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Connexins are crucial cardiac proteins that form hemichannels and gap junctions. Gap junctions are responsible for the propagation of electrical and chemical signals between myocardial cells and cells of the specialized conduction system in order to synchronize the cardiac cycle and steer cardiac pump function. Gap junctions are normally open, while hemichannels are closed, but pathological circumstances may close gap junctions and open hemichannels, thereby perturbing cardiac function and homeostasis. Current evidence demonstrates an emerging role of hemichannels in myocardial ischemia and arrhythmia, and tools are now available to selectively inhibit hemichannels without inhibiting gap junctions as well as to stimulate hemichannel incorporation into gap junctions. We review available experimental evidence for hemichannel contributions to cellular pro-arrhythmic events in ventricular and atrial cardiomyocytes, and link these to insights at the level of molecular control of connexin-43-based hemichannel opening. We conclude that a double-edged approach of both preventing hemichannel opening and preserving gap junctional function will be key for further research and development of new connexin-based experimental approaches for treating heart disease., Introduction The coordinated functioning of the heart as a pump heavily relies on communication between more than 3 billion cardiomyocytes via connexin-based gap junctions (GJs). GJs connecting cardiomyocytes and cells [...]

Introduction: Esophageal safety following radiofrequency (RF) left atrial (LA) linear ablation has not been established. To determine the esophageal safety profile of LA linear RF lesions, we performed systematic esophagogastroduodenoscopy in all patients with intraesophageal temperature rise (ITR) ≥ 38.5°C. Methods and Results: Between December 2021 and July 2023, a total of 200 consecutive patients with atrial tachyarrhythmia (ATA) underwent linear ablation with posterior dome (roof or floor) or posterior mitral isthmus line transection. Patients with ITR ≥ 38.5°C were scheduled for esophageal endoscopy ~3 weeks after ablation. Patient and ATA characteristics, procedural parameters, endoscopy findings and ablation lesion data were collected and analyzed. One hundred thirty‐three out of 200 (67%) patients showed ITR ≥ 38.5°C during LA linear ablation. ITR (with maximal temperature of 45.7°C) was more frequently observed during floor line ablation (82% of cases). ITR was less observed during roof line ablation (34%) and posterior mitral isthmus ablation (4%). Endoscopy, performed in 115 patients after 24 ± 10 days, showed esophageal ulceration in four patients (two patients Kansas City classification [KCC] 2a and two patients KCC 2b). No patient showed esophageal perforation or fistula. Conclusion: Temperature rise during LA linear ablation is frequent and ulceration risk exists, particularly when floor line is performed. Safety measures are needed to avoid potential severe complications like esophageal perforation and fistula. [ABSTRACT FROM AUTHOR]

The outcomes of persistent atrial fibrillation (AF) ablation are modest with various adjunctive strategies beyond pulmonary vein isolation (PVI) yielding largely disappointing results in randomised controlled trials. Linear ablation is a commonly employed adjunct strategy but is limited by difficulty in achieving durable bidirectional block, particularly at the mitral isthmus. Epicardial connections play a role in AF initiation and perpetuation. The ligament of Marshall has been implicated as a source of AF triggers and is known to harbour sympathetic and parasympathetic nerve fibres that contribute to AF perpetuation. Ethanol infusion into the Vein of Marshall, a remnant of the superior vena cava and key component of the ligament of Marshall, may eliminate these AF triggers and can facilitate the ease of obtaining durable mitral isthmus block. While early trials have demonstrated the potential of Vein of Marshall 'ethanolisation' to reduce arrhythmia recurrence after persistent AF ablation, further randomised trials are needed to fully determine the potential long-term outcome benefits afforded by this technique. [ABSTRACT FROM AUTHOR]

Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic [Ca.sup.2+] release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic [Ca.sup.2+] release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel [Ca.sup.2+] entry and coupling to [Ca.sup.2+] release microdomains at the intercalated disc, resulting in enhanced [Ca.sup.2+] dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and [Ca.sup.2+] release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure., Introduction The pumping function of the heart is coordinated by electrical waves of excitation propagating through the myocardium and initiating cardiac contraction. Propagation of action potentials between cardiomyocytes is coordinated [...]

Persistent atrial fibrillation (AF) is a diverse condition that includes various subtypes and underlying causes of arrhythmia. Progress made in catheter ablation technology in recent years has significantly enhanced the durability of ablation. Despite these advances however, the effectiveness of ablation in treating persistent AF is still relatively modest. Studies exploring the mechanisms behind persistent AF have identified substrate-driven focal and re-entrant sources within the atrial body as crucial in sustaining AF among individuals with persistent AF. Furthermore, the widespread adoption of atrial late gadolinium enhancement cardiac magnetic resonance (CMR) imaging and the ongoing refinement of invasive voltage mapping techniques have allowed for detailed assessment of fibrotic remodelling prior to or at the time of procedure. Translation into clinical practice, however, has yielded overall disappointing results. The clinical application of AF mapping in ablation procedures has not shown any substantial advantages beyond the use of pulmonary vein isolation (PVI) alone and adjunct ablation of fibrotic areas has yielded conflicting results in recent randomized trials. The emergence of pulsed field ablation represents a welcome development in the field and several studies have demonstrated an enhanced safety profile and increased procedural efficiency with this non-thermal energy modality. Pulsed field ablation also holds promise for safe and efficient substrate ablation beyond the pulmonary veins, but further trials are needed to assess its impact on longer term success rates. Continued advancements in our comprehension of AF mechanisms, alongside ongoing developments in catheter technology aimed at safe formation of transmural lesions, are essential for achieving better clinical outcomes for patients with persistent AF. [ABSTRACT FROM AUTHOR]

Background: Sudden cardiac death (SCD) is generally associated with life-threatening ventricular arrhythmias. Supraventricular arrhythmias are an accepted cause of SCD in Wolff-Parkinson-White syndrome and complex congenital heart disease. However, the role of atrial tachyarrhythmias (ATAs) in SCD in patients with structurally normal hearts is unclear., Objectives: The goal of this study was to present data on resuscitated patients without structural heart disease (SHD), experiencing recurrent implantable cardioverter-defibrillator (ICD) shocks, who share common clinical and electrical features suggesting that ATAs can cause SCD., Methods: We describe the clinical characteristics and ICD analysis of syncopal events terminated with shock delivery in 5 young SCD survivors without SHD. Details on the follow-up after ablation of the arrhythmia causing the syncopal episode are also reported., Results: In all patients (4 male, 1 female; median age 23 years; age range 15-47 years), a surface electrocardiogram recording in the resuscitation setting suggested ventricular fibrillation. After the index event, all patients exhibited recurrent arrhythmic syncopal episodes in a setting of elevated adrenergic tone, treated with ICD shocks. ICD interrogation suggested ATAs (atrial fibrillation in 4 patients, atrial tachycardia in 1 patient), conducting to the ventricles at rates approaching 300 beats/min, as the underlying arrhythmia leading to the syncopal events. ATA ablation abolished episodes of arrhythmic syncope and shock delivery in all patients after a median follow-up of 34 months. No patient died suddenly during follow-up., Conclusions: Common clinical and electrical features define a distinct entity of SCD caused by ATAs with ultra-rapid ventricular response in otherwise healthy patients. Catheter ablation of the ATA is an effective treatment in these patients., 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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: none declared.

Aims: Achieving acute and durable mitral isthmus (MI) block remains challenging using radiofrequency (RF) catheter ablation alone. Vein of Marshall (VoM) ethanolization results in chemical damage along the MI resulting in the creation of a durable transmural lesion with a very high rate of procedural block. However, no studies have systematically assessed the efficacy of MI ablation alone when no anatomical VoM is present., Methods and Results: Thirty seven patients without VoM evidenced after careful angiographic examination were included. Ablation parameters and result were compared with a matched control group in whom the posterior MI line was performed without assessing the presence of the VoM. Mitral isthmus block was achieved in 36 out of 37 patients without VoM (97%), with endocardial ablation only in 5/37 (14%) and combined endocardial and coronary sinus ablation in 32/37 patients (86%). There was a significant difference in the occurrence of block between patients without a VoM and the control group (97.3% vs. 65% respectively, P < 0.01), with a trend towards less needed RF {26 [interquartile range (IQR) 20-38] vs. 29 [IQR 19-40] tags [P = 0.8], 611 [IQR 443-805] vs. 746 [IQR 484-1193] seconds [P = 0.08]}., Conclusion: The absence of a VoM is associated with a very high rate of procedural block during posterior MI ablation. The higher rate of MI block in this specific population would also suggest the crucial role of the VoM (when present) in resistant MI block., Competing Interests: Conflict of interest: All authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Left ventricular (LV) summit arrhythmias account for up to 14% of LV arrhythmias. The ablation of LV summit arrhythmias is challenging, as testified by the fact that radiofrequency (RF) catheter ablation failure is frequent. Retrograde coronary venous ethanol infusion has been proposed as an alternative approach for the ablation of LV summit arrhythmias., Case Summary: A 47-year-old man with Lamin A/C cardiomyopathy was referred for the ablation of a pleiomorphic ventricular tachycardia (VT) storm, with dominant morphology compatible with LV summit origin. He first received a combined endo- and epicardial RF ablation with the elimination of three clinically relevant VTs. However, the dominant VT could not be ablated due to the proximity of the coronary vasculature and phrenic nerve and remained inducible. Accordingly, an urgent rescue redo procedure consisting of retrograde coronary venous ethanol ablation was performed. Based on the best pace-match and precocity, the first septal, retro-pulmonary branch and the first diagonal branch were infused with ethanol with immediate cessation of the tachycardia and non-inducibility. Anti-arrhythmic drugs were withdrawn, while guideline-directed medical therapy for heart failure was continued. No complications occurred. After 3 months, the patient remained free from any arrythmias., Discussion: Ablation of LV summit arrythmias is challenging, especially in the context of an electrical storm or in patients with structural heart disease. In such a situation, rescue ablation with retrograde coronary venous ethanol infusion represents an attractive alternative ablation modality., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Recurrent atrial tachycardia (AT) is a common phenomenon after catheter ablation for AF, particularly in the setting of additional substrate ablation, with many studies demonstrating gap-related macro re-entrant AT (predominantly mitral and roof dependent) to be the dominant mechanism. Although multiple inducible ATs after ablation of the clinical AT are commonly described at repeat procedures, the optimal ablation strategy, and procedural endpoints are unclear in this setting. A recent randomized study addressing the question of non-inducibility as a procedural endpoint demonstrated no additional benefits to the ablation of all induced, non-clinical ATs, but it was limited by small numbers and high rates of non-inducibility. Nevertheless, once ablation of the clinical AT has been successfully performed, ensuring durable linear block and PV isolation may be sufficient for the prevention of further AT. Durable linear block, particularly at the mitral isthmus, is difficult to achieve but may be facilitated by the real-time evaluation of lesion quality and contiguity and the novel technique of vein of Marshall ethanol infusion. Large-scale, randomized trials are needed, nonetheless, to fully assess the optimal ablation strategy in the setting of recurrent AT post-AF ablation., 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 O’Neill, De Becker, De Smet, Le Polain De Waroux, Tavernier, Duytschaever and Knecht.)

Aims: Connexin-based gap junctions are crucial for electrical communication in the heart; they are each composed of two docked hemichannels (HCs), supplied as unpaired channels via the sarcolemma. When open, an unpaired HC forms a large pore, high-conductance and Ca2+-permeable membrane shunt pathway that may disturb cardiomyocyte function. HCs composed of connexin 43 (Cx43), a major cardiac connexin, can be opened by electrical stimulation but only by very positive membrane potentials. Here, we investigated the activation of Cx43 HCs in murine ventricular cardiomyocytes voltage-clamped at -70 mV., Methods and Results: Using whole-cell patch-clamp, co-immunoprecipitation, western blot analysis, immunocytochemistry, proximity ligation assays, and protein docking studies, we found that stimulation of ryanodine receptors (RyRs) triggered unitary currents with a single-channel conductance of ∼220 pS, which were strongly reduced by Cx43 knockdown. Recordings under Ca2+-clamp conditions showed that both RyR activation and intracellular Ca2+ elevation were necessary for HC opening. Proximity ligation studies indicated close Cx43-RyR2 apposition (<40 nm), and both proteins co-immunoprecipitated indicating physical interaction. Molecular modelling suggested a strongly conserved RyR-mimicking peptide sequence (RyRHCIp), which inhibited RyR/Ca2+ HC activation but not voltage-triggered activation. The peptide also slowed down action potential repolarization. Interestingly, alterations in the concerned RyR sequence are known to be associated with primary familial hypertrophic cardiomyopathy., Conclusion: Our results demonstrate that Cx43 HCs are intimately linked to RyRs, allowing them to open at negative diastolic membrane potential in response to RyR activation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)