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Patients with ventricular tachycardia and ischemic cardiomyopathy are at high risk for adverse outcomes. Catheter ablation is commonly used when antiarrhythmic drugs do not suppress ventricular tachycardia. Whether catheter ablation is more effective than antiarrhythmic drugs as a first-line therapy in patients with ventricular tachycardia is uncertain. In an international trial, we randomly assigned in a 1:1 ratio patients with previous myocardial infarction and clinically significant ventricular tachycardia (defined as ventricular tachycardia storm, receipt of appropriate implantable cardioverter-defibrillator [ICD] shock or antitachycardia pacing, or sustained ventricular tachycardia terminated by emergency treatment) to receive antiarrhythmic drug therapy or to undergo catheter ablation. All the patients had an ICD. Catheter ablation was performed within 14 days after randomization; sotalol or amiodarone was administered as antiarrhythmic drug therapy according to prespecified criteria. The primary end point was a composite of death from any cause during follow-up or, more than 14 days after randomization, ventricular tachycardia storm, appropriate ICD shock, or sustained ventricular tachycardia treated by medical intervention. A total of 416 patients were followed for a median of 4.3 years. A primary end-point event occurred in 103 of 203 patients (50.7%) assigned to catheter ablation and in 129 of 213 (60.6%) assigned to drug therapy (hazard ratio, 0.75; 95% confidence interval, 0.58 to 0.97; P = 0.03). Among patients in the catheter ablation group, adverse events within 30 days after the procedure included death in 2 patients (1.0%) and nonfatal adverse events in 23 patients (11.3%). Among the patients assigned to drug therapy, adverse events that were attributed to antiarrhythmic drug treatment included death from pulmonary toxic effects in 1 patient (0.5%) and nonfatal adverse events in 46 patients (21.6%). Among patients with ischemic cardiomyopathy and ventricular tachycardia, an initial strategy of catheter ablation led to a lower risk of a composite primary end-point event than antiarrhythmic drug therapy. (Funded by the Canadian Institutes of Health Research and others; VANISH2 ClinicalTrials.gov number, NCT02830360.).

Orthosteric beta blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by adverse effects such as fatigue, hypotension, and reduced exercise capacity, due in part to nonselective inhibition of multiple βAR subtypes. These challenges are particularly problematic in treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease characterized by lethal tachyarrhythmias directly triggered by cardiac β1AR activation. To identify small-molecule allosteric modulators of the β1AR with enhanced subtype specificity and robust functional antagonism of β1AR-mediated signaling, we conducted a DNA-encoded small-molecule library screen and discovered Compound 11 (C11). C11 selectively potentiates the binding affinity of orthosteric agonists to the β1AR while potently inhibiting downstream signaling after β1AR activation. C11 prevents agonist-induced spontaneous contractile activity, Ca2+ release events, and exercise-induced ventricular tachycardia in the CSQ2-/- murine model of CPVT. Our studies demonstrate that C11 belongs to an emerging class of allosteric modulators termed positive allosteric modulator antagonists that positively modulate agonist binding but block downstream function. Its pharmacological properties and selective functional antagonism of β1AR-mediated signaling make C11 a promising therapeutic candidate for the treatment of CPVT and other forms of cardiac disease associated with excessive β1AR activation.

Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in Na V 1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to Na V 1.5 upregulation after RT. Clinically, RT was associated with increased Na V 1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients. Noninvasive cardiac radiotherapy may effectively manage ventricular tachycardia in refractory patients, but its radiobiologic mechanisms of action are unclear. Here, the authors show that photon radiation durably and favourably reprograms cardiac conduction in the absence of transmural fibrosis suggesting this could be the mechanism through which cardiac radiotherapy to modulates arrhythmia susceptibility.

In five patients with refractory ventricular tachycardia, stereotactic body radiation therapy was directed to the targeted site by means of electrocardiographic mapping, which resulted in a 99.9% reduction in the ventricular tachycardia burden.

A guinea-pig model of cardiac injury is used to show that human embryonic stem-cell-derived cardiomyocyte grafts can electrically integrate into the injured heart, improving mechanical function and reducing spontaneous and induced ventricular tachycardia; this is a major step towards clinical adoption of cell replacement therapies for cardiovascular diseases using human cardiomyocytes. Heart repair by cell replacement This study extends previous findings that transplantation of fetal cardiomyocytes can improve the function of infarcted hearts, despite having only a modest effect on the organ's mechanical properties. The investigators developed a guinea pig model of cardiac injury, because the heart rate of these animals is at the upper end of what is tolerable to human cardiomyocytes, and much lower than that of the mice and rats often used as models. The authors show that cardiomyocytes derived from human embryonic stem cells can integrate electrically into the guinea pig heart and protect against arrhythmias. This is the first convincing evidence that cardiomyocytes generated from cultured human embryonic stem cells can integrate into the adult heart, and is therefore a major step towards the clinical adoption of cell-replacement therapies for cardiovascular disease. Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts 1 , 2 , 3 , but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo , we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4 , 5 ). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.

Background Ventricular tachycardia (VT) is the primary cause of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). However, the strategy for VT treatment in HCM patients remains unclear. This study is aimed to compare the effectiveness of catheter ablation versus antiarrhythmic drug (AAD) therapy for sustained VT in patients with HCM. Methods A total of 28 HCM patients with sustained VT at 4 different centers between December 2012 and December 2021 were enrolled. Twelve underwent catheter ablation (ablation group) and sixteen received AAD therapy (AAD group). The primary outcome was VT recurrence during follow-up. Results Baseline characteristics were comparable between two groups. After a mean follow-up of 31.4 ± 17.5 months, the primary outcome occurred in 35.7% of the ablation group and 90.6% of the AAD group (hazard ratio [HR], 0.29 [95%CI, 0.10–0.89]; P  = 0.021). No differences in hospital admission due to cardiovascular cause (25.0% vs. 71.0%; P  = 0.138) and cardiovascular cause-related mortality/heart transplantation (9.1% vs. 50.6%; P  = 0.551) were observed. However, there was a significant reduction in the composite endpoint of VT recurrence, hospital admission due to cardiovascular cause, cardiovascular cause-related mortality, or heart transplantation in ablation group as compared to that of AAD group (42.9% vs. 93.7%; HR, 0.34 [95% CI, 0.12–0.95]; P  = 0.029). Conclusions In HCM patients with sustained VT, catheter ablation reduced the VT recurrence, and the composite endpoint of VT recurrence, hospital admission due to cardiovascular cause, cardiovascular cause-related mortality, or heart transplantation as compared to AAD.

ObjectiveTo establish a birth rate for catecholaminergic polymorphic ventricular tachycardia (CPVT) diagnosed in childhood and observe trends in presentation and management.DesignRetrospective cohort study.SettingThe Inherited Arrhythmia Clinic at The Sydney Children’s Hospitals Network, a paediatric tertiary referral network, New South Wales (NSW), Australia (2002–2021), where there are 86 000–97 000 live births/year.PatientsChildren diagnosed with CPVT aged 0–16 years.InterventionsClinical data were extracted and evaluated for trends. Using birth year data, the birth rate of CPVT detected in childhood was calculated.Main outcome measuresBirth rate of CPVT detected in childhood in NSW (with post hoc comparison to New Zealand), trends in diagnosis and management, and outcome at last follow-up.Results32 children in NSW were diagnosed with CPVT between 2002 and 2021 (0–16 years, median 9 years, 14 (54%) female). Of these, 28 (88%) presented with symptoms (cardiac arrest 20/32, 62.5%) and four (12%) were identified through family screening. Relevant genetic variants were identified in 25/31 (78%). During follow-up (median 4.5 years), symptomatic cardiac events (death n=1) occurred in 10 (33%), largely related to suboptimal adherence or monotherapy beta blocker. In NSW, CPVT was diagnosed during childhood following 1 in 65 000 live births (95% CI 1 in 91 000 to 1 in 46 000). In New Zealand, the corresponding figure was 1 in 84 000 live births (95% CI 1 in 138 000 to 1 in 52 000).ConclusionsThe rate of infants born who are later diagnosed with CPVT in childhood is approximately 1 in 65 000 live births. Suboptimal adherence and beta blocker therapy without flecainide appeared related to recurrent cardiac events.

Background Ventricular tachyarrhythmia (VTA) in ischemic cardiomyopathy (ICM) is a life‐threatening condition influenced by genetic factors and electrical remodeling. This study investigated the association between KCNQ1 gene polymorphisms (rs2237892 and rs2237895) and the development of VTA in ICM patients to improve risk stratification and guide device implantation decisions. Methods This single‐center study included 213 ICM patients with implantable cardioverter‐defibrillators (ICD) for primary prevention of VTA. Patients were divided into arrhythmia and control groups based on device interrogation findings. Genetic analysis for rs2237892 and rs2237895 polymorphisms was performed using real‐time polymerase chain reaction (PCR). Clinical, electrocardiographic, and laboratory parameters were analyzed. Correlation and logistic regression analyses evaluated the association between KCNQ1 polymorphisms and VTA risk. Results The arrhythmia group demonstrated significantly higher QT dispersion, frontal QRS‐T angle, and T‐wave peak‐to‐end interval compared to the control group. The TT genotype of rs2237892 and the AC genotype of rs2237895 were significantly associated with increased VTA risk (p < 0.001). Multivariate analysis confirmed these genotypes as independent predictors of VTA. No significant differences in other clinical or laboratory risk factors were observed. Conclusions KCNQ1 gene polymorphisms (rs2237892 and rs2237895) are strongly associated with VTA in ICM patients, suggesting a potential role as biomarkers for risk stratification. These findings may assist in tailoring ICD implantation decisions and improving patient outcomes. Potassium Channels and Ventricular Arrhythmia Risk. Altered potassium channel function modifies cardiac repolarization: gain‐of‐function shortens, loss‐of‐function prolongs the QT interval. Both increase susceptibility to ventricular tachyarrhythmias, especially with myocardial scarring. Shown: action potential phases, ionic currents, and key channel contributions.

In this systematic review and meta-analysis, we aim to evaluate the efficacy and safety of catheter ablation as the first-line treatment of ventricular tachycardia (VT) in patients with structural heart disease (SHD) and preserved left ventricular ejection fraction (LVEF). Patients with SHD are particularly susceptible to VT, a condition that increases the risk of sudden cardiac death (SCD). Implantable cardioverter-defibrillators (ICDs) can terminate VT and prevent SCD but do not prevent VT recurrence. The efficacy and safety of CA as a first-line treatment in SHD patients with preserved LVEF remain unclear. We searched PubMed/Medline, EMBASE, Web of Science, and Cochrane CENTRAL for studies reporting the outcomes of CA therapy in patients with VT and preserved LVEF, published up to January 19, 2023. The primary outcome was the incidence of SCD following catheter ablation as the first-line treatment of VT in patients with SHD and preserved LVEF. Secondary outcomes included all-cause mortality, VT recurrence, procedural complications, CA success rate, and ICD implantation after catheter ablation. We included seven studies in the meta-analysis, encompassing a total of 920 patients. The pooled success rate of catheter ablation was 84.6% (95% CI 67.2–93.6). Complications occurred in 6.4% (95% CI 4.0–9.9) of patients, and 13.9% (95% CI 10.1–18.8) required ICD implantation after ablation. VT recurrence was observed in 23.2% (95% CI 14.8–34.6) of patients, while the rate of sudden cardiac death (SCD) was 3.1% (95% CI 1.7–5.6). The overall prevalence of all-cause mortality in this population was 5% (95% CI 1.8–13). CA appears promising as a first-line VT treatment in patients with SHD and preserved LVEF, especially for monomorphic hemodynamically tolerated VT. However, due to the lack of direct comparisons with ICDs and anti-arrhythmic drugs, further research is needed to confirm these findings.

Management strategies for ventricular arrhythmias are guided by the risk of sudden death and severity of symptoms. Patients with a substantial risk of sudden death usually need an implantable cardioverter defibrillator (ICD). Although ICDs effectively end most episodes of ventricular tachycardia or ventricular fibrillation and decrease mortality in specific populations of patients, they have inherent risks and limitations. Generally, antiarrhythmic drugs do not provide sufficient protection from sudden death, but do have a role in reducing arrhythmias that cause symptoms. Catheter ablation is likewise important for reducing the frequency of spontaneous arrhythmias and is curative for some patients, usually those with idiopathic arrhythmias and no heart disease. Arrhythmia surgery is now infrequent, offered by only a few specialised centres for refractory arrhythmias. Advances in understanding of genetic arrhythmia syndromes and in technology for mapping and ablation of ventricular arrhythmias, and enhanced algorithms in implantable devices for rhythm management, have contributed to improved outcomes.