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Introduction: A hybrid approach with very high-power short-duration (vHPSD) posteriorly and ablation-index guided HPSD (50 W) anteriorly seems to be an optimal balance between efficiency and effectiveness for point-by-point pulmonary vein isolation (PVI). The aim of the current study is to compare vHPSD/HPSD ablation to cryoballoon ablation (CBA) in patients with symptomatic atrial fibrillation (AF)., Methods and Results: In this retrospective single-center study, we identified 110 consecutive patients who underwent their first PVI with either vHPSD/HPSD (n = 54) or CBA (n = 56). We compared procedural efficacy, efficiency, safety, and long-term outcomes. Baseline characteristics of both groups were comparable; however, patients in the vHPSD/HPSD group had larger left atrial volume index (35, IQR 27-45 vs. 28, IQR 21-36 ml/m 2 , P = 0.005). Complete PVI was achieved in all patients except two CBA cases (100% vs. 96.4%, P = 0.50). First-pass isolation rate was 79.6% in the hybrid group. Procedure times were similar between groups (53, IQR 47-63 vs. 55, IQR 49-65 min, P = 0.35), but fluoroscopy time was shorter in the vHPSD/HPSD group (3.9 [2.7, 5.6] vs. 11.9 [9.3, 14.9] min, P < 0.001). There were 3 temporary phrenic nerve palsies (5.4%) in the CBA group which resolved within 1 year. The 1-year freedom from any atrial tachyarrhythmias after a single procedure was similar between groups (68.5% vs. 73.2%, P = 0.56). During repeat procedure, the durability of PVI was comparable., Conclusions: The use of vHPSD/HPSD ablation renders point-by-point PVI as fast and effective as CBA. Furthermore, it has lower radiation exposure compared to CBA., Competing Interests: Declarations. Conflict of interest: Dr. Yap has received honoraria from Boston Scientific, Medtronic, Biotronik, Acutus Medical, and Sanofi. In addition, he has received research grants from Medtronic, Biotronik, and Boston Scientific. The other authors have no conflict of interest., (© 2025. The Author(s).)

Background: The use of an antibacterial envelope is cost-effective for patients at high risk of developing cardiac implantable electronic device (CIED) infection. The identification of these high-risk patients may be facilitated using a clinical risk score. The aim of the current study is to evaluate the PADIT score for identifying high-risk patients in patients undergoing a CIED procedure in a tertiary academic center., Methods: This was a retrospective single-center study of consecutive patients undergoing a CIED procedure between January 2016 and November 2021. Patients who received an antibacterial envelope were excluded from this study. The primary endpoint was hospitalization for a CIED infection in the first year after the procedure., Results: A total of 2333 CIED procedures were performed in the study period (mean age 61.6 ± 16.3 years, male sex 64.5%, previous CIED infection 1.7%, immunocompromised 5.4%). The median PADIT score was 4 (interquartile range, 2-6). CIED infection occurred in 10 patients (0.43%). The PADIT score had good discrimination in predicting major CIED infection (C-statistic 0.70; 95% confidence interval [CI] 0.54 to 0.86, P = 0.03). Using an optimal PADIT score cut-off value of 7, the risk of CIED infection was higher in the patients with a PADIT score of ≥ 7 in comparison to those with a lower PADIT score (1.23% vs. 0.26%, P = 0.02; odds ratio 4.8, 95% CI 1.4 to 16.6, P = 0.01)., Conclusions: The PADIT score is a clinically useful score for identifying patients at high risk of developing CIED infection. The use of an antibacterial envelope in these high-risk patients may be cost-effective., (© 2024. The Author(s).)

Background: A chronic total coronary occlusion (CTO) is associated with ventricular arrhythmias (VA) in patients with an implantable cardioverter-defibrillator (ICD). Limited data is available on the incidence of VA in CTO patients without an ICD., Objectives: To investigate the incidence of sustained VA in CTO patients after successful CTO revascularization and in patients with untreated CTO or failed CTO revascularization., Methods: Prospective, multicenter observational pilot study including CTO patients who were not eligible for an ICD and had a left ventricular ejection fraction >35 %. We enrolled patients with a successful CTO revascularization (group A) and patients with untreated CTO or failed CTO revascularization (group B). All patients received an implantable loop recorder with remote monitoring. The primary endpoint was sustained VA., Results: Ninety patients were enrolled (mean age 63 ± 10 years, 83.3 % man, mean LVEF 55 ± 8 %). Group A (n = 45) had a higher prevalence of CTO in the left anterior descending artery in comparison to group B (n = 45) (28.9 % versus 4.4 %, P = 0.002). Other baseline characteristics were similar. During a median follow-up time of 26 months (IQR, 19-35), five patients (5.6 %) had a sustained VA. There was no difference in the incidence of sustained VA between groups (3-year cumulative event rate: 8.8 % (group A) versus 4.5 % (Group B), log-rank P = 0.71)., Conclusion: Patients with an CTO, who do not qualify for an ICD, have a substantial risk of sustained VA. In our study the incidence was not different between patients with revascularized and those with untreated CTO., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SCY has received consultancy and speaker fees from Boston Scientific, and institutional research grants from Medtronic, Biotronik and Boston Scientific. The other authors have nothing to declare., (© 2023 The Authors.)

Introduction: Pulmonary vein isolation (PVI) is a pivotal part of ablative therapy for atrial fibrillation (AF). Currently, there are multiple techniques available to realize PVI, including: manual-guided cryoballoon (MAN-CB), manual-guided radiofrequency (MAN-RF), and robotic magnetic navigation-guided radiofrequency ablation (RMN-RF). There is a lack of large prospective trials comparing contemporary RMN-RF with the more conventional ablation techniques. This study prospectively compared three catheter ablation techniques as treatment of paroxysmal AF., Methods: This multicenter, prospective study included patients with paroxysmal AF who underwent their first ablation procedure. Procedural parameters (including procedural efficiency), complication rates, and freedom of AF during 12-month follow-up, were compared between three study groups which were defined by the utilized ablation technique., Results: A total of 221 patients were included in this study. Total procedure time was significantly shorter in MAN-CB (78 ± 21 min) compared to MAN-RF (115 ± 41 min; p < .001) and compared to RMN-RF (129 ± 32 min; p < .001), whereas it was comparable between the two radiofrequency (RF) groups (p = .062). A 3% complication rate was observed, which was comparable between all groups. At 12-month follow-up, AF recurrence was observed in 40 patients (19%) and was significantly lower in the robotic group (MAN-CB 19 [24%], MAN-RF 16 [23%], RMN-RF 5 [8%] AF recurrences, p = .045) (multivariate hazard ratio of RMN-RF on AF recurrence 0.32, 95% confidence interval: 0.12-0.87, p = .026)., Conclusion: RMN-guided PVI results in high freedom of AF in patients with paroxysmal AF, when compared to cryoablation and manual RF ablation. Cryoablation remains the most time-efficient ablation technique, whereas RMN nowadays has comparable efficiency with manual RF ablation., (© 2023 The Authors. Journal of Cardiovascular Electrophysiology published by Wiley Periodicals LLC.)

Background: The presence of an untreated chronic total coronary occlusion (CTO) is associated with a higher risk of ventricular arrhythmias (VAs). This increased risk may be modulated by the presence of an existing scar., Objectives: To evaluate whether scar size is associated with VA in patients with an implantable cardioverter-defibrillator (ICD) and a CTO., Methods: In this retrospective study we included patients with a CTO that received an ICD between 2005 and 2015. Scar size was estimated using the Selvester QRS score on a baseline 12‑lead ECG. The primary endpoint was any appropriate ICD therapy., Results: Our study population comprised 148 CTO patients with a median scar size at baseline of 18% (IQR, 9-27%). Patients with a scar size ≥18% more often had a CTO located in the left anterior descending artery and a higher proportion of poor left ventricular function (<35%) and infarct-related CTO compared to patients with a smaller scar size (<18%). During a median follow-up of 35 months (interquartile range [IQR], 8-60 months), 42 patients (28%) received appropriate ICD therapy. The cumulative 5-year event rate was higher in the patients with a large scar in comparison to those with a smaller or no scar (36% versus 19%, P = 0.04). Multivariable Cox regression analysis demonstrated that large scar and diabetes mellitus were independent factors associated with appropriate ICD therapy., Conclusion: In ICD recipients with an untreated CTO, a larger scar is an independent factor associated with an increased risk of VA., (Copyright © 2023. Published by Elsevier B.V.)

Background: Short runs of atrial tachycardias (ATs) and infrequent premature atrial contractions (PACs) are difficult to map and ablate using sequential electrophysiology mapping techniques. The AcQMap mapping system allows for highly accurate mapping of a single atrial activation., Objectives: We aimed to test the value of a novel dipole charge density-based high-resolution mapping technique (AcQMap) in the treatment of brief episodes of ATs and PACs., Methods: Data of all patients undergoing catheter ablation (CA) using the AcQMap mapping system were reviewed., Results: Thirty-one out of 219 patients (male n = 8; female n = 23) had short runs of ATs (n = 23) and PACs (n = 8). The mean procedural time was 155.3 ± 46.6 min, with a mean radiation dose of 92.0 (IQR 37.0-121.0) mGy. Total radiofrequency application duration 504.0 (271.0-906.0) s. Left atrial localization of ATs and PACs was identified in 45.1% of the cases, right atrium localization in 45.1%, and septal origins in 9.8% of the cases. Acute success was achieved in 30/31 (96.8%), and recurrence during the follow-up developed in six patients (19.4%), including four patients with PACs and two patients with short-lived ATs. One patient presented procedure-related groin hematoma as minor complication., Conclusion: Brief episodes of highly symptomatic ATs and infrequent PACs can be mapped using charge density mapping and successfully ablated with high acute and long-term success rates., (© 2022. The Author(s).)

Aims: Robotic magnetic navigation (RMN) provides increased catheter precision and stability. Formerly, only the CARTO 3 mapping system was integrated with the RMN system (CARTO-RMN). Recently, a novel high-resolution non-contact mapping system (AcQMap) has been integrated with the RMN system (AcQMap-RMN) for the treatment of atrial fibrillation (AF) and atrial tachycardias (AT). We aim to compare the safety, efficiency, and efficacy of AcQMap-RMN with CARTO-RMN guided catheter ablation (CA) procedures., Material and Methods: In this prospective registry, procedural safety efficiency and outcome data from total of 238 consecutive patients (147 AcQMap-RMN and 91 CARTO-RMN patients) were compared., Results: AcQMap-RMN is non-inferior in the primary endpoint of safety as compared to CARTO-RMN across the whole group (overall procedural complications in 5 (3.4%) vs. 3 (3.3%) patients, p = 1.0). Overall procedure durations were longer and associated with more fluoroscopy use with AcQMap-RMN (172.5 vs. 129.6 min, p < 0.01; 181.0 vs. 131.0 mGy, p = 0.02, respectively). Procedure duration and fluoroscopy use decreased significantly between the first 30 and the last 30 AcQMap-RMN procedures. The AcQMap-RMN system had fewer recurrences after persistent AF ablations and was non-inferior in paroxysmal AF patients compared to CARTO-RMN at 12 months (36.6% vs. 75.0%, p = 0.04, PAF 6.6% vs. 12.5%, p = 0.58; respectively). CA of AT outcomes were better using the AcQMap-RMN system (1 year recurrence 17.1% vs. 38.7%, p < 0.05)., Conclusion: AcQMap-RMN integration has no negative impact on the excellent safety profile of RMN guided ablations. It improves outcomes of CA procedures for persAF and AT but requires longer procedure times and higher fluoroscopy use during the initial learning phase., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background: The clinical value of non-invasive mapping system depends on its accuracy under common variations of the inputs. The View Into Ventricular Onset (VIVO) system matches simulated QRS complexes of a patient-specific anatomical model with a 12-lead ECG to estimate the origin of ventricular arrhythmias. We aim to test the performance of the VIVO system and its sensitivity to changes in the anatomical model, time marker placement to demarcate the QRS complex and body position. Methods: Non-invasive activation maps of idiopathic premature ventricular complexes (PVCs) using a patient-specific or generic anatomical model were matched with the location during electrophysiological studies. Activation maps were analyzed before and after systematically changing the time marker placement. Morphologically identical PVCs recorded in supine and sitting position were compared in a subgroup. Results: Non-invasive activation maps of 48 patients (age 51 ± 14 years, 28 female) were analyzed. The origin of the PVCs as determined by VIVO system matched with the clinical localization in 36/48 (75%) patients. Mismatches were more common for PVCs of left than right ventricular origin [11/27 (41%) vs. 1/21 (5%) of cases, p < 0.01]. The first 32 cases were analyzed for robustness testing of the VIVO system. Changing the patient-specific vs. the generic anatomical model reduced the accuracy from 23/32 (72%) to 15/32 (47%), p < 0.05. Time marker placement in the QRS complex (delayed onset or advanced end marker) or in the ST-segment (delaying the QRS complex end marker) resulted in progressive shifts in origins of PVCs. Altered body positions did not change the predicted origin of PVCs in most patients [clinically unchanged 11/15 (73%)]. Conclusion: VIVO activation mapping is sensitive to changes in the anatomical model and time marker placement but less to altered body position., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lesina, Szili-Torok, Peters, de Wit, Wijchers, Bhagwandien, Yap, Hirsch and Hoogendijk.)

Background: Sleep-disordered breathing (SDB) may hamper the outcome of catheter ablation of atrial fibrillation (AF). However, SDB is underdiagnosed in clinical practice and the relevancy of undiagnosed SDB on the outcome of catheter ablation is unclear., Objective: To evaluate if undiagnosed SDB has an impact on AF recurrence after catheter ablation., Methods: In this single-center cohort study we enrolled patients who had a catheter ablation of AF 12 to 18 months prior to enrolment. Patients with diagnosed SDB at the time of catheter ablation were excluded. Enrolled patients underwent screening using WatchPAT (WP). SDB was defined as an apnea-hypopnea index (AHI) ≥ 15., Results: A total of 164 patients were screened for eligibility. After exclusion of patients with previously diagnosed SDB (n = 30), 104 of 134 eligible patients were enrolled and underwent SDB screening. The median AHI was 11.5 (interquartile range 6.8-21.9) and 39 patients (38%) had SDB which was undiagnosed during the first year after ablation. AF recurrence in the first year after catheter ablation occurred in 40 patients (38%). The risk of AF recurrence was higher in the group with undiagnosed SDB in comparison to those without SDB (51% versus 31%, P = 0.04). Interestingly, the prevalence of AF recurrence was similar between patients with previously diagnosed and undiagnosed SDB (51% versus 50%, P = 0.92)., Conclusion: A significant proportion of patients undergoing catheter ablation of AF have undiagnosed SDB which is associated with a twofold higher risk of AF recurrence. SDB screening may improve patient counselling regarding the efficacy of catheter ablation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Purpose: During transvenous lead extraction (TLE), the femoral snare has mainly been used as a bail-out procedure. The purpose of the present study is to evaluate the efficacy and safety of a TLE approach with a low threshold to use a combined superior and femoral approach., Methods: This is a single-center observational study including all TLE procedures between 2012 till 2019., Results: A total of 264 procedures (median age 63 (51-71) years, 67.0% male) were performed in the study period. The main indications for TLE were lead malfunction (67.0%), isolated pocket infection (17.0%) and systemic infection (11.7%). The median dwelling time of the oldest targeted lead was 6.8 (4.0-9.7) years. The techniques used to perform the procedure were the use of a femoral snare only (30%), combined rotational powered sheath and femoral snare (25%), manual traction only (20%), rotational powered sheath only (17%) and locking stylet only (8%). The complete and clinical procedural success rate was 90.2% and 97.7%, respectively, and complete lead removal rate was 94.1% of all targeted leads. The major and minor procedure-related complication rates were 1.1% and 10.2%, respectively. There was one case (0.4%) of emergent sternotomy for management of cardiac avulsion. Furthermore, there were 5 in-hospital non-procedure-related deaths (1.9%), of whom 4 were related to septic shock due to a Staphylococcus aureus endocarditis after an uncomplicated TLE with complete removal of all leads., Conclusion: An effective and safe TLE procedure can be achieved by using the synergy between a superior and femoral approach., (© 2020. The Author(s).)

Introduction: The presence of a chronic total occlusion (CTO) is associated with an increased risk of ventricular arrhythmias., Areas Covered: This review provides an overview of the relationship between CTO and ventricular arrhythmias, arrhythmogenic mechanisms, and the effect of revascularization., Expert Opinion: Studies in recipients of an implantable cardioverter-defibrillator (ICD) have shown that a CTO is an independent predictor of appropriate ICD therapy. The myocardial territory supplied by a CTO is a pro-arrhythmogenic milieu characterized by scar tissue, large scar border zone, hibernating myocardium, residual ischemia despite collaterals, areas of slow conduction, and heterogeneity in repolarization. Restoring coronary flow by revascularization might be associated with electrical homogenization as reflected by a decrease in QT(c) dispersion, decrease in T wave peak-to-end interval, reduction of late potentials, and decrease in scar border zone area. Future research should explore whether CTO revascularization results in a lower burden of ventricular arrhythmias. Furthermore, risk stratification of CTO patients without severe LV dysfunction is interesting to identify potential ICD candidates. Potential tools for risk stratification are the use of electrocardiographic parameters, body surface mapping, electrophysiological study, and close rhythm monitoring using an insertable cardiac monitor.

Premature ventricular complexes (PVCs) are the most common ventricular arrhythmia. Despite the high prevalence, the cause of PVCs remains elusive in most patients. A better understanding of the underlying pathophysiological mechanism may help to steer future research. This review aims to provide an overview of the potential pathophysiological mechanisms of PVCs and their differentiation., (Copyright © 2020 Hoogendijk, Géczy, Yap and Szili-Torok.)

Aims: After the introduction of the European Society of Cardiology (ESC) guidelines on prevention, diagnosis, and treatment of infective endocarditis (IE) in 2009, prophylaxis for patients at risk became less strict. We hypothesize that there will be a rise in IE after the introduction of the guideline update., Methods and Results: We performed a nationwide retrospective trend study using segmented regression analysis of the interrupted time series. The patient data were obtained via the national healthcare insurance database, which collects all the diagnoses nationwide. We compared the data before and after the introduction of the 2009 ESC guideline. Between 2005 and 2011, a total of 5213 patients were hospitalized with IE in the Netherlands. During this period, there was a significant increase in IE from 30.2 new cases per 1 000 000 in 2005 to 62.9 cases per 1 000 000 in 2011 (P < 0.001). In 2009, the incidence of IE increased significantly above the projected historical trend (rate ratio: 1.327, 95% CI: 1.205-1.462; P < 0.001). This coincides with the introduction of the 2009 ESC guideline. After the introduction of the ESC guideline, the streptococci-positive cultures increased significantly in the following years 2010-11 from 31.1 to 53.2% (P = 0.0031)., Conclusion: This observational study shows that there has been a steady increase in the IE incidence between 2005 and 2011. After the introduction of the 2009 ESC guidelines, the incidence increased more than expected from previous historical trends. Furthermore, there was a significant increase in streptococci-related IE cases., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: Transgenic mice are frequently used to investigate the role of genes involved in cardiac conduction. The QRS duration calculated from the electrocardiogram (ECG) is a commonly used measure for ventricular conduction time. However, the relation between ventricular activation and QRS duration calculated from a mouse surface ECG is not well understood. We aim to relate ventricular activation and repolarization patterns with the mouse ECG., Methods and Results: Ventricular activation and repolarization patterns generated by high-density optical mapping and a six-lead pseudo-ECG were compared in isolated mouse hearts. In addition, mouse ECGs were simulated in silico. Right-ventricular activation ends later than left-ventricular activation. Final activation coincided with the end of the QRS complex in leads III and aVF, but not in leads I, II, aVR, and aVL. The pattern of early repolarization (at 20% of repolarization, RT20) but not of RT50 or RT80 followed the activation pattern. After sodium channel blockade by ajmaline, total ventricular activation time increased by 10.0 ms, whereas QRS duration increased by only 2.1 ms. In mice carrying a mutation in Scn5a (1798insD), ventricular activation ended after the end of the QRS complex (12.9 ± 0.1 vs. 10.8 ± 0.3)., Conclusion: In the mouse, ventricular myocardium activation and early repolarization waves are simultaneously present. This hampers unequivocal interpretation of the duration of the QRS complex as a measure of ventricular activation duration, especially when conduction is slowed. Under these conditions mapping of local activation and repolarization patterns is required for correct interpretation of the ECG.

Objective: Atrial fibrosis is related to atrial fibrillation but may differ in patients with mitral valve disease or lone atrial fibrillation. Therefore, we studied atrial fibrosis in patients with atrial fibrillation+mitral valve disease or with lone atrial fibrillation and compared it with controls., Methods: Left and right atrial appendages amputated during Maze III surgery for lone atrial fibrillation (n=85) or atrial fibrillation+mitral valve disease (n=26) were embedded in paraffin, sectioned, and stained with picrosirius red. Atria from 10 deceased patients without a cardiovascular history served as controls. A total of 1048 images (4-μm sections, 10-fold magnification, 4 images per appendage) were obtained and digitized. The percentage of fibrous tissue was calculated by quantitative morphometry., Results: Irrespective of the presence or absence of atrial fibrillation or mitral valve disease, more fibrous tissue was present in right atrial appendages than in left atrial appendages (12.7%±5.7% vs 8.2%±3.9%; P<.0001). The mean amount of fibrous tissue in the atria was significantly larger in patients with atrial fibrillation+mitral valve disease than in patients with lone AF and controls (13.6%±5.8%, 9.7%±3.2%, and 8.8%±2.4%, respectively; P<.01). No significant differences existed between patients with lone atrial fibrillation and patients without a cardiovascular history (controls)., Conclusions: Atria of patients with atrial fibrillation and mitral valve disease have more fibrosis than atria of patients with lone atrial fibrillation. However, patients with lone atrial fibrillation have an equal amount of atrial fibrosis compared with controls. These findings support the notion that fibrosis plays a more important role in the pathogenesis of atrial fibrillation secondary to mitral valve disease than in lone atrial fibrillation and potentially explains the relatively poor success of antiarrhythmic surgery in patients with mitral valve disease., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada syndrome are distinct clinical entities which diagnostic criteria exclude their coexistence in individual patients. ARVC is a myocardial disorder characterized by fibro-fatty replacement of the myocardium and ventricular arrhythmias. In contrast, the Brugada syndrome has long been considered a functional cardiac disorder: no gross structural abnormalities can be identified in the majority of patients and its electrocardiographic hallmark of coved-type ST-segment elevation in right precordial leads is dynamic. Nonetheless, a remarkable overlap in clinical features has been demonstrated between these conditions. This review focuses on this overlap and discusses its potential causes and consequences.

Objectives: We used a murine model of arrhythmogenic right ventricular cardiomyopathy (ARVC) to test whether reducing ventricular load prevents or slows development of this cardiomyopathy., Background: At present, no therapy exists to slow progression of ARVC. Genetically conferred dysfunction of the mechanical cell-cell connections, often associated with reduced expression of plakoglobin, is thought to cause ARVC., Methods: Littermate pairs of heterozygous plakoglobin-deficient mice (plako(+/-)) and wild-type (WT) littermates underwent 7 weeks of endurance training (daily swimming). Mice were randomized to blinded load-reducing therapy (furosemide and nitrates) or placebo., Results: Therapy prevented training-induced right ventricular (RV) enlargement in plako(+/-) mice (RV volume: untreated plako(+/-) 136 ± 5 μl; treated plako(+/-) 78 ± 5 μl; WT 81 ± 5 μl; p < 0.01 for untreated vs. WT and untreated vs. treated; mean ± SEM). In isolated, Langendorff-perfused hearts, ventricular tachycardias (VTs) were more often induced in untreated plako(+/-) hearts (15 of 25), than in treated plako(+/-) hearts (5 of 19) or in WT hearts (6 of 21, both p < 0.05). Epicardial mapping of the RV identified macro-re-entry as the mechanism of ventricular tachycardia. The RV longitudinal conduction velocity was reduced in untreated but not in treated plako(+/-) mice (p < 0.01 for untreated vs. WT and untreated vs. treated). Myocardial concentration of phosphorylated connexin43 was lower in plako(+/-) hearts with VTs compared with hearts without VTs and was reduced in untreated plako(+/-) compared with WT (both p < 0.05). Plako(+/-) hearts showed reduced myocardial plakoglobin concentration, whereas β-catenin and N-cadherin concentration was not changed., Conclusions: Load-reducing therapy prevents training-induced development of ARVC in plako(+/-) mice., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Recently, we demonstrated that ajmaline caused ST segment elevation in the heart of an SCN5A mutation carrier by excitation failure in structurally discontinuous myocardium. In patients with Brugada syndrome, ST segment elevation is modulated by cardiac sodium (I(Na)), transient outward (I(to)), and L-type calcium currents (I(CaL))., Objective: To establish experimentally whether excitation failure by current-to-load mismatch causes ST segment elevation and is modulated by I(to) and I(CaL)., Methods: In porcine epicardial shavings, isthmuses of 0.9, 1.1, or 1.3 mm in width were created parallel to the fiber orientation. Local activation was recorded electrically or optically (di-4-ANEPPS) simultaneously with a pseudo-electrocardiogram (ECG) before and after ajmaline application. Intra- and extracellular potentials and ECGs were simulated in a computer model of the heart and thorax before and after introduction of right ventricular structural discontinuities and during varying levels of I(Na), I(to), and I(CaL)., Results: In epicardial shavings, conduction blocked after ajmaline in a frequency-dependent manner in all preparations with isthmuses ≤ 1.1 mm width. Total conduction block occurred in three of four preparations with isthmuses of 0.9 mm versus one of seven with isthmuses ≥ 1.1 mm (P<.05). Excitation failure resulted in ST segment elevation on the pseudo-ECG. In computer simulations, subepicardial structural discontinuities caused local activation delay and made the success of conduction sensitive to I(Na), I(to), and I(CaL). Reduction of I(to) and increase of I(CaL) resulted in a higher excitatory current, overcame subepicardial excitation failure, and reduced the ST segment elevation., Conclusions: Excitation failure by current-to-load mismatch causes ST segment elevation and, like ST segment elevation in Brugada patients, is modulated by I(to) and I(CaL)., (Copyright © 2011 Heart Rhythm Society. All rights reserved.)

Background: The Brugada sign has been associated with mutations in SCN5A and with right ventricular structural abnormalities. Their role in the Brugada sign and the associated ventricular arrhythmias is unknown., Objective: The purpose of this study was to delineate the role of structural abnormalities and sodium channel dysfunction in the Brugada sign., Methods: Activation and repolarization characteristics of the explanted heart of a patient with a loss-of-function mutation in SCN5A (G752R) and dilated cardiomyopathy were determined after induction of right-sided ST-segment elevation by ajmaline. In addition, right ventricular structural discontinuities and sodium channel dysfunction were simulated in a computer model encompassing the heart and thorax., Results: In the explanted heart, disappearance of local activation in unipolar electrograms at the basal right ventricular epicardium was followed by monophasic ST-segment elevation. The local origin of this phenomenon was confirmed by coaxial electrograms. Neither early repolarization nor late activation correlated with ST-segment elevation. At sites of local ST-segment elevation, the subepicardium was interspersed with adipose tissue and contained more fibrous tissue than either the left ventricle or control hearts. In computer simulations entailing right ventricular structural discontinuities, reduction of sodium channel conductance or size of the gaps between introduced barriers resulted in subepicardial excitation failure or delayed activation by current-to-load mismatch and in the Brugada sign on the ECG., Conclusion: Right ventricular excitation failure and activation delay by current-to-load mismatch in the subepicardium can cause the Brugada sign. Therefore, current-to-load mismatch may underlie the ventricular arrhythmias in patients with the Brugada sign.

Background: Brugada syndrome (BrS) is associated with lethal arrhythmias, which are linked to specific ST-segment changes (type-1 BrS-ECG) and the right ventricle (RV). The pathophysiological basis of the arrhythmias and type-1 BrS-ECG is unresolved. We studied the electrophysiological characteristics of the RV endocardium in BrS., Methods and Results: RV endocardial electroanatomical mapping and stimulation studies were performed in controls (n=12) and BrS patients with a type-1 (BrS-1, n=10) or type-2 BrS-ECG (BrS-2, n=12) during the studies. BrS-1 patients had prominent impairment of RV endocardial impulse propagation when compared with controls, as represented by: (1) prolonged activation-duration during sinus rhythm (86+/-4 versus 65+/-3 ms), (2) increased electrogram fractionation (1.36+/-0.04 versus 1.15+/-0.01 deflections per electrogram), (3) longer electrogram duration (83+/-3 versus 63+/-2 ms), (4) activation delays on premature stimulation (longitudinal: 160+/-26 versus 86+/-9 ms; transversal: 112+/-5 versus 58+/-6 ms), and (5) abnormal transversal conduction velocity restitution (42+/-8 versus 18+/-2 ms increase in delay at shortest coupling intervals). Wider and more fractionated electrograms were also found in BrS-2 patients. Repolarization was not different between groups., Conclusions: BrS-1 and BrS-2 patients are characterized by wide and fractionated electrograms at the RV endocardium. BrS-1 patients display additional conduction slowing during sinus rhythm and premature stimulation along with abnormal transversal conduction velocity restitution. These patients may thus exhibit a substrate for slow and discontinuous conduction caused by abnormal active membrane processes and electric coupling. Our findings support the emerging notion that BrS is not solely attributable to abnormal electrophysiological properties but requires the conspiring effects of conduction slowing and tissue discontinuities.