Preclinical Study of Pulsed Field Ablation of Difficult Ventricular Targets: Intracavitary Mobile Structures, Interventricular Septum, and Left Ventricular Free Wall.

BACKGROUND: Endocardial catheter-based pulsed field ablation (PFA) of the ventricular myocardium is promising. However, little is known about PFA's ability to target intracavitary structures, epicardium, and ways to achieve transmural lesions across thick ventricular tissue. METHODS: A lattice-tip catheter was used to deliver biphasic monopolar PFA to swine ventricles under general anesthesia, with electroanatomical mapping, fluoroscopy and intracardiac echocardiography guidance. We conducted experiments to assess the feasibility and safety of repetitive monopolar PFA applications to ablate (1) intracavitary papillary muscles and moderator bands, (2) epicardial targets, and (3) bipolar PFA for midmyocardial targets in the interventricular septum and left ventricular free wall. RESULTS: (1) Papillary muscles (n=13) were successfully ablated and then evaluated at 2, 7, and 21 days. Nine lesions with stable contact measured 18.3±2.4 mm long, 15.3±1.5 mm wide, and 5.8±1.0 mm deep at 2 days. Chronic lesions demonstrated preserved chordae without mitral regurgitation. Two targeted moderator bands were transmurally ablated without structural disruption. (2) Transatrial saline/carbon dioxide assisted epicardial access was obtained successfully and epicardial monopolar lesions had a mean length, width, and depth of 30.4±4.2, 23.5±4.1, and 9.1±1.9 mm, respectively. (3) Bipolar PFA lesions were delivered across the septum (n=11) and the left ventricular free wall (n=7). Twelve completed bipolar lesions had a mean length, width, and depth of 29.6±5.5, 21.0±7.3, and 14.3±4.7 mm, respectively. Chronically, these lesions demonstrated uniform fibrotic changes without tissue disruption. Bipolar lesions were significantly deeper than the monopolar epicardial lesions. CONCLUSIONS: This in vivo evaluation demonstrates that PFA can successfully ablate intracavitary structures and create deep epicardial lesions and transmural left ventricular lesions.

Active Arrhythmia Pattern: A Novel Predictor of ICD Shocks-A Subanalysis From the PARTITA Study.

BACKGROUND: In the PARTITA trial (Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients With an Implantable Cardioverter Defibrillator?), antitachycardia pacing (ATP) predicted the occurrence of implantable cardioverter defibrillator (ICD) shocks. Catheter ablation of ventricular tachycardia after the first shock reduced the risk of death or worsening heart failure. A threshold of ATPs that might warrant an ablation procedure before ICD shocks is unknown. Our aim was to identify a threshold of ATPs and clinical features that predict the occurrence of shocks and cardiovascular events. METHODS: We analyzed data from 517 patients in phase A of the PARTITA study. We used classification and regression tree analysis to develop and test a risk stratification model based on arrhythmia patterns and clinical data to predict ICD shocks. Secondary end points were worsening heart failure and cardiovascular hospitalization. RESULTS: Classification and regression tree classified patients into 6 leaves by increasing shock probability. Patients treated with ≥5 ATPs in 6 months (active arrhythmia pattern) had the highest risk of ICD shocks (93% and 86%, training and testing samples, respectively). Patients without ATPs had the lowest (1% and 2%). Other predictors included left ventricle ejection fraction<35%, age of <60 years, and obesity. Survival analysis revealed a higher risk of worsening heart failure (hazard ratio, 5.45 [95% CI, 1.62-18.4]; P=0.006) and cardiovascular hospitalization (hazard ratio, 7.29 [95% CI, 3.66-14.5]; P<0.001) for patients with an active arrhythmia pattern compared with those without ATPs. CONCLUSIONS: Patients with an active arrhythmia pattern (≥5 ATPs in 6 months) are associated with an increased risk of ICD shocks, as well as heart failure hospitalization and cardiovascular hospitalization. These data suggest that additional treatments may be helpful to this high-risk group as a preventive strategy to reduce the incidence of major events. Further prospective randomized trials are needed to confirm the benefits of early ventricular tachycardia ablation in this setting.

Extracellular Kir2.1C122Y Mutant Upsets Kir2.1-PIP2 Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

BACKGROUND: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K+ channel Kir2.1. The extracellular Cys (cysteine)122-to-Cys154 disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state. METHODS: We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1C122Y variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments. RESULTS: Kir2.1C122Y mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1C122Y cardiomyocytes showed significantly reduced inwardly rectifier K+ (IK1) and inward Na+ (INa) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1C122Y mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and NaV1.5 proteins. CONCLUSIONS: The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the NaV1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.

Expanded application of wearable cardioverter defibrillators beyond current guidelines: proposal for a European register explained through single clinical scenarios.

The wearable cardioverter defibrillator (WCD) is becoming a more and more widely used instrument for the prevention of sudden cardiac death of patients either with a secondary prevention implantable cardioverter defibrillator indication or with a transient high risk of sudden cardiac death. Although clinical practice has demonstrated a benefit of protecting patients for a period as long as 3-6 months with such devices, the current European guidelines concerning ventricular arrhythmias and sudden cardiac death are still extremely restrictive in the patient selection in part because of the costs derived from such a prevention device, in part because of the lack of robust randomised trials.To illustrate expanded use cases for the WCD, four real-life clinical cases are presented where patients received the device slightly outside the established guidelines. These cases demonstrate the broader utility of WCDs in situations involving acute myocarditis, thyrotoxicosis, pre-excited atrial fibrillation and awaiting staging/prognosis of a lung tumour. The findings prompt expansion of the existing guidelines for WCD use to efficiently protect more patients whose risk of arrhythmic cardiac death is transient or uncertain. This could be achieved by establishing a European register of the patients who receive a WCD for further analysis.

Discrimination between ventricular tachycardia and wide-QRS preexcited tachycardia.

BACKGROUND: To develop a new algorithm to differentiate ventricular tachycardia (VT) from preexcited tachycardia (pre-ET) according to left bundle branch block (LBBB) and right bundle branch block (RBBB) patterns. METHODS: This study included 67 electrocardiograms (ECGs) with VT and 63 ECGs with pre-ET, collected from our hospital and through PubMed. Of those, 64 were allocated to the derivation cohort and the rest to the validation cohort. The diagnoses of the ECGs were confirmed using an electrophysiological study. Parameters and classifiers from prior algorithms along with the propagation speeds in the early portion of the QRS complex (initial deflection index) in leads V1, V6, aVR, II, and III were manually measured. The performance of the new algorithm was compared with that of prior algorithms. RESULTS: The initial deflection index in lead III was the strongest predictor of pre-ET in LBBB-pattern wide-QRS tachycardia (p = 0.003, AUC 0.805). The initial deflection index in lead V1 was the most powerful predictor of pre-ET in RBBB-pattern wide-QRS tachycardia (p = 0.001, AUC 0.848). Compared to earlier algorithms, those using the initial deflection indexes: lead III in LBBB patterns (cutoff value >0.3) and lead V1 in RBBB patterns (cutoff value ≤0.48), demonstrated superior performance in screening VT, with AUC values of 0.828. The initial deflection indexes proved effective as discriminators between VT and pre-ET in the validation cohort. CONCLUSIONS: In LBBB-pattern wide-QRS tachycardia, the early propagation speed of pre-ET was faster than that in VT. Conversely, in RBBB-pattern wide-QRS tachycardia, it was slower.

Review of the National Institute for Health and Care Excellence guidelines on the management of atrial and ventricular arrhythmias.

The National Institute for Health and Care Excellence (NICE) guidelines present a synopsis of extensive internal evidence and technology reviews, with a particular focus on clinical efficacy and cost-effectiveness within the NHS in England. This approach has delivered a novel perspective on arrhythmia management, with important distinctions from other policymakers' recommendations. For example, when compared with the European Society of Cardiology (ESC) and the American Heart Association (AHA)/Heart Rhythm Society (HRS)/American College of Cardiology (ACC) guidelines on atrial fibrillation (AF), NICE advocates unique strategies regarding arrhythmia detection, stroke and bleeding risk stratification, and rhythm control (NICE CG 196). Likewise, for patients at risk of sudden cardiac death, NICE TA314 not only recommends device therapy based on New York Heart Association class and ECG findings, but also incorporates quality-adjusted life year data from analysis of key randomised controlled trials.This review examines the NICE guidelines, together with those from the AHA/HRS/ACC and ESC, on the management of AF and ventricular arrhythmias and highlights the key common features and discrepancies between these important documents.

Management of arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease characterised by fibrofatty replacement of the ventricular myocardium due to specific mutations, leading to ventricular arrhythmias and sudden cardiac death. Treating this condition can be challenging due to progressive fibrosis, phenotypic variations and small patient cohorts limiting the feasibility of conducting meaningful clinical trials. Although widely used, the evidence base for anti-arrhythmic drugs is limited. Beta-blockers are theoretically sound, yet their efficacy in reducing arrhythmic risk is not robust. Additionally, the impact of sotalol and amiodarone is inconsistent with studies reporting contradictory results. Emerging evidence suggests that combining flecainide and bisoprolol may be efficacious.Radiofrequency ablation has shown some potential in disrupting ventricular tachycardia circuits, with combined endo and epicardial ablation yielding better results which could be considered at the index procedure. In addition, stereotactic radiotherapy may be a future option that can decrease arrhythmias beyond simple scar formation by altering levels of Nav1.5 channels, Connexin 43 and Wnt signalling, potentially modifying myocardial fibrosis.Future therapies, such as adenoviruses and GSk3b modulation, are still in early-stage research. While implantable cardioverter-defibrillator implantation is a key intervention for reducing arrhythmic death, the risks of inappropriate shocks and device complications must be carefully considered.

Arrhythmic Risk in Biventricular Pacing Compared With Left Bundle Branch Area Pacing: Results From the I-CLAS Study.

BACKGROUND: Left bundle branch area pacing (LBBAP) may be associated with greater improvement in left ventricular ejection fraction and reduction in death or heart failure hospitalization compared with biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy. We sought to compare the occurrence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and new-onset atrial fibrillation (AF) in patients undergoing BVP and LBBAP. METHODS: The I-CLAS study (International Collaborative LBBAP Study) included patients with left ventricular ejection fraction ≤35% who underwent BVP or LBBAP for cardiac resynchronization therapy between January 2018 and June 2022 at 15 centers. We performed propensity score-matched analysis of LBBAP and BVP in a 1:1 ratio. We assessed the incidence of VT/VF and new-onset AF among patients with no history of AF. Time to sustained VT/VF and time to new-onset AF was analyzed using the Cox proportional hazards survival model. RESULTS: Among 1778 patients undergoing cardiac resynchronization therapy (BVP, 981; LBBAP, 797), there were 1414 propensity score-matched patients (propensity score-matched BVP, 707; propensity score-matched LBBAP, 707). The occurrence of VT/VF was significantly lower with LBBAP compared with BVP (4.2% versus 9.3%; hazard ratio, 0.46 [95% CI, 0.29-0.74]; P<0.001). The incidence of VT storm (>3 episodes in 24 hours) was also significantly lower with LBBAP compared with BVP (0.8% versus 2.5%; P=0.013). Among 299 patients with cardiac resynchronization therapy pacemakers (BVP, 111; LBBAP, 188), VT/VF occurred in 8 patients in the BVP group versus none in the LBBAP group (7.2% versus 0%; P<0.001). In 1194 patients with no history of VT/VF or antiarrhythmic therapy (BVP, 591; LBBAP, 603), the occurrence of VT/VF was significantly lower with LBBAP than with BVP (3.2% versus 7.3%; hazard ratio, 0.46 [95% CI, 0.26-0.81]; P=0.007). Among patients with no history of AF (n=890), the occurrence of new-onset AF >30 s was significantly lower with LBBAP than with BVP (2.8% versus 6.6%; hazard ratio, 0.34 [95% CI, 0.16-0.73]; P=0.008). The incidence of AF lasting >24 hours was also significantly lower with LBBAP than with BVP (0.7% versus 2.9%; P=0.015). CONCLUSIONS: LBBAP was associated with a lower incidence of sustained VT/VF and new-onset AF compared with BVP. This difference remained significant after adjustment for differences in baseline characteristics between patients with BVP and LBBAP. Physiological resynchronization by LBBAP may be associated with lower risk of arrhythmias compared with BVP.

Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction.

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.