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Cardiac arrhythmias are increasingly recognized as dynamic clinical phenotypes arising from the interplay between myocardial substrate, systemic biology, and modifiable exposures rather than as isolated disorders of cardiac electrophysiology. Advances in the field have broadened the conceptual framework of arrhythmia medicine to include structural remodeling, inflammation, autonomic dysfunction, metabolic perturbation, endothelial injury, and aging-related vulnerability as central determinants of arrhythmic risk, progression, and treatment response. In parallel, diagnostic paradigms are evolving from rhythm classification alone toward multidimensional phenotyping that integrates clinical, physiological, and imaging-based markers to identify susceptibility earlier and with greater precision. These developments are also reshaping therapeutic strategy, supporting a shift from uniform treatment algorithms toward individualized care in which rhythm control, surveillance, risk-factor modification, anticoagulation, and antiarrhythmic drug selection are aligned with the underlying biological context. This more integrated view positions arrhythmias not simply as electrical events to be suppressed, but as manifestations of broader cardiovascular and systemic disease processes that require mechanistically informed and phenotype-directed management.

Mitral valve prolapse (MVP) is a common valvular heart defect with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. Herein, we report a clinical and genetic investigation of a family with bileaflet MVP and a history of syncopes and resuscitated sudden cardiac death. Using family based whole exome sequencing, we identified two missense variants in the SCN5A gene. A rare variant SCN5A:p.Ala572Asp and the well-known functional SCN5A:p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father and sister carried only the SCN5A:p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as the potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history.

A new automated vector-based mapping algorithm (AMA) for 3-dimensional (3D) mapping has been introduced. The aim of this study was to present our experience using AMA to recognize additional catheter ablation targets in patients with ventricular arrhythmias (VA). A total of 16 patients (ICM; ischemic cardiomyopathy, n  = 6; NICM; non-ischemic cardiomyopathy n  = 10) suffering from VA underwent catheter ablation. Following bipolar voltage mapping, AMA was utilized to reveal zones of decelerated conduction velocity vectors (CVV) and this information was superimposed onto the 3D reconstructions and compared with the presence of scar. Mapping time was 28.1 ± 10 min for the endocardial reconstruction of the left ventricle (LV) and 17 ± 5.4 min for the epicardium ( n  = 6 patients). The mean area of LV low voltage was 13.9 ± 15% (endocardial) and 11.9 ± 5.7% (epicardial). Decelerating CVV zones were revealed in all patients (mean conduction velocity threshold of 39.3 ± 13%). Sustained VA have been terminated through ablation and substrate modification was performed in all patients. Correlation between the presence of CVV deceleration zones and areas of abnormal low voltage from bipolar mapping was revealed in only 37.5% of patients, but there was good correlation between scar from unipolar voltage mapping and the presence of CCV deceleration zones (94%; p  = 0.008). The novel AMA may improve the understanding of individual VA substrates due to the visualization of decelerated CVV zones and their correlation with abnormal low voltage predominantly from unipolar mapping.

Abstract Background This case reviews the cardiac involvement of myotonic dystrophy type 2 in terms of ventricular arrhythmias (VAs) and individual myocardial scar formation as target for catheter ablation. Case summary A 62-year-old woman with myotonic dystrophy type 2 and a severely reduced left ventricular ejection fraction (25%) presented with recurrent episodes of VAs and consecutive implantable cardioverter-defibrillator therapies. The patient already underwent two VA ablation attempts focusing on an ischaemia-related arrhythmia substrate in the left ventricle. The patient was scheduled for repeat ablation after the progression of coronary artery disease was ruled out. Interestingly bipolar voltage as well as activation mapping revealed an arrhythmia substrate along with the basal and inferior aspects of the right ventricle (RV). Catheter ablation of this scarred area in the RV resulted in specific termination of the VAs. Due to end-stage heart failure, key heart transplant criteria were met. The patient was evaluated for heart transplantation and added to the waiting list. Hitherto, no further VAs were documented during follow-up. Discussion As these patients present with specific dystrophia-related arrhythmia substrates, we propose pre-procedural visualization of dystrophy-associated arrhythmia substrates using cardiac magnetic resonance imaging allowing for personalized ablation approaches in these patients.

This chapter contains sections titled: Introduction Pericardial anatomy Pericardial access Applications of pericardial access Percutaneous subxiphoid technique for pericardial access for catheter mapping and ablation of arrhythmias Cleveland Clinic Foundation experience with percutaneous subxiphoid epicardial catheter mapping and ablation Prediction of epicardial arrhythmia substrate Unique challenges posed by percutaneous epicardial ablation Other applications of percutaneous pericardial access Summary

This chapter contains sections titled: Introduction Substrate ablation for VT Semianatomic approach to ablation of polymorphic VT Anatomic ablation of AF Summary

Heart failure (HF) and atrial fibrillation (AF) are 2 cardiac conditions that are increasing in prevalence and incidence. The 2 conditions frequently coexist, and are associated with increased morbidity and mortality. Catheter ablation of AF has been successfully performed in patients with HF, with an improvement in HF and AF, when compared to amiodarone, but further data is required to compare this to rate control. The primary objective is to determine whether AF treated by catheter ablation, with or without antiarrhythmic drugs reduces all-cause mortality and hospitalizations for HF as compared with rate control in patients with HF and a high burden AF. This is a multi-center prospective randomized open blinded endpoint (PROBE) study. Patients with NYHA class II-III HF (HF with reduced ejection fraction (<35%) or HF with preserved ejection fraction), and high burden AF are included in the trial. Patients are randomized to either rate control or catheter ablation-based AF rhythm control in a 1:1 ratio. Patients in the rate control group receive optimal HF therapy and rate control measures to achieve a resting hazard ratio (HR) < 80 bpm and 6-minute walk HR < 110 bpm. Patients randomized to catheter ablation-based AF rhythm control group receive optimal HF therapy and one or more aggressive catheter ablation, which include PV antral ablation and LA substrate ablation with or without adjunctive antiarrhythmic drug. The primary outcome is a composite of all-cause mortality and hospitalization for heart failure defined as an admission to a health care facility. The sample size is 600. Enrolment has been completed.

Cardiovascular toxicity is a potential complication of cancer chemotherapy (CC) that increases the morbidity and mortality of cancer patients. Cardiac arrhythmias have been reported as an adverse effect of many chemotherapeutic drugs, including novel targeted therapies. The relationship between chemotherapy and arrhythmias has not been well-established and the proarrhythmogenic mechanisms remain uncertain as they can be the result of a direct electrophysiological effect or of changes in cardiac structure and function, including myocardial ischaemia and heart failure, which create an arrhythmogenic substrate. In this review we summarise available evidence of proarrhythmia induced by CC, discuss the possible mechanisms involved in this adverse effect and emphasise the importance of cardiac monitoring for the early diagnosis, intervention and surveillance of those patients more susceptible to develop proarrhythmia in an attempt to reduce the morbidity and mortality. Oncologists should be fully aware of proarrhythmia and the close collaboration between cardiologists and oncologists would result in a better cardiovascular assessment, risk stratification, cardiac monitoring and treatment during CC and during the follow-up. The final objective is to understand the mechanisms of proarrhythmia and evaluate its real incidence and clinical relevance so as to select the safest and most effective treatment for cancer patients.

Background Stereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75–85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation. Objective A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. Methods Patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D. Discussion DEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure. Trial registration NCT05594368.

Background Cardiac resynchronization therapy (CRT) can provide cardiac reverse remodeling (RR), which may include mechanical reverse remodeling (MRR) and/or electrical reverse remodeling (ERR). However, uncoupling of MRR and ERR is not uncommon, and the underlying mechanisms are not clear. This study aimed to evaluate the relationship of myocardial substrate characteristics as assessed by myocardial perfusion imaging (MPI) and cardiac RR post-CRT. Materials and methods Forty-one patients (26 men, mean age 66 ± 10 years) with heart failure received CRT for at least 12 months were assigned to three groups according to their levels of RR: I, MRR + ERR (ESV reduced ≥15 % and intrinsic QRS duration reduced ≥10 ms); II, MRR only (ESV reduced ≥15 %); and III, non-responder (the others). All the patients also underwent MPI under transient CRT-off to evaluate the intrinsic myocardial substrates, including myocardial scar, LV volumes and function, systolic dyssynchrony, and activation sequences. In addition, ventricular tachycardia (VT) and ventricular fibrillation (VF) detected by the CRT devices during follow-up periods were also recorded. Results Quantitative analysis of MPI showed that there were significant differences for scar burden [15.9 ± 9.5, 26.8 ± 16.1, and 45.6 ± 15.1 % for group I ( n  = 15), II ( n  = 16), and III ( n  = 10), respectively, p  < 0.001], EDV (136.6 ± 64.9, 221.6 ± 123.9, and 351.8 ± 216.3 ml, p  = 0.002), ESV (82.6 ± 59.8, 172.3 ± 117.2, and 293.3 ± 209.6 ml, p  = 0.001), LVEF (44.9 ± 15.0, 25.6 ± 10.9, and 21.5 ± 11.7 %, p  < 0.001), systolic phase SD (23.4° ± 10.3°, 36.0° ± 16.2°, and 57.0° ± 22.2°, p  < 0.001), and bandwidth (72.5° ± 31.1°, 113.4° ± 56.4°, and 199.1° ± 90.1°, p  < 0.001). Myocardial scar interfered with the normal propagation of mechanical activation, resulting in heterogeneous activation sequences. Compared with group II (MRR only), group I (ERR + MRR) had significantly less initial activation segments (1.9 ± 1.0 vs. 2.6 ± 0.7, p  < 0.05) and shorter maximal contraction delay (46.9° ± 12.9° vs. 58.8° ± 18.5°, p  < 0.05). During the periods of follow-up, 21 patients developed VT/VF, including only 1 patient (1 VT) in group I (6.7 %), 8 patients (7 VT and 1 VF) in group II (50 %), and 9 patients (7 VT and 5 VF) in group III (90 %). Conclusion The characteristics of myocardial substrates as assessed by MPI differed significantly between different levels of cardiac RR post-CRT. Myocardial scar played an important role in the development of ERR. Different cardiac RR levels contributed to different incidences of ventricular arrhythmia, and the combination of ERR and MRR provided highest anti-arrhythmic effects.