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Background: Brugada syndrome (BrS) is a primary arrhythmia syndrome affecting 1 in 2000 of the general population. Genetic testing identifies pathogenic variants in the sodium voltage-gated channel α-subunit 5 gene (SCN5A) in up to 25% of familial BrS. Balanced translocations, which involve the exchange of the ends of 2 different chromosomes, are found in approximately 1 in 500 people. They usually are benign and only rarely are reported to cause arrhythmogenic disorders., Objective: The purpose of this study was to identify the genetic mechanism underlying a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages., Methods: We clinically evaluated family members with an electrocardiogram, 2-dimensional echocardiogram, and provocation testing with ajmaline challenge. Cytogenetic testing included karyotype and fluorescent in situ hybridization (FISH) analysis. We performed gene panel, exome, and genome sequencing analysis., Results: Sequencing of 128 cardiac genes and exome sequencing of a family with BrS, sick sinus syndrome, cardiac hypertrophy, sudden cardiac death, and multiple miscarriages did not reveal a pathogenic variant. Karyotype and FISH analysis identified a balanced translocation breaking the SCN5A gene on chromosome 3 and the multiple chromosome maintenance 10 gene (MCM10) on chromosome 10 t(3;10)(p22.2;p13). We characterized both translocation breakpoint junctions using genome sequencing and found no regions of sequence homology., Conclusion: A balanced translocation breaking SCN5A is a novel mechanism underlying disease in a family with BrS, sick sinus syndrome, cardiac hypertrophy, and sudden cardiac death. Genome sequencing can identify rare chromosomal aberrations causing inherited diseases that may otherwise be missed using gene panel and exome sequencing-based approaches., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The BioMonitor 2 Pilot Study assessed the implantation procedure, the sensing amplitude and the remote monitoring transmission success rate of the second generation implantable cardiac monitor, the BioMonitor 2 (Biotronik, Berlin, Germany)., Methods: This was a prospective, multi-centre, single-arm, non-randomised study involving seven operators in five sites across Australia. Data were collected at implantation, during clinic visits at 1 week and 1 month post-implantation, and through wireless remote monitoring., Results: Thirty patients with indications for long-term cardiac monitoring underwent successful insertion of a study device. The median implantation time was 9 minutes (interquartile range (IQR) 5-14 mins). The mean R-wave amplitude at 1 week was 0.75±0.39mV and remained stable over the follow-up period. Within 1 day, 97% of the patients connected to the remote monitoring network and daily messages were transmitted on 93.8% of all study days. Seventy-six per cent of patients transmitted at least one subcutaneous ECG (sECG), with a median number of sECGs per patient of seven (IQR 3-37) within 28 days., Conclusions: The results of the BioMonitor 2 Pilot study confirm the excellent sensing amplitudes afforded by this new device and the utility of the implantation tools and technique. Patient compliance with and the transmission success rate of the home monitoring system were excellent., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Aims: The phrenic nerves may be damaged during catheter ablation of atrial fibrillation. Phrenic nerve function is routinely monitored during ablation by stimulating the right phrenic nerve from a site in the superior vena cava (SVC) and manually assessing the strength of diaphragmatic contraction. However the optimal stimulation site, method of assessing diaphragmatic contraction, and techniques for monitoring the left phrenic nerve have not been established. We assessed novel techniques to monitor phrenic nerve function during cryoablation procedures., Methods and Results: Pacing threshold and stability of phrenic nerve capture were assessed when pacing from the SVC, left and right subclavian veins. Femoral venous pressure waveforms were used to monitor the strength of diaphragmatic contraction. Stable capture of the left phrenic nerve by stimulation in the left subclavian vein was achieved in 96 of 100 patients, with a median capture threshold of 2.5 mA [inter-quartile range (IQR) 1.4-5.0 mA]. Stimulation of the right phrenic nerve from the subclavian vein was superior to stimulation from the SVC with lower pacing thresholds (1.8 mA IQR 1.4-3.3 vs. 6.0 mA IQR 3.4-8.0, P < 0.001). Venous pressure waveforms were obtained in all patients and attenuation of the waveform was always observed prior to onset of phrenic nerve palsy., Conclusion: The left phrenic nerve can be stimulated from the left subclavian vein. The subclavian veins are the optimal sites for phrenic nerve stimulation. Monitoring the femoral venous pressure waveform is a novel technique for detecting impending phrenic nerve damage., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that can lead to sudden cardiac death. The diagnostic criterion has recently been revised and through the use of cardiac magnetic resonance (CMR) imaging this study aimed to assess the clinical impact of comparing the original 1994 task force (TF) criterion to the revised 2010 criterion., Methods: We evaluated 173 consecutive CMR scans of patients referred with clinical suspicion of ARVC between 2008 and 2011. We then compared the prevalence of major and minor CMR criteria by applying the two criteria., Results: Using the 1994 TF criterion, 13 (7.5%) patients had definite, 11 (6.4%) had borderline, and 39 (22.5%) had possible ARVC. Using the 2010 TF criterion, 10 (5.8%) patients had definite, 1 had borderline, and 7 had (0.04%) possible ARVC. With the 1994 criterion, 81 patients satisfied CMR criterion, of which 36 (44%) had major and 45 (56%) had minor criteria. Upon reclassification with the revised criterion, 61 of the 81 patients were not assigned any criteria, even though many patients had significant risk factors. The negative predictive values (NPV) for both CMR criteria were 100% but the positive predictive values (PPV) for combined CMR major or minor criteria improved from 23% to 55%., Conclusions: Revision of the criterion has enhanced the diagnostic capabilities of CMR but has resulted in a large cohort of patients not classified. In these patients, there is presently no official consensus on imaging or clinical strategy for surveillance of the evolution of pathology over time., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary vein isolation by cryoballoon ablation is an accepted method of treating atrial fibrillation. Little data exist regarding factors affecting late electrical reconnection of pulmonary veins following cryoballoon ablation., Objective: To investigate factors determining pulmonary vein reconnection in patients undergoing repeat catheter ablation for recurrent atrial fibrillation following cryoballoon ablation., Methods: Fifty-one consecutive patients undergoing repeat catheter ablation for recurrent atrial fibrillation following initial cryoballoon ablation underwent retrospective assessment of initial cryoablation characteristics, including balloon and vein sizes, venogram occlusion score, balloon freezing time from 0 to -30 °C, nadir temperature, and balloon warming time from -30 to +15 °C, recorded during the initial cryoballoon procedure., Results: Of 199 veins assessed, 91 had reconnected (1.8 per patient). Balloon warming time (odds ratio [OR] 3.21; 95% confidence interval [CI] 2.00-5.13; P < .0001), nadir temperature (OR 1.94; 95% CI 1.42-2.66; P < .0001), vein occlusion score (OR 1.74; 95% CI 1.29-2.34; P = .0003), and balloon freezing time (OR 1.58; 95% CI 1.03-2.42; P = .037) predicted pulmonary vein reconnection. On multivariate analysis, balloon warming time (OR 3.71; 95% CI 2.2-6.24; P ≤ .0001), pulmonary vein size (OR 1.63; 95% CI 1.08-2.43; P = .020), and vein occlusion score (OR 1.48; 95% CI 1.06-2.08; P = .021) remained statistically significant independent predictors of pulmonary vein reconnection. The receiver operating characteristic for the multivariate model yielded an area under the curve of 0.82., Conclusions: Balloon warming time, vein occlusion score, and pulmonary vein size predict pulmonary vein reconnection. Balloon warming time was the most important predictive factor, and the manipulation of balloon warming may be a novel therapeutic strategy for improving outcomes of cryoballoon ablation for atrial fibrillation., (© 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Persistent phrenic nerve palsy is the most frequent complication of cryoballoon ablation for atrial fibrillation and can be disabling., Objectives: To describe a technique-immediate balloon deflation (IBD)-for the prevention of persistent phrenic nerve palsy, provide data for its use, and describe in vitro simulations performed to investigate the effect of IBD on the atrium and pulmonary vein., Methods: Cryoballoon procedures for atrial fibrillation were analyzed retrospectively (n = 130). IBD was performed in patients developing phrenic nerve dysfunction (n = 22). In vitro simulations were performed by using phantoms., Results: No adverse events occurred, and all patients recovered normal phrenic nerve function before leaving the procedure room. No patient developed persistent phrenic nerve palsy. The mean cryoablation time to onset of phrenic nerve dysfunction was 144 ± 64 seconds. Transient phrenic nerve dysfunction was seen more frequently with the 23-mm balloon than with the 28-mm balloon (11 of 39 cases vs 11 of 81 cases; P = .036). Balloon rewarming was faster following IBD. The time to return to 0 and 20° C was shorter in the IBD group (6.7 vs 8.9 seconds; P = .007 and 16.7 vs 37.6 seconds; P<.0001). In vitro simulations confirmed that IBD caused more rapid tissue warming (time to 0°C, 14.0 ± 3.4 seconds vs 46.0 ± 8.1; P = .0001) and is unlikely to damage the atrium or pulmonary vein., Conclusions: IBD results in more rapid tissue rewarming, causes no adverse events, and appears to prevent persistent phrenic nerve palsy. Simulations suggest that IBD is unlikely to damage the atrium or pulmonary vein., (Copyright © 2013 Heart Rhythm Society. All rights reserved.)

Objectives: The purpose of this study was to perform a detailed analysis of the P-wave morphology (PWM) in focal atrial tachycardia (AT) and construct and prospectively evaluate an algorithm for identification of the anatomic site of origin., Background: Although smaller studies have described the PWM from particular anatomic locations, a detailed algorithm characterizing the likely location of a tachycardia associated with a P-wave of unknown origin has been lacking., Methods: The PWMs for 126 consecutive patients undergoing successful radiofrequency ablation of 130 ATs are reported. P waves were included only when the onset was preceded by a discernible isoelectric segment. P waves were classified as positive (+), negative (-), isoelectric, or biphasic. Sensitivity, specificity, and predictive values were calculated. On the basis of these results, an algorithm was constructed and prospectively evaluated in 30 new consecutive ATs., Results: The distribution of ATs was right atrial (RA) in 82 of 130 (63%) and left atrial (LA) in 48 of 130 (37%). Right atrial sites included crista (n = 28), tricuspid annulus (n = 29), coronary sinus (CS) ostium (n = 14), perinodal (n = 7), right septum (n = 1), and RA appendage (n= 3). Left atrial sites included pulmonary veins (n = 32), mitral annulus (n = 8), CS body (n= 3), left septum (n = 3), and LA appendage (n = 2). In electrocardiographic lead V1, a negative or +/- P-wave demonstrated a specificity of 100% for a RA focus, and a + or -/+ P-wave demonstrated a sensitivity of 100% for a LA focus. A characteristic PWM was associated with high sensitivity and specificity at common atrial sites for tachycardia foci. A P-wave algorithm correctly identified the focus in 93%., Conclusions: Characteristic PWMs corresponding to known anatomic sites for focal AT are associated with high specificity and sensitivity. A P-wave algorithm correctly identified the site of tachycardia origin in 93%.

Background and Aim: There is an increasing use of active-fixation leads for cardiac pacing, yet concerns remain regarding initial high stimulation thresholds. The aim was to perform a detailed analysis of pacing parameters at the time of implantation to determine when lead repositioning should be considered., Methods: We performed a prospective observational study of consecutive new pacemaker implants. Detailed analysis of pacing parameters was collected at 2-minute intervals for 10 minutes, and at day 1 and week 8 following implant., Results: Ninety-four patients underwent implantation of 79 dual-chamber and 15 single-chamber pacemakers using active-fixation leads in both chambers. An initial threshold of >1 V was demonstrated in 45/94 (48%) ventricular leads (mean threshold 1.5 +/- 0.3 V). This declined rapidly to 0.9 +/- 0.3 V at 4 minutes (P < 0.01), 0.7 +/- 0.3 V at 10 minutes (P < 0.01), and 0.6 +/- 0.3 V at day 1 (P < 0.01). At day 1, 43/45 leads were <1 V. There were 79 atrial leads. An initial threshold of >1 V (mean 1.7 +/- 0.6 V) was demonstrated in 41/79 (52%) leads falling significantly to 1.1 +/- 0.5 V at 4 minutes (P < 0.01), 0.9 +/- 0.4 V at 10 minutes (P < 0.01), and 0.6 +/- 0.2 V at day 1 (P < 0.01). At 10 minutes, 32 of 41 leads demonstrated a threshold of <1 V with all leads <1 V at day 1. Thresholds were maintained medium term., Conclusions: Active-fixation leads are commonly associated with initially high thresholds that fall rapidly. An initial threshold of 2 V should be provisionally accepted and retested at 4 minutes. The majority will have a threshold of <1 V the following day. A failure of a high threshold to decline at 4 minutes requires lead repositioning.

Background: The aim of this study was to characterize acute and medium-term pacemaker lead performance with the two most commonly used glucocorticosteroids: dexamethasone sodium phosphate and dexamethasone acetate., Methods: Forty sets of atrial and ventricular passive-fixation leads containing either dexamethasone sodium phosphate or dexamethasone acetate were implanted as dual chamber pacemakers. Randomization was equally distributed to both arms of the study. Stimulation thresholds, lead impedance, and sensing were measured on the day of implant, day 1, 1 month, 3 months, and 6 months following the implant., Results: For the dexamethasone sodium phosphate arm, the atrial stimulation thresholds were 0.9 +/- 0.1 V at implant and 0.8 +/- 0.1 V at 6 months, and in the ventricle 0.5 +/- 0.1 V at implant and 0.6 +/- 0.1 V at 6 months. In the dexamethasone acetate arm, the atrial stimulation thresholds were 0.7 +/- 0.1 V at implant and at 6 months, and in the ventricle 0.5 +/- 0.1 V at implant and at 6 months. There were no significant differences between dexamethasone sodium phosphate or dexamethasone acetate leads for stimulation thresholds at any of the intervals of follow-up. P- and R-wave sensing were similarly maintained over the duration of follow-up with no significant differences between groups at any of the intervals of follow-up. Pacing lead impedance showed a trend towards lower values in the dexamethasone acetate arm, which only reached statistical significance at 3 months and beyond for ventricular leads., Conclusions: Leads containing dexamethasone sodium phosphate and dexamethasone acetate demonstrate equivalent and excellent acute and medium-term pacemaker lead performance characteristics.

Introduction: As a molecular model of the effect of ischemia on drug block of the transient outward potassium current, the effect of acidosis on the blocking properties of flecainide and quinidine on Kv4.3 currents was studied., Methods and Results: Kv4.3 channels were stably expressed in Chinese hamster ovary cells. Whole-cell, voltage clamp techniques were used to measure the effect of flecainide and quinidine on Kv4.3 currents in solutions of pH 7.4 and 6.0. Extracellular acidosis attenuated flecainide block of Kv4.3 currents, with the IC50 for flecainide (based on current-time integrals) increasing from 7.8 +/- 1.1 microM at pH 7.4 to 125.1 +/- 1.1 microM at pH 6.0. Similar effects were observed for quinidine (IC50 5.2 +/- 1.1 microM at pH 7.4 and 22.1 +/- 1.3 microM at pH 6.0). Following block by either drug, Kv4.3 channels showed a hyperpolarizing shift in the voltage sensitivity of inactivation and a slowing in the time to recover from inactivation/block that was unaffected by acidosis. In contrast, acidosis attenuated the effects on the time course of inactivation and the degree of tonic- and frequency-dependent block for both drugs., Conclusion: Extracellular acidosis significantly decreases the potency of blockade of Kv4.3 by both flecainide and quinidine. This change in potency may be due to allosteric changes in the channel, changes in the proportion of uncharged drug, and/or changes in the kinetics of drug binding or unbinding. These findings are in contrast to the effects of extracellular acidosis on block of the fast sodium channel by these agents and provide a molecular mechanism for divergent modulation of drug block potentially leading to ischemia-associated proarrhythmia.

We investigated the effects of three components of ischemia: external acidosis (pH=6.0), extracellular hyperkalemia ([K(+)]=20 mmol/l), and resting membrane depolarization to -60 mV, on Kv4.3 current stably expressed in Chinese Hamster Ovary cells. We used single electrode whole cell patch clamp techniques to study changes in the current elicited. External acidosis caused a positive shift in the steady state activation curve from -13.4 +/- 2.1 mV to -3.3 +/- 1.5 mV (n=8, P=0.004) and the steady state inactivation curve from -56.5 +/- 0.4 mV to -46.7 +/- 0.5 mV (n=14, P<0.0001). Acidosis also caused an acceleration of recovery from inactivation with the t(1/2) decreasing from 306 ms (95% CI 287-327 ms) to 194 ms (95% CI 182-207 ms), (n=14, P<0.05). Hyperkalemia did not affect any of these parameters. Combined acidosis and hyperkalemia produced effects similar to those seen with acidosis. Changing the holding potential from -90 mV to -60 mV with test potentials of +5 and +85 mV decreased the peak currents by 34.1% and 32.4% respectively (n=14). However, in the presence of external acidosis the decrease in peak currents induced by changing the holding potential was less marked. In acidotic bath the peak current at -60 mV was reduced by only 13.6% at a test potential of +5 mV and 12.3% at a test potential of +85 mV (n=14). Taken together our data suggest that the membrane depolarization and changes in pH which occur under ischemic conditions would be accompanied by relative preservation of Kv4.3 currents and provide a molecular basis for the observation of preserved epicardial I(to) and epicardial action potential duration (APD) shortening in ischemia., (Copyright 2002 Academic Press.)