Recurrent Ventricular Fibrillation Research Articles

High-resolution repolarization changes preceding short-coupled ectopy in idiopathic ventricular fibrillation, and effects of quinidine

Abstract Background Idiopathic ventricular fibrillation (VF) is linked to early repolarization, increased repolarization heterogeneity, and (short-coupled) premature ventricular complexes (PVCs). Quinidine, an antiarrhythmic drug with class-IA and -III effects, reduces the occurrence of PVCs and VF, but its effects on repolarization have not yet been studied at the whole-heart level in idiopathic-VF patients. Purpose To study dynamic changes in repolarization preceding short-coupled PVCs using noninvasive electrocardiographic imaging (ECGI) in a patient with idiopathic VF, and the antiarrhythmic effects of quinidine. Methods ECGI was performed during sinus rhythm in a 61-year-old male with an ICD (secondary prevention; 2.5 mg nebivolol daily) two days after recurrent idiopathic VF (Fig. A). This was done 1) at baseline, 2 minutes before short-coupled ectopy ("baseline"); 2) at baseline, 10 seconds before the short-coupled PVC ("pre PVC"); and 3) at 2 hours after start of quinidine 200 mg ("on-quinidine"). The ECGI procedure consisted of a 224-electrode body surface potential map and a contrast-enhanced CT scan to obtain torso and heart geometries. After reconstruction of epicardial unipolar electrograms (UEGs), local activation and repolarization times (ATs and RTs) were derived from UEGs by assessing the steepest downslope of the QRS complex and steepest upslope of the T waves, respectively, of 10-second signal-averaged beats. AT and RT duration (first to last AT or RT) were assessed. Results At baseline, QRS duration and QT interval measured 107 ms and 343 ms, respectively, on the standard 12-lead ECG. ECGI-derived epicardial AT duration was 72 ms, and RT histogram span 92 ms. The coupling interval of the PVC that triggered VF in the ICD readout was 340 ms (Fig. A). During 44 minutes of ECGI, 157 short-coupled PVCs from the moderator-band region were recorded (Fig. B; no tachycardia or VF). Just prior to a PVC, epicardial early repolarization at the PVC origin decreased by 26 ms (star in Figs. C-E), and the RT histogram broadened to 109 ms (Fig. E). While on-quinidine, (25 minutes; QRS duration 107 ms, QT interval 419 ms), epicardial repolarization was prolonged (Fig. C/D), also at the site of abnormal impulse formation. Quinidine had increased the epicardial AT duration to 79 ms, and RT histogram span to 133 ms. PVCs were completely suppressed. The patient remained free of sustained arrhythmias while on-quinidine. Conclusion(s) In this case of short-coupled idiopathic VF, epicardial early repolarization shortened momentarily prior to abnormal impulse formation. We found dynamic substrate-trigger characteristics that likely facilitate reentrant excitation. Quinidine prolonged the duration of epicardial activation and repolarization, suppressing the ectopy and VF recurrence.

Recurrence of ventricular fibrillation in out-of-hospital cardiac arrest: Clinical evidence and underlying ionic mechanisms.

Defibrillation remains the optimal therapy for terminating ventricular fibrillation (VF) in out-of-hospital cardiac arrest (OHCA) patients, with reported shock success rates of ∼90%. A key persistent challenge, however, is the high rate of VF recurrence (∼50-80%) seen during post-shock cardiopulmonary resuscitation (CPR). Studies have shown that the incidence and time spent in recurrent VF are negatively associated with neurologically-intact survival. Recurrent VF also results in the administration of extra shocks at escalating energy levels, which can cause cardiac dysfunction. Unfortunately, the mechanisms underlying recurrent VF remain poorly understood. In particular, the role of chest-compressions (CC) administered during CPR in mediating recurrent VF remains controversial. In this review, we first summarize the available clinical evidence for refibrillation occurring during CPR in OHCA patients, including the postulated contribution of CC and non-CC related pathways. Next, we examine experimental studies highlighting how CC can re-induce VF via direct mechano-electric feedback. We postulate the ionic mechanisms involved by comparison with similar phenomena seen in commotio cordis. Subsequently, the hypothesized contribution of partial cardiac reperfusion (either as a result of CC or CC independent organized rhythm) in re-initiating VF in a globally ischaemic heart is examined. An overview of the proposed ionic mechanisms contributing to VF recurrence in OHCA during CPR from a cellular level to the whole heart is outlined. Possible therapeutic implications of the proposed mechanistic theories for VF recurrence in OHCA are briefly discussed.

Ablation of the epicardial substrate in patients with long-QT syndrome at risk of sudden death.

Sudden cardiac death remains a critical public health concern globally, affecting millions annually. Recent advances in cardiac arrhythmia mapping have demonstrated that the ventricular epicardial region has a critical arrhythmogenic role in some inherited cardiogenetic diseases. Among these, long-QT syndrome (LQTS) exposes patients to the risk of life-threatening arrhythmic events. Despite advancements, there is a need for more effective therapeutic strategies. A recent study has uncovered a noteworthy connection between LQTS and epicardial structural abnormalities, challenging the traditional view of LQTS as purely an electrical disorder. High-density mapping revealed electroanatomic abnormalities in the right ventricular epicardium, presenting a potential target for catheter ablation, to finally suppress ventricular fibrillation recurrences in high-risk LQTS patients.

The impact of alternate defibrillation strategies on shock-refractory and recurrent ventricular fibrillation: A secondary analysis of the DOSE VF cluster randomized controlled trial

BackgroundThe DOSE VF randomized controlled trial (RCT) employed a pragmatic definition of refractory ventricular fibrillation (VF after three successive shocks). However, it remains unclear whether the underlying rhythm during the first three shocks was shock-refractory or recurrent VF. ObjectiveTo explore the relationship between alternate defibrillation strategies employed during the DOSE VF RCT and the type of VF, either shock-refractory VF or recurrent VF, on patient outcomes. MethodsWe performed a secondary analysis of the DOSE VF RCT. We categorized cases as shock-refractory or recurrent VF based on pre-randomization shocks (shocks 1–3). We then analyzed all subsequent (post-randomization) shocks to assess the impact of standard, vector change (VC) or double sequential external defibrillation (DSED) shocks on clinical outcomes employing logistic regression adjusted for Utstein variables, antiarrhythmics, and epinephrine. ResultsWe included 345 patients; 60 (17%) shock-refractory VF, and 285 (83%) recurrent VF. Patients in recurrent VF had greater survival than shock-refractory VF (OR: 2.76 95% CI [1.04, 7.27]). DSED was superior to standard defibrillation for survival overall, and for patients with shock-refractory VF (28.6% vs 0%, p = 0.041) but not for those in recurrent VF. DSED was superior to standard defibrillation for return of spontaneous circulation (ROSC) and neurologic survival for shock-refractory and recurrent VF. VC defibrillation was not superior for survival or ROSC overall, for shock-refractory, or recurrent VF groups, but was superior for VF termination across all groups. ConclusionDSED appears to be the superior defibrillation strategy in the DOSE VF trial, irrespective of whether the preceding VF is shock-refractory or recurrent.

Coronary Artery Bypass Grafting for Refractory Ventricular fibrillation after the Release of the Aortic Cross-Clamp in Patients Undergoing Aortic Valve Replacement: A Case Report

Background: Ventricular fibrillation (VF) is a known complication after the release of the aortic cross-clamp (ACC) during cardiopulmonary bypass (CPB) surgery. Various factors contribute to persistent refractory VF, making its management challenging. This case report describes the successful treatment of postoperative refractory VF by coronary artery bypass grafting (CABG) in a patient undergoing aortic valve replacement (AVR) with ACC release. Case Presentation: A 52-year-old woman with a history of hypertension and ischemic cerebral infarction presented with symptoms of chest tightness, dyspnoea and palpitations. She underwent a modified maze procedure of radiofrequency ablation, mitral repair, left atrial appendage closure and mechanical AVR under a CPB procedure. Following the ACC release, the patient experienced recurrent VF that was unresponsive to standard interventions such as lidocaine, amiodarone and direct current shocks. The suspicion of right coronary artery (RCA) insufficiency led to the decision to perform CABG using the great saphenous vein. After the CABG procedure, the patient's heart rhythm gradually returned to sinus rhythm, and she had an uneventful recovery. Discussion and Conclusions: Refractory VF after the ACC release can pose diagnostic and treatment challenges. In this case, RCA insufficiency was suspected as the cause of refractory VF. The absence of blood flow in the proximal RCA and the presence of distal blood return during cardiac surface exploration supported this suspicion. Coronary artery bypass grafting using the great saphenous vein successfully restored normal sinus rhythm, confirming the diagnosis. This case emphasises the importance of considering coronary artery stenosis or occlusion as a potential cause of refractory VF after the ACC release during CPB, with CABG serving as a viable alternative treatment.

High-risk Brugada syndrome: factors associated with arrhythmia recurrence and benefits of epicardial ablation in addition to implantable cardioverter defibrillator implantation.

This study aims to evaluate the prognostic impact of the arrhythmogenic substrate size in symptomatic Brugada syndrome (BrS) as well as to validate the long-term safety and effectiveness of epicardial radiofrequency ablation (RFA) compared with no-RFA group. In this prospective investigational long-term registry study, 257 selected symptomatic BrS patients with implantable cardioverter defibrillator (ICD) implantation were included. Among them, 206 patients underwent epicardial RFA and were monitored for over 5 years post-ablation (RFA group), while 51 patients received only ICD implantation declining RFA. Primary endpoints included risk factors for ventricular fibrillation (VF) events pre-ablation and freedom from VF events post-ablation. In the RFA group, BrS substrates were identified in the epicardial surface of the right ventricle. During the pre-RFA follow-up period (median 27 months), VF episodes and VF storms were experienced by 53 patients. Independent risk factors included substrate size [hazard ratio (HR), 1.13; 95% confidence interval (CI), 1.08-1.18; P < 0.001], aborted cardiac arrest (HR, 2.98; 95% CI, 1.68-5.28; P < 0.001), and SCN5A variants (HR, 2.22; 95% CI, 1.15-4.27; P = 0.017). In the post-RFA follow-up (median 40 months), the RFA group demonstrated superior outcomes compared with no-RFA (P < 0.001) without major procedure-related complications. Our study underscores the role of BrS substrate extent as a crucial prognostic factor for recurrent VF and validates the safety and efficacy of RFA when compared with a no-RFA group. Our findings highlight the importance of ajmaline in guiding epicardial mapping/ablation in symptomatic BrS patients, laying the groundwork for further exploration of non-invasive methods to guide informed clinical decision-making.

Dysfunction of CRT-D in acute myocardial infarction: is there a place for programing?

The article describes a clinical case of a patient with a previously implanted cardiac resynchronization therapy with defibrillator function (CRT-D). For a long time, the patient was observed in the implanting clinic and the data was also transmitted via remote monitoring. The developing acute myocardial infarction in the right coronary artery caused a change in the parameter of the amplitude of the spontaneous R-wave in the patient. Subsequent ventricular fibrillation (VF) due to stent thrombosis was undetected by the defibrillator and resulted in no detection and cessation of VF, despite the implanted CRT-D. Changing the programming parameters did not affect the possibility of detecting a recurrent VF. The VF that occurred twice was stopped by the first discharge of the external device. In view of the remaining low hyposensing, a decision was made to reimplant the detecting part of the right ventricular electrode, after which defibrillation test proved to be effective for termination induced VF. We believe that at critically low parameters of spontaneous R-wave hyposensing, for the device to detect low-amplitude ventricular arrhythmias, programming the parameters does not solve the problem of hyposensing. Current myocardial infarction as the cause of hyposensing may require active surgical tactics replacement of the pacing and sensing electrode, in cases where the device connector allows this.

Sympathetic Denervation Abolishes Recurrent Ventricular Fibrillation and Intractable Coronary Spasm: Autonomic Dysfunction: A Shared Mechanism?

Sympathetic Denervation Abolishes Recurrent Ventricular Fibrillation and Intractable Coronary Spasm: Autonomic Dysfunction: A Shared Mechanism?

Out-of-hospital cardiac arrest treated with prehospital double sequential external defibrillation during eCPR in refractory VF — a case report

BackgroundDouble sequential external defibrillation (DSED) has demonstrated increased survival with good neurological outcome in a recent randomized controlled trial. DSED has not been studied in patients with extracorporeal cardiopulmonary resuscitation (eCPR).CaseWe present the first case of prehospital eCPR with ongoing refractory ventricular fibrillation (VF), terminated by DSED. After six shocks, return of spontaneous circulation was initially achieved; however, the patient went into recurrent VF. ECPR was performed prehospital, with VF still refractory after three more shocks. DSED successfully terminated VF and showed a further increase in etCO2 and near-infrared spectroscopy cerebral oximetry values.ConclusionDSED can be a sufficient strategy for patients in refractory VF while on eCPR and should be evaluated in further studies.

Acute myocardial infarction complicated by sudden out-of-hospital cardiac arrest: a clinical case

Justification. One of the serious complications of acute myocardial infarction (AMI) is out-of-hospital cardiac arrest, which is associated with electrical instability of the myocardium, ventricular arrhythmias. The development of a complication in the presence of an emergency medical team requires immediate resuscitation measures, including basic resuscitation measures and defibrillation.Aim: To present a clinical case of a patient with AMI with ST segment elevation complicated by recurrent ventricular fibrillation, hospitalized in an emergency hospital with the possibility of performing invasive interventions.Methodology and methods of research. The analysis of anamnesis, electrocardiographic data of the patient, the results of coronary angiography and stenting of the coronary artery, echocardiography examination, Holter monitoring, laboratory studies was carried out.Results. Patient P., female, 81 years old, was taken to the emergency hospital 2 hours and 15 minutes after the start of the clinic. At the prehospital stage, recurrent ventricular fibrillation, stopped by repeated three defibrillations. Non-contact, twice bouts of motor arousal. The council decided to conduct coronary angiography with possible stenting of the coronary arteries immediately. It was performed by femoral access on the right in 30 minutes after hospitalization. Complete occlusion of the anterior interventricular artery was revealed. Conductor recanalization and stenting of permanent residence was performed using a drug-coated stent. In the intensive care unit, drip administration of dopamine, noninvasive ventilation of the lungs, heparin administration were continued; double antiplatelet therapy, atorvastatin, amiodarone were prescribed. Since the fourth day, a beta-blocker has been added to therapy. Physical and psychological rehabilitation was carried out. She was discharged on the 15th day in a satisfactory condition.Conclusion. Out-of-hospital cardiac death requires urgent resuscitation measures, among which defibrillation occupies a special place, as well as immediate hospitalization to a cardiology center with the possibility of performing invasive interventions. Early rehabilitation plays an important role in the treatment of patients.

Generation of an induced pluripotent stem cell line from a patient with conduction disease and recurrent ventricular fibrillation with a sodium voltage-gated channel alpha subunit 5 (SCN5A) gene c.392 + 3A > G splice-site variant

Variants in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) produce variable cardiac phenotypes including Brugada syndrome, conduction disease and cardiomyopathy. These phenotypes can lead to life-threatening arrhythmias, heart failure, and sudden cardiac death. Novel variants in splice-site regions of SCN5A require functional studies to characterise their pathogenicity as they are poorly understood. The generation of an induced pluripotent stem cell line provides a valuable resource to investigate the functional effects of potential splice-disrupting variants in SCN5A.

Long-term follow-up of idiopathic ventricular fibrillation: A 30-year experience from our hospital

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Idiopathic ventricular fibrillation (IVF) is responsible for 5-7% of sudden cardiac arrests in the absence of substrate for ventricular arrhythmia, structural diseases, or primary arrhythmic syndromes. The characteristics, management, and prognosis of these patients are unclear. Purpose To investigate the clinical features, management, and prognosis of IVF in our hospital healthcare system Methods Mayo Database Explorer software was used to identify IVF patients from our hospital electronic medical records between 1990 to 2022 in 5 states. The medical records were manually reviewed. Results A total of 132 patients were initially diagnosed with IVF. During the 9.2±6.8 years mean follow-up, 36 [27.3%] patients were later diagnosed with structural diseases or primary arrhythmic syndromes (dilated cardiomyopathy [41.7%], Long QT syndrome [27.8%], catecholaminergic polymorphic ventricular tachycardia [8.3%], Brugada syndrome [5.6%], mitral valve-related arrhythmia [5.6%], and short QT syndrome [2.8%]). Among the rest of the 96 patients with true IVF (mean age 38.4±15.7 years, male 59.4%, Caucasian 80.2%, hypertension 28.1%, diabetes 8.3%), 91 (94.8%) patients presented with out-of-hospital cardiac arrest and 88 (91.7%) patients had a history of syncope. Early repolarization and fragmented QRS were noted in 32 (33.3%) and 28 (29.1%) patients, respectively. Defibrillators were implanted in 92 (95.8%) patients. Genetic testing was performed in 35 (36.5%) patients, and possible associated mutations were found in 13 (37.1%) patients. An Electrophysiology study was conducted in 55 (57.3%) patients, and ventricular fibrillation was induced in 17 (30.9%) patients. The medical management with antiarrhythmic drugs was selected in 60 (62.5%) patients, and the catheter ablation ± anti-arrhythmic drugs was selected in 36 (37.5%) patients. The recurrence of ventricular fibrillation during 9.2±6.8 years of mean follow-up was significantly higher in the ablation strategy group (p=0.0003) (Figure 1). Conclusions We reported the largest cohort of IVF patients from a single healthcare system. Early repolarization and fragmented QRS were common in IVF. The possible associated mutations were found in one-third of IVF who underwent genetic testing. The ventricular fibrillation recurrences were significantly higher in the catheter ablation strategy group.

PO-05-035 FASCICULAR SUBSTRATE MODIFICATION TO TREAT HUMAN VENTRICULAR FIBRILLATION: A MULTICENTER STUDY

Purkinje fibers play an important role in initiation and maintenance of ventricular fibrillation (VF). Fascicular substrate modification approaches have been suggested to treat recurrent VF in isolated case reports and small case series. To investigate the outcomes of catheter-based fascicular substrate modification to treat recurrent VF. Out of 2,212 consecutive patients with ventricular arrhythmia undergoing catheter ablation at our centers, 18 (0.81%) underwent fascicular substrate modification by targeting with short (<20 s) RF lesions in the most distal segment of the Purkinje fibers as identified with high-density mapping during sinus rhythm. Demographic, clinical, and follow-up characteristics were prospectively collected in our institutional database. A total of 18 patients (mean age: 56±3.8 years, female: 4, 22%) were included in the study. Of those, 11 (61.1%) had idiopathic VF (normal heart VF), 3 (16.7%) had non-ischemic cardiomyopathy and 4 (22.2%) had mixed cardiomyopathy. Average LVEF was 42.5%. Patients had failed ≥2 antiarrhythmic drugs pre-ablation. At baseline, all patients had inducible VF and non-inducibility of VF at the end of the procedure was achieved in 16 (88.9%) patients. In select patients, remapping revealed elimination of the targeted Purkinje potentials. At the end of the procedure, no patient demonstrated new evidence of fascicular block or bundle branch block. VF initiation and final lesion sets are shown in figure 1. There were no procedure-related complications. After a median follow-up of 24 months, 16 (88.9%) patients were arrhythmia-free on- or off-drugs; 11/11 (100%) patients with normal heart VF vs 5/7 (71.4%) with underlying cardiomyopathy (p=0.06). Catheter ablation of human VF with distal fascicular substrate modification is feasible, safe and appears highly effective with high rates of acute VF non-inducibility and long-term freedom from recurrent VF.

CE-454610-2 STEREOTACTIC ARRHYTHMIA RADIOABLATION IN VENTRICULAR FIBRILLATION WITH LEFT VENTRICULAR THROMBUS

Stereotactic arrhythmia radioablation (STAR) has been studied for management of refractory ventricular tachycardia (VT) that is not amenable to traditional catheter ablation. We present the case of a patient with recurrent ventricular tachycardia (VT) and left ventricular (LV) thrombus successfully treated with STAR therapy. A 48-year-old man with morbid obesity, paroxysmal atrial fibrillation and infarct related cardiomyopathy was admitted with late presentation of new anterolateral ST elevation myocardial infarction complicated by cardiogenic shock, managed with mechanical circulatory support. He was found to have a 3 x 2.7 cm thrombus in the LV apex (Panel A). He underwent successful percutaneous intervention to an acute left anterior descendinig coronary artery occlusion. During hospitalization, despite aggressive measures, he was noted to have polymorphic ventricular tachycardia (VT), triggered by premature ventricular contractions (PVCs) arising from his LV apical infarct (Panel B). He was treated with multiple antiarrhythmic medications (amiodarone, lidocaine) in addition to electrolyte repletion but unfortunately required repeated external defibrillation for PVC induced VF (Panel C). A dual chamber implantable cardioverter-defibrillator was placed and despite overdrive pacing, he suffered from recurrent life-threatening VT and ventricular fibrillation (VF) requiring additional defibrillation (Panel D). Because he was not a candidate for endocardial ablation, orthotopic heart transplantation, and was deemed too unstable for epicardial ablation, the decision was made to pursue STAR. Surface ECG and 4D computed tomography (Panel E) were used to localize the focus of the VT trigger. A single dose of 25 Gray of radiation was delivered to the LV apex. Our patient has been free of ventricular arrhythmias for 14 months. There has been no clinical evidence of early or late toxicity related to radiotherapy thus far. In challenging cases of PVC induced VT and VF not amenable to traditional therapies, such as our patient, STAR may offer a therapeutic option. Further studies are required.

The Brugada syndrome: pharmacological therapy.

Brugada syndrome is an inherited channelopathy with an increased risk of sudden cardiac death (SCD) due to ventricular arrhythmias (VA) and an increased incidence of supraventricular arrhythmias, as compared with the general population. For the prevention of SCD, the guidelines recommend the implantable cardioverter-defibrillator (ICD); however, ICD does not prevent VA. In this article, we provide a brief review of the literature on the Brugada syndrome pharmacological therapy, mainly focusing on quinidine treatment. The efficacy of quinidine therapy in the prevention of VA in Brugada syndrome has been demonstrated by several small studies in patients with ICD and recurrent shocks or in asymptomatic patients with inducible ventricular fibrillation (VF) at electrophysiological study. Quinidine has also been tested for the prophylaxis of supraventricular arrhythmias, especially atrial fibrillation/flutter, and in paediatric patients. In these studies, quinidine proved highly effective in preventing re-induction of VF and spontaneous recurrences of both ventricular and supraventricular arrhythmias. Unfortunately, this therapy is burdened by a high incidence of side effects, which may lead to drug discontinuation.

Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2

Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in KCNH2. LQT2 may manifest as QT prolongation on an electrocardiogram and present with arrhythmic syncope/seizures and sudden cardiac arrest/death. Progestin-based oral contraceptives may increase the risk of LQT2-triggered cardiac events in women. We previously reported on a woman with LQT2 and recurrent cardiac events temporally related and attributed to the progestin-based contraceptive medroxyprogesterone acetate ("Depo-Provera" [Depo] MilliporeSigma, Catalog# 1378001, St. Louis, MO). The purpose of this study was to evaluate the arrhythmic risk of Depo in a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model of LQT2. An iPSC-CM line was generated from a 40-year-old woman with p.G1006Afs∗49-KCNH2. A CRISPR/Cas9 gene-edited/variant-corrected isogenic control iPSC-CM line was generated. FluoVolt (Invitrogen, F10488, Waltham, MA) was used to measure the action potential duration after treatment with 10 μM Depo. Erratic beating patterns characterized as alternating spike amplitudes, alternans, or early afterdepolarization-like phenomena were assessed using multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment. Depo treatment shortened the action potential duration at 90% repolarization of G1006Afs∗49 iPSC-CMs from 394 ± 10 to 303 ± 10 ms (P < .0001). Combined Depo + ISO treatment increased the percentage of electrodes displaying erratic beating in G1006Afs∗49 iPSC-CMs (baseline: 18% ± 5% vs Depo + ISO: 54% ± 5%; P < .0001) but not in isogenic control iPSC-CMs (baseline: 0% ± 0% vs Depo + ISO: 10% ± 3%; P = .9659). This cell study provides a potential mechanism for the patient's clinically documented Depo-associated episodes of recurrent ventricular fibrillation. This invitro data should prompt a large-scale clinical assessment of Depo's potential proarrhythmic effect in women with LQT2.

Vagal response is involved in the occurrence of ventricular fibrillation in patients with early repolarization syndrome

Patients with early repolarization syndrome (ERS) and Brugada syndrome (BruS) have comparable clinical symptoms. In both conditions, ventricular fibrillation (VF) is experienced often near midnight or in the early morning hours when the parasympathetic tone is augmented. However, differences between ERS and BruS regarding the risk of VF occurrence have recently been reported. The role of vagal activity remains especially unclear. The study's goal was to determine the relationship between VF occurrence and autonomic nervous activity in patients with ERS and BruS. We enrolled 50 patients with ERS (n = 16) and BruS (n = 34) who received implantable cardioverter-defibrillators. Of these, 20 patients (5 ERS and 15 BruS) experienced VF recurrence (recurrent-VF group). We investigated baroreflex sensitivity (BaReS) with the phenylephrine method and heart rate variability (HRV) using a Holter ECG in all patients to estimate autonomic nervous function. In both patients with ERS and BruS, there was no significant difference in HRV between the recurrent-VF and the non-recurrent-VF groups. However, in patients with ERS, BaReS was significantly higher in the recurrent-VF group than in the non-recurrent-VF group (p = 0.03); this difference was not evident in BruS patients. High BaReS was independently associated with VF recurrence in patients with ERS, according to Cox proportional hazards regression analyses (HR: 1.52; 95% CI: 1.031-3.061; p = 0.032). Our findings suggest that in patients with ERS, an exaggerated vagal response, as represented by increased BaReS indices, may be involved in the risk of VF occurrence.

The Utility of Sodium Channel Provocation in Unexplained Cardiac Arrest Survivors and Electrocardiographic Predictors of Ventricular Fibrillation Recurrence.

The implications of a drug-induced type 1 Brugada ECG pattern following sodium channel blocker provocation (SCBP) are not fully understood. Baseline clinical and ECG data were obtained from consecutive unexplained cardiac arrest survivors undergoing SCBP at 3 centers. A further 15 SCBP positive (SCBP+) unexplained cardiac arrest survivors were recruited from 3 additional centers to explore ventricular fibrillation recurrence. A total of 121 consecutive unexplained cardiac arrest survivors underwent SCBP. The yield of the drug-induced type 1 Brugada ECG pattern was 17%. A baseline type 2/3 Brugada pattern (T2/3BP) (adjusted odds ratio, 19.36 [2.74-136.61]; P=0.003) and PR interval (odds ratio, 1.03 [1.01-1.05] per ms; P=0.017) were independent predictors of SCBP+ response. A pathogenic SCN5A variant was identified in 36% of the SCBP+ group versus 0% in the SCBP- group (P<0.001). Amongst SCBP+ patients, a spontaneous type 1 Brugada pattern was identified in 19% during follow up and in 24% a type 1 Brugada pattern was identified in a relative. Prior syncope (adjusted hazard ratio, 3.83 [1.36-10.78]; P=0.011) and the presence of global early repolarization (hazard ratio, 7.91 [3.22-19.44]; P<0.001) were independent predictors of 5-year ventricular fibrillation recurrence. There was a nonsignificant trend toward greater 5-year ventricular fibrillation recurrence in the SCBP- group (23/95 [24%] versus 3/34 [9%]; P=0.055). The yield of the drug-induced type 1 Brugada ECG pattern in consecutive unexplained cardiac arrest survivors undergoing SCBP is 17%. A baseline T2/3BP and PR interval were independent predictors of the drug-induced type 1 Brugada ECG pattern. Greater heritability of BrS phenotype in this group was evidenced by a greater prevalence of pathogenic SCN5A variants and relatives with a type 1 Brugada pattern. A history of prior syncope and the presence of global early repolarization were independent predictors of ventricular fibrillation recurrence.

Risk stratification of ventricular fibrillation in patients with symptomatic Brugada syndrome using pharmacological tests.

Brugada syndrome (BrS), which is characterized by J-point elevation in right precordial leads of a 12-lead electrocardiogram, is associated with the occurrence of ventricular fibrillation (VF). However, risk stratification of VF in patients with BrS remains challenging. The aim of this study was to identify a risk predictor of VF in patients with BrS using pharmacological tests. Twenty-one consecutive patients with BrS and a history of documented spontaneous VF (n = 16) or syncope presumed to be caused by lethal ventricular arrhythmia (n = 5) were enrolled. J-wave changes in response to intravenous verapamil, propranolol, and pilsicainide were separately assessed. During the median follow-up period of 86.0 months, 8 patients had VF recurrence (recurrence group) and 13 patients did not have VF recurrence (non-recurrence group). Intravenous propranolol injection induced significant J-wave augmentation (i.e., increase in amplitude >0.1 mV) in the inferior and/or lateral leads in the recurrence group compared to the non-recurrence group (p = .048 and p = .015, respectively). Kaplan-Meier analysis revealed that VF recurrence is significantly higher in patients with BrS and J-wave augmentation due to intravenous propranolol than in patients without J-wave augmentation (p = .014). The study results show that propranolol-induced J-wave augmentation is involved in the risk of VF in patients with BrS. The results suggest that early repolarization patterns in response to pharmacological tests may be useful for risk stratification of VF in patients with symptomatic BrS.

Real-World Outcomes and Cardiac Implications of FLT3 Inhibitors in Acute Myeloid Leukemia

Background:FLT3 is a member of the class III receptor tyrosine kinase family and constitutively activating mutations of FLT3 are found in ∼30% of adult patients with acute myeloid leukemia (AML). Clinically, FLT3-ITD mutations are associated with earlier time to relapse and poorer overall survival (OS). FLT3 inhibitors are divided into first generation multi-kinase inhibitors (such as sorafenib, lestaurtinib, midostaurin) and next generation inhibitors (such as quizartinib, crenolanib, gilteritinib) or based on their specificity of FLT3 inhibition [type I inhibitors (midostaurin, gilteritinib) inhibit FLT3 ITD and TKD mutations whereas type II inhibitors (sorafenib, quizartinib) have only FLT3 ITD activity]. Though FLT3 inhibition has showed marginal survival benefit in the front line setting for AML, some of the benefits may be offset by cardiovascular toxicities such as cardiomyopathies, QT prolongation and arrythmias. Therefore, outcomes and cardiac safety profile of FLT3 inhibitors in AML at our institution was investigated in the real-life scenario. Methods: In this retrospective study, we included all FLT3MTAML patient with ECOG status of ≤ 2 at our institute who either received FLT3 inhibitors (1) at diagnosis, (2) in a study after being refractory to ≥1 treatment, or (3) relapsing after achieving prior remission. We analyzed the safety and tolerability of type I and type II FLT3 inhibitors in terms of dose-limiting toxicities (DLT) and treatment-emergent adverse events (TEAE) from a cardiac standpoint. Baseline 2D Echocardiograms, EKGs pre- and post-treatment, metabolic profile through each hospitalization, major cardiac events in correlation to prior cardiac history and electrolyte abnormalities were included in the final analysis. Results: From June 2016 to April 2021, 63 FLT3MT AML patients were treated at our institution, 41 (65%) with primary AML and 22 with secondary AML (35%). 52 patients (83%) had ITD and 11 (17%) had FLT3 TKD mutations. Furthermore, 29 patients (56%) with FLT3 ITD and 3 (27%) with FLT3 TKD were treated with FLT3 inhibitors. Of the patients who received FLT3 inhibitors, 21 (66%) received type-2, and 11 (34%) got type I FLT3 inhibitors. 17 patients received FLT3 inhibitors as mono-therapy, and 15 in combination with chemotherapy. Median age of patients on FLT3 inhibitor treatment was 77 years (range 40- 83), and median duration of treatment was 96 days (range 45-180). CRi and CRp were seen as the best response in 12 (38%) and 5 (17%) of the 32 FLT3MT patients respectively, and the median time to CRi/CRp was 33 days (range 22 to 36). Time to relapse in patients with CRi/CRp was 4.5 months (range 2 to 7.5 months). Median overall survival of FLT3 ITD patients treated with type II inhibitors was 18 months, versus 14.5 months for type I inhibitors (p = 0.782), and 5.6 months in patients who did not receive FLT3 inhibitor therapy. The most common non-cardiac treatment emergent adverse events (TEAEs) in patients on FLT3 inhibitors were fatigue, muscle weakness, anemia, and decreased appetite. In the total FLT3MT AML cohort, cardiac adverse events were observed in 16 patients (16/63), 12 of which were on FLT3 inhibitors and 4 were not on FLT3 inhibitors (p = 0.0006). All cardiac TEAEs with FLT3 inhibitor therapy were observed only with type II inhibitors (p=0.0018). Notably, 12 (12/32) patients were classified to have serious cardiac TEAEs, and all of them were receiving type II FLT3-inhibitors. Serious cardiac TEAEs included Torsades in 5 (41%) patients, recurrent ventricular fibrillation in 2 (17%), third-degree AV block necessitating emergent pacemaker in 2 (17%), permanent atrial fibrillation in 2 (17%), and asystole culminating in death in 1 patient (8%) [Fig.1]. 12 patients who developed cardiac TEAEs with FLT3 inhibitors had hyperkalemia, 5 had a preceding history of atrial fibrillation and PVC, suggesting a decreased threshold of development of cardiac TEAEs in the presence of known risk factors. Conclusions: Type II FLT3 TKIs had worse cardiac safety profile in our cohort and an increased risk of cardiac toxicity, particularly in patients with prior reduced ejection fraction or A-fib. A careful cardiac history and management of predisposing conditions to serious cardiac events could help improve drug tolerance, morbidity, and mortality. Further studies are required to elucidate the precise mechanisms of increased incidence of cardiac arrythmias and ways to mitigate them. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal