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.

Ventricular tachycardia characteristics and outcomes with catheter ablation vs. antiarrhythmic therapy: insights from the VANISH trial.

AIMS: Catheter ablation is superior to escalated antiarrhythmic drugs among patients with ventricular tachycardia (VT) and prior myocardial infarction (MI). However, it is uncertain whether clinical VT characteristics, should influence choice of therapy. The purpose of this study was to evaluate whether presentation with electrical storm and the clinical VT cycle length predicted response to ablation vs. escalated antiarrhythmic therapy. METHODS AND RESULTS: All patients enrolled in the Ventricular Tachycardia Ablation vs. Escalated Antiarrhythmic Drug Therapy in Ischaemic Heart Disease (VANISH) trial were included. The association between VT cycle length and presentation with electrical storm and the primary outcome of death, subsequent VT storm or appropriate ICD shock was evaluated. Among the study population of 259 patients, escalated antiarrhythmic drug therapy had worse outcomes for those presenting with a VT cycle length >400 ms [<150 b.p.m., 89/259, hazard ratio (HR) 1.7 (1.02-3.13)]. This effect was more pronounced among those taking amiodarone at baseline [HR of 2.22 (1.19-4.16)]. Presentation with VT storm (32/259) did not affect the primary outcome between groups. However, those presenting with VT storm on amiodarone had a trend towards worse outcomes with escalated antiarrhythmic therapy [HR 4.31 (0.55-33.93)]. CONCLUSION: The VT cycle length can influence response to either ablation or escalated drug therapy in patients with VT and prior MI. Those with slow VT had improved outcomes with ablation. Patients presenting with electrical storm demonstrated similar outcomes to the overall trial population, with a trend to benefit of catheter ablation, particularly in those on amiodarone.

Comparative effectiveness of ventricular tachycardia ablation vs. escalated antiarrhythmic drug therapy by location of myocardial infarction: a sub-study of the VANISH trial.

AIMS: Complexity of the ventricular tachycardia (VT) substrate and the size and thickness of infarction area border zones differ based on location of myocardial infarctions (MIs). These differences may translate into heterogeneity in the effectiveness of treatments. This study aims to examine the influence of infarct location on the effectiveness of VT ablation in comparison with escalated pharmacological therapy in patients with prior MI and antiarrhythmic drug (AAD)-refractory VT. METHODS AND RESULTS: VANISH trial participants were categorized based on the presence or absence of an inferior MI scar. Inverse probability of treatment weighted Cox models were calculated for each subgroup. Of 259 randomized patients (median age 69.8 years, 7.0% women), 135 had an inferior MI and 124 had a non-inferior MI. Among patients with an inferior MI, no statistically significant difference in the composite primary outcome of all-cause mortality, appropriate implantable cardioverter-defibrillator (ICD) shock, and VT storm was detected between treatment arms [adjusted hazard ratio (aHR) 0.80, 95% confidence interval (CI) 0.51-1.20]. In contrast, patients with non-inferior MIs had a statistically significant reduction in the incidence of the primary outcome with ablation (aHR 0.48, 95% CI 0.27-0.86). In a sensitivity analysis of anterior MI patients (n = 83), a trend towards a reduction in the primary outcome with ablation was detected (aHR 0.50, 95% CI 0.23-1.09). CONCLUSION: The effectiveness of VT ablation versus escalated AADs varies based on the location of the MI. Patients with MI scars located only in non-inferior regions of the ventricles derive greater benefit from VT ablation in comparison to escalation of AADs in reducing VT-related events.

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.

Improving Online ECG Interpretation Through Self-Generation of Diagnoses During Practice: A Randomized Study.

Although electrocardiography (ECG) is a fundamental skill for most physicians, trainees have poor diagnostic performance when interpreting ECGs. In this study, we examine a strategy to improve learning ECG interpretation: self-generation of diagnoses during online practice. We randomly assigned medical students and residents to one of 2 ECG interpretation training formats: multiple-choice (MCQ) or self-generation (SG) format, where participants free-text type their diagnosis aided by an autocomplete feature. The training phase consisted of 30 ECGs, after which participants completed an immediate post test and delayed post test (3-4 weeks later). Forty-eight participants completed the training module, 45 completed the immediate post test, and 27 completed the delayed post test. Participants assigned to the SG format scored higher on the immediate post test compared with those who practiced with the MCQ format, with a large effect size (78% vs 57%; d = 0.94; P = 0.02). There was a trend favouring SG on the delayed post test, with a moderate effect size (67% vs 56%; d = 0.65; P = 0.09). However, only 60% of participants completed the delayed post test, which hindered the detection of a statistically significant difference. The SG group made the correct primary diagnosis at a faster rate (32 vs 56 seconds; P < 0.001) but had a lower detection of secondary diagnoses (22 vs 42%; P = 0.007). Practicing ECG interpretation using self-generation of diagnoses improved immediate post test performance and fluency. Replication in other contexts and with other populations is required to confirm our findings and to further study retention.

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.

Safety of Lead Repair Compared to Lead Revision for Visible Lead Insulation Defects in Patients With Cardiac Implantable Electronic Devices.

BACKGROUND: Cardiac implantable electronic devices deliver life-sustaining therapy and may be prone to hardware degeneration over time. Functioning transvenous endocardial leads with visible insulation breaks are amenable to lead revision (LRV) or lead repair (LRP), with medical adhesive. The latter is a less invasive and more cost-effective strategy. However, data are sparse on the overall safety of such an approach. METHODS: This is a retrospective cohort study of patients with lead insulation defects managed by either LRV or LRP with medical adhesive. The data analyzed were from January 2010 to January 2021. All-cause mortality, and both early and late complications, was ascertained for all cases. RESULTS: A total of 57 cases were identified, with a mean age (standard deviation) of 75 (±11.8) years; 18 (31.6%) were women. A total of 35 patients (62.5%) underwent LRV for an insulation defect, and 21 (37.5%) underwent LRP. There was no statistical difference in the rate of early and late complications between the 2 groups over a mean follow-up period of 1.15 (±0.78) years [3 (8%)] LRV vs 1 (5%) LRP, P = 0.88). One death was identified in each group, unrelated to either the device or a device-related procedure. There was no association between device type and the likelihood of LRP vs LRV as an attempted strategy (χ2 = 2.25, P = 0.53). CONCLUSIONS: The results of this study suggest that the use of a lead-repair strategy, with silicone adhesive glue and an anchoring sleeve, is not associated with an increased rate of early or late complications, compared with lead revision in the management of visible lead insulation defects with stable lead function.

INTRODUCTION: Les dispositifs cardiaques électroniques implantables offrent un traitement essentiel au maintien de la vie, mais peuvent subir une détérioration de leur matériel au fil du temps. Le fonctionnement des sondes endocavitaires transveineuses ayant des ruptures visibles de l'isolant se prête à la révision de sonde (RVS) ou à la réparation de sonde (RPS) au moyen d'un adhésif médical. Cette dernière stratégie est moins invasive et plus efficiente. Toutefois, les données sur l'innocuité générale d'une telle approche sont rares. MÉTHODES: Il s'agit d'une étude de cohorte rétrospective de patients dont les sondes montrent des défaillances de l'isolant prises en charge par RVS ou par RPS au moyen d'un adhésif médical. Les données analysées s'échelonnaient de janvier 2010 à janvier 2021. La mortalité toutes causes confondues ainsi que les complications précoces et tardives étaient établies pour tous les cas. RÉSULTATS: Nous avons trouvé un total de 57 cas, dont l'âge moyen (écart type) était de 75 (± 11,8) ans; 18 (31,6 %) étaient des femmes. Au total, 35 patients (62,5 %) avaient subi une RVS en raison d'une défaillance de l'isolant, et 21 (37,5 %) avaient subi une RPS. Il n'y avait aucune différence statistique dans le taux de complications précoces et tardives entre les deux groupes durant une période moyenne de suivi 1,15 (± 0,78) an [3 (8 %)] RVS vs un (5 %) RPS, P = 0,88. Dans chaque groupe, nous avons noté 1 décès non associé au dispositif ou à une intervention liée au dispositif. Il n'y avait aucune association entre le type de dispositif et la probabilité de tentative d'une stratégie de RPS vs d'une stratégie de RVS (χ2 = 2,25, P = 0,53). CONCLUSIONS: Les résultats de cette étude montrent que l'utilisation d'une stratégie de RPS au moyen d'un adhésif de silicone et d'une douille d'ancrage n'est pas associée à un taux plus élevé de complications précoces ou tardives que la RVS dans la prise en charge des défaillances visibles de l'isolant de la sonde lors de fonctionnement stable de la sonde.

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.

Treatment with corticosteroids is associated with an increase in ventricular arrhythmia burden in patients with clinically manifest cardiac sarcoidosis: Insights from implantable cardioverter-defibrillator diagnostics.

INTRODUCTION: We sought to explore the relationship between ventricular tachycardia (VT) and premature ventricular complex (PVC) burden (from implantable cardioverter-defibrillator diagnostics), before and during corticosteroid use in patients with newly diagnosed clinically manifest cardiac sarcoidosis (CS). METHODS: A single-centre, prospective cohort study was performed in consecutive patients who met all of the following criteria: (1) presentation with clinically manifest CS, (2) abnormal myocardial fluoro-deoxyglucose (FDG) uptake on positron emission tomography scan, (3) plan for implantation with implantable cardioverter-defibrillator device that reports accurate PVC count, (4) plan to initiate corticosteroids after the device healing period. Data were collected during each device interrogation visit for all patients in the study. For each inter-visit period the total number of episodes of VT-sustained and nonsustained, and the number of PVCs was obtained. Each inter-visit period was classified into one of the following three periods: (1) New diagnosis of treatment-naive active disease without corticosteroids during the period. (2) Known treatment-naive active disease with corticosteroids initiated during the inter-visit period. (3) On corticosteroid therapy during the entire period. RESULTS: A total of 20 patients with a mean age of 59.7 ± 7.7 years were recruited and 82 inter-visit periods were analyzed. All patients were corticosteroid responders based on FDG uptake. The maximum left ventricular standardized uptake value was 11.14 ± 5.19 before corticosteroid initiation and 4.07 ± 0.88 after (p < .001). Patients with active untreated CS had an average of 496.4 ± 879.1 PVCs per day. After treatment with corticosteroids, the average PVC count increased to 1332.4 ± 1865.7/day during Period 2 (p = .036) and to 1590.1 ± 2362.2 per day during Period 3 (p = .008). There was also a statistically significant increase in episodes of nonsustained ventricular tachycardia (NSVT) before and after treatment with corticosteroids (p = .017). There were too few episodes of sustained ventricular arrhythmia to analyze. Overall, 18 out of 20 patients (90%) had an increase in PVC burden after corticosteroid initiation. CONCLUSION: This study demonstrated, on average, a threefold increase in daily PVC count in clinically manifest CS patients during treatment with corticosteroids compared to pretreatment. There was also a significant increase in episodes of NSVT. Clinicians and patients with active manifest CS should be aware that corticosteroids are unlikely to lead to a reduction in the burdens of PVC and NSVT.

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.

Cardiac Sarcoidosis multi-center randomized controlled trial (CHASM CS- RCT).

Approximately 5% of patients with sarcoidosis have clinically manifest cardiac involvement. Clinical features of Cardiac Sarcoidosis are dependent on the location, extent, and activity of the disease. First line therapy is usually with prednisone and this is recommended based on clinician experience, expert opinion and small observational cohorts. There are no published clinical trials in cardiac sarcoidosis and multiple experts in the field have called for randomized clinical trials to answer important patient care questions. Corticosteroid are associated with multiple adverse effects including hypertension, diabetes, weight gain, osteoporosis, and increased risk of infections. In contrast Methotrexate is generally well tolerated and is increasingly used in other forms of sarcoidosis. OBJECTIVES: The Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial (CHASM CS-RCT; NCT03593759) is a multicenter randomized controlled trial designed to evaluate the optimal initial treatment strategy for patients with active cardiac sarcoidosis. We hypothesize that (1) a low dose prednisone/methotrexate combination will have non-inferior efficacy to standard dose prednisone and that (2) the low dose prednisone/ methotrexate combination will result in significantly better quality of life than standard dose prednisone, as a result of reduced burden of side effects. METHODS/DESIGN: Eligible study subjects will have active clinically manifest cardiac sarcoidosis presenting with one or more of the following clinical findings: advanced conduction system disease, significant sinus node dysfunction, non-sustained or sustained ventricular arrhythmia, left ventricular dysfunction or right ventricular dysfunction. Subjects will be randomized in a 1:1 ratio to prednisone 0.5 mg/kg/day for 6 months (maximum dose 30 mg daily) OR to prednisone 20 mg daily for 1 month, then 10 mg daily for 1 month, then 5 mg daily for one month then stop AND methotrexate 15-20 mg once weekly for 6 months. The primary endpoint is summed perfusion rest score on 6-month PET (blinded core-lab review). The summed perfusion rest score is measure of myocardial fibrosis/scar. The design is non-inferiority with a sample size of 97 per group. DISCUSSION: Given the multiorgan system potential adverse side effects of prednisone, proving noninferiority of an alternate regimen would be sufficient to make the alternative compare favorably to standard dose steroids. This is the first ever clinical trial in cardiac sarcoidosis and thus in addition to the listed goals of the trial, we will also establish a multi-center, multinational cardiac sarcoidosis clinical trials network. Such a collaborative infrastructure will enable a new era of high quality data to guide physicians when treating cardiac sarcoidosis patients.