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Antoine Leenhardt

Publications and source records attributed to Antoine Leenhardt.

At least 19 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

Clinical implications of "pure" Hisian pacing in addition to para-Hisian pacing for the diagnosis of supraventricular tachycardia.

BACKGROUND: Para-Hisian pacing is an effective method of differentiating between pathways for retrograde conduction over the accessory pathway (AP) and over the atrioventricular node (AVN). When performing para-Hisian pacing, the pacing spike sometimes captures only the His bundle, which we named "pure" Hisian pacing (Hc). OBJECTIVE: We evaluated the significance of pure Hisian pacing for predicting the pathways of ventriculoatrial conduction. METHODS: In 62 patients with supraventricular tachycardia, both para-Hisian and pure Hisian pacing were carried out during the sinus rhythm, resulting in three different types of electrocardiographic complexes with wide (local ventricular myocardial capture), slightly narrow (both local myocardial and His bundle capture), and very narrow QRS widths (Hc). A change of atrial activation sequence as demonstrated by these pacing modes indicated the presence of multiple retrograde pathways. The diagnosis of retrograde pathways by para-Hisian pacing with or without Hc was evaluated. RESULTS: In 22 patients with AVN reentrant tachycardia, para-Hisian pacing alone was able to correctly predict ventriculo-atrial conduction exclusively through the AVN without requiring findings from Hc. In 40 AP patients, para-Hisian pacing showed a pattern of retrograde conduction through the AVN in six, through both the AVN and AP in 10, and through an AP in 24 patients. Four of these 24 patients were diagnosed as having multiple pathways (AP+AVN or dual APs) by the addition of Hc. CONCLUSION: Pure Hisian pacing can help disclose another pathway for retrograde conduction in AP patients, which is unpredicted by ordinary para-Hisian pacing.

Atrioventricular Node↗
PubMed2006

Quantitative assessment of ST segment elevation in Brugada patients.

BACKGROUND: ST segment elevation in the right precordial leads constitutes the electrocardiogram (ECG) hallmark of Brugada syndrome (BS). This pattern is variable and can be concealed, but the magnitude and the cause of ST segment fluctuations have been poorly investigated. OBJECTIVE: Our goal was to quantify ST changes and to assess rate and autonomic influences on ST level. METHODS: A 12-lead ECG was continuously recorded during 24 hours in 20 patients with BS (ages 49 +/- 12) and 10 healthy subjects (ages 32 +/- 7). Using two-dimensional binning we obtained average QRS-T complexes every 30 minutes (time bins) and at different RR intervals (rate bins) for each subject. ST level was measured at five different points located 90, 100, 110, 120, and 140 ms after Q onset (Qo). In BS patients, the highest ST elevation was measured 110 ms after Qo (Qo+110). RESULTS: ST level changes between time points were significantly greater in patients with BS compared with control subjects: on lead V2, the range of ST level at Qo+110 was 264 +/- 85 microV in BS and 91 +/- 22 microV in control subjects (P <.01). In BS, ST level decreased with heart rate acceleration: the difference in ST level at Qo+110 for RR = 900 and 600 ms was 55 +/- 53 microV (P <.01). HFnu was positively, although weakly, correlated with ST level (R(2) = 0.02, P <.01). CONCLUSIONS: ECG changes observed in patients with BS are related in part to heart rate influences on ST segment level. These spontaneous fluctuations over a 24-hour time period suggest that Holter recordings may improve the ECG diagnosis sensitivity in BS.

Adult↗
PubMed2006

Control of rapid heart rate changes for electrocardiographic analysis: implications for thorough QT studies.

BACKGROUND: Following an abrupt change in heart rate (HR), QT adaptation is achieved within a delayed time frame. HYPOTHESIS: The exclusion of electrocardiograms (ECGs) showing rapid HR changes influences the level of a drug-induced QT prolongation. METHODS: Continuous 12-lead ECG-Holter monitoring was performed in 31 healthy subjects. Using the "bin" method, we evaluated moxifloxacin effects on (1) QT interval duration at different RR intervals and (2) on the rate dependence of QT interval. These endpoints were calculated separately for five types of ECG analysis: classification of cardiac complexes based on (a) the single preceding RR interval (RR-1) and (b) RR filters excluding rapid HR changes according to the formula RR-1 = RR[time-window] +/- threshold, where the time-window could be 30 or 60 s (R30 and R60) and the threshold 15 or 30 ms (th15 or th30). RESULTS: Moxifloxacin-induced QT prolongation was consistently higher using the stable models when compared with the RR-1 model. Moxifloxacin-induced QT prolongation at RR = 1000 ms was 8.2 +/- 11.2 vs. 10.9 +/- 10.4 ms using the RR-1 and R60th15 stable models, respectively (p < 0.05). Moxifloxacin-induced QT prolongation was more pronounced at slow than at fast HR. This so-called "reverse rate-dependent" effect was more pronounced when assessed using stable HR models (0.023 IC95% [0.019;0.027] vs. 0.015 IC95% [0.012;0.017] using the RR-1 model). CONCLUSION: The exclusion of ECGs with rapid HR changes influences the magnitude of drug-induced QT changes. The hysteresis phenomenon should not be neglected when dedicated QT studies are performed.

Adolescent↗
PubMed2005

Spironolactone reduces fibrosis of dilated atria during heart failure in rats with myocardial infarction.

AIMS: Congestive heart failure (CHF) is associated with severe structural changes of atria, contributing to impaired atrial function and the risk of arrhythmia. This study investigated the effects of CHF treatments on atrial remodelling. METHODS AND RESULTS: Three months after myocardial infarction (MI), rats were treated for 1 month with spironolactone, lisinopril, or atenolol alone or in combination. Echocardiography-Doppler tissue imaging, haemodynamic measurements, and 24-h Holter monitoring were used to characterize the cardiomyopathy. Atrial fibrosis was quantified with Picrosirius Red staining. Left atrial diameter was increased (5.8+/-0.6 mm in MI vs. 3.6+/-0.3 mm in sham; P<0.0001), as was atrial fibrosis (26.7+/-3.8% in MI vs. 10.5+/-2.2% in sham; P<0.0001), which correlated with left ventricular (LV) dysfunction after 3 months of MI. P-wave duration was also increased and premature atrial beats were frequent on the 24-h electrocardiogram. Similar improvements in LV dysfunction were observed after 1 month of spironolactone, ACE-inhibitor, or beta-blocker therapy alone or in combination. Atrial hyperexcitability was reduced by all the treatments, but only spironolactone attenuated atrial fibrosis and reduced P-wave duration. CONCLUSION: Atrial fibrosis caused by chronic CHF is reduced by spironolactone.

Animals↗
PubMed2005

Usefulness of ventricular repolarization dynamicity in predicting arrhythmic deaths in patients with ischemic cardiomyopathy (from the European Myocardial Infarct Amiodarone Trial).

The European Myocardial Infarct Amiodarone Trial (EMIAT) investigated the effects of amiodarone versus placebo in patients after myocardial infarction who had left ventricular ejection fraction </=40% and were </=75 years of age. The present substudy examined whether ventricular repolarization (VR) dynamicity could differentiate patients who died from cardiac death from their matched survivors in this EMIAT population. In addition, we assessed whether VR dynamicity could differentiate patients who died from arrhythmic cardiac death (ACD) and from non-ACD. VR dynamicity (determined from Holter's recordings at baseline) was compared before antiarrhythmic therapy in 118 patients who had cardiac death and 118 matched survivors according to age, gender, left ventricular ejection fraction, and subsequent administration or nonadministration of amiodarone. VR dynamicity was compared within the cardiac death group between the 59 patients who died from ACD and the 59 who died from non-ACD. VR dynamicity was expressed as the slope of the linear regression between QTo (measured automatically) and stable RR intervals. Patients who died were found to have a significant steeper rate dependence of QTo intervals during the 3 periods than their matched survivors. In multivariate analysis, the QTo/RR nocturnal interval appeared to be the best independent predictor of cardiac death. In addition, patients who died from ACD were found to have a significant steeper rate dependence of QTo intervals during the morning period than those who died from non-ACD. In the multivariate analysis, the QTo/RR morning interval remained the best independent predictor of ACD. Thus, in the EMIAT trial, evaluation of QT dynamicity is a strong predictor of cardiac death. In addition, QT dynamicity could predict the occurrence of ACD in cases of cardiac death.

Aged↗
PubMed2005

Heart rate influences on repolarization duration and morphology in symptomatic versus asymptomatic KCNQ1 mutation carriers.

QT and Tp/Te intervals were longer in patients with LQT1 (n = 67) than in nonaffected subjects (n = 52) but did not differentiate symptomatic (n = 21) from asymptomatic patients (n = 46). At fast heart rate, the time to accumulate the last part of total T-wave area (the t50-97 interval) was longer in symptomatic carriers compared with asymptomatic patients (119 +/- 19 vs 106 +/- 15 ms, p <0.01). The latter group had significantly longer t50-97 intervals than nonaffected subjects (96 +/- 14 ms, p <0.01).

Adolescent↗
PubMed2005

Clinical assessment of drug-induced QT prolongation in association with heart rate changes.

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.

Adrenergic alpha-Antagonists↗
PubMed2005

Spironolactone improves carotid artery fibrosis and distensibility in rat post-ischaemic heart failure.

Myocardial infarction causes neurohormonal activation involving aldosterone and angiotensin II (AngII). These hormones may increase arterial stiffness, an independent cardiovascular risk factor contributing to progression of congestive heart failure (CHF). This study aimed to determine the effect of aldosterone and AngII blockade on carotid artery distensibility and collagen density in adult Wistar rats with MI-induced CHF. Five groups were studied: Sham-operated, CHF, CHF + spironolactone, CHF + lisinopril, CHF + Spironolactone + Lisinopril. After echocardiography, in vitro isobaric carotid distensibility (echo-tracking technique) and collagen density were measured, and the incremental elastic modulus (Einc) calculated. In the CHF group, intra-ventricular pressure and cardiac weight were increased; carotid distensibility was reduced (CHF: 0.42 +/- 0.30 per mmHg(3) versus sham: 1.75 +/- 0.50 per mmHg(3); P < 0.001), and collagen content increased by 87% when compared to sham. All treatments reduced intra-ventricular pressure, carotid distensibility and fibrosis when compared to CHF but did not change cardiac weight. However, carotid distensibility and intra-ventricular pressure were not completely restored towards sham values and were significantly and inversely related. Spironolactone, which did not decrease significantly blood pressure, was the only drug reducing Einc independently of wall stress (WS). Thus, MI-induced CHF was associated with carotid artery remodeling. This vascular change, which may contribute to maintain cardiac hypertrophy and CHF, is largely prevented by AngII and aldosterone blockade. Only spironolactone reduced the stiffness of carotid wall material independently of blood pressure and WS.

Animals↗
PubMed2005

Individual QT-R-R relationship: average stability over time does not rule out an individual residual variability: implication for the assessment of drug effect on the QT interval.

BACKGROUND: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT-R-R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT-R-R relationship stability over time needs to be evaluated. METHODS: The present report is part of randomized, double-dummy, and placebo-controlled 4-way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run-in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the "bin" approach. For each period, individual QT-R-R relationship were calculated using two different models (linear and parabolic log-log models). RESULTS: The mean intrasubject variability for the alpha coefficient of the linear modeling (SDintra = 0.011 +/- 0.005) reached 28.6 +/- 10.2%. When the parabolic model was considered, the SDintra was 0.026 +/- 0.009 for the alpha coefficient. The QT-R-R relationship variability was in part related to long-term RR changes (R2 = 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT-R-R coefficients. Moxifloxacin significantly increased the alpha coefficient of the QT-R-R relationship from 0.07 +/- 0.018 to 0.085 +/- 0.019, P < 0.05 (linear model). CONCLUSIONS: The individual QT-R-R relationship shows a residual variability in part related to long-term autonomic changes. In addition, the QT-R-R relationship might be modulated by the drug tested. As a consequence, pretherapy QT-R-R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.

Aza Compounds↗
PubMed2004

Hydroquinidine therapy in Brugada syndrome.

OBJECTIVES: We sought to assess hydroquinidine (HQ) efficacy in selected patients with Brugada syndrome (BrS). BACKGROUND: Management of asymptomatic patients with BrS and inducible arrhythmias remains a key issue. Effectiveness of class Ia antiarrhythmic drugs, which inhibit the potassium transient outward current of the action potential, has been suggested in BrS. METHODS: From a cohort of 106 BrS patients, we studied 35 who received HQ (32 men; mean age 48 +/- 11 years). Patients had asymptomatic BrS and inducible arrhythmia (n = 31) or multiple appropriate shocks from an implantable cardioverter-defibrillator (ICD) (n = 4). Asymptomatic patients with inducible arrhythmia underwent electrophysiologic (EP)-guided therapy. When ventricular tachycardia (VT)/ventricular fibrillation (VF) inducibility was not prevented, or in case of HQ intolerance, an ICD was placed. RESULTS: Hydroquinidine prevented VT/VF inducibility in 76% of asymptomatic patients who underwent EP-guided therapy. Syncope occurred in two of the 21 patients who received long-term (17 +/- 13 months) HQ therapy (1 syncope associated with QT interval prolongation and 1 unexplained syncope associated with probable noncompliance). In asymptomatic patients who received an ICD (n = 10), one appropriate shock occurred during a follow-up period of 13 +/- 8 months. In patients with multiple ICD shocks, HQ prevented VT/VF recurrence in all cases during a mean follow-up of 14 +/- 8 months. CONCLUSIONS: Hydroquinidine therapy prevented VT/VF inducibility in 76% of asymptomatic patients with BrS and inducible arrhythmia, as well as VT/VF recurrence in all BrS patients with multiple ICD shocks. These preliminary data suggest that preventive treatment by HQ may be an alternative strategy to ICD placement in asymptomatic patients with BrS and inducible arrhythmia.

Adolescent↗
PubMed2004

High-flow perfusion of sheaths for prevention of thromboembolic complications during complex catheter ablation in the left atrium.

INTRODUCTION: Mechanisms for thromboembolic complications during complex ablation procedures in left atrium (LA) have not been defined. The aim of this study was to determine the effect of the perfusion rate of the transseptal sheath on the incidence of thromboembolic complications during catheter ablation for atrial fibrillation (AF) or LA macroreentrant tachycardia. METHODS AND RESULTS: We analyzed clinical and procedural data from 86 consecutive patients (153 procedures) referred for catheter ablation of AF (74 patients) or LA macroreentrant tachycardia (12 patients). The transseptal sheath was continuously perfused at a low flow rate (3 mL/hour) for the first 32 patients and at a high flow rate (180 mL/hour) for the subsequent 54 patients. Ablation was mainly performed using map-guided isolation of pulmonary veins for AF and three-dimensional electroanatomic mapping for LA macroreentrant tachycardia. Five patients (6% of patients and 3.5% of procedures) developed a cerebral thromboembolic complication, all during procedures using low-flow perfusion. Sheath perfusion rate and total procedure duration were the two variables significantly associated with the occurrence of stroke (P = 0.013 and 0.001, respectively). After adjustment in a multivariable analysis, sheath perfusion rate remained the only risk factor for stroke. The risk was 17 times higher using low-flow than high-flow perfusion (odds ratio 17.26, 95% confidence interval 1.14-260.81, P = 0.04). No other clinical or procedural parameters had any significant effect. CONCLUSION: Sheath perfusion rate is an important determinant of the risk factor for stroke during complex LA ablation procedures. Continuous high-flow perfusion appears to be effective in preventing this complication.

Adult↗
PubMed2004

Death due to an implantable cardioverter defibrillator.

Inappropriate therapy due to noise oversensing caused a true ventricular fibrillation (VF) and death of a patient. A 49-year-old patient with a history of dilated cardiomyopathy received a double-chamber implantable cardioverter defibrillator (ICD) in 1991 for a sustained inducible ventricular tachycardia (VT). One appropriate shock delivered in 1994 terminated an episode of VT. The generator was replaced in 1995 and in 2000, and was connected to the initial leads. Three months after the second replacement, the patient received six consecutive shocks related to detection of noise interpreted as VF. Unfortunately, the sixth shock triggered a true VF, which was not treated due to end of the therapeutic sequence, and the patient died. The causes of the dysfunction are discussed.

Adult↗
PubMed2003

Mapping and ablation of ventricular fibrillation associated with long-QT and Brugada syndromes.

BACKGROUND: The long-QT and Brugada syndromes are important substrates of malignant ventricular arrhythmia. The feasibility of mapping and ablation of ventricular arrhythmias in these conditions has not been reported. METHODS AND RESULTS: Seven patients (4 men; age, 38+/-7 years; 4 with long-QT and 3 with Brugada syndrome) with episodes of ventricular fibrillation or polymorphic ventricular tachycardia and frequent isolated or repetitive premature beats were studied. These premature beats were observed to trigger ventricular arrhythmias and were localized by mapping the earliest endocardial activity. In 4 patients, premature beats originated from the peripheral right (1 Brugada) or left (3 long-QT) Purkinje conducting system and were associated with variable Purkinje-to-muscle conduction times (30 to 110 ms). In the remaining 3 patients, premature beats originated from the right ventricular outflow tract, being 25 to 40 ms ahead of the QRS. The accuracy of mapping was confirmed by acute elimination of premature beats after 12+/-6 minutes of radiofrequency applications. During a follow-up of 17+/-17 months using ambulatory monitoring and defibrillator memory interrogation, no patients had recurrence of symptomatic ventricular arrhythmia but 1 had persistent premature beats. CONCLUSIONS: Triggers from the Purkinje arborization or the right ventricular outflow tract have a crucial role in initiating ventricular fibrillation associated with the long-QT and Brugada syndromes. These can be eliminated by focal radiofrequency ablation.

Adult↗