A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Efficacy and safety of supraclavicular and pectoralis nerve blocks as primary peri-procedural analgesia for cardiac electronic device implantation: A pilot study.

BACKGROUND: Cardiac implantable electronic devices (CIEDs) are routinely implanted using intravenous drugs for sedation. However, some patients are poor candidates for intravenous sedation. OBJECTIVE: We present a case series demonstrating the safety and efficacy of a novel, ultrasound-guided nerve block technique that allows for pre-pectoral CIED implantation. The targets are the supraclavicular nerve (SCN) and pectoral nerve (PECS1). METHODS: We enrolled 20 patients who were planned for new CIED implantation. Following US-localization of the SCN and PECS1, local anesthetic (LA) was instilled at least 30-60 min pre-procedure. Successful nerve block was determined if < 5 mL of intraprocedural LA was used, along with lack of sensation with skin and deep tissue pinprick. Optional sedation was offered to patients' pre-procedure if discomfort was reported. RESULTS: Seventeen patients (85%) had a successful periprocedural nerve block, with only three patients exceeding 5 mL of LA. SCN and PECS1 success occurred in 19 (95%) and 18 (90%) patients, respectively. The overall success of nerve block by fulfilling all the criteria was demonstrated in 17 out of 20 patients (85%). Patients who reported no pain (VAS score = 0) were distributed as follows: 13 patients (65%) in the immediate post-procedure interval, 18 patients (90%) at the 1 h post-implant interval, and 14 patients (70%) at the 24 h post- implant interval. The median cumulative VAS score was 0 (IQR = 0 - 1). There were no reported significant adverse effects. CONCLUSION: SCN and PECS1 nerve blocks are safe and effective for patients undergoing CIED implantation to minimize or eliminate the use of intravenous sedation.

Hemodynamically Tolerated Ventricular Tachycardia With Mildly Impaired Ejection Fraction: Do These Patients Have VT/VF Recurrence and ICD Therapies?

BACKGROUND: Patients with hemodynamically tolerated ventricular tachycardia (VT) and minimally reduced left ventricular ejection fraction (LVEF) remain a group that presents a prognostic and therapeutic dilemma. METHODS: We studied patients from our implanted cardioverter-defibrillator (ICD) database who received ICDs for hemodynamically tolerated VT and mildly reduced LVEF (36%-49%) at time of implant between May 2015 and December 2019. Time to appropriate ICD therapy was assessed. Clinical features associated with recurrent VT/ventricular fibrillation (VF) with ICD therapies were explored using binary logistic regression. RESULTS: Among 2037 ICDs placed between May 2015 and December 2019, 64 subjects met the inclusion criteria. The mean age of the study group was 68 ± 12 years, and 58 (90.6%) subjects were male. Average ejection fraction was 40% ± 4.4 (range 36%-49%). Twenty-two (34%) subjects received antitachycardia pacing (ATP) for VT at 229 ± 265 days after ICD placement. Fifteen (23%) subjects received appropriate ICD shocks 305 ± 321 days after implant. The rate of recurrent VT/VF among the 37 patients with ICD therapy was 195 ± 39 beats per minute (bpm). This was significantly more rapid than initial presenting VT rates before ICD placement (183 ± 27 bpm) (P = 0.048). Multivariate analysis showed no factors independently associated with recurrent VT/VF. CONCLUSIONS: Patients with mildly impaired LV function and hemodynamically tolerated VT receive appropriate ICD therapies over the 3 years following implant. This patient group warrants further investigation, as their recurrent VT/VF rates can be much more rapid, and 23% go on to receive appropriate ICD shocks.

Evaluating Polygenic Risk Scores in "Lone" Atrial Fibrillation.

BACKGROUND: Polygenic scores incorporating varying numbers of single nucleotide polymorphisms (SNPs) have been demonstrated to exert a prominent role in atrial fibrillation (AF). We sought to compare the relative discriminatory capacities of 2 previously validated polygenic scores in "lone" AF. METHODS: A total of 186 lone AF cases of European ancestry underwent SNP genotyping. A genome-wide polygenic score (GPS) and polygenic risk score (PRS) involving 6,730,541 and 1168 SNPs, respectively, were calculated for 186 cases and 423 controls of European ancestry from the 1000 Genomes (1KG) Project. The distribution of the polygenic scores was compared between the cases and controls and their discriminatory capacities were evaluated using receiver operating characteristic (ROC) curves. RESULTS: A total of 34.4% of patients with lone AF had GPS scores greater than the top 10th percentile of 1KG controls, corresponding to a 4.64-fold increased odds (95% confidence interval [CI], 2.99-7.18; P < 0.001) for AF. A PRS score in the top 10th percentile of 1KG controls was observed in 26.3% of cases, which equated to a 3.16-fold increased odds (95% CI, 2.01-4.98; P < 0.001) for AF. Comparison of C-statistics from ROC curves indicated improved discriminatory capacity of the GPS (0.76) relative to the PRS (0.70) (P = 0.002). CONCLUSIONS: Our study evaluating 2 polygenic scores for AF suggests that the GPS, containing more than 6.7 million SNPs, exhibits an improved discriminatory capacity in lone AF compared with a PRS possessing 1168 SNPs. Our findings suggest that genetic risk scores for AF that maximally leverage genomic data may provide improved predictive power.

CONTEXTE: Il a été démontré que des scores polygéniques intégrant un nombre variable de polymorphismes mononucléotidiques (PMN) jouent un rôle important en ce qui concerne la fibrillation auriculaire (FA). Nous avons comparé le potentiel discriminatoire relatif de deux scores polygéniques déjà validés dans la FA idiopathique. MÉTHODOLOGIE: Au total, 186 sujets d'ascendance européenne atteints de FA idiopathique ont été soumis à un génotypage des PMN. Un score polygénique génomique (SPG) et un score de risque polygénique (SRP) comprenant respectivement 6 730 541 et 1 168 PMN ont été calculés pour les 186 sujets et pour 423 témoins d'ascendance européenne dont les données sont tirées du projet 1000 Genomes (1KG). Les distributions des scores polygéniques des sujets et des témoins ont été comparées, et leur potentiel discriminatoire a été évalué au moyen des courbes caractéristiques de la performance d'un test (courbes ROC, de l'anglais Receiver Operating Characteristic). RÉSULTATS: Au total, 34,4 % des patients atteints de FA idiopathique avaient un SPG supérieur à celui des témoins du 10e centile supérieur du projet 1KG, ce qui représente une probabilité de FA 4,64 fois plus élevée (intervalle de confiance [IC] à 95 % : 2,99 à 7,18; p < 0,001). Un SRP situé dans le 10e centile supérieur des témoins du projet 1KG a été observé chez 26,3 % des patients atteints de FA, soit une probabilité de FA 3,16 fois plus élevée (IC à 95 % : 2,01 à 4,98; p < 0,001). Les résultats de la comparaison des statistiques C des courbes ROC indiquent que le SPG (0,76) a un potentiel discriminatoire supérieur à celui du SRP (0,70) (p = 0,002). CONCLUSIONS: Les résultats de notre étude de deux scores polygéniques relatifs à la FA indiquent que le potentiel discriminatoire du SPG, qui comprend plus de 6,7 millions de PMN, pour prédire une FA idiopathique est supérieur à celui du SRP, qui comprend 1 168 PMN. Ces résultats indiquent que les scores de risque génétique de FA qui exploitent pleinement les données génomiques pourraient avoir un pouvoir prédictif supérieur.

Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in 'lone' atrial fibrillation.

AIMS: Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in 'lone' AF. METHODS AND RESULTS: Whole-exome sequencing was performed in 255 early onset 'lone' AF cases, defined as arrhythmia onset prior to 60 years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11-14.2; P = 0.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P = 0.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with 'lone' AF. CONCLUSION: 'Lone' AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.

Para-Hisian Pacing During Sinus Rhythm: Establishing Threshold Values to Distinguish Nodal From Septal Pathway Conduction.

OBJECTIVES: This study sought to identify minimum threshold values below which conduction over the atrioventricular (AV) node would be unexpected. BACKGROUND: Para-Hisian pacing is used to evaluate for the presence of a septal accessory pathway (AP); however, threshold values to differentiate nodal from AP conduction are unknown. METHODS: The authors performed high- and low-output para-Hisian pacing during sinus rhythm to capture the His and para-Hisian ventricular myocardium (H+V) and para-Hisian ventricular myocardium (V) alone, respectively. The change in stimulation (stim)-to-atrial electrogram interval after loss of His bundle capture in patients with (AP+) and without (AP-) a septal AP was evaluated. Stim-to-proximal coronary sinus (PCS) and stim-to-high right atrium (HRA) intervals were measured and within-patient differences (△) for V and H+V capture were calculated. RESULTS: A total of 23 AP+ and 45 AP- patients were evaluated. The difference in stimulus to earliest atrial signal in the high right atrial catheter seen with the loss of His bundle capture (△-stim-HRA) (21 ms; interquartile range [IQR]: 3 to 43 ms vs. 64 ms; IQR: 56 to 73 ms; p < 0.001) and difference in stimulus to earliest atrial signal in the proximal coronary sinus catheter seen with the loss of His Bundle capture (△-stim-PCS) (11 ms; IQR: 0 to 30 ms vs. 61 ms; IQR: 52 to 72 ms; p < 0.001) were shorter in AP+ patients. The shortest △-stim-PCS and △-stim-HRA in AP- patients were 37 ms and 32 ms, respectively, whereas the longest corresponding intervals in AP+ patients were 51 ms and 75 ms, respectively. CONCLUSIONS: A △-stim-PCS <37 ms or △-stim-HRA <32 ms confirmed the presence of a septal AP, whereas a value >51 ms for △-stim-PCS or >75 ms for △-stim-HRA excluded it. Alternatively, the minimum △-stim-PCS with loss of His capture compatible with AV nodal conduction in isolation was 37 ms, and a △-stim-PCS >51 ms effectively ruled out the presence of a septal AP.

A simple maneuver to determine if septal accessory pathway ablation requires a left atrial approach.

INTRODUCTION: Septal accessory pathway (AP) ablation can be challenging due to the complex anatomy of the septal region. The decision to access the left atrium (LA) is often made after failure of ablation from the right. We sought to establish whether the difference between ventriculo-atrial (VA) time during right ventricular (RV) apical pacing versus the VA during tachycardia would help establish the successful site for ablation of septal APs. METHODS: Intracardiac electrograms of patients with orthodromic reciprocating tachycardia (ORT) using a septal AP with successful catheter ablation were reviewed. The ∆VA was the difference between the VA interval during RV apical pacing and the VA interval during ORT. The difference in the VA interval during right ventricular entrainment and ORT (StimA-VA) was also measured. RESULTS: The median ∆VA time was significantly less in patients with a septal AP ablated on the right side compared with patients with a septal AP ablated on the left side (12 ± 19 vs. 56 ± 10 ms, p < .001). The StimA-VA was significantly different between the two groups (22 ± 14 vs. 53 ± 9 ms, p < .001). The ∆VA and StimA-VA were always ≤ 40 ms in patients with non-decremental septal APs ablated from the right side and always greater than 40 ms in those with septal APs ablated from the left. CONCLUSION: ΔVA and StimA-VA values identified with RV apical pacing in the setting of ORT involving a septal AP predict when left atrial access will be necessary for successful ablation.

2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Position Statement on the Management of Ventricular Tachycardia and Fibrillation in Patients With Structural Heart Disease.

This Canadian Cardiovascular Society position statement is focused on the management of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) that occurs in patients with structural heart disease (SHD), including previous myocardial infarction, dilated cardiomyopathy, and other forms of nonischemic cardiomyopathy. This patient population is rapidly increasing because of advances in care and improved overall survival of patients with all forms of SHD. In this position statement, the acute and long-term management of VT/VF are outlined, and the many unique aspects of care in this population are emphasized. The initial evaluation, acute therapy, indications for chronic suppressive therapy, choices of chronic suppressive therapy, implantable cardioverter-defibrillator programming, alternative therapies, and psychosocial care are reviewed and recommendations for optimal care are provided. The target audience for this statement includes all health professionals involved in the continuum of care of patients with SHD and VT/VF.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Incremental Value of Implantable Cardiac Device Diagnostic Variables Over Clinical Parameters to Predict Mortality in Patients With Mild to Moderate Heart Failure.

Background Heart failure remains a leading cause of morbidity and mortality. Clinical prediction models provide suboptimal estimates of mortality in this population. We sought to determine the incremental value of implantable device diagnostics over clinical prediction models for mortality. Methods and Results RAFT (Resynchronization/Defibrillation for Ambulatory Heart Failure Trial) patients with implanted devices capable of device diagnostic monitoring were included, and demographic and clinical parameters were used to compute Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) heart failure risk scores. Patients were classified according to MAGGIC score into low (0-16), intermediate (17-24), or high (>24) risk groups. Mortality was evaluated from 6 months postimplant in accordance with the RAFT protocol. In a subset of 1036 patients, multivariable analysis revealed that intermediate and high MAGGIC scores, fluid index, atrial fibrillation, and low activity flags were independent predictors of mortality. A device-integrated diagnostic parameter that included a fluid index flag and either a positive atrial fibrillation flag or a positive activity flag was able to significantly differentiate higher from lower risk for mortality in the intermediate MAGGIC cohort. The effect was more pronounced in the high-risk MAGGIC cohort, in which device-integrated diagnostic-positive patients had a shorter time to death than those who were device-integrated diagnostic negative. Conclusions Device diagnostics using a combination of fluid index trends, atrial fibrillation burden, and patient activity provide significant incremental prognostic value over clinical heart failure prediction scores in higher-risk patients. This suggests that combining clinical and device diagnostic parameters may lead to models with better predictive power. Whether this risk is modifiable with early medical intervention would warrant further studies. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT00251251.

Challenge and Impact of Quinidine Access in Sudden Death Syndromes: A National Experience.

OBJECTIVES: This study sought to determine the nature of quinidine use and accessibility in a national network of inherited arrhythmia clinics. BACKGROUND: Quinidine is an antiarrhythmic medication that has been shown to be beneficial in select patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation. Because of the low prevalence of these conditions and restricted access to quinidine through a single regulatory process, quinidine use is rare in Canada. METHODS: Subjects prescribed quinidine were identified through the Hearts in Rhythm Organization that connects the network of inherited arrhythmia clinics across Canada. Cases were retrospectively reviewed for patient characteristics, indications for quinidine use, rate of recurrent ventricular arrhythmia, and issues with quinidine accessibility. RESULTS: In a population of 36 million, 46 patients are currently prescribed quinidine (0.0000013%, age 48.1 ± 16.1 years, 25 are male). Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation constituted a diagnosis in 13 subjects (28%), 6 (13%), and 21 (46%), respectively. Overall, 37 subjects (81%) had cardiac arrest as an index event. After initial presentation, subjects experienced 7.47 ± 12.3 implantable cardioverter-defibrillator shocks prior to quinidine use over 34.3 ± 45.9 months, versus 0.86 ± 1.69 implantable cardioverter-defibrillator shocks in 43.8 ± 41.8 months while on quinidine (risk ratio: 8.7, p < 0.001). Twenty-two patients access quinidine through routes external to Health Canada's Special Access Program. CONCLUSIONS: Quinidine use is rare in Canada, but it is associated with a reduction in recurrent ventricular arrhythmias in patients with Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation, with minimal toxicity necessitating discontinuation. Drug interruption is associated with frequent breakthrough events. Access to quinidine is important to deliver this potentially lifesaving therapy.