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Frederic Sacher

Publications and source records attributed to Frederic Sacher.

10 recordsLinked to original sources
PubMed2026

Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification.

BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. RESULTS: A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Humans↗
PubMed2026

Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome.

Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis-regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.

Journal Article↗
PubMed2006

Localized sources maintaining atrial fibrillation organized by prior ablation.

BACKGROUND: Endocardial mapping of localized sources driving atrial fibrillation (AF) in humans has not been reported. METHODS AND RESULTS: Fifty patients with AF organized by prior pulmonary vein and linear ablation were studied. AF was considered organized if mapping during AF showed irregular but discrete atrial complexes exhibiting consistent activation sequences for >75% of the time using a 20-pole catheter with 5 radiating spines covering 3.5-cm diameter or sequential conventional mapping. A site or region centrifugally activating the remaining atrial tissue defined a source. During AF with a cycle length of 211+/-32 ms, activation mapping identified 1 to 3 sources at the origin of atrial wavefronts in 38 patients (76%) predominantly in the left atrium, including the coronary sinus region. Electrograms at the earliest area varied from discrete centrifugal activation to an activity spanning 75% to 100% of the cycle length in 42% of cases, the latter indicating complex local conduction or a reentrant circuit. A gradient of cycle length (>20 ms) to the surrounding atrium was observed in 28%. Local radiofrequency ablation prolonged AF cycle length by 28+/-22 ms and either terminated AF or changed activation sequence to another organized rhythm. In 4 patients, the driving source was isolated, surrounded by the atrium in sinus rhythm, and still firing at high frequency (228+/-31 ms) either permanently or in bursts. CONCLUSIONS: AF associated with consistent atrial activation sequences after prior ablation emanates mostly from localized sources that can be mapped and ablated. Some sources harbor electrograms suggesting the presence of localized reentry.

Aged↗
PubMed2006

Flutter localized to the anterior left atrium after catheter ablation of atrial fibrillation.

INTRODUCTION: Organized atrial arrhythmias following atrial fibrillation (AF) ablation are typically due to recovered pulmonary vein (PV) conduction or reentry at incomplete ablation lines. We describe the role of nonablated anterior left atrium (LA) in arrhythmias observed after AF ablation. METHODS: A total of 275 consecutive patients with paroxysmal (n = 200) or chronic (n = 75) AF had PV isolation with/without additional linear ablation at the mitral isthmus (n = 106), LA roof (n = 23), or both (n = 88). Organized arrhythmias occurring after ablation were evaluated utilizing activation and entrainment mapping. RESULTS: Fourteen patients (11 female, 65 +/- 13 years, 10 chronic AF, 10 structural heart disease) demonstrated tachycardia localized to the anterior LA, an area not targeted by prior ablation. Eight had ECG features during sinus rhythm suggestive of impaired anterior LA conduction at baseline. These arrhythmias demonstrated a distinctive ECG flutter morphology in 7 of 10 (70%) with discrete -/+ or +/-/+ aspect in inferior leads. Mapping the anterior LA revealed electrograms spanning the entire tachycardia cycle length (325 +/- 125 msec). Entrainment was possible in all with a postpacing interval exceeding the tachycardia cycle length by 9 +/- 10 msec. Electroanatomic mapping in 6 demonstrated small reentrant circuits rotating clockwise in 4 and counterclockwise in 2. Low-amplitude, fractionated mid-diastolic potentials with long duration (200 +/- 80 msec) occupying 63 +/- 22% of the cycle length were targeted for ablation resulting in termination and subsequent noninducibility. CONCLUSION: Organized arrhythmias occurring after AF ablation can be due to reentrant circuits localized to the anterior LA, predominantly in females with chronic AF, structural heart disease, and abnormal atrial conduction. They are characterized by a distinctive surface ECG and highly responsive to RF ablation at the slow conduction area.

Aged↗
PubMed2006

Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation.

INTRODUCTION: Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. METHODS AND RESULTS: Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. CONCLUSION: The present study shows that the most common phenotype of gene carriers of a BS-type SCN5A mutation is progressive cardiac conduction defects similar to the Lenègre disease phenotype. In consequence, we propose that carriers of a SCN5A mutation need a clinical and ECG follow-up because of the risk associated with severe conduction defects.

Adolescent↗
PubMed2005

High-density circumferential pulmonary vein mapping with a 20-pole expandable circular mapping catheter.

The differentiation of pulmonary vein (PV) electrograms from atrial far-field signals during PV isolation (PVI) for atrial fibrillation (AF) may be difficult. In addition, owing to highly variable PV ostial sizes, current fixed-diameter circular PV mapping catheters may not yield optimal electrograms. We evaluated an expandable, circular 15-25 mm diameter, 20-pole mapping catheter for PV mapping during sustained AF in 25 patients. After selective PV angiography to define the ostial position and size, the catheter was introduced into each PV and withdrawn to the most stable proximal position, with optimal wall contact ensured by progressive loop expansion. At each PV ostium, electrograms recorded at high resolution (HR) were compared with those recorded at a resolution similar to that of a standard 10-pole Lasso catheter. After PVI performed during ongoing AF, the presence of residual far-field potentials (FFP) under both set-ups was compared. We mapped 97 PV, including 4 pairs with common ostia. In the HR recordings, the PV potentials had greater amplitude (0.5 +/- 0.1 vs 0.3 +/- 0.1 mV, P = 0.001) and fragmentation, whereas left atrial FFP were minimized. After successful isolation of all PV, FFP were observed in 33% of left superior and 28% of left inferior PV on the HR recordings, compared to 66% and 61%, respectively under normal resolution. Catheter stability and optimal wall contact, in combination with HR electrograms can optimize circumferential PV mapping during AF and improve the discrimination of FFP postablation.

Atrial Fibrillation↗
PubMed2005

Incidence and prevention of cardiac tamponade complicating ablation for atrial fibrillation.

Cardiac tamponade complicating catheter ablation of atrial fibrillation (AF) occurs in approximately 1% of pulmonary vein isolation (PVI), and up to 6% of linear ablation procedures. We reviewed 348 consecutive AF ablation (including repeat) procedures over 1 year, which all included PVI, with additional linear lesions at the mitral isthmus in 73%, and cavotricuspid isthmus (CTI) in 76%. An irrigated-tip ablation catheter was used, with power limited to 25-35 W for PVI and 45-60 W for linear lesions. Tamponade occurred in seven men and three women (2.9% of the population) during the creation of linear ablation lesions. Mechanical perforations occurred in two patients, and "popping" during radiofrequency (RF) energy delivery at the mitral isthmus in six, and at the CTI in two patients. Peak RF power was significantly higher in patients with than without tamponade (53 +/- 4 W vs 48 +/- 7 W; P = 0.02), and was greater than 48 W in all cases of "popping." In the following year, RF power for linear ablation was limited to </=42 W. Among 398 procedures, tamponade occurred in four patients (1.0%; P = 0.047 vs first year), three from "popping" and one from mechanical trauma. Procedural success rate remained the same despite reduction of power. Risk of tamponade was highest during linear ablation, mainly associated with high energy delivery and "popping." Reducing the energy limited, though did not eliminate this complication.

Aged↗
PubMed2005

Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination.

BACKGROUND: The relative contributions of different atrial regions to the maintenance of persistent atrial fibrillation (AF) are not known. METHODS: Sixty patients (53 +/- 9 years) undergoing catheter ablation of persistent AF (17 +/- 27 months) were studied. Ablation was performed in a randomized sequence at different left atrial (LA) regions and comprised isolation of the pulmonary veins (PV), isolation of other thoracic veins, and atrial tissue ablation targeting all regions with rapid or heterogeneous activation or guided by activation mapping. Finally, linear ablation at the roof and mitral isthmus was performed if sinus rhythm was not restored after addressing the above-mentioned areas. The impact of ablation was evaluated by the effect on the fibrillatory cycle length in the coronary sinus and appendages at each step. Activation mapping and entrainment maneuvers were used to define the mechanisms and locations of intermediate focal or macroreentrant atrial tachycardias. RESULTS: AF terminated in 52 patients (87%), directly to sinus rhythm in 7 or via the ablation of 1-6 intermediate atrial tachycardias (total 87) in 45 patients. This conversion was preceded by prolongation of fibrillatory cycle length by 39 +/- 9 msec, with the greatest magnitude occurring during ablation at the anterior LA, coronary sinus and PV-LA junction. Thirty-eight atrial tachycardias were focal (originating dominantly from these same sites), while 49 were macroreentrant (involving the mitral or cavotricuspid isthmus or LA roof). Patients without AF termination displayed shorter fibrillatory cycles at baseline: 130 +/- 14 vs 156 +/- 23 msec; P = 0.002. CONCLUSION: Termination of persistent AF can be achieved in 87% of patients by catheter ablation. Ablation of the structures annexed to the left atrium-the left atrial appendage, coronary sinus, and PVs-have the greatest impact on the prolongation of AF cycle length, the conversion of AF to atrial tachycardia, and the termination of focal atrial tachycardias.

Atrial Fibrillation↗
PubMed2005

Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is challenging in patients with long-standing persistent AF. The clinical outcome and subsequent arrhythmia recurrence after using an ablation method targeting multiple left atrial sites with the aim of achieving acute AF termination has not been characterized. METHODS: Sixty patients (mean age: 53 +/- 9 years) with persistent AF (mean duration: 17 +/- 27 months) were prospectively followed after catheter ablation. Catheter ablation targeting the following sites was performed in a random sequence: (i) electrical isolation of all pulmonary veins (PV); (ii) disconnection of other thoracic veins; (iii) atrial ablation at sites possessing complex electrical activity, activation gradients, or short cycle lengths. Finally, linear ablation of the LA roof and mitral isthmus was performed if sinus rhythm was not restored following energy delivery to the above sites. At 1, 3, 6, and 12 months after ablation, patients underwent clinical review and 24-hour ambulatory ECG monitoring to identify asymptomatic arrhythmia. Repeat mapping and catheter ablation was performed in any patient experiencing recurrent atrial tachycardia (AT). Clinical success was defined as the absence of any sustained atrial arrhythmia. RESULTS: AF terminated during ablation in 52 patients (87%). The fluoroscopy and procedural durations were 84 +/- 30 minutes and 264 +/- 77 minutes, respectively. Three months after ablation, sustained ATs were documented in 24 patients (associated with AF in 2). Mapping in 23 patients showed a single AT in 7 while multiple ATs were observed in 16. Macroreentry was confirmed to be due to gaps in the ablation lines, while focal ATs originated from discrete sites or isthmuses near the left atrial appendage, coronary sinus, pulmonary veins, or fossa ovalis; these sites were similar to those at which the greatest impact was observed on the fibrillatory process during the initial ablation procedure. After repeat ablation, at 11 +/- 6 months of follow-up, 57 patients (95%) were in sinus rhythm and 3 developed recurrent AF or AT. All patients in sinus rhythm demonstrated improved exercise capacity and all but 2 had evidence of atrial transport as assessed by Doppler echocardiography (mitral A wave velocity 34 +/- 17 cm/sec) by 6 months. CONCLUSION: Catheter ablation of long-lasting persistent AF associated with acute AF termination achieves medium to long-term restoration and maintenance of sinus rhythm in 95% of patients. Arrhythmia recurrence in the majority of patients is AT.

Adult↗