Two siblings with early repolarization syndrome: clinical and genetic characterization by whole-exome sequencing.

AIMS: The early repolarization syndrome (ERS) can cause ventricular fibrillation (VF) and sudden death in young, otherwise healthy individuals. There are limited data suggesting that ERS might be heritable. The aim of this study was to characterize the clinical phenotype and to identify a causal variant in an affected family using an exome-sequencing approach. METHODS AND RESULTS: Early repolarization syndrome was diagnosed according to the recently proposed Shanghai ERS Score. After sequencing of known ERS candidate genes, whole-exome sequencing (WES) was performed. The index patient (23 years, female) showed a dynamic inferolateral early repolarization (ER) pattern and electrical storm with intractable VF. Isoproterenol enabled successful termination of electrical storm with no recurrence on hydroquinidine therapy during 33 months of follow-up. The index patient's brother (25 years) had a persistent inferior ER pattern with malignant features and a history of syncope. Both parents were asymptomatic and showed no ER pattern. While there was no pathogenic variant in candidate genes, WES detected a novel missense variant affecting a highly conserved residue (p. H2245R) in the ANK3 gene encoding Ankyrin-G in the two siblings and the father. CONCLUSION: We identified two siblings with a malignant ERS phenotype sharing a novel ANK3 variant. A potentially pathogenic role of the novel ANK3 variant is suggested by the direct interaction of Ankyrin-G with the cardiac sodium channel, however, more patients with ANK3 variants and ERS would be required to establish ANK3 as novel ERS susceptibility gene. Our study provides additional evidence that ERS might be a heritable condition.

Haemodynamic vector personalization of a quadripolar left ventricular lead used for cardiac resynchronization therapy: use of surface electrocardiogram and interventricular time delays.

AIMS: The choice of left ventricular pacing configurations (LVPCs) of quadripolar leads used for cardiac resynchronization therapy (CRT) affects haemodynamic response and thus may be a tool for device optimization. The value of surface electrocardiograms and interventricular time delays (IVDs) for optimization is unknown. METHODS AND RESULTS: Sixteen patients implanted with a CRT device with a quadripolar LV lead underwent invasive testing of LV dP/dt. QRS durations at baseline (bl) and during biventricular pacing (biv) were measured using different LVPCs (total of 141 LVPCs; 8.8 per patient). Variations in QRS duration during biv were calculated for each patient (ΔQRS) and, when compared with intrinsic QRS duration, for all LVPCs (ΔQRSLVPC). Interventricular time delays between the poles of the LV lead were obtained from intracardiac electrograms. ΔIVD was calculated as IVDmax - IVDmin. Parameters were correlated with LV dP/dt. ΔQRS and ΔQRSLVPC both significantly correlated with LV dP/dt (P < 0.01). Correlation was found for patients with ischaemic (P < 0.001) and non-ischaemic cardiomyopathy (P < 0.05), and for patients with bl QRS duration >168 ms (P < 0.001), but not <168 ms (P = ns). The LVPC with shortest QRS duration also yielded maximal LV dP/dt in 6 of 16 patients (37.5%), and was equal or better in LV dP/dt in 12 of 16 patients (75%). ΔIVD neither correlated with ΔQRS nor ΔLV dP/dt. CONCLUSION: ΔQRS predicts the maximal value of vector personalization in the individual. Reductions in QRS width, but not IVDs, correlate with acute haemodynamic response. Intraindividually, in 75% of patients, the LVPC with the shortest QRS duration gives equal or superior haemodynamic results when compared with the LVPC with longest QRS duration.

Impact of high-resolution 3D-mapping with micro-electrodes on catheter ablation of Wolff-Parkinson-White syndrome.

Background: It is currently unknown whether high-resolution 3D-mapping and micro-electrodes add meaningful benefits in catheter ablation of Wolff-Parkinson-White (WPW) syndrome and challenging, e.g. para-Hisian accessory pathways (APs). Objectives: To compare the mapping resolution, acute success and complication rates in patients with WPW syndrome undergoing a first-time catheter ablation using only a contact force-sensing ablation catheter for mapping or a multi-electrode high-resolution mapping catheter. Methods: Fifty consecutive 3D-mapping procedures for WPW syndrome using a 3.5-mm ablation catheter (n = 27) or a multi-electrode high-resolution catheter (n = 23) were retrospectively analyzed regarding mapping resolution defined as first 5/10 msec isochronal activation area, number of RF applications to achieve AP block, occurence of AP automaticity during RF delivery, and acute success and complication rates. Results: Catheter ablation was successful in 48/50 patients with a median of 1 (IQR 1-2) RF applications. Compared to ablation catheter mapping, high-resolution mapping showed a significantly smaller isochronal activation area in the first 5/10 msec (1.25 ± 0.29 vs 0.15 ± 0.03 cm2; P < 0.001 and 3.41 ± 0.58 vs 0.55 ± 0.12 cm2; P < 0.0001) and significantly higher incidence of AP automaticity during RF delivery (0 vs 22 %; P < 0.05). In para-Hisian APs, micro-electrodes recorded distinct His electrograms and AP potentials without fusion and without AP bumping permitting safe and effective para-Hisian AP ablation. Conclusions: High-resolution mapping increases the mapping accuracy of the AP and its insertion site leading to a significantly higher incidence of AP automaticity during RF delivery. Micro-electrodes provide clinically relevant advantages in para-hisian AP mapping improving efficacy and safety of para-Hisian AP ablation.

Initial Clinical Experience With a Novel 8-Spline High-Resolution Mapping Catheter.

BACKGROUND: The Octaray (Biosense Webster) is a novel, multispline mapping catheter with 48 closely spaced microelectrodes enabling high-resolution electroanatomical mapping. OBJECTIVES: This study sought to report the initial clinical mapping experience with this novel catheter in a variety of cardiac arrhythmias and to compare the mapping performance with the 5-spline Pentaray. METHODS: Fifty consecutive procedures among 46 patients were retrospectively analyzed regarding safety, efficacy, and acute procedural success defined as termination or noninducibility of clinical tachycardia, conduction block across an ablation line, or pulmonary vein isolation. In addition, another 10 patients with sustained atrial tachycardia mapped with the 5-spline catheter (2-5-2 spacing) or the novel 8-spline catheter (2-2-2-2-2 spacing) were analyzed. RESULTS: Left atrial and ventricular mapping by either transseptal (n = 41) or retroaortic (n = 2) access was feasible without any complications related to the multispline design of the novel catheter. The acute procedural success rate was 94%. In sustained atrial tachycardia compared with the 5-spline catheter, the novel 8-spline catheter recorded more electrograms per map (3,628 ± 714 vs 11,350 ± 1,203; P < 0.001) in a shorter mapping time (13 ± 2 vs 9 ± 1 minutes; P = 0.08) resulting in a higher point density (18 ± 4 vs 59 ± 10 electrograms/cm2; P < 0.01) and point acquisition rate (308 ± 69 vs 1,332 ± 208 electrograms/min.; P < 0.01). CONCLUSIONS: In this initial experience, mapping with the novel catheter was safe and efficient with a high electroanatomical resolution. In sustained atrial tachycardia the novel 8-spline catheter demonstrated a marked increase in point density and mapping speed compared with those of the 5-spline catheter. These initial results should be validated in a larger multicenter cohort with longer follow-up.

Catheter ablation of short-coupled variant of torsade de pointes.

BACKGROUND: The short-coupled variant of torsade de pointes (sc-TdP) is a malignant arrhythmia that frequently presents with ventricular fibrillation (VF) electrical storm. Verapamil is considered the first-line therapy of sc-TdP while catheter ablation is not widely adopted. The aim of this study was to determine the origin of sc-TdP and to assess the outcome of catheter ablation using 3D-mapping. METHODS AND RESULTS: We retrospectively analyzed five patients with sc-TdP who underwent 3D-mapping and ablation of sc-TdP at five different institutions. Four patients initially presented with sudden cardiac arrest, one patient experienced recurrent syncope as the first manifestation. All patients demonstrated a monomorphic premature ventricular contraction (PVC) with late transition left bundle branch block pattern, superior axis, and a coupling interval of less than 300 ms. triggering recurrent TdP and VF. In four patients, the culprit PVC was mapped to the free wall insertion of the moderator band (MB) with a preceding Purkinje potential in two patients. Catheter ablation using 3D-mapping and intracardiac echocardiography eliminated sc-TdP in all patients, with no recurrence at mean 2.7 years (range 6 months to 8 years) of follow-up. CONCLUSION: 3D-mapping and intracardiac echocardiography demonstrate that sc-TdP predominantly originates from the MB free wall insertion and its Purkinje network. Catheter ablation of the culprit PVC at the MB free wall junction leads to excellent short- and long-term results and should be considered as first-line therapy in recurrent sc-TdP or electrical storm.

Incidental finding of a pulmonary embolus by intracardiac echocardiography during an atrial fibrillation ablation procedure.

A 71-year-old female patient was referred for catheter ablation of drug-refractory, symptomatic atrial fibrillation. Initial intracardiac echocardiography (ICE) incidentally showed a mobile embolus stuck at a bifurcation of the right pulmonary artery. The procedure was suspended and the finding was subsequently confirmed by computed tomography pulmonary angiography. This case illustrates a potential value of real-time imaging by ICE during invasive procedures.

Mahaim pathway potential revealed by high-resolution three-dimensional mapping.

Mapping and ablation of atriofascicular fibers can be highly challenging due to the complex and dynamic anatomy of the tricuspid valve annulus. This case highlights the utility of a multi-electrode catheter three-dimensional mapping approach to localize the Mahaim pathway along the tricuspid annulus in order to guide catheter ablation.

Mortality in patients with atrial fibrillation has significantly decreased during the last three decades: 35 years of follow-up in 1627 pacemaker patients.

AIM: The impact of atrial fibrillation (AF) on mortality is not fully understood. We therefore sought to investigate long-term effects of AF on mortality in patients with the need for pacemaker (PM) therapy. METHODS AND RESULTS: A total of 1627 PM recipients with AF at implantation were followed in a single-centre, longitudinal study for up to 35 years. Baseline factors affecting survival and long-term follow-up were analysed. A total of 7362 patient-years of follow-up (PM implanted between 1971 and 2000, followed until 31 December 31 2005) were analysed. Female PM recipients lived significantly longer than male (P = 0.025; mean survival 91.9 vs. 72.1 months) despite older age at time of inclusion. Mean survival times almost doubled for patients implanted in the last decade, with 139.8 months in the nineties vs. 66.8 months in the seventies and 75.7 months in the eighties (P < 0.001). Male gender, age at implantation, non-syncopal bradycardia, and decade of implantation influenced survival. CONCLUSION: Life expectancy in AF patients after PM implantation has doubled within the last three decades, with a mean survival in the overall population of 7.6 years for women and 6.0 years for men. Survival is influenced by several simple baseline characteristics, which may help to identify patients with very long survival times.

Fascicular parasystole and recurrent syncope - a case report.

INTRODUCTION: Parasystole refers to an ectopic pacemaker that discharges with a constant rate competing with the primary pacemaker of the heart the sinus node. Parasystolic pacemakers have been described in the atrium, atrioventricular node, His bundle, and in the ventricle. Ventricular parasystole usually carries a benign prognosis, but there are a few reports of ventricular tachyarrhythmia initiated by parasystolic beats. CASE PRESENTATION: We present a case of a 15-year-old otherwise healthy teenager with recurrent most likely arrhythmic syncope who was diagnosed with ventricular parasystole from the left posterior fascicle. After exclusion of structural and primary electrical heart disease, the patient was deemed at increased risk of parasystole-induced tachyarrhythmia, and thus catheter ablation of the ectopic focus was performed. Since catheter ablation the patient continues to be free of any symptoms. DISCUSSION: This report highlights the potential risks of parasystole in context of recurrent syncope and reviews the available literature on parasystole and ventricular tachyarrhythmia.

Pacemaker therapy in very elderly patients: long-term survival and prognostic parameters.

BACKGROUND: Permanent pacing is the therapy of choice for treating severe and/or symptomatic bradyarrhythmia. However, augmented life expectancy and increasing health care expenditures have led to questions concerning the routine use of electrotherapy in very elderly patients. This study is aimed at assessing data on the actual number, characteristics, and survival of patients requiring pacing therapy at age > or =80 years. METHODS: Between 1971 and 2000, 1588 patients aged > or =80 years completed a standardized 6- to 12-month follow-up after pacemaker (PM) implantation, resulting in a total of 5244 patient years. Kaplan-Meier analyses were computed to visualize survival differences in various subgroups and implantation periods. RESULTS: Today, patients aged > or =80 years account for 32% of all PM implantations. An increasing 5-year survival after PM implantation to the current rate of 66% was found, compared to 37% and 47% in the previous decades. Based on a mean survival time of 8 years, clinical symptoms can be effectively treated with costs of < or =500 dollars per patient per year. Prognostic parameters were the decade of implantation (relative risk [RR] 0.80, CI 0.67-0.96, P < or =.02), a history of presyncope (RR 0.73, CI 0.57-0.95, P < or =.02), and male sex (RR 1.20, CI 1.04-1.40, P < or =.02). However, none of these parameters can be recommended for estimating outcome or for guiding device selection. CONCLUSIONS: Patients aged > or =80 years account for an increasing portion of PM implantations. Considering the remaining life expectancy of 8 years in these patients, PM therapy is a clinically and economically effective therapeutic option to control bradyarrhythmia-related symptoms.

A unique pacemaker complication of thrombus formation in the right internal jugular vein due to unusual migration of an atrial pacemaker electrode.

Our report describes the late migration of an atrial screw-in lead into the right internal jugular vein causing subsequent subclinical thrombus formation at the tip of the electrode. Previously initiated anticoagulation for atrial fibrillation may have prevented complete occlusion of the internal jugular vein. Therefore, prophylactic anticoagulation should be considered for patients in whom permanent pacing leads are dislodged into central veins and cannot be removed.

[Ventricular tachycardia under stress : Characteristic symptom or prognostic relevance?]. / Ventrikuläre Tachykardien unter Belastung : Typisches Merkmal oder prognostische Relevanz?

Exercise-induced ventricular tachycardia (EIVT) is typical and quite common in patients with long QT-Syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT). Although patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or hypertrophic cardiomyopathy (HCM) experience EIVT infrequently, the occurrence of EIVT is of great prognostic value in these patients. The following overview will introduce these cardiomyopathies and highlight the importance of their EIVT.

Early Heparin Administration Reduces Risk for Left Atrial Thrombus Formation during Atrial Fibrillation Ablation Procedures.

Objective. Despite the use of anticoagulation during left atrial (LA) ablation procedures, ischemic cerebrovascular accidents (CVAs) are recognized as a serious complication. Heparin is usually given after safe transseptal access has been obtained, resulting in a short unprotected dwell time of catheters within the LA, which may account for CVAs. We investigated the frequency of CVAs and LA thrombus formation as detected by intracardiac ultrasound (ICE) depending on the timing of heparin administration. Methods and Results. Sixty LA ablation procedures with the use of ICE were performed in 55 patients. Patients were grouped by heparin administration after (Group I, n = 13) and before (Group II, n = 47) transseptal access. Group I patients were younger (56.6 ± 13.7 versus 65.9 ± 9.9 years, P = .01); other clinical and echocardiographic characteristics did not differ between groups. Early thrombus formation was observed in 2 (15.4%) of group I patients as compared to 0% of group II patients (P = .04). One CVA (2.1%) occurred in one group II patient without prior thrombus detection, and none occurred in group I patients (P = ns). Conclusion. Early administration of heparin reduces the risk of early intracardiac thrombus formation during LA ablation procedures. This did not result in reduced rate of CVAs.

Atrial fibrillation reduces the atrial impedance amplitude during cardiac cycle: a novel detection algorithm to improve recognition of atrial fibrillation in pacemaker patients.

AIMS: In carriers of dual chamber pacemakers and implantable cardioverter-defibrillators (ICD), detection of atrial fibrillation (AF) is crucial for adequate mode switch function and to avoid inappropriate shock delivery. Detection algorithms rely on the atrial rate and on the relationship of atrial to ventricular intracardiac electrograms, but the relative portion of misclassified AF episodes remains high. Although myocardial impedance is a reliable indicator of contraction, little is known about atrial impedance as a marker of atrial arrhythmias. Methods During an electrophysiological study, we investigated the effect of induced AF on impedance at the right atrial free wall (RAFW) and right atrial appendage (RAA) in 20 patients. Using biphasic square-wave pulses (128 Hz, 200 microA/15 micros), impedance changes were recorded during sinus rhythm (SR-1), atrial pacing at 120 beats/min, AF induced by rapid atrial burst pacing, and after spontaneous AF termination (SR-2). Results At the RAA, peak-to-peak impedance amplitude during cardiac cycle (DeltaZ) dropped from 51.7 +/- 35.3 Omega (SR-1) or 49.6 +/- 30.6 Omega (pacing) to 24.6 +/- 22.0 Omega (AF, P< or =0.0005), and subsequently increased to 37.7 +/- 24.7 Omega (SR-2, P < or = 0.0004 v. AF). At the RAFW, DeltaZ changed from 16.2 +/- 15.5 Omega (SR-1) or 13.5 +/- 9.9 Omega (pacing) to 5.9 +/- 4.1 Omega (AF, P < or = 0.003), and to 11.4 +/- 10.7 Omega (SR-2, P < or = 0.015). Given a discrimination threshold of 65%, the sensitivity and the specificity of DeltaZ to detect AF were 79 +/- 18 and 89 +/- 14%, respectively (95% confidence interval). CONCLUSION: AF causes DeltaZ drop in pacemaker and ICD recipients. This impedance based algorithm can be used as an alternative method of AF detection.

Incidence of ventricular tachyarrhythmias during permanent pacemaker therapy in low-risk patients results from the German multicentre EVENTS study.

AIMS: Current studies found an incidence of 12-31% ventricular tachyarrhythmias and sudden cardiac death during cardiac pacing months or even years after pacemaker insertion. MADIT(12) and MUSTT(13) demonstrated that patients with poor LV function after Myocardial infarction (MI) showing non-sustained ventricular tachycardia (nsVT) and inducibility during electrophysiologic testing benefit from an ICD. The present study was dedicated to assess the global incidence of non-sustained ventricular arrhythmias in a general population of pacemaker patients. Special regard was on patients with a potential ICD indication, e.g. those matching the MADIT/MUSTT criteria. METHODS AND RESULTS: Two hundred and thirty-one patients (72 +/- 11 years; 134 men) with an indication for dual chamber pacing entered the study. In all patients pacemaker systems capable of automatic storing of intracardiac electrocardiograms were implanted (Pulsar, Discovery, Guidant). Follow-up time was 15 months after inclusion. In 54 (25.7%) of 210 patients with at least one follow-up, episodes of nsVT were documented by stored electrocardiograms (up to >30 beats, >200 b.p.m.). Multiple-up to nine-episodes of ventricular tachycardia were retrieved in 31 of these patients. Three out of 14 patients with an LVEF <40% after MI presented nsVT during the follow-up. One of these patients received an ICD. CONCLUSION: A significant number of pacemaker patients present with ventricular tachycardia. Intracardiac electrocardiograms and alert functions from pacemakers may enhance physicians' awareness of the patient's intrinsic arrhythmic profile and help uncover underlying mechanisms of arrhythmias by storing the initiation of the arrhythmia.

Real-time assessment of acute myocardial ischaemia by an intra-thoracic 6-lead ECG: evaluation of a new diagnostic option in the implantable defibrillator.

AIM: In the presence of coronary artery disease, implantable cardioverter-defibrillators (ICD) are used effectively for treating life-threatening tachyarrhythmias. Continuous monitoring of myocardial ischaemia would provide a new diagnostic option in future ICD generations. METHODS AND RESULTS: In 22 selected patients undergoing coronary angioplasty, percutaneous transluminal coronary angioplasty (PTCA), three electrodes, similar to those used in the ICD, were inserted aiming to create six intra-thoracic ECG (IT-ECG) leads according to Einthoven and Goldberger. In total, 27 PTCA were conducted. The diagnostic efficacy for ischaemia assessment was compared with the surface ECG. The IT-ECG proved to be more sensitive than conventional ECG in early and overall ischaemia assessment. At 30 s of coronary artery occlusion, ischaemic ST-segment alterations (> or =0.25 mV) were present in the IT-ECG 2.3 times more often (23 vs. 10/27 PTCA attempts, P<0.01) and at 90 s 1.4 times more often compared with conventional ECG leads (18 vs. 26/27, P<0.05). Intra-thoracic Einthoven 2 (SVC+RVA vs. ICD-housing) and Goldberger 3 (SVC+ICD-housing vs. RVA) had the highest sensitivity (88/85%). Using > or =4 IT-ECG, ischaemia monitoring was independent of severity and site of origin. IT-ECG signals showed double ST-T signal amplitude (4.19+/-0.6 vs. 2.15+/-0.3 mV, ratio: 1.95, P<0.01) at a QRS/ST amplitude ratio similar in the two ECG techniques. CONCLUSION: This study provides strong evidence that the ICD-based IT 6-lead ECG would provide a new and efficient means of assessing a patient's daily ischaemic burden.

Delayed adaptation of ventricular repolarization after sudden changes in heart rate due to conversion of atrial fibrillation. A potential risk factor for proarrhythmia?

AIMS: Onset and termination of atrial fibrillation are often associated with abrupt changes in heart rate. Presence and time-course of delayed adaptation of the QT/QTc interval are unknown, but a temporary "mismatch" between rate and the QT interval may enhance the risk of proarrhythmia. METHODS: In a prospective two-part study, time-course of adaptation of ventricular repolarization after abrupt changes in heart rate was assessed during termination of Holter ECG-documented atrial fibrillation episodes (Group 1, 32 patients) and subsequently in 20 patients with sick sinus syndrome and cardiac pacing initiating abrupt bi-directional changes in paced heart rate (Group 2). RESULTS: Conversion of atrial fibrillation showed a 32+/-21 bpm fall in heart rate (P<0.05). Restoration of the QTc interval afterwards was delayed by < or =1 min in 27%, by 1-2 min in 21%, by 2-5 min in 11% and by >5 min in 41% of the cases. Atrial pacing simulating a 30 bpm fall/increase in atrial rate demonstrated that a subsequent transient rate-QT mismatch is a physiological phenomenon (fall of 100 to 70 bpm: initially 90% of the proper QTc interval, compared with 94% after conversion of atrial fibrillation). The restoration curve of QTc adaptation showed an initially fast and subsequently slower time component, with interindividual variation. Clinical parameters, baseline heart rate or the direction of rate changes were not predictive. CONCLUSION: Delayed adaptation of ventricular repolarization following atrial fibrillation onset and termination is common, requiring minutes for restoring the QT/QTc steady state. Clinical parameters fail to predict patients with a long-lasting rate-QT mismatch. It may carry a significant arrhythmogenic risk particularly in patients on QT altering medication.

Beat-to-beat assessment of QT/RR interval ratio in severe heart failure and overt myocardial ischemia: a measure of electrical integrity in diseased hearts.

The study was designed to assess the beat-to-beat variation of ventricular repolarization in patients with myocardial ischemia, hear failure, and in normal subjects. Autonomic tone may alter the dynamic QT/RR interval relation and thus may be involved in ventricular arrhythmia development, especially in the diseased heart. The study included 145 patients (age 16-86 years) with CHF (LVEF < or = 0.30) or unstable angina pectoris (LVEF > 0.60). The control group consisted of healthy volunteers giving physiological baseline measures for the evaluated parameters: cycle length, QT interval, and QT/RR interval ratio during three time periods. In patients with myocardial ischemia (LVEF > 0.60) and healthy subjects the QT/RR interval ratio did not reveal significant differences between both groups (QT/RR(CAD) = 0.36 +/- 0.77 vs QT/RR(controls) = 0.28 +/- 0.83; NS). In sharp contrast, in patients with severe heart failure, RR dependent instantaneous variation of the QT interval was almost missing and regression line analysis disclosed a QT/RR interval slope substantially enhanced by 196% (compared to normal subjects) and 131% (compared to CAD patients; P < 0.05) with a complete loss of circadian modulation (QT/RR(CHF) = 0.83 +/- 0.71 vs QT/RR(CAD) = 0.36 +/- 0.77 vs QT/RR(controls) = 0.28 +/- 0.83; P < 0.05). Beat-to-beat QT interval assessment provides a dynamic parameter of physiological and altered repolarization in defined study groups. Compared to other groups (preserved LVEF), patients with left ventricular impairment exhibited a significantly increased sensitivity of repolarization to cycle length (enhanced QT/RR interval ratio) and a blunted circadian modulation of the QT interval. This is consistent with concept that increased repolarization disparity may be deleterious being a potential pathophysiological basis for enhanced arrhythmic risk.