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.

NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis.

BACKGROUND: Few clinical data are available on NEXN mutation carriers, and the gene's involvement in cardiomyopathies or sudden death has not been fully established. Our objectives were to assess the prevalence of putative pathogenic variants in NEXN and to describe the phenotype and prognosis of patients carrying the variants. METHODS: DNA samples from consecutive patients with cardiomyopathy or sudden cardiac death/sudden infant death syndrome/idiopathic ventricular fibrillation were sequenced with a custom panel of genes. Index cases carrying at least one putative pathogenic variant in the NEXN gene were selected. RESULTS: Of the 9516 index patients sequenced, 31 were carriers of a putative pathogenic variant in NEXN only, including 2 with double variants and 29 with a single variant. Of the 29 unrelated probands with a single variant (16 males; median age at diagnosis, 32.0 [26.0-49.0] years), 21 presented with dilated cardiomyopathy (prevalence, 0.33%), and 3 presented with hypertrophic cardiomyopathy (prevalence, 0.14%). Three patients had idiopathic ventricular fibrillation, and there were 2 cases of sudden infant death syndrome (prevalence, 0.46%). For patients with dilated cardiomyopathy, the median left ventricle ejection fraction was 37.5% (26.25-50.0) at diagnosis and improved with treatment in 13 (61.9%). Over a median follow-up period of 6.0 years, we recorded 3 severe arrhythmic events and 2 severe hemodynamic events. CONCLUSIONS: Putative pathogenic NEXN variants were mainly associated with dilated cardiomyopathy; in these individuals, the prognosis appeared to be relatively good. However, severe and early onset phenotypes were also observed-especially in patients with double NEXN variants. We also detected NEXN variants in patients with hypertrophic cardiomyopathy and sudden infant death syndrome/idiopathic ventricular fibrillation, although a causal link could not be established.

ATE Score Diagnostic Accuracy for Predicting the Absence of Intra-Atrial Thrombi Before AF Ablation.

BACKGROUND: In a preliminary study in patients hospitalized for catheter ablation of atrial fibrillation (AF), the atrial thrombus exclusion (ATE) score (stroke, hypertension, heart failure, and D-dimers >270 ng/mL) was developed to rule out the diagnosis of intra-atrial thrombus, with a negative predictive value (NPV) of 100%, and to avoid performing transesophageal echocardiography (TEE). OBJECTIVES: The present study was designed to prospectively confirm the NPV of the ATE score in an independent population. METHODS: Consecutive patients hospitalized for catheter ablation of AF or left atrial tachycardia (LAT) were prospectively enrolled in a multicenter study. D-dimer levels were measured within 48 hours before ablation. An ATE score of 0 was considered predictive of no thrombus. TEE was routinely performed at the beginning or just before the ablation procedure. The primary endpoint was the presence of atrial thrombus diagnosed by TEE. RESULTS: The analysis included 3,072 patients (53.3% paroxysmal AF, 36.7% persistent AF, and 10% LAT). A thrombus was detected in 29 patients (0.94%; 95% CI: 0.63%-1.35%), all on appropriate anticoagulant therapy. An ATE score of 0 was observed in 818 patients (26.6%), and the sensitivity, specificity, positive predictive value, and NPV were 93.1%, 26.8%, 1.2%, and 99.8%, respectively. Follow-up of the 2 false negative patients revealed the persistence of chronic organized thrombi. CONCLUSIONS: In patients hospitalized for catheter ablation of AF or LAT, the ATE score identifies a population at very low risk for atrial thrombus. In consultation with the patient, the cardiologist may consider not performing a preoperative TEE in case of an ATE score of 0.

Subcutaneous Implantable Cardioverter-Defibrillators in Patients With Congenital Heart Disease.

BACKGROUND: Very few data have been published on the use of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in patients with congenital heart disease (CHD). OBJECTIVES: The aim of this study was to analyze outcomes associated with S-ICDs in patients with CHD. METHODS: This nationwide French cohort including all patients with an S-ICD was initiated in 2020 by the French Institute of Health and Medical Research. Characteristics at implantation and outcomes were analyzed in patients with CHD. RESULTS: From October 12, 2012, to December 31, 2019, among 4,924 patients receiving an S-ICD implant in 150 centers, 101 (2.1%) had CHD. Tetralogy of Fallot, univentricular heart, and dextro-transposition of the great arteries represented almost one-half of the population. Patients with CHD were significantly younger (age 37.1 ± 15.4 years vs 50.1 ± 14.9 years; P < 0.001), more frequently female (37.6% vs 23.0%; P < 0.001), more likely to receive an S-ICD for secondary prevention (72.3% vs 35.9%; P < 0.001), and less likely to have severe systolic dysfunction of the systemic ventricle (28.1% vs 53.1%; P < 0.001). Over a mean follow-up period of 1.9 years, 16 (15.8%) patients with CHD received at least 1 appropriate shock, with all shocks successfully terminating the ventricular arrhythmia. The crude risk of appropriate S-ICD shock was twice as high in patients with CHD compared with non-CHD patients (annual incidences of 9.0% vs 4.4%; HR: 2.1; 95% CI: 1.3-3.4); however, this association was no longer significant after propensity matching (especially considering S-ICD indication, P = 0.12). The burden of all complications (HR: 1.2; 95% CI: 0.7-2.1; P = 0.4) and inappropriate shocks (HR: 0.9; 95% CI: 0.4-2.0; P = 0.9) was comparable in both groups. CONCLUSIONS: In this nationwide study, patients with CHD represented 2% of all S-ICD implantations. Our findings emphasize the effectiveness and safety of S-ICD in this particularly high-risk population. (S-ICD French Cohort Study [HONEST]; NCT05302115).

Impact of Neuroeffector Adrenergic Receptor Polymorphisms on Incident Ventricular Fibrillation During Acute Myocardial Ischemia.

Background Cardiac adrenergic receptor gene polymorphisms have the potential to influence risk of developing ventricular fibrillation (VF) during ST-segment-elevation myocardial infarction, but no previous study has comprehensively investigated those most likely to alter norepinephrine release, signal transduction, or biased signaling. Methods and Results In a case-control study, we recruited 953 patients with ST-segment-elevation myocardial infarction without previous cardiac history, 477 with primary VF, and 476 controls without VF, and genotyped them for ADRB1 Arg389Gly and Ser49Gly, ADRB2 Gln27Glu and Gly16Arg, and ADRA2C Ins322-325Del. Within each minor allele-containing genotype, haplotype, or 2-genotype combination, patients with incident VF were compared with non-VF controls by odds ratios (OR) of variant frequencies referenced against major allele homozygotes. Of 156 investigated genetic constructs, 19 (12.2%) exhibited significantly (P<0.05) reduced association with incident VF, and none was associated with increased VF risk except for ADRB1 Gly389 homozygotes in the subset of patients not receiving ß-blockers. ADRB1 Gly49 carriers (prevalence 23.0%) had an OR (95% CI) of 0.70 (0.49-0.98), and the ADRA2C 322-325 deletion (Del) carriers (prevalence 13.5%) had an OR of 0.61 (0.39-0.94). When present in genotype combinations (8 each), both ADRB1 Gly49 carriers (OR, 0.67 [0.56-0.80]) and ADRA2C Del carriers (OR, 0.57 [0.45- 0.71]) were associated with reduced VF risk. Conclusions In ST-segment-elevation myocardial infarction, the adrenergic receptor minor alleles ADRB1 Gly49, whose encoded receptor undergoes enhanced agonist-mediated internalization and ß-arrestin interactions leading to cardioprotective biased signaling, and ADRA2C Del322-325, whose receptor causes disinhibition of norepinephrine release, are associated with a lower incidence of VF. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT00859300.

Impact of Pulmonary Valve Replacement on Ventricular Arrhythmias in Patients With Tetralogy of Fallot and Implantable Cardioverter-Defibrillator.

OBJECTIVES: This study aimed to assess the impact of pulmonary valve replacement (PVR) on ventricular arrhythmias burden in a population of tetralogy of Fallot (TOF) patients with continuous cardiac monitoring by implantable cardioverter-defibrillators (ICDs). BACKGROUND: Sudden cardiac death is a major cause of death in TOF, and right ventricular overload is commonly considered to be a potential trigger for ventricular arrhythmias. METHODS: Data were analyzed from a nationwide French ongoing study (DAI-T4F) including all TOF patients with an ICD since 2000. Survival data with recurrent events were used to compare the burden of appropriate ICD therapies before and after PVR in patients who underwent PVR over the study period. RESULTS: A total of 165 patients (mean age 42.2 ± 13.3 years, 70.1% male) were included from 40 centers. Over a median follow-up period of 6.8 (interquartile range: 2.5 to 11.4) years, 26 patients (15.8%) underwent PVR. Among those patients, 18 (69.2%) experienced at least 1 appropriate ICD therapy. When considering all ICD therapies delivered before (n = 62) and after (n = 16) PVR, the burden of appropriate ICD therapies was significantly lower after PVR (HR: 0.21; 95% confidence interval [CI]: 0.08 to 0.56; p = 0.002). Respective appropriate ICD therapies rates per 100 person-years were 44.0 (95% CI: 35.7 to 52.5) before and 13.2 (95% CI: 7.7 to 20.5) after PVR (p < 0.001). In the overall cohort, PVR before ICD implantation was also independently associated with a lower risk of appropriate ICD therapy in primary prevention patients (HR: 0.29 [95% CI: 0.10 to 0.89]; p = 0.031). CONCLUSIONS: In this cohort of high-risk TOF patients implanted with an ICD, the burden of appropriate ICD therapies was significantly reduced after PVR. While optimal indications and timing for PVR are debated, these findings suggest the importance of considering ventricular arrhythmias in the overall decision-making process. (French National Registry of Patients With Tetralogy of Fallot and Implantable Cardioverter Defibrillator [DAI-T4F]; NCT03837574).

Prognostic significance of a low T/R ratio in Brugada syndrome.

OBJECTIVES: To determine the prognostic value of a low T/R ratio, defined as the amplitude ratio between the T waves and the R waves, in patients (pts) with a spontaneous type-1 Brugada pattern (SBT1). BACKGROUND: Abnormalities of myocardial repolarization may play a key role in the initiation of ventricular fibrillation (VF) in Brugada syndrome (BrS). Recent studies have shown that the height of the T waves and the T/R ratio are inversely proportional to sudden cardiac arrest (SCA) risk in early repolarization syndrome and hypertrophic cardiomyopathy. METHODS: In an international retrospective study, we reviewed 115 pts. (105 males, 91.3%). 45 had VF and/or SCA (38.7 ±â€¯11.5 years old, all males), while 70 (49.3 ±â€¯12.0 years, 10 women) remained free of ventricular arrhythmia. 6 ECG markers plus the T/R ratio in leads V5 & II were studied. RESULTS: The T/R ratio among leads II & V5 was significantly lower in the VF/SCA group (0.24 [0.14; 0.38]vs. 0.34 [0.24; 0.45]; p = 0.006). 44.4% of pts. in the VF/SCA group had a lowest T/R ratio among leads II & V5 ≤ 0.17 compared to 11.4% in the non-VF/SCA group (p < 0.001). In multivariate analysis, a lowest T/R ratio among leads II & V5 ≤ 0.17 was independently associated with VF/SCA (OR 6.10, 95% CI 1.92-19.40; p = 0.002). Type 1 Brugada pattern in the peripheral leads (OR 10.78) and early repolarization (OR 3.60) were other independent markers of VF/SCA. CONCLUSION: A low T/R ratio among leads II & V5 is an independent marker for VF/SCA risk in patients with type-1 Brugada pattern.

Prediction of ventricular arrhythmias in patients with a spontaneous Brugada type 1 pattern: the key is in the electrocardiogram.

AIMS: There is currently no reliable tool to quantify the risks of ventricular fibrillation or sudden cardiac arrest (VF/SCA) in patients with spontaneous Brugada type 1 pattern (BrT1). Previous studies showed that electrocardiographic (ECG) markers of depolarization or repolarization disorders might indicate elevated risk. We aimed to design a VF/SCA risk prediction model based on ECG analyses for adult patients with spontaneous BrT1. METHODS AND RESULTS: This retrospective multicentre international study analysed ECG data from 115 patients (mean age 45.1 ± 12.8 years, 105 males) with spontaneous BrT1. Of these, 45 patients had experienced VF/SCA and 70 patients did not experience VF/SCA. Among 10 ECG markers, a univariate analysis showed significant associations between VF/SCA and maximum corrected Tpeak-Tend intervals ≥100 ms in precordial leads (LMaxTpec) (P < 0.001), BrT1 in a peripheral lead (pT1) (P = 0.004), early repolarization in inferolateral leads (ER) (P < 0.001), and QRS duration ≥120 ms in lead V2 (P = 0.002). The Cox multivariate analysis revealed four predictors of VF/SCA: the LMaxTpec [hazard ratio (HR) 8.3, 95% confidence interval (CI) 2.4-28.5; P < 0.001], LMaxTpec + ER (HR 14.9, 95% CI 4.2-53.1; P < 0.001), LMaxTpec + pT1 (HR 17.2, 95% CI 4.1-72; P < 0.001), and LMaxTpec + pT1 + ER (HR 23.5, 95% CI 6-93; P < 0.001). Our multidimensional penalized spline model predicted the 1-year risk of VF/SCA, based on age and these markers. CONCLUSION: LMaxTpec and its association with pT1 and/or ER indicated elevated VF/SCA risk in adult patients with spontaneous BrT1. We successfully developed a simple risk prediction model based on age and these ECG markers.

Exclusion of Intra-Atrial Thrombus Diagnosis Using D-Dimer Assay Before Catheter Ablation of Atrial Fibrillation.

OBJECTIVES: This study hypothesized that the association of D-dimer blood level and several clinical items in a new risk score could predict the absence of atrial thrombus. BACKGROUND: Symptomatic and drug resistant atrial fibrillation (AF) can be treated by catheter ablation. The procedure-related risk of thromboembolism is limited by the pre-operative use of transesophageal echocardiography (TEE) to detect atrial thrombi. METHODS: Patients admitted for catheter ablation of AF (n = 2,494) were prospectively included in a multicenter study. TEE was systematically performed before the procedure to search for atrial thrombus (primary endpoint). D-dimer level, CHADS2 score, left ventricular ejection fraction, pre-operative anticoagulation regimen, and medical history were collected. A logistic regression model was used to identify factors associated with the presence of atrial thrombus (hypertension, history of stroke, heart failure, D-dimer level >270 ng/ml). These factors were aggregated in a new score called atrial thrombus exclusion (ATE). RESULTS: The incidence of atrial thrombus was 1.92%. CHADS2 score and D-dimer level were significantly associated with atrial thrombus (p < 0.0001 and p < 0.0001, respectively). A zero CHADS2 score failed to exclude all atrial thrombi (5 false negatives; sensitivity: 89.58%, specificity: 52.2%). No false negative was found with a zero ATE score, which had a specificity of 37% and a higher sensitivity (100%) than the CHADS2 score (p < 0.031) to predict the absence of intra-atrial thrombi on TEE. Conversely, the positive predictive value was poor, and the ATE score should not be used to conclude a positive diagnosis of thrombus. CONCLUSIONS: An ATE score of zero was strongly associated with the absence of atrial thrombus. This new score could be useful to rule out a diagnosis of atrial thrombus before catheter ablation of AF.

Occurrence of Incomplete Endothelialization Causing Residual Permeability After Left Atrial Appendage Closure.

AIMS: Percutaneous left atrial appendage (LAA) occlusion is occasionally incomplete, with residual permeability of the LAA on cardiac computed tomography. The cause for this is unclear. Our objective was to determine if residual permeability was related to incomplete endothelialization. METHODS: A total of 35 consecutive patients contraindicated for anticoagulant therapy admitted for LAA occlusion were included; 12 patients received a Watchman device (Boston Scientific) and 23 patients received an Amplatzer Cardiac Plug (St. Jude Medical). Incomplete endothelialization was defined as residual permeability on cardiac computed tomography without peridevice leak on transesophageal echocardiography at follow-up. RESULTS: Five patients did not receive cardiac computed tomography. After 10 ± 6 months of follow-up, residual permeability of the LAA (at least partial) was recorded on cardiac computed tomography in 21 of 30 patients (70%). Seven of 30 patients presented with a peridevice leak on transesophageal echocardiography. Among the remaining 23 patients, 14 (61%) presented with incomplete endothelialization and 9 (39%) presented with complete endothelialization. There was no statistical difference between the patients presenting with complete vs incomplete endothelialization. CONCLUSION: We found that incomplete endothelialization, defined as residual permeability on cardiac computed tomography without peridevice leak on transesophageal echocardiography, occurred in 61% of the patients after 10 ± 6 months of percutaneous LAA closure. Predisposing factors and appropriate monitoring of LAA patients remain to be determined in larger cohorts.

Real-time atrial wall imaging during radiofrequency ablation in a porcine model.

BACKGROUND: Real-time monitoring of radiofrequency (RF) ablation remains challenging. OBJECTIVE: We used intravascular ultrasound (IVUS) to describe atrial wall changes during RF ablation and to assess the extent of RF-induced lesions. METHODS: In 9 piglets, RF and IVUS catheters were coupled and introduced into the right atrium. RF applications were performed along the intercaval line. Corresponding IVUS images were analyzed. Wall thickness was correlated with electrogram (EGM) changes (n = 9) and histology (n = 5). RESULTS: There were 66 RF applications performed in 57 sites. IVUS provided real-time imaging of the atrial wall during RF application in all but 2 sites. IVUS demonstrated significant (>20%) and immediate increase in atrial wall thickness in 71.4% of RF applications. It showed epicardial or intramyocardial effusion in 30% of cases, 2 steam pops, 1 intramural hematoma, and 1 thrombus. EGM amplitude decreased and thickness increased after RF application than at baseline (2.20 ± 1.11 to 0.99 ± 0.62 mV and 1.34 ± 0.53 to 1.93 ± 0.80 mm, respectively; P < .001 for each). However, EGM and thickness changes were poorly correlated (r = 0.43; P < .05). Histologically and echographically measured thicknesses were correlated (r = 0.71; P = .004), but echographic thickness change was not related to histological lesion transmurality. CONCLUSION: An IVUS probe coupled to an RF catheter can provide relevant real-time imaging of the atrial wall during ablation. Although thickness change does not appear as a good predictor of the transmural extent, direct visualization and monitoring of RF application may provide new information to guide and secure RF ablation.

Detection of T-wave beat-by-beat variations prior to ventricular arrhythmias onset in ICD-stored intracardiac electrograms: the Endocardial T-Wave Alternans Study (ETWAS).

BACKGROUND: The aim of the Endocardial T-Wave Alternans Study was to prospectively assess the presence of T-wave alternans (TWA) or beat-to-beat repolarization changes on implantable cardioverter-defibrillator (ICD)-stored electrograms (EGMs) immediately preceding the onset of spontaneous ventricular tachycardia (VT) or fibrillation (VF). METHODS: Thirty-seven VT/VF episodes were compared to 116 baseline reference EGMs from the same 57 patients. A Bayesian model was used to estimate the T-wave waveform in each cardiac beat and a set of 10 parameters was selected to segment each detected T wave. Beat-by-beat differences in each T-wave parameter were computed using the absolute value of the difference between each beat and the following one. Fisher criterion was used for determining the most discriminant T-wave parameters, then top-M ranked parameters yielding a normalized cumulative Fisher score > 95% were selected, and analysis was applied on these selected parameters. Simulated TWA EGMs were used to validate the algorithm. RESULTS: In the simulation study, TWA was detectable even in the case of the smallest simulated alternans of 25 µV. In 13 of the 37 episodes (35%) occurring in nine of 16 patients, significant larger beat-to-beat variations before arrhythmia onset were detected compared to their respective references (median one positive episode per patient). Parameters including the T-wave apex amplitude seem the more discriminant parameters. CONCLUSIONS: Detection of beat-by-beat repolarization variations in ICD-stored EGMs is feasible in a significant subset of cases and may be used for predicting the onset of ventricular arrhythmias.

A case of cardiomyopathy induced by inappropriate sinus tachycardia and cured by ivabradine.

We present the case of a 67-year-old woman with cardiomyopathy induced by inappropriate sinus tachycardia (IST) and a particularly high average heart rate. The patient was resistant and/or intolerant to treatment with conventional rate-slowing medications. We used ivabradine--a specific sinus node I(f) current inhibitor--and successfully lowered the heart rate (33 beats per minute mean heart rate decrease). Symptoms, systolic function, and heart rate variability parameters recovered dramatically. No side effect was noted. We suggest that ivabradine--evaluated in trials to treat stable angina--should be considered as a second-line treatment in patients with very symptomatic and refractory IST.