Abstract Background Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural ...history studies of LMNA -associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain. Objectives This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype. Methods The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined. Results The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death. Conclusions LMNA -related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.
Biventricular pacing (BVP) may not achieve complete electrical resynchronization.
The purpose of this study was to assess whether the resynchronizing effect of BVP varies among patients depending on ...the underlying electrical substrate.
High-resolution electrocardiographic mapping with invasive measurement of the maximal rate of systolic left ventricular (LV) pressure rise (LVdP/dtmax) was performed during baseline activation and during BVP in 61 patients with heart failure with various conduction delays: 13 with narrow QRS duration (<120 ms), 22 with nonspecific intraventricular conduction disturbance, and 26 with left bundle branch block. Electrical dyssynchrony, both during baseline activation and BVP, was quantified by total and LV activation times (TAT and LVTAT) and by ventricular electrical uncoupling (VEU = mean LVTAT - mean right ventricular activation time). Response to BVP was defined as a ≥10% increase in LVdP/dtmax.
The electrical activation pattern during BVP was similar for all patient groups and, hence, not dependent on baseline conduction disturbance. During BVP, TAT, LVTAT, and VEU were similar for all groups and were either not correlated or weakly correlated with the change in LVdP/dtmax. In contrast, changes in electrical dyssynchrony correlated significantly with the change in LVdP/dtmax: r=0.71, 0.69, and 0.69 for ∆TAT, ∆LVTAT, and ∆VEU, respectively (all P < .001). Responders showed higher baseline dyssynchrony levels and BVP-induced dyssynchrony reduction than did nonresponders (all P < .001); in nonresponders, BVP worsened activation times than did baseline activation.
BVP does not eliminate electrical dyssynchrony, but rather brings it to a common level independent of the patient's underlying electrical substrate. Therefore, BVP is of benefit to patients with dyssynchrony but not to patients with insufficient electrical dyssynchrony in whom it induces an iatrogenic electropathy.
Objectives This study evaluated the efficacy and safety of flecainide in addition to conventional drug therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). ...Background CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca2+ release channels. Sudden cardiac death is incompletely prevented by conventional drug therapy with β-blockers with or without Ca2+ channel blockers. The antiarrhythmic agent flecainide directly targets the molecular defect in CPVT by inhibiting premature Ca2+ release and triggered beats in vitro. Methods We collected data from every consecutive genotype-positive CPVT patient started on flecainide at 8 international centers before December 2009. The primary outcome measure was the reduction of ventricular arrhythmias during exercise testing. Results Thirty-three patients received flecainide because of exercise-induced ventricular arrhythmias despite conventional (for different reasons, not always optimal) therapy (median age 25 years; range 7 to 68 years; 73% female). Exercise tests comparing flecainide in addition to conventional therapy with conventional therapy alone were available for 29 patients. Twenty-two patients (76%) had either partial (n = 8) or complete (n = 14) suppression of exercise-induced ventricular arrhythmias with flecainide (p < 0.001). No patient experienced worsening of exercise-induced ventricular arrhythmias. The median daily flecainide dose in responders was 150 mg (range 100 to 300 mg). During a median follow-up of 20 months (range 12 to 40 months), 1 patient experienced implantable cardioverter-defibrillator shocks for polymorphic ventricular arrhythmias, which were associated with a low serum flecainide level. In 1 patient, flecainide successfully suppressed exercise-induced ventricular arrhythmias for 29 years. Conclusions Flecainide reduced exercise-induced ventricular arrhythmias in patients with CPVT not controlled by conventional drug therapy.
Objectives This study evaluated the role of pre-procedural clinical variables to predict procedural and clinical outcomes of catheter ablation in patients with long-lasting persistent atrial ...fibrillation (AF). Background Catheter ablation of persistent AF remains a challenging task. Methods Catheter ablation was performed in 90 patients (76 men, age 57 ± 11 years) with long-lasting persistent AF. The history of AF, echocardiographic parameters, presence of structural heart disease, and surface electrocardiogram (ECG) AF cycle length (CL) were assessed before ablation and analyzed with respect to procedural termination and clinical outcome. Mean follow-up was 28 ± 4 months. Results Persistent AF was terminated in 76 of 90 patients (84%) by ablation. The duration of continuous AF was shorter (p < 0.0001), the surface ECG AFCL was longer (p < 0.0001), and the left atrium was smaller (p < 0.01) in patients in whom AF was terminated by catheter ablation. The surface ECG AFCL was the only independent predictor of AF termination (p < 0.01). Maintenance of sinus rhythm was associated with a shorter duration of continuous AF (p < 0.0001), a longer surface ECG AFCL (p < 0.001), and a smaller left atrium (p < 0.05) compared with those with recurrent arrhythmia. In multivariate analysis, the surface ECG AFCL and the AF duration predicted clinical success of persistent AF ablation (p < 0.01 and p < 0.05, respectively). Conclusions The surface ECG AFCL is a clinically useful pre-ablation tool for predicting patients in whom sinus rhythm can be restored by catheter ablation. The duration of continuous AF and the surface ECG AFCL are predictive of maintenance of sinus rhythm.
Risk stratification in Brugada syndrome (BS) remains controversial. The time interval between the peak and the end of the T wave (Tpe interval), a marker of transmural dispersion of repolarization, ...has been linked to malignant ventricular arrhythmias in various settings but leads to discordant results in BS.
We study the correlation of the Tpe interval with arrhythmic events in a large cohort of patients with BS.
A total of 325 consecutive patients with BS (mean age 47±13 years, 259 men-80%) with spontaneous (n=143, 44%) or drug-induced (n=182, 56%) type 1 electrocardiogram were retrospectively included. 235 were asymptomatic (70%), 80 presented with unexplained syncope (22%), and 10 presented with sudden death (SD) or appropriate implantable cardioverter-defibrillator therapy (AT) (8%) at diagnosis or over a mean follow-up of 48 ± 34 months. The Tpe interval was calculated as the difference between the QT interval and the QT peak interval as measured in each of the precordial leads.
The Tpe interval from lead V1 to lead V4, maximum value of the Tpe interval (max Tpe), and Tpe dispersion in all precordial leads were significantly higher in patients with SD/AT or in patients with syncope than in asymptomatic patients (P < .001). A max Tpe of ≥100 ms was present in 47 of 226 asymptomatic patients (21%), in 48 of 73 patients with syncope (66%), and in 22 of 26 patients with SD/AT (85%) (P < .0001). In multivariate analysis, a max Tpe of ≥100 ms was independently related to arrhythmic events (odds ratio 9.61; 95% confidence interval 3.13-29.41; P < .0001).
The Tpe interval in the precordial leads is highly related to malignant ventricular arrhythmias in this large cohort of patients with BS. This simple electrocardiographic parameter could be used to refine risk stratification.
Objectives Our purpose was to evaluate the efficacy of antiarrhythmic drugs (AADs) in recurrent ventricular fibrillation (VF) associated with inferolateral early repolarization pattern on the ...electrocardiogram. Background Although an implantable cardioverter-defibrillator is the treatment of choice, additional AADs may be necessary to prevent frequent episodes of VF and reduce implantable cardioverter-defibrillator shock burden or as a lifesaving therapy in electrical storms. Methods From a multicenter cohort of 122 patients (90 male subjects, age 37 ± 12 years) with idiopathic VF and early repolarization abnormality in the inferolateral leads, we selected all patients with more than 3 episodes of VF (multiple) including those with electrical storms (≥3 VF in 24 h). The choice of AAD was decided by individual physicians. Follow-up data were obtained for all patients using monitoring with implantable defibrillator. Successful oral AAD was defined as elimination of all recurrences of VF with a minimal follow-up period of 12 months. Results Multiple episodes of VF were observed in 33 (27%) patients. Electrical storms (34 ± 47 episodes) occurred in 16 and were unresponsive to beta-blockers (11 of 11), lidocaine/mexiletine (9 of 9), and verapamil (3 of 3), while amiodarone was partially effective (3 of 10). In contrast, isoproterenol infusion immediately suppressed electrical storms in 7 of 7 patients. Over a follow-up of 69 ± 58 months, oral AADs were poorly effective in preventing recurrent VF: beta-blockers (2 of 16), verapamil (0 of 4), mexiletine (0 of 4), amiodarone (1 of 7), and class 1C AADs (2 of 9). Quinidine was successful in 9 of 9 patients, decreasing recurrent VF from 33 ± 35 episodes to nil for 25 ± 18 months. In addition, quinidine restored a normal electrocardiogram. Conclusions Multiple recurrences of VF occurred in 27% of patients with early repolarization abnormality and may be life threatening. Isoproterenol in acute cases and quinidine in chronic cases are effective AADs.
Abstract Background The underlying mechanisms sustaining human persistent atrial fibrillation (PsAF) is poorly understood. Objectives This study sought to investigate the complexity and distribution ...of AF drivers in PsAF of varying durations. Methods Of 135 consecutive patients with PsAF, 105 patients referred for de novo ablation of PsAF were prospectively recruited. Patients were divided into 3 groups according to AF duration: PsAF presenting in sinus rhythm (AF induced), PsAF <12 months, and PsAF >12 months. Patients wore a 252-electrode vest for body surface mapping. Localized drivers (re-entrant or focal) were identified using phase-mapping algorithms. Results In this patient cohort, the most prominent re-entrant driver regions included the pulmonary vein (PV) regions and inferoposterior left atrial wall. Focal drivers were observed in 1 or both PV regions in 75% of patients. Comparing between the 3 groups, with longer AF duration AF complexity increased, reflected by increased number of re-entrant rotations (p < 0.05), number of re-entrant rotations and focal events (p < 0.05), and number of regions harboring re-entrant (p < 0.01) and focal (p < 0.05) drivers. With increased AF duration, a higher proportion of patients had multiple extra-PV driver regions, specifically in the inferoposterior left atrium (p < 0.01), superior right atrium (p < 0.05), and inferior right atrium (p < 0.05). Procedural AF termination was achieved in 70% of patients, but decreased with longer AF duration. Conclusions The complexity of AF drivers increases with prolonged AF duration. Re-entrant and focal drivers are predominantly located in the PV antral and adjacent regions. However, with longer AF duration, multiple drivers are distributed at extra-PV sites. AF termination rate declines as patients progress to longstanding PsAF, underscoring the importance of early intervention.
Epicardial ablation is often necessary for the treatment of complex arrhythmias refractory to endocardial ablation. Conventional needle access to the pericardial space is considered quite ...challenging, and it is often associated with several potential complications, particularly inadvertent right ventricular puncture. The novel EpiAccess needle tip is embedded with a pressure sensor able to report the pressure waveform in real time when used with the EpiAccess System.
We prospectively evaluated the feasibility and safety of the EpiAccess System by EpiEP, Inc., with a novel epicardial access needle in a multicenter study.
Twenty-five patients with a clinical need for epicardial access were enrolled. The EpiAccess needle and EpiAccess System were used for epicardial access in each case. Successful epicardial access, defined as the ability to introduce a guidewire into the epicardial space, was assessed via the device and confirmed with fluoroscopy. Significant pericardial bleeding was defined as >80 mL of blood by using peer review article definitions.
Patients were men (76%) with a mean age of 62 years (range 28-84 years). Epicardial access for ventricular tachycardia ablation was indicated in 80% of the patients. Successful epicardial access was obtained in all cases, with pressure monitoring guiding pericardial wire access in all cases. One delayed pericardial effusion occurred.
Epicardial access with the novel EpiAccess needle and System with real-time pressure monitoring is feasible and safe. The pressure monitoring capability identifies successfully the epicardial space, facilitating access and potentially minimizing complications. This has relevant clinical implications.
Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance ...and expressivity of the disease are highly variable, and new tools for risk stratification are needed.
We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.
We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with <or=90% (M(active)) or >90% (M(inactive)) peak I(Na) reduction were analyzed separately.
The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group.
In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.
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