F32 HL160163 (Dr Hadaya) and R01 HL159001 (Drs Ajijola, Shivkumar, and Ardell). University of California-Los Angeles has patents developed by Drs Ardell and Shivkumar relating to cardiac neural diagnostics and therapeutics. Drs Ardell, Ajijola, and Shivkumar are cofounders of NeuCures, Inc. All other authors have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

The sympathetic nervous system is crucial for controlling multiple cardiac functions. However, a comprehensive, detailed neuroanatomical map of the sympathetic innervation of the heart is unavailable. Here, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical distribution of the sympathetic postganglionic innervation in whole atria of C57Bl/6 J mice. We found that (1) 4-5 major extrinsic TH-IR nerve bundles entered the atria at the superior vena cava, right atrium (RA), left precaval vein and the root of the pulmonary veins (PVs) in the left atrium (LA). Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the atria with the greatest density of innervation near the sinoatrial node region (P < 0.05, n = 6). (3) TH-IR axons also innervated blood vessels and adipocytes. (4) Many principal neurons in intrinsic cardiac ganglia and small intensely fluorescent cells were also strongly TH-IR. Our work provides a comprehensive topographical map of the catecholaminergic efferent axon morphology, innervation, and distribution in the whole atria at single cell/axon/varicosity scale that may be used in future studies to create a cardiac sympathetic-brain atlas., (© 2023. The Author(s).)

Sympathetic efferent axons regulate cardiac functions. However, the topographical distribution and morphology of cardiac sympathetic efferent axons remain insufficiently characterized due to the technical challenges involved in immunohistochemical labeling of the thick walls of the whole heart. In this study, flat-mounts of the left and right atria and ventricles of FVB mice were immunolabeled for tyrosine hydroxylase (TH), a marker of sympathetic nerves. Atrial and ventricular flat-mounts were scanned using a confocal microscope to construct montages. We found (1) In the atria: A few large TH-immunoreactive (IR) axon bundles entered both atria, branched into small bundles and then single axons that eventually formed very dense terminal networks in the epicardium, myocardium and inlet regions of great vessels to the atria. Varicose TH-IR axons formed close contact with cardiomyocytes, vessels, and adipocytes. Multiple intrinsic cardiac ganglia (ICG) were identified in the epicardium of both atria, and a subpopulation of the neurons in the ICG were TH-IR. Most TH-IR axons in bundles traveled through ICG before forming dense varicose terminal networks in cardiomyocytes. We did not observe varicose TH-IR terminals encircling ICG neurons. (2) In the left and right ventricles and interventricular septum: TH-IR axons formed dense terminal networks in the epicardium, myocardium, and vasculature. Collectively, TH labeling is achievable in flat-mounts of thick cardiac walls, enabling detailed mapping of catecholaminergic axons and terminal structures in the whole heart at single-cell/axon/varicosity scale. This approach provides a foundation for future quantification of the topographical organization of the cardiac sympathetic innervation in different pathological conditions., (© 2023 Wiley Periodicals LLC.)