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.

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.

Antisense Oligonucleotide Therapy for Calmodulinopathy.

BACKGROUND: Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in CALM1, CALM2, or CALM3, which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function. METHODS: We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of CALM1 pathogenic variants. RESULTS: Human CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of CALM1F142L/+ induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in Calm1N98S/+ mice without a deleterious effect on cardiac electrical or contractile function. CONCLUSIONS: These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.

Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction.

BACKGROUND: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function. METHODS: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/- mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/- mutation. RESULTS: As in humans, RyR2-I4855M+/- mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/- mice were highly susceptible to electrical stimulation-induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/- mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/- mutation abolished sarcoplasmic reticulum store overload-induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/- mutant compared with wild type. CONCLUSIONS: The RyR2-I4855M+/- mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/- mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.

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.

Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients With an Implantable Cardioverter Defibrillator? Results From the Multicenter Randomized PARTITA Trial.

BACKGROUND: Optimal timing for catheter ablation of ventricular tachycardia is an important unresolved issue. There are no randomized trials evaluating the benefit of ablation after the first implantable cardioverter defibrillator (ICD) shock. METHODS: We conducted a 2-phase, prospective, multicenter, randomized clinical trial. Patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock (phase A). After reconsenting, patients were randomly assigned 1:1 in phase B to immediate ablation (within 2 months from shock delivery) or continuation of standard therapy. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure. Amiodarone intake was not allowed except for documented atrial tachyarrhythmias. On July 23, 2021, phase B of the trial was interrupted as a result of the first interim analysis on the basis of the Bayesian adaptive design. RESULTS: Of the 517 patients enrolled in phase A, 154 (30%) had ventricular tachycardia, 56 (11%) received an appropriate shock over a median follow-up of 2.4 years (interquartile range, 1.4-4.4), and 47 of 56 (84%) agreed to participate in phase B. After 24.2 (8.5-24.4) months, the primary end point occurred in 1 of 23 (4%) patients in the ablation group and 10 of 24 (42%) patients in the control group (hazard ratio, 0.11 [95% CI, 0.01-0.85]; P=0.034). The results met the prespecified termination criterion of >99% Bayesian posterior probability of superiority of treatment over standard therapy. No deaths were observed in the ablation group versus 8 deaths (33%) in the control group (P=0.004); there was 1 worsening heart failure hospitalization in the ablation group (4%) versus 4 in the control group (17%; P=0.159). ICD shocks were less frequent in the ablation group (9%) than in the control group (42%; P=0.039). CONCLUSIONS: Ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined death or worsening heart failure hospitalization end point, lower mortality, and fewer ICD shocks. These findings provide support for considering ventricular tachycardia ablation after the first ICD shock. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01547208.

First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent With Defibrillator Implantation: The PAUSE-SCD Randomized Trial.

BACKGROUND: Catheter ablation as first-line therapy for ventricular tachycardia (VT) at the time of implantable cardioverter defibrillator (ICD) implantation has not been adopted into clinical guidelines. Also, there is an unmet clinical need to prospectively examine the role of VT ablation in patients with nonischemic cardiomyopathy, an increasingly prevalent population that is referred for advanced therapies globally. METHODS: We conducted an international, multicenter, randomized controlled trial enrolling 180 patients with cardiomyopathy and monomorphic VT with an indication for ICD implantation to assess the role of early, first-line ablation therapy. A total of 121 patients were randomly assigned (1:1) to ablation plus an ICD versus conventional medical therapy plus an ICD. Patients who refused ICD (n=47) were followed in a prospective registry after stand-alone ablation treatment. The primary outcome was a composite end point of VT recurrence, cardiovascular hospitalization, or death. RESULTS: Randomly assigned patients had a mean age of 55 years (interquartile range, 46-64) and left ventricular ejection fraction of 40% (interquartile range, 30%-49%); 81% were male. The underlying heart disease was ischemic cardiomyopathy in 35%, nonischemic cardiomyopathy in 30%, and arrhythmogenic cardiomyopathy in 35%. Ablation was performed a median of 2 days before ICD implantation (interquartile range, 5 days before to 14 days after). At 31 months, the primary outcome occurred in 49.3% of the ablation group and 65.5% in the control group (hazard ratio, 0.58 [95% CI, 0.35-0.96]; P=0.04). The observed difference was driven by a reduction in VT recurrence in the ablation arm (hazard ratio, 0.51 [95%CI, 0.29-0.90]; P=0.02). A statistically significant reduction in both ICD shocks (10.0% versus 24.6%; P=0.03) and antitachycardia pacing (16.2% versus 32.8%; P=0.04) was observed in patients who underwent ablation compared with control. No differences in cardiovascular hospitalization (32.0% versus. 33.7%; hazard ratio, 0.82 [95% CI, 0.43-1.56]; P=0.55) or mortality (8.9% versus 8.8%; hazard ratio, 1.40 [95% CI, 0.38-5.22]; P=0.62]) were observed. Ablation-related complications occurred in 8.3% of patients. CONCLUSIONS: Among patients with cardiomyopathy of varied causes, early catheter ablation performed at the time of ICD implantation significantly reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. These findings were driven by a reduction in ICD therapies. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02848781.

RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.

RATIONALE: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide's efficacy in CPVT. OBJECTIVE: To determine whether RyR2 block independently contributes to flecainide's efficacy for suppressing spontaneous sarcoplasmic reticulum Ca release and for preventing ventricular tachycardia in vivo. METHODS AND RESULTS: We synthesized N-methylated flecainide analogues (QX-flecainide and N-methyl flecainide) and showed that N-methylation reduces flecainide's inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N-methylation did not alter flecainide's inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes-lacking intact sarcolemma and devoid of sodium channel contribution-flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and N-methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas N-methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block. CONCLUSIONS: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.

Polymorphic Ventricular Tachycardia: Terminology, Mechanism, Diagnosis, and Emergency Therapy.

Polymorphic ventricular tachyarrhythmias are highly lethal arrhythmias. Several types of polymorphic ventricular tachycardia have similar electrocardiographic characteristics but have different modes of therapy. In fact, medications considered the treatment of choice for one form of polymorphic ventricular tachycardia, are contraindicated for the other. Yet confusion about terminology, and thus diagnosis and therapy, continues. We present an in-depth review of the different forms of polymorphic ventricular tachycardia and propose a practical step-by-step approach for distinguishing these malignant arrhythmias.

Preventive or Deferred Ablation of Ventricular Tachycardia in Patients With Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial.

BACKGROUND: Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implantable cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation to prevent ICD shocks for VT) and deferred ablation after 3 ICD shocks for VT. METHODS: The BERLIN VT study (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population. RESULTS: During a mean follow-up of 396±284 days, the primary end point occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09 [95% CI, 0.62-1.92]; P=0.77). On the basis of prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, 6 versus 2 patients died (7.9% versus 2.4%; P=0.18), 8 versus 2 patients were admitted for worsening heart failure (10.4% versus 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% versus 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% versus 48.2%; P=0.050) and appropriate ICD therapy (34.2% versus 47.0%; P=0.020) were numerically reduced in the preventive ablation group. CONCLUSIONS: Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up compared with the deferred ablation strategy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02501005.

Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association.

Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important.

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Quinidine-Responsive Polymorphic Ventricular Tachycardia in Patients With Coronary Heart Disease.

BACKGROUND: Polymorphic ventricular tachycardia (VT) without QT prolongation is well described in patients without structural heart disease (mainly idiopathic ventricular fibrillation and Brugada syndrome) and in patients with acute ST-elevation myocardial infarction. METHODS: Retrospective study of patients with polymorphic VT related to coronary artery disease, but without evidence of acute myocardial ischemia. RESULTS: The authors identified 43 patients in whom polymorphic VT developed within days of an otherwise uncomplicated myocardial infarction or coronary revascularization procedure. The polymorphic VT events were invariably triggered by extrasystoles with short (364±36 ms) coupling interval. Arrhythmic storms (4-16 events of polymorphic VT deteriorating to ventricular fibrillation) occurred in 23 (53%) patients. These arrhythmic storms were always refractory to conventional antiarrhythmic therapy, including intravenous amiodarone, but invariably responded to quinidine therapy. In-hospital mortality was 17% for patients with arrhythmic storm. Patients treated with quinidine invariably survived to hospital discharge. During long-term follow-up (of 5.6±6 years; range, 1 month to 18 years), 3 (16%) of patients discharged without quinidine developed recurrent polymorphic VT. There were no recurrent arrhythmias during quinidine therapy Conclusions: Arrhythmic storm with recurrent polymorphic VT in patients with coronary disease responds to quinidine therapy when other antiarrhythmic drugs (including intravenous amiodarone) fail.

The Evolving Role of the Cardiac Catheterization Laboratory in the Management of Patients With Out-of-Hospital Cardiac Arrest: A Scientific Statement From the American Heart Association.

Coronary artery disease is prevalent in different causes of out-of-hospital cardiac arrest (OHCA), especially in individuals presenting with shockable rhythms of ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT). The purpose of this report is to review the known prevalence and potential importance of coronary artery disease in patients with OHCA and to describe the emerging paradigm of treatment with advanced perfusion/reperfusion techniques and their potential benefits on the basis of available evidence. Although randomized clinical trials are planned or ongoing, current scientific evidence rests principally on observational case series with their potential confounding selection bias. Among patients resuscitated from VF/pVT OHCA with ST-segment elevation on their postresuscitation ECG, the prevalence of coronary artery disease has been shown to be 70% to 85%. More than 90% of these patients have had successful percutaneous coronary intervention. Conversely, among patients resuscitated from VF/pVT OHCA without ST-segment elevation on their postresuscitation ECG, the prevalence of coronary artery disease has been shown to be 25% to 50%. For these patients, early access to the cardiac catheterization laboratory is associated with a 10% to 15% absolute higher functionally favorable survival rate compared with more conservative approaches of late or no access to the cardiac catheterization laboratory. In patients with VF/pVT OHCA refractory to standard treatment, a new treatment paradigm is also emerging that uses venoarterial extracorporeal membrane oxygenation to facilitate return of normal perfusion and to support further resuscitation efforts, including coronary angiography and percutaneous coronary intervention. The burden of coronary artery disease is high in this patient population, presumably causative in most patients. The strategy of venoarterial extracorporeal membrane oxygenation, coronary angiography, and percutaneous coronary intervention has resulted in functionally favorable survival rates ranging from 9% to 45% in observational studies in this patient population. Patients with VF/pVT should be considered at the highest severity in the continuum of acute coronary syndromes. These patients have a significant burden of coronary artery disease and acute coronary thrombotic events. Evidence from randomized trials will further define optimal clinical practice.

Preoperative Predictors of Death and Sustained Ventricular Tachycardia After Pulmonary Valve Replacement in Patients With Repaired Tetralogy of Fallot Enrolled in the INDICATOR Cohort.

BACKGROUND: Risk factors for adverse clinical outcomes have been identified in patients with repaired tetralogy of Fallot before pulmonary valve replacement (PVR). However, pre-PVR predictors for post-PVR sustained ventricular tachycardia and death have not been identified. METHODS: Patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort (International Multicenter TOF Registry), a 4-center international cohort study, who had a comprehensive preoperative evaluation and subsequently underwent PVR were included. Preprocedural clinical, ECG, cardiovascular magnetic resonance, and postoperative outcome data were analyzed. Cox proportional hazards multivariable regression analysis was used to evaluate factors associated with time from pre-PVR cardiovascular magnetic resonance until the primary outcome: death, aborted sudden cardiac death, or sustained ventricular tachycardia. RESULTS: Of the 452 eligible patients (median age at PVR, 25.8 years), 36 (8%) reached the primary outcome (27 deaths, 2 resuscitated death, and 7 sustained ventricular tachycardia) at a median time after PVR of 6.5 years. Cox proportional hazards regression identified pre-PVR right ventricular ejection fraction <40% (hazard ratio, 2.39; 95% CI, 1.18-4.85; P=0.02), right ventricular mass-to-volume ratio ≥0.45 g/mL (hazard ratio, 4.08; 95% CI, 1.57-10.6; P=0.004), and age at PVR ≥28 years (hazard ratio, 3.10; 95% CI, 1.42-6.78; P=0.005) as outcome predictors. In a subgroup analysis of 230 patients with Doppler data, predicted right ventricular systolic pressure ≥40 mm Hg was associated with the primary outcome (hazard ratio, 3.42; 95% CI, 1.09-10.7; P=0.04). Preoperative predictors of a composite secondary outcome, postoperative arrhythmias and heart failure, included older age at PVR, pre-PVR atrial tachyarrhythmias, and a higher left ventricular end-systolic volume index. CONCLUSIONS: In this observational investigation of patients with repaired tetralogy of Fallot, an older age at PVR and pre-PVR right ventricular hypertrophy and dysfunction were predictive of a shorter time to postoperative death and sustained ventricular tachycardia. These findings may inform the timing of PVR if confirmed by prospective clinical trials.

2018 American Heart Association Focused Update on Advanced Cardiovascular Life Support Use of Antiarrhythmic Drugs During and Immediately After Cardiac Arrest: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

Antiarrhythmic medications are commonly administered during and immediately after a ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest. However, it is unclear whether these medications improve patient outcomes. This 2018 American Heart Association focused update on advanced cardiovascular life support guidelines summarizes the most recent published evidence for and recommendations on the use of antiarrhythmic drugs during and immediately after shock-refractory ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest. This article includes the revised recommendation that providers may consider either amiodarone or lidocaine to treat shock-refractory ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest.

2018 American Heart Association Focused Update on Pediatric Advanced Life Support: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2018 American Heart Association focused update on pediatric advanced life support guidelines for cardiopulmonary resuscitation and emergency cardiovascular care follows the 2018 evidence review performed by the Pediatric Task Force of the International Liaison Committee on Resuscitation. It aligns with the International Liaison Committee on Resuscitation's continuous evidence review process, and updates are published when the group completes a literature review based on new published evidence. This update provides the evidence review and treatment recommendation for antiarrhythmic drug therapy in pediatric shock-refractory ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest. As was the case in the pediatric advanced life support section of the "2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care," only 1 pediatric study was identified. This study reported a statistically significant improvement in return of spontaneous circulation when lidocaine administration was compared with amiodarone for pediatric ventricular fibrillation/pulseless ventricular tachycardia cardiac arrest. However, no difference in survival to hospital discharge was observed among patients who received amiodarone, lidocaine, or no antiarrhythmic medication. The writing group reaffirmed the 2015 pediatric advanced life support guideline recommendation that either lidocaine or amiodarone may be used to treat pediatric patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

Temporal trends of survival and utilization of mechanical circulatory support devices in patients with in-hospital cardiac arrest secondary to ventricular tachycardia/ventricular fibrillation.

BACKGROUND: Pulseless ventricular tachycardia/ventricular fibrillation (VT/VF) is the initial rhythm in a third of in-hospital cardiac arrest patients. Mechanical circulatory support (MCS) device use remains poorly understood in this population. METHODS: We conducted an observational analysis of temporal trends in the utilization of MCS in VT/VF IHCA between January 2008 and December 2014 utilizing the Nationwide Inpatient Sample (NIS) database. Using multivariable analysis, we assessed factors associated with MCS use and survival to discharge. RESULTS: Among 151,628 hospitalizations with VT/VF IHCA, 14,981 (9.9%) received MCS. Intra-aortic balloon pump (IABP) was the most commonly used MCS (9.1%). From 2008 to 2014, there was significant increase in the utilization of MCS (8.7-11%; ptrend < 0.0001). On multivariable analysis, there was 12-fold increase and three-fold increase in the utilization of PVAD and ECMO respectively; however, there was no significant change in the use of IABP. Over the seven-year sample period, there was significant increase in the overall survival to hospital discharge (35.4-43.5%; ptrend < 0.0001). Survival to hospital discharge increased in both MCS and non-MCS groups. CONCLUSION: There was significant increase in utilization of MCS after VT/VF IHCA during the study period. IABP was the most commonly utilized MCS. The survival to hospital discharge increased in the overall study population including both MCS and non-MCS groups. Future studies are needed to identify patient population most likely to benefit from the use of MCS after VT/VF IHCA.

Brain Emboli After Left Ventricular Endocardial Ablation.

BACKGROUND: Catheter ablation for ventricular tachycardia and premature ventricular complexes (PVCs) is common. Catheter ablation of atrial fibrillation is associated with a risk of cerebral emboli attributed to cardioversions and numerous ablation lesions in the low-flow left atrium, but cerebral embolic risk in ventricular ablation has not been evaluated. METHODS: We enrolled 18 consecutive patients meeting study criteria scheduled for ventricular tachycardia or PVC ablation over a 9-month period. Patients undergoing left ventricular (LV) ablation were compared with a control group of those undergoing right ventricular ablation only. Patients were excluded if they had implantable cardioverter defibrillators or permanent pacemakers. Radiofrequency energy was used for ablation in all cases and heparin was administered with goal-activated clotting times of 300 to 400 seconds for all LV procedures. Pre- and postprocedural brain MRI was performed on each patient within a week of the ablation procedure. Embolic infarcts were defined as new foci of reduced diffusion and high signal intensity on fluid-attenuated inversion recovery brain MRI within a vascular distribution. RESULTS: The mean age was 58 years, half of the patients were men, half had a history of hypertension, and the majority had no known vascular disease or heart failure. LV ablation was performed in 12 patients (ventricular tachycardia, n=2; PVC, n=10) and right ventricular ablation was performed exclusively in 6 patients (ventricular tachycardia, n=1; PVC, n=5). Seven patients (58%) undergoing LV ablation experienced a total of 16 cerebral emboli, in comparison with zero patients undergoing right ventricular ablation (P=0.04). Seven of 11 patients (63%) undergoing a retrograde approach to the LV developed at least 1 new brain lesion. CONCLUSIONS: More than half of patients undergoing routine LV ablation procedures (predominately PVC ablations) experienced new brain emboli after the procedure. Future research is critical to understanding the long-term consequences of these lesions and to determining optimal strategies to avoid them.