Type 3 long QT syndrome: Is the effectiveness of treatment with beta-blockers population-specific?

BACKGROUND: The efficacy of beta-blocker treatment in type 3 long QT syndrome (LQT3) remains debated. OBJECTIVES: The purpose of this study was to test the hypothesis that beta-blocker use is associated with cardiac events (CEs) in a French cohort of LQT3 patients. METHODS: All patients with a likely pathogenic/pathogenic variant in the SCN5A gene (linked to LQT3) were included and followed-up. Documented ventricular tachycardia/ventricular fibrillation, torsades de pointes, aborted cardiac arrest, sudden death, and appropriate shocks were considered as severe cardiac events (SCEs). CEs also included syncope. RESULTS: We included 147 patients from 54 families carrying 23 variants. Six of the patients developed symptoms before the age of 1 year and were analyzed separately. The 141 remaining patients (52.5% male; median age at diagnosis 24.0 years) were followed-up for a median of 11 years. The probabilities of a CE and an SCE from birth to the age of 40 were 20.5% and 9.9%, respectively. QTc prolongation (hazard ratio [HR] 1.12 [1.0-1.2]; P = .005]) and proband status (HR 4.07 [1.9-8.9]; P <.001) were independently associated with the occurrence of CEs. Proband status (HR 8.13 [1.7-38.8]; P = .009) was found to be independently associated with SCEs, whereas QTc prolongation (HR 1.11 [1.0-1.3]; P = .108) did not reach statistical significance. The cumulative probability of the age at first CE/SCE was not lower in patients treated with a beta-blocker. CONCLUSION: In agreement with the literature, proband status and lengthened QTc were associated with a higher risk of CEs. Our data do not show a protective effect of beta-blocker treatment.

Systemic primary carnitine deficiency induces severe arrhythmia due to shortening of QT interval.

BACKGROUND: Systemic primary carnitine deficiency (PCD) is characterized by cardiomyopathy and arrhythmia. Without carnitine supplementation, progression is usually towards fatal cardiac decompensation. While the cardiomyopathy is most likely secondary to energy deficiency, the mechanism of arrhythmia is unclear, and may be related to a short QT interval. OBJECTIVE: We aim to describe rhythmic manifestations at diagnosis and with carnitine supplementation. METHODS: French patients diagnosed for PCD were retrospectively included. Clinical and para clinical data at diagnosis and during follow-up were collected. Electrocardiograms with QT interval measurements were blinded reviewed by two paediatric cardiologists. RESULTS: Nineteen patients (median age at diagnosis 2.3 years (extremes 0.3-28.9)) followed in 8 French centres were included. At diagnosis, 21% of patients (4/19) had arrhythmia (2 ventricular fibrillations, 1 ventricular tachycardia and 1 sudden death), and 84% (16/19) had cardiomyopathy. Six electrocardiograms before treatment out of 11 available displayed a short QT (QTc < 340 ms). Median corrected QTc after carnitine supplementation was 404 ms (extremes 341-447) versus 350 ms (extremes 282-421) before treatment (p < 0.001). The whole QTc was prolonged, and no patient reached the criterion of short QT syndrome with carnitine supplementation. Three patients died, probably from rhythmic cause without carnitine supplementation (two extra-hospital sudden deaths and one non-recoverable rhythmic storm before carnitine supplementation), whereas no rhythmic complication occurred in patients with carnitine supplementation. CONCLUSION: PCD is associated with shortening of the QT interval inducing severe arrhythmia. A potential explanation would be a toxic effect of accumulated fatty acid and metabolites on ionic channels embedded in the cell membrane. Carnitine supplementation normalizes the QTc and prevents arrhythmia. Newborn screening of primary carnitine deficiency would prevent avoidable deaths.

Comparison of first- and second-generation leadless pacemakers in patients with sinus rhythm and complete atrioventricular block.

INTRODUCTION: The efficacy and safety of leadless cardiac pacemakers (LPMs) as an alternative to conventional transvenous cardiac pacing have been largely reported. The first generation of the MicraTM transcatheter pacing system (VR; Medtronic) was able to provide single-chamber VVI(R) pacing mode only, with a potential risk of pacemaker syndrome in sinus rhythm patients. A second-generation system (AV) now provides atrioventricular synchrony through atrial mechanical (Am) sensing capability (VDD mode). OBJECTIVE: We sought to compare VR and AV systems in sinus rhythm patients with chronic ventricular pacing (Vp) for complete atrioventricular block. METHODS: All consecutive patients implanted with an LPM in our department for complete atrioventricular block were retrospectively screened. Patients with atrial fibrillation, sinus dysfunction, or Vp burden <20% at 1 month postimplantation were excluded. Patients were systematically followed with a visit at 1 month, and then at least once a year. RESULTS: A total of 93 patients-45 VR (2015-2020) and 48 AV (2020-2021)-were included. VR and AV patients had similar baseline characteristics, except for VR patients being older (80 ± 8 vs. 77 ± 9 years, p = 0.049). The mean Vp burden was 77% in the VR and 82% in the AV group (p = 0.38). In AV patients, the median AV synchronous beats rate was 78%, with 65% having a >66% rate. An E/A ratio <1.2 as measured on echocardiography was the only independent predictor of accurate atrial mechanical tracking (p = 0.01). One-year survival rate was similar in both groups. Five patients in the VR and 0 in the AV group eventually developed pacemaker syndrome within 1 year post-implantation (p = 0.02). CONCLUSION: In sinus rhythm patients with chronic Vp for complete atrioventricular block implanted with an LPM, the atrial mechanical sensing algorithm allowed significant atrioventricular synchrony in most patients and was associated with no occurrence of-otherwise rare-pacemaker syndrome.

Leadless cardiac pacing: Results from a large single-centre experience.

BACKGROUND: The efficacy and safety of leadless cardiac pacing as an alternative to conventional transvenous cardiac pacing in selected patients have been widely reported. AIM: To report the experience of a high-volume implantation centre with older and new generations of leadless pacemakers. METHODS: This retrospective observational study included the first consecutive 400 patients who underwent implantation of a leadless pacemaker in our centre. Complications and electrical parameters were evaluated during follow-up, comparing patients implanted with first-generation (Micra™ VR) and second-generation (Micra™ AV) leadless pacemakers (Medtronic, Minneapolis, MN, USA). Data were collected by a review of medical files. RESULTS: Among 400 procedures, there were 328 Micra™ VR pacemakers and 72 Micra™ AV pacemakers implanted, followed for a median of 16 months (694 patient-years). The mean age was 77 years and both groups had a high burden of co-morbidities. Implantation success rate was 99.5%. A total of 87.5% of patients were discharged the day after the procedure. The pacing threshold remained stable and<2V in 96.5% of all patients. The perioperative complication rate at 30 days was 3.5%. Outcomes were similar between the two groups. CONCLUSION: Leadless cardiac pacing is a safe and efficient alternative to conventional transvenous cardiac pacing.

Dual-chamber ICD for left bundle branch area pacing: the cardiac resynchronization and arrhythmia sensing via the left bundle (cross-left) pilot study.

BACKGROUND: Left bundle branch area pacing (LBBAP) has emerged as a promising technique to deliver cardiac resynchronization therapy (CRT). However, safety and efficacy of ventricular arrhythmia sensing via the left bundle in implantable cardioverter-defibrillator (ICD) recipients remain unclear. We sought to evaluate the feasibility of a single LBBAP lead connected to a dual-chamber ICD in patients indicated with a CRT-D implantation. METHODS: The CROSS-LEFT pilot study prospectively included 10 consecutive patients with a reduced ejection fraction and a complete left bundle branch block, indicated with a prophylactic CRT-D. A DF-1 lead was implanted at the right ventricular (RV) apex, and an LBBAP lead through the interventricular septum. Ventricular fibrillation was induced at implantation in both conventional (RV) and left bundle branch area sensing configurations. The latter was the final sensing configuration, and patients were implanted with a dual-chamber DF-1 ICD connected to the atrial lead (RA port), the LBBAP lead (RV IS-1 port), and the defibrillation lead (RV DF-1 port), the IS-1 pin being capped. Atrioventricular delay was optimized to ensure fusion between LBBAP and native conduction from the right bundle. Patients were followed during 6 months. RESULTS: No difference between both configurations was observed regarding R-wave sensing in sinus rhythm (p = 0.22), ventricular fibrillation median interval detection (p = 1.00), or total induced episode duration (p = 0.78). LBBAP resulted in a significant reduction of median QRS width from 164 to 126 ms (p = 0.002). Median ventricular sensing significantly improved from 9.7 at implantation to 18.8 mV at 6 months (p = 0.01). Median LVEF also significantly improved from 29 to 44% at 6 months (p = 0.002). CONCLUSION: Ventricular arrhythmia sensing and defibrillation can be performed via a single LBBAP lead connected to a dual-chamber ICD, and is associated with significant electromechanical reverse remodeling. CLINICAL TRIAL REGISTRATION NUMBER: NCT05102227 In patients presenting with left bundle branch block and left ventricular systolic dysfunction, a left bundle branch area pacing lead connected to a DF-1 dual-chamber implantable cardioverter-defibrillator provides safe ventricular arrhythmia sensing and efficient electro-mechanical resynchronization.

Leadless or Conventional Transvenous Ventricular Permanent Pacemakers: A Nationwide Matched Control Study.

Background Leadless ventricular permanent pacemakers (leadless VVI or LPM) were designed to reduce lead-related complications of conventional VVI pacemakers (CPM). The aim of our study was to assess and compare real-life clinical outcomes within the first 30 days and during a midterm follow-up with the 2 techniques. Methods and Results This French longitudinal cohort study was based on the national hospitalization database. All adults (age ≥18 years) hospitalized in French hospitals from January 1, 2017 to September 1, 2020, who underwent a first LPM or CPM were included. The study included 40 828 patients with CPM and 1487 with LPM. After propensity score matching 1344 patients with CPM were matched 1:1 with patients treated with LPM. Patients with LPM had a lower rate of all-cause and cardiovascular death within the 30 days after implantation. During subsequent follow-up (mean: 8.6±10.5 months), risk of all-cause death in the unmatched population was significantly higher in the LPM group than in the CPM group, whereas risk of cardiovascular death and of endocarditis was not significantly different. After matching on all baseline characteristics including comorbidities (mean follow-up 6.2±8.7 months), all-cause death, cardiovascular death, and infective endocarditis were not statistically different in the 2 groups. Conclusions Patients treated with leadless VVI pacemakers had better clinical outcomes in the first month compared with the patients treated with conventional VVI pacing. During a midterm follow-up, risk of all-cause death, cardiovascular death, and endocarditis in patients treated with leadless VVI pacemaker was not statistically different after propensity score matching.

Physiological pacing with a DF-1 single chamber defibrillator in a patient with permanent atrial fibrillation and heart block: A case report.

We report a case report of a 68-year-old man with chemotherapy-induced cardiomyopathy and uncontrolled permanent atrial fibrillation. Cardiac resynchronization therapy implantation and atrioventricular junction ablation were planned. DF-1 single chamber defibrillator was connected to lead's defibrillation and a lead destinated to left bundle branch area pacing. This system leads to reduce costs by one-third, improve battery longevity, and provide a more physiological pacing.

Atrioventricular Nodal Reentrant Tachycardia Ablation Using Mini-Electrode Recordings.

Catheter ablation of the slow pathway in patients with atrioventricular nodal reentrant tachycardia (AVNRT) is mainly performed using anatomical landmarks. We sought to see whether a new ablation catheter equipped with mini-electrodes may facilitate the mapping of slow pathway potentials for AVNRT ablation. We prospectively included patients referred for AVNRT in our center. Mapping and ablation were performed using an irrigated catheter equipped with 3 insulated mini-electrodes on the distal tip. Thirteen consecutive patients were included (85% female, median age 46 years). Slow pathway potentials could be identified in 77% of cases on mini-electrode bipolar tracings, versus 15% on conventional bipolar tracings (p = 0.0009). At the end of the procedure, double potentials on the ablation line were identified in all patients, only on mini-electrode bipolar tracings. Following ablation, an interval separating double potentials in sinus rhythm ≥15% of baseline tachycardia cycle length was associated with non-inducibility in all patients (p < 0.0001). No recurrence occurred during 1 year of follow-up. The use of mini-electrodes may help target slow pathway potentials during AVNRT ablation. Identification of sufficiently split double potentials on the ablation line might represent an electrophysiological endpoint in these patients.

Ischemic Stroke in Patients With Hypertrophic Cardiomyopathy According to Presence or Absence of Atrial Fibrillation.

BACKGROUND AND PURPOSE: Patients with hypertrophic cardiomyopathy (HCM) have high risk of ischemic stroke (IS), especially if atrial fibrillation (AF) is present. Improvements in risk stratification are needed to help identify those patients with HCM at higher risk of stroke, whether AF is present or not. METHODS: This French longitudinal cohort study from the database covering hospital care from 2010 to 2019 analyzed adults hospitalized with isolated HCM. A logistic regression model was used to construct a French HCM score, which was compared with the HCM Risk-CVA and CHA2DS2-VASc scores using c-indexes and calibration analysis. RESULTS: In 32 206 patients with isolated HCM, 12 498 (38.8%) had AF, and 2489 (7.7%) sustained an IS during follow-up. AF in patients with HCM was independently associated with a higher risk for death (hazard ratio, 1.129 [95% CI, 1.088-1.172]), cardiovascular death (hazard ratio, 1.254 [95% CI, 1.177-1.337]), IS (hazard ratio, 1.210 [95% CI, 1.111-1.317]), and other major cardiovascular events. Independent predictors of IS in HCM were older age, heart failure, AF, prior IS, smoking and poor nutrition (all P<0.05). For the HCM Risk-CVA score, CHA2DS2-VASc score and a French HCM score, all c-indexes were 0.65 to 0.70, with good calibration. Among patients with AF, the CHA2DS2-VASc score had marginal improvement over the HCM Risk-CVA score but was less predictive compared with the French HCM score (P=0.001). In patients without AF, both HCM Risk-CVA score and the French HCM score had significantly better prediction compared with CHA2DS2-VASc (both P<0.0001). Decision curve analysis demonstrated that the French HCM score had the best clinical usefulness of the 3 tested risk scores. CONCLUSIONS: Patients with HCM have a high prevalence of AF and a significant risk of IS, and the presence of AF in patients with HCM was independently associated with worse outcomes. A simple French HCM score shows good prediction of IS in patients with HCM and clinical usefulness, with good calibration.

Anodal Capture for Multisite Pacing with a Quadripolar Left Ventricular Lead: A Feasibility Study.

BACKGROUND: Up to 40% of patients are CRT non-responders. Multisite pacing, using a unique quadripolar lead, also called multipoint/multipole pacing (MPP), is a potential alternative. We sought to determine the feasibility of intentional anodal capture using a single LV quadripolar lead, to reproduce MPP without the need of a specific algorithm (so-called "pseudo MPP"). METHODS: Consecutive patients implanted with a commercially available CRT device and a quadripolar LV lead in our department were prospectively included. The electric charge (Q, in Coulomb) of RV and LV pacing spikes were calculated for all available LV pacing configurations at the threshold. The best MPP was defined as the configuration with the lowest consumption (QRV + Qbest LV1 + Qbest LV2). The best "pseudo MPP" (QRV + QLV1-LV2 with anodal capture) and best BVp (QRV + Qbest LV) were also calculated. A theoretical longevity was estimated for each configuration at the threshold without a safety margin. RESULTS: A total of 235 configurations were tested in 15 consecutive patients. "Pseudo-MPP" was feasible in 80% of patients with 3.1 ± 2.6 vectors available per-patient and LVproximal-LVdistal (most distant electrodes) vectors were available in 47% of patients. Each MPP pacing spike electrical charge was comparable to "pseudo-MPP" (18,428 ± 6863 µC and 20,528 ± 5509 µC, respectively, p = 0.15). Theoretical longevity was 6.2 years for MPP, 5.6 years for "pseudo-MPP" and 13.7 years for BVp. CONCLUSIONS: "Pseudo MPP" using intentional anodal capture with a quadripolar left ventricular lead, mimicking conventional multisite pacing, is feasible in most of CRT patients, with comparable energy consumption. Further studies on their potential clinical impact are needed.

Leadless pacemakers in critically ill patients requiring prolonged cardiac pacing: A multicenter international study.

BACKGROUND: Temporary transvenous pacing in critically ill patients requiring prolonged cardiac pacing is associated with a high risk of complications. We sought to evaluate the safety and efficacy of self-contained intracardiac leadless pacemaker (LPM) implantation in this population. METHODS AND RESULTS: Consecutive patients implanted with a Micra LPM during the hospitalization in an intensive care unit were retrospectively included. Inclusion criteria were: more than or equal to 1 supracaval central venous line, or a ventilation tube, or intravenous antibiotic therapy for ongoing sepsis or bacteremia. Patients with a history of the previous implantation of a pacemaker were excluded. Out of 1016 patients implanted with an LPM, 99 met the inclusion criteria. Mean age was 75 years and Charlson comorbidity index 7. LPM implantation was successfully performed in 98% of cases, with a perioperative complication rate of 5%, mainly cardiac injuries. In-hospital mortality rate was 6%. No late (>30 days) device-related complication occurred, especially no infection. CONCLUSIONS: LPM appears as an acceptable alternative to conventional temporary transvenous pacing in selected critically ill patients requiring prolonged cardiac pacing, especially regarding the risk of infection.

The Defibrillation Conundrum: New Insights into the Mechanisms of Shock-Related Myocardial Injury Sustained from a Life-Saving Therapy.

Implantable cardiac defibrillators (ICDs) are recommended to prevent the risk of sudden cardiac death. However, shocks are associated with an increased mortality with a dose response effect, and a strategy of reducing electrical therapy burden improves the prognosis of implanted patients. We review the mechanisms of defibrillation and its consequences, including cell damage, metabolic remodeling, calcium metabolism anomalies, and inflammatory and pro-fibrotic remodeling. Electrical shocks do save lives, but also promote myocardial stunning, heart failure, and pro-arrhythmic effects as seen in electrical storms. Limiting unnecessary implantations and therapies and proposing new methods of defibrillation in the future are recommended.

Outcomes associated with pacemaker implantation following transcatheter aortic valve replacement: A nationwide cohort study.

BACKGROUND: Conduction abnormalities following transcatheter aortic valve replacement (TAVR) often may require permanent pacemaker implantation (PPM). OBJECTIVE: The purpose of this study was to evaluate outcomes associated with PPM after a TAVR procedure in a large, nationwide-level population. METHODS: Based on the administrative hospital discharge database, the incidence of all-cause death, cardiovascular death, and hospitalization for heart failure (HF) were retrospectively collected, based on the presence or absence of PPM, in the first 30 days following all TAVRs in France from 2010 to 2019. RESULTS: Among 520,662 patients hospitalized for aortic stenosis, 49,201 were treated with TAVR. A total of 29,422 patients had follow-up ≥6 months (median 1.7 years), 22% already had PPM at baseline, and 22% underwent PPM within the first 30 days post-TAVR. Adjusted hazard ratios for the combined risk of all-cause death and hospitalization for HF, during the whole follow-up, were higher in both patients with a previous PPM and in those implanted within 30 days (hazard ratio [95% confidence interval] 1.12 [1.07-1.17] and 1.11 [1.06-1.16], respectively). CONCLUSION: PPM at baseline and within 30 days post-TAVR are independently associated with higher mortality and HF hospitalization during follow-up.

Left bundle area pacing, an elegant alternative in failed cardiac resynchronization therapy implantation: A case report.

Left ventricular lead placement for cardiac resynchronization therapy may be challenging or even impossible. Left bundle area pacing has emerged as an interesting alternative method in case of failed implantation.

The IC-D score for predicting prophylactic cardioverter-defibrillator implantation following acute myocardial infarction.

BACKGROUND: A reduced left ventricular ejection fraction (LVEF) ≤35% ≥6 weeks following an acute myocardial infarction (MI) may indicate prophylactic implantation of a cardioverter-defibrillator (ICD). We sought to find predictors of absence of significant left ventricular (LV) remodeling post-MI. METHODS: All consecutive patients hospitalized for acute MI with an LVEF ≤35% at discharge in our institution from 2010 were retrospectively included. Patients were assigned to two groups according to the persistence of an LVEF ≤35% (ICD+) or a recovery >35% (ICD-). Logistic regression was performed to build a predictive score, which was then externally validated. RESULTS: Among a total of 1533 consecutive MI patients, 150 met inclusion criteria, 53 (35%) in the ICD+ group and 97 in the ICD group. After multivariable analyses, an LVEF ≤25% at discharge (adjusted OR 6.23 [2.47 to 17.0], p < .0001) and a CPK peak at the MI acute phase >4600 UI/L (adjusted OR 9.99 [4.27 to 25.3], p < .0001) both independently predicted non-recovery at 6 weeks. The IC-D (Increased Cpk-LV Dysfunction) score predicted persistent LVEF ≤35% with areas under curve of 0.83 and 0.73, in the study population and in a multicenter validation cohort of 150 patients, respectively (p < .0001). CONCLUSIONS: The association of a severely reduced LVEF and a major release of myocardial necrosis biomarkers at the acute phase of MI predict unfavorable remodeling, and prophylactic ICD implantation.

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Acute pathophysiological myocardial changes following intra-cardiac electrical shocks using a proteomic approach in a sheep model.

Implantable cardioverter-defibrillators (ICD) are meant to fight life-threatening ventricular arrhythmias and reduce overall mortality. Ironically, life-saving shocks themselves have been shown to be independently associated with an increased mortality. We sought to identify myocardial changes at the protein level immediately after ICD electrical shocks using a proteomic approach. ICD were surgically implanted in 10 individuals of a healthy male sheep model: a control group (N = 5) without any shock delivery and a shock group (N = 5) with the delivery of 5 consecutive shocks at 41 J. Myocardial tissue samples were collected at the right-ventricle apex near to the lead coil and at the right ventricle basal free wall region. Global quantitative proteomics experiments on myocardial tissue samples were performed using mass spectrometry techniques. Proteome was significantly modified after electrical shock and several mechanisms were associated: protein, DNA and membrane damages due to extreme physical conditions induced by ICD-shock but also due to regulated cell death; metabolic remodeling; oxidative stress; calcium dysregulation; inflammation and fibrosis. These proteome modifications were seen in myocardium both "near" and "far" from electrical shock region. N-term acetylated troponin C was an interesting tissular biomarker, significantly decreased after electrical shock in the "far" region (AUC: 0.93). Our data support an acute shock-induced myocardial tissue injury which might be involved in acute paradoxical deleterious effects such as heart failure and ventricular arrhythmias.