Pub Date : 2026-01-01DOI: 10.1016/j.jacep.2025.08.027
Sanghamitra Mohanty MD, MS , Prem Geeta Torlapati MD, MPH , Vincenzo Mirco La Fazia MD , Rashi Sharma MD , Carola Gianni MD, PhD , Amin Al-Ahmad MD , John D. Burkhardt MD , G.J. Gallinghouse MD , Rodney Horton MD , John Allison MD , Weeranun Bode MD , Luigi Di Biase MD, PhD , Andrea Natale MD
Background
Peridevice leak (PDL) is commonly observed after Watchman implantation for left atrial appendage occlusion (LAAO) in atrial fibrillation (AF). Because the LAA is actively contractile, it is fair to assume that some degree of device shifting could occur because of LAA contraction during the initial period of device implantation.
Objectives
This study examined PDL prevalence in Watchman patients with vs without electrical isolation of LAA that consequentially leads to loss of contractility of the appendage.
Methods
Consecutive patients with AF undergoing the Watchman procedure were included in the study and prospectively followed up. Based on prior LAA isolation (LAAI), patients were divided into Group 1 (prior LAAI) and Group 2 (no LAAI). In all patients in Group 1, electroanatomical mapping and transesophageal echocardiogram (TEE) were used to confirm LAAI and absence of contractility of the appendage before the Watchman implantation. Repeat TEE was scheduled at 45 to 60 days’ post-Watchman implantation to assess for PDL on color Doppler. The leaks were reassessed by computed tomography imaging at 6 months. If leaks were detected during the first follow-up TEE, another TEE/computed tomography imaging was performed at 12 months to exclude persistent leak.
Results
A total of 495 patients were included in Group 1 and 810 in Group 2. Baseline characteristics were comparable between groups. At the first follow-up TEE at 45 to 60 days, leaks of any size were noted in 90 (18.2%) patients in Group 1 and 199 (24.6%) patients in Group 2 (P = 0.007). The majority of the leaks in Group 2 were ≥3 mm in size (Group 1: 26 [28.9%] vs Group 2: 109 [54.8%]; P < 0.001). Prior LAAI was found to be an independent predictor (OR: 0.662; 95% CI: 0.488-0.900; P = 0.008) of lower risk of leaks.
Conclusions
In this large prospective series of real-world patients, prior LAAI was seen to be associated with a lower risk of PDL in patients with AF and a Watchman device in situ.
{"title":"Prevalence of Peridevice Leak in Patients With Left Atrial Appendage-Occlusion vs Without Electrically Isolated Left Atrial Appendage","authors":"Sanghamitra Mohanty MD, MS , Prem Geeta Torlapati MD, MPH , Vincenzo Mirco La Fazia MD , Rashi Sharma MD , Carola Gianni MD, PhD , Amin Al-Ahmad MD , John D. Burkhardt MD , G.J. Gallinghouse MD , Rodney Horton MD , John Allison MD , Weeranun Bode MD , Luigi Di Biase MD, PhD , Andrea Natale MD","doi":"10.1016/j.jacep.2025.08.027","DOIUrl":"10.1016/j.jacep.2025.08.027","url":null,"abstract":"<div><h3>Background</h3><div>Peridevice leak (PDL) is commonly observed after Watchman implantation for left atrial appendage occlusion (LAAO) in atrial fibrillation (AF). Because the LAA is actively contractile, it is fair to assume that some degree of device shifting could occur because of LAA contraction during the initial period of device implantation.</div></div><div><h3>Objectives</h3><div>This study examined PDL prevalence in Watchman patients with vs without electrical isolation of LAA that consequentially leads to loss of contractility of the appendage.</div></div><div><h3>Methods</h3><div>Consecutive patients with AF undergoing the Watchman procedure were included in the study and prospectively followed up. Based on prior LAA isolation (LAAI), patients were divided into Group 1 (prior LAAI) and Group 2 (no LAAI). In all patients in Group 1, electroanatomical mapping and transesophageal echocardiogram (TEE) were used to confirm LAAI and absence of contractility of the appendage before the Watchman implantation. Repeat TEE was scheduled at 45 to 60 days’ post-Watchman implantation to assess for PDL on color Doppler. The leaks were reassessed by computed tomography imaging at 6 months. If leaks were detected during the first follow-up TEE, another TEE/computed tomography imaging was performed at 12 months to exclude persistent leak.</div></div><div><h3>Results</h3><div>A total of 495 patients were included in Group 1 and 810 in Group 2. Baseline characteristics were comparable between groups. At the first follow-up TEE at 45 to 60 days, leaks of any size were noted in 90 (18.2%) patients in Group 1 and 199 (24.6%) patients in Group 2 (<em>P</em> = 0.007). The majority of the leaks in Group 2 were ≥3 mm in size (Group 1: 26 [28.9%] vs Group 2: 109 [54.8%]; <em>P</em> < 0.001). Prior LAAI was found to be an independent predictor (OR: 0.662; 95% CI: 0.488-0.900; <em>P</em> = 0.008) of lower risk of leaks.</div></div><div><h3>Conclusions</h3><div>In this large prospective series of real-world patients, prior LAAI was seen to be associated with a lower risk of PDL in patients with AF and a Watchman device in situ.</div></div>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":"12 1","pages":"Pages 108-115"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.jacep.2025.08.028
William Whang MD , Devi Nair MD , Rahul Bhardwaj MD , Marc Lahiri MD , Dinesh Sharma MD , Taisei Kobayashi MD , Shephal K. Doshi MD , Andrea Natale MD , Craig Moskowitz MD , Moussa Mansour MD , Vijay Swarup MD , Mohit K. Turagam MD , Srinivas Dukkipati MD , Matthew C. Hyman MD, PhD , Sanghamitra Mohanty MD, MS , Jeff Lam MS , Ugur Gurol BS , Carla Perdomo Silva BA , Vivek Y. Reddy MD
Background
During atrial fibrillation (AF) ablation, adjunctive renal denervation (RDN), by virtue of its effect on the sympathetic/renin-angiotensin-aldosterone axis, has improved AF control. However, patients in these studies mostly had uncontrolled hypertension.
Objectives
The aim of this study was to assess the effect of RDN using an ultrasound catheter to improve rhythm outcomes in patients with hypertension (including controlled hypertension) undergoing AF ablation.
Methods
This investigator-initiated, sham-controlled, single-blind randomized controlled U.S. Food and Drug Administration trial included first-ever paroxysmal or persistent AF ablation patients with histories of hypertension receiving ≥1 antihypertensive medication. Post–AF ablation randomization was 1:1 to RDN using a circumferential ultrasound system or sham control; patients with ineligible renal arterial anatomy were screen failures. The primary endpoint was 12-month freedom from AF or atrial flutter (AFL) (≥30 seconds) off antiarrhythmic medications after 90-day blanking.
Results
At 9 centers, 107 patients were randomized; excluding 7 screen failures, the 100-patient cohort (mean age 66 ± 9 years, 35% women, paroxysmal and persistent AF in 86% and 14%) underwent radiofrequency ablation (55%) or cryoablation (45%) for AF. The 1-year Kaplan-Meier estimates for freedom from AF or AFL were 49% for sham vs 67% for RDN (log-rank P = 0.17). In a Cox analysis adjusted for age, sex, and persistent AF, the HR for recurrent AF or AFL with RDN was 0.65 (95% CI: 0.32-1.31; P = 0.23). There were no RDN-related adverse events.
Conclusions
In this AF ablation cohort, adjunctive RDN was safe and reduced AF and AFL recurrence by 35%, an effect not reaching statistical significance in this pilot trial. A fully powered randomized trial is warranted to define the impact of RDN among patients planned for AF ablation.
{"title":"Ultrasound-Based Renal Sympathetic Denervation as Adjunctive Upstream Therapy During Atrial Fibrillation Ablation","authors":"William Whang MD , Devi Nair MD , Rahul Bhardwaj MD , Marc Lahiri MD , Dinesh Sharma MD , Taisei Kobayashi MD , Shephal K. Doshi MD , Andrea Natale MD , Craig Moskowitz MD , Moussa Mansour MD , Vijay Swarup MD , Mohit K. Turagam MD , Srinivas Dukkipati MD , Matthew C. Hyman MD, PhD , Sanghamitra Mohanty MD, MS , Jeff Lam MS , Ugur Gurol BS , Carla Perdomo Silva BA , Vivek Y. Reddy MD","doi":"10.1016/j.jacep.2025.08.028","DOIUrl":"10.1016/j.jacep.2025.08.028","url":null,"abstract":"<div><h3>Background</h3><div>During atrial fibrillation (AF) ablation, adjunctive renal denervation (RDN), by virtue of its effect on the sympathetic/renin-angiotensin-aldosterone axis, has improved AF control. However, patients in these studies mostly had uncontrolled hypertension.</div></div><div><h3>Objectives</h3><div>The aim of this study was to assess the effect of RDN using an ultrasound catheter to improve rhythm outcomes in patients with hypertension (including controlled hypertension) undergoing AF ablation.</div></div><div><h3>Methods</h3><div>This investigator-initiated, sham-controlled, single-blind randomized controlled U.S. Food and Drug Administration trial included first-ever paroxysmal or persistent AF ablation patients with histories of hypertension receiving ≥1 antihypertensive medication. Post–AF ablation randomization was 1:1 to RDN using a circumferential ultrasound system or sham control; patients with ineligible renal arterial anatomy were screen failures. The primary endpoint was 12-month freedom from AF or atrial flutter (AFL) (≥30 seconds) off antiarrhythmic medications after 90-day blanking.</div></div><div><h3>Results</h3><div>At 9 centers, 107 patients were randomized; excluding 7 screen failures, the 100-patient cohort (mean age 66 ± 9 years, 35% women, paroxysmal and persistent AF in 86% and 14%) underwent radiofrequency ablation (55%) or cryoablation (45%) for AF. The 1-year Kaplan-Meier estimates for freedom from AF or AFL were 49% for sham vs 67% for RDN (log-rank <em>P</em> = 0.17). In a Cox analysis adjusted for age, sex, and persistent AF, the HR for recurrent AF or AFL with RDN was 0.65 (95% CI: 0.32-1.31; <em>P</em> = 0.23). There were no RDN-related adverse events.</div></div><div><h3>Conclusions</h3><div>In this AF ablation cohort, adjunctive RDN was safe and reduced AF and AFL recurrence by 35%, an effect not reaching statistical significance in this pilot trial. A fully powered randomized trial is warranted to define the impact of RDN among patients planned for AF ablation.</div></div>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":"12 1","pages":"Pages 71-81"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.jacep.2025.09.044
Udhayvir S. Grewal MD , Stefano H. Byer MD, MS , Sidharth Mahajan MD , Aakash R. Sheth MD , Kavitha Beedupalli MD , Michael G. Fradley MD , Eric H. Yang MD , Andrea M. Russo , Aarti Asnani MD , Paari Dominic MD
A bidirectional relationship between cancer and atrial fibrillation (AF) is well known. Although systemic inflammation and the effects of cancer treatment significantly increase the risk of AF in patients with cancer, new-onset AF has also been shown to independently predict the risk of active malignancy. With a continued growth in our understanding of the molecular pathogenesis of AF and with the advent of novel anticancer agents with unique cardiotoxic effects, there is a need to study if the management of AF in patients with cancer requires a more “personalized” approach rather than a generalized approach. The current review focuses on the application of “precision cardio-oncology” to the screening, diagnosis, and management of AF in patients with cancer through biomarkers, cardiac imaging, and personalized risk stratification. Through this review, we highlight the growing need to incorporate personalized interventions into clinical studies and analyze the feasibility of integrating these into the routine care of patients with cancer.
{"title":"Atrial Fibrillation and Cancer","authors":"Udhayvir S. Grewal MD , Stefano H. Byer MD, MS , Sidharth Mahajan MD , Aakash R. Sheth MD , Kavitha Beedupalli MD , Michael G. Fradley MD , Eric H. Yang MD , Andrea M. Russo , Aarti Asnani MD , Paari Dominic MD","doi":"10.1016/j.jacep.2025.09.044","DOIUrl":"10.1016/j.jacep.2025.09.044","url":null,"abstract":"<div><div>A bidirectional relationship between cancer and atrial fibrillation (AF) is well known. Although systemic inflammation and the effects of cancer treatment significantly increase the risk of AF in patients with cancer, new-onset AF has also been shown to independently predict the risk of active malignancy. With a continued growth in our understanding of the molecular pathogenesis of AF and with the advent of novel anticancer agents with unique cardiotoxic effects, there is a need to study if the management of AF in patients with cancer requires a more “personalized” approach rather than a generalized approach. The current review focuses on the application of “precision cardio-oncology” to the screening, diagnosis, and management of AF in patients with cancer through biomarkers, cardiac imaging, and personalized risk stratification. Through this review, we highlight the growing need to incorporate personalized interventions into clinical studies and analyze the feasibility of integrating these into the routine care of patients with cancer.</div></div>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":"12 1","pages":"Pages 183-199"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.jacep.2025.09.047
Eduardo Back Sternick MD, PhD , Justin T. Tretter MD , Robert H. Anderson BSc, MD
{"title":"Sketches Need to Reflect Anatomy to Create Realistic and Believable Figures","authors":"Eduardo Back Sternick MD, PhD , Justin T. Tretter MD , Robert H. Anderson BSc, MD","doi":"10.1016/j.jacep.2025.09.047","DOIUrl":"10.1016/j.jacep.2025.09.047","url":null,"abstract":"","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":"12 1","pages":"Pages 178-179"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.jacep.2025.08.009
Mustapha Amin MD , Maarten De Smet MD, PhD , Adi Lador MD , Apoor Patel MD , Paul A. Schurmann MD , Amish Dave MD, PhD , Rene Tavernier MD, PhD , Sebastien Knecht MD, PhD , Mattias Duytschaever MD, PhD , Jean-Benoît le Polain de Waroux MD, PhD , Miguel Valderrábano MD, PhD
Background
Venous ethanol ablation (VEA) can be effective in radiofrequency ablation (RFA) failure but has not been tested as a stand-alone procedure.
Objectives
The goal of this study was to determine the value of VEA alone as the sole ablation strategy in intramural ventricular arrhythmias (VAs).
Methods
Patients (N = 52; prior failed RFA procedures in 24 patients) underwent mapping of the right and left ventricular endocardium and coronary sinus (CS) branches identified by venography. VEA was a first strategy if the CS intramural veins had earlier pre-systolic or mid-diastolic signals than those elsewhere. If VEA was successful, RFA was omitted. Ablated volume was estimated by intracardiac echocardiography or cardiac magnetic resonance imaging.
Results
VAs were either premature ventricular contraction (n = 36) or ventricular tachycardia (VT) (n = 16). Intramural venous signals were 40 milliseconds pre-QRS (Q1-Q3: 32-44 milliseconds) compared with 8 milliseconds (Q1-Q3: 0-15 milliseconds) for best endocardial or CS signals (P < 0.0001). Acute VA suppression occurred in all patients after a median 8 mL (Q1-Q3: 5-15 mL) of ethanol. Ablated volume was 2.5 mL (Q1-Q3: 1.6-4 mL) according to intracardiac echocardiography or 2.8 mL (Q1-Q3: 2.3-7.4 mL) according to cardiac magnetic resonance imaging. VEA resulted in reduction in premature ventricular contraction burden from 21% to 0.5% (P < 0.0001) and the need for ICD therapy in 71% of patients. Six patients experienced recurrence after a median follow-up of 9.5 months, which required repeat procedures in 3 patients. Postoperative complications included pericarditis in 3 patients, groin hematoma in 1, and transient right bundle branch block in 2.
Conclusions
VEA-only can be effective as the sole ablation strategy when vein mapping indicates an intramural origin.
{"title":"Venous Ethanol Ablation as the Sole Treatment for Intramural Ventricular Arrhythmias","authors":"Mustapha Amin MD , Maarten De Smet MD, PhD , Adi Lador MD , Apoor Patel MD , Paul A. Schurmann MD , Amish Dave MD, PhD , Rene Tavernier MD, PhD , Sebastien Knecht MD, PhD , Mattias Duytschaever MD, PhD , Jean-Benoît le Polain de Waroux MD, PhD , Miguel Valderrábano MD, PhD","doi":"10.1016/j.jacep.2025.08.009","DOIUrl":"10.1016/j.jacep.2025.08.009","url":null,"abstract":"<div><h3>Background</h3><div>Venous ethanol ablation (VEA) can be effective in radiofrequency ablation (RFA) failure but has not been tested as a stand-alone procedure.</div></div><div><h3>Objectives</h3><div>The goal of this study was to determine the value of VEA alone as the sole ablation strategy in intramural ventricular arrhythmias (VAs).</div></div><div><h3>Methods</h3><div>Patients (N = 52; prior failed RFA procedures in 24 patients) underwent mapping of the right and left ventricular endocardium and coronary sinus (CS) branches identified by venography. VEA was a first strategy if the CS intramural veins had earlier pre-systolic or mid-diastolic signals than those elsewhere. If VEA was successful, RFA was omitted. Ablated volume was estimated by intracardiac echocardiography or cardiac magnetic resonance imaging.</div></div><div><h3>Results</h3><div>VAs were either premature ventricular contraction (n = 36) or ventricular tachycardia (VT) (n = 16). Intramural venous signals were 40 milliseconds pre-QRS (Q1-Q3: 32-44 milliseconds) compared with 8 milliseconds (Q1-Q3: 0-15 milliseconds) for best endocardial or CS signals (<em>P</em> < 0.0001). Acute VA suppression occurred in all patients after a median 8 mL (Q1-Q3: 5-15 mL) of ethanol. Ablated volume was 2.5 mL (Q1-Q3: 1.6-4 mL) according to intracardiac echocardiography or 2.8 mL (Q1-Q3: 2.3-7.4 mL) according to cardiac magnetic resonance imaging. VEA resulted in reduction in premature ventricular contraction burden from 21% to 0.5% (<em>P</em> < 0.0001) and the need for ICD therapy in 71% of patients. Six patients experienced recurrence after a median follow-up of 9.5 months, which required repeat procedures in 3 patients. Postoperative complications included pericarditis in 3 patients, groin hematoma in 1, and transient right bundle branch block in 2.</div></div><div><h3>Conclusions</h3><div>VEA-only can be effective as the sole ablation strategy when vein mapping indicates an intramural origin.</div></div>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":"12 1","pages":"Pages 16-27"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01DOI: 10.1016/j.jacep.2025.08.016
Ching Zhu MD, PhD , Takako Makita PhD , Emilio Y. Lucero MD, PhD , Arun Jyothidasan PhD , Rhea Patel PhD , Jessica J. Wang MD, PhD , Yang Cao PhD , Howard A. Rockman MD , Kalyanam Shivkumar MD, PhD, FACC
Background
Ventricular arrhythmias (VAs) are a leading cause of death and arise from a combination of cardiac muscle injury and dysfunction of the intramyocardial sympathetic nerves that control cardiac electrophysiology. The adrenergic mechanisms by which intramyocardial nerves contribute to arrhythmogenesis are poorly understood. Semaphorin-plexin signaling pathways are responsible for developmental guidance of sympathetic nerves onto the heart and have previously been associated with VAs in humans.
Objectives
This study sought to investigate adrenergic control of arrhythmogenesis, and explored the cardiac electrophysiology of a Plexin-A3/-A4 double knockout mouse model with loss of cardiac adrenergic nerves.
Methods
Cardiac structure and function were studied by using tissue clearing, immunohistochemistry, and echocardiography. Electrocardiogram and optical mapping of action potentials were used to evaluate electrophysiological responses to pharmacologic β-adrenergic stimulation and blockade. Circulating catecholamines were measured and β-adrenergic receptor density quantified in cardiac membranes. Finally, a phenome-wide association study was performed by using data from the UK Biobank to search for associations between PLXNA4 and human arrhythmias.
Results
Mice with loss of plexin-dependent cardiac innervation had structurally normal hearts but displayed spontaneous VAs driven by adrenergic hypersensitivity, as well as increased cardiac β-adrenergic receptor density. Several human PLXNA4 variants were associated with arrhythmia phenotypes.
Conclusions
These data establish a model of VAs driven by enhanced adrenergic receptor signaling, in the absence of structural heart disease. This model can be used to investigate adrenergic mechanisms of arrhythmogenesis and to identify novel antiarrhythmic targets.
{"title":"Adrenergic Hypersensitivity Drives Ventricular Arrhythmias Following Loss of Plexin-Mediated Cardiac Innervation","authors":"Ching Zhu MD, PhD , Takako Makita PhD , Emilio Y. Lucero MD, PhD , Arun Jyothidasan PhD , Rhea Patel PhD , Jessica J. Wang MD, PhD , Yang Cao PhD , Howard A. Rockman MD , Kalyanam Shivkumar MD, PhD, FACC","doi":"10.1016/j.jacep.2025.08.016","DOIUrl":"10.1016/j.jacep.2025.08.016","url":null,"abstract":"<div><h3>Background</h3><div>Ventricular arrhythmias (VAs) are a leading cause of death and arise from a combination of cardiac muscle injury and dysfunction of the intramyocardial sympathetic nerves that control cardiac electrophysiology. The adrenergic mechanisms by which intramyocardial nerves contribute to arrhythmogenesis are poorly understood. Semaphorin-plexin signaling pathways are responsible for developmental guidance of sympathetic nerves onto the heart and have previously been associated with VAs in humans.</div></div><div><h3>Objectives</h3><div>This study sought to investigate adrenergic control of arrhythmogenesis, and explored the cardiac electrophysiology of a <em>Plexin-A3/-A4</em> double knockout mouse model with loss of cardiac adrenergic nerves.</div></div><div><h3>Methods</h3><div>Cardiac structure and function were studied by using tissue clearing, immunohistochemistry, and echocardiography. Electrocardiogram and optical mapping of action potentials were used to evaluate electrophysiological responses to pharmacologic β-adrenergic stimulation and blockade. Circulating catecholamines were measured and β-adrenergic receptor density quantified in cardiac membranes. Finally, a phenome-wide association study was performed by using data from the UK Biobank to search for associations between <em>PLXNA4</em> and human arrhythmias.</div></div><div><h3>Results</h3><div>Mice with loss of plexin-dependent cardiac innervation had structurally normal hearts but displayed spontaneous VAs driven by adrenergic hypersensitivity, as well as increased cardiac β-adrenergic receptor density. Several human <em>PLXNA4</em> variants were associated with arrhythmia phenotypes.</div></div><div><h3>Conclusions</h3><div>These data establish a model of VAs driven by enhanced adrenergic receptor signaling, in the absence of structural heart disease. This model can be used to investigate adrenergic mechanisms of arrhythmogenesis and to identify novel antiarrhythmic targets.</div></div>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":"12 1","pages":"Pages 44-58"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号