Intracardiac Recordings Research Articles

Noninvasive Activation Imaging of Ventricular Arrhythmias by Spatial Gradient Sparse in Frequency Domain-Application to Mapping Reentrant Ventricular Tachycardia.

The aim of this paper is to develop and evaluate a novel imaging method [spatial gradient sparse in frequency domain (SSF)] for the reconstruction of activation sequences of ventricular arrhythmia from noninvasive body surface potential map (BSPM) measurements. We formulated and solved the electrocardiographic inverse problem in the frequency domain, and the activation time was encoded in the phase information of the imaging solution. A cellular automaton heart model was used to generate focal ventricular tachycardia (VT). Different levels of Gaussian white noise were added to simulate noise-contaminated BSPM. The performance of SSF was compared with that of weighted minimum norm inverse solution. We also evaluated the method in a swine model with simultaneous intracardiac and body surface recordings. Four reentrant VTs were observed in pigs with myocardial infarction generated by left anterior descending artery occlusion. The imaged activation sequences of reentrant VTs were compared with those obtained from intracardiac electrograms. In focal VT simulation, SSF has increased the correlation coefficient (CC) by 5% and decreased localization errors (LEs) by 2.7 mm on average under different noise levels. In the animal validation with reentrant VT, SSF has achieved an average CC of 88% and an average LE of 6.3 mm in localizing the earliest and latest activation site in the reentry circuit. Our promising results suggest that the SSF provides noninvasive imaging capability of detecting and mapping macro-reentrant circuits in 3-D ventricular space. The SSF may become a useful imaging tool of identifying and localizing the potential targets for ablation of focal and reentrant VT.

Active periodic electrograms in remote monitoring of pacemaker recipients: the PREMS study.

AimsRemote monitoring (RM) is considered as a standard of care for pacemaker recipients. Remote monitoring systems provide calendar-based intracardiac electrogram recordings (IEGM) only with the current pacemaker settings (passive IEGM). PREMS (Pacemaker Remote Electrogram Monitoring Study), an observational, multicentre trial, prospectively evaluated the clinical value of an active IEGM (aIEGM), including three 10-s sections (passive IEGM, encouraged sensing, and encouraged pacing), compared to other RM data and to its passive IEGM section. Secondary objectives included the added value of the aIEGM to fully assess the sensing and pacing functions of each lead.Methods and resultsPatients were enrolled within 3 months after pacemaker implantation and followed until the first transmitted aIEGM, which was analysed together with all other RM data. In total, 567 patients were enrolled (79 ± 9 years, 62% men, 19% single-chamber, and 81% dual-chamber pacemakers). Of 547 aIEGMs transmitted in 547 patients, 161 [29.4%; 95% confidence interval (95% CI) 25.6–33.3%] indicated at least one anomaly non-detectable with certainty—or at all—on other RM data, including atrial arrhythmia, extrasystoles, undersensing, oversensing, and loss of capture. In 21.7% of cases the detected events deserved a corrective action. The sensing and pacing function of each lead could be fully assessed in 77.3% of aIEGM (95% CI 72.6–82.0%) vs. 15.5% (95% CI 11.4–19.6%) when considering only the passive IEGM section (P < 0.001).ConclusionAn active IEGM improves the clinical value of remote pacemaker follow-up. Furthermore, compared to a passive IEGM, the aIEGM increases the capability to fully assess remotely the sensing and pacing functions.

Is human atrial fibrillation stochastic or deterministic?-Insights from missing ordinal patterns and causal entropy-complexity plane analysis.

The mechanism of atrial fibrillation (AF) maintenance in humans is yet to be determined. It remains controversial whether cardiac fibrillatory dynamics are the result of a deterministic or a stochastic process. Traditional methods to differentiate deterministic from stochastic processes have several limitations and are not reliably applied to short and noisy data obtained during clinical studies. The appearance of missing ordinal patterns (MOPs) using the Bandt-Pompe (BP) symbolization is indicative of deterministic dynamics and is robust to brief time series and experimental noise. Our aim was to evaluate whether human AF dynamics is the result of a stochastic or a deterministic process. We used 38 intracardiac atrial electrograms during AF from the coronary sinus of 10 patients undergoing catheter ablation of AF. We extracted the intervals between consecutive atrial depolarizations (AA interval) and converted the AA interval time series to their BP symbolic representation (embedding dimension 5, time delay 1). We generated 40 iterative amplitude-adjusted, Fourier-transform (IAAFT) surrogate data for each of the AA time series. IAAFT surrogates have the same frequency spectrum, autocorrelation, and probability distribution with the original time series. Using the BP symbolization, we compared the number of MOPs and the rate of MOP decay in the first 1000 timepoints of the original time series with that of the surrogate data. We calculated permutation entropy and permutation statistical complexity and represented each time series on the causal entropy-complexity plane. We demonstrated that (a) the number of MOPs in human AF is significantly higher compared to the surrogate data (2.7 ± 1.18 vs. 0.39 ± 0.28, p < 0.001); (b) the median rate of MOP decay in human AF was significantly lower compared with the surrogate data (6.58 × 10-3 vs. 7.79 × 10-3, p < 0.001); and (c) 81.6% of the individual recordings had a rate of decay lower than the 95% confidence intervals of their corresponding surrogates. On the causal entropy-complexity plane, human AF lay on the deterministic part of the plane that was located above the trajectory of fractional Brownian motion with different Hurst exponents on the plane. This analysis demonstrates that human AF dynamics does not arise from a rescaled linear stochastic process or a fractional noise, but either a deterministic or a nonlinear stochastic process. Our results justify the development and application of mathematical analysis and modeling tools to enable predictive control of human AF.

Intracardiac electrocardiographic assessment of precordial TASER shocks in human subjects: A pilot study

BackgroundCase reports of cardiac arrest in temporal proximity to Conducted Electrical Weapon(CEW) exposure raise legitimate concerns about this as a rare possibility. In this pilot study, we respectfully navigate the oversight and regulatory hurdles and demonstrate the intra-shock electrocardiographic effects of an intentional transcardiac CEW discharge using subcutaneous probes placed directly across the precordium of patients with a previously implanted intracardiac EKG sensing lead. MethodsAdults scheduled to undergo diagnostic EP studies or replacement of an implanted cardiac device were enrolled. Sterile subcutaneous electrodes were placed at the right sternoclavicular junction and the left lower costal margin at the midclavicular line. A standard police issue TASER Model X26 CEW was attached to the subcutaneous electrodes and a 5 s discharge was delivered. Continuous surface and intracardiac EKG monitoring was performed. ResultsA total of 157 subjects were reviewed for possible inclusion and 21 were interviewed. Among these, 4 subjects agreed and completed the study protocol. All subjects tolerated the 5 s CEW discharge without clinical complications. There were no significant changes in mean heart rate or blood pressure. Interrogation of the devices after CEW discharge revealed no ventricular pacing, dysrhythmias, damage or interference with the implanted devices. ConclusionsIn this pilot study, we have successfully navigated the regulatory hurdles and demonstrated the feasibility of performing intracardiac EKG recording during intentional precordial CEW discharges in humans. While no CEW-associated dysrhythmias were noted, the size of this preliminary dataset precludes making conclusions about the risk of such events. Larger studies are warranted and should consider exploring variations of the CEW electrode position in relation to the cardiac silhouette.

Intracardiac electrogram envelope detection during atrial fibrillation using fast orthogonal search.

The performance of any intracardiac electrogram processing method is limited by the accuracy of its activation detection approach. The most common activation detection approaches in the literature aim to find the highest peak in the activation envelope disregarding the start and end points. However, the duration of the activation can be used to extract useful information such as wave collisions. In this work, we propose a novel orthogonal based approach for fast and accurate estimation of the start and end of the activations (activation envelope) in intracardiac recordings during atrial fibrillation. Wavelet decomposition of the signals was used to create a pool of basis functions for the proposed modeling method. The database included 24 recordings of approximate length of 6s obtained from atrial endocardium of 5 patients who underwent catheter ablation therapy. The start and end of activations in each electrogram was manually annotated by an expert electrophysiologist and the annotations were used as a gold standard to calculate the performance of our envelope detection method. The results show promising performance and excellent robustness to training data for our proposed method with respect to envelope estimation error.

The use of a novel signal analysis to identify the origin of idiopathic right ventricular outflow tract ventricular tachycardia during sinus rhythm: Simultaneous amplitude frequency electrogram transformation mapping.

IntroductionThe signal characteristics of intracardiac bipolar electrograms at the origin of idiopathic RVOT-VT during sinus rhythm remain unclear.ObjectiveThe study sought to develop a novel real-time/online technique, simultaneous amplitude frequency electrogram transformation (SAFE-T), to quantify and localize the diseased ventricular substrate in idiopathic RVOT-VT.MethodsWe retrospectively investigated the intracardiac bipolar recordings in 70 consecutive patients (26% male, mean age 42±12 years) who underwent successful radiofrequency catheter ablation of idiopathic RVOT-VT. We quantified the extent of the frequency fraction of ventricular potentials during sinus rhythm or ventricular pacing using a novel formula, the product of instantaneous amplitude and frequency, and showed that in a 3D geometry as an online SAFE-T map.ResultsThe characteristics of the HHT spectra of electrograms derived from VT origins demonstrated high frequency components (>70 Hz), which were independent of the rhythm. The density of the abnormal potentials at the VT origins were higher (VT origins, 7.5±2.3 sites/cm2 vs. surrounding myocardium, 1.5±1.3 sites/cm2, p<0.001), and were significantly decreased after ablation (0.7±0.6 sites/cm2, p<0.001). A small region of abnormal potentials were observed in the VT origins (mean area of 1.5±0.8 cm2). The SAFE-T maps predicted the VT origins with 92% sensitivity, 78% specificity with optimal cut-off value of >3.0 Hz·mV.ConclusionThe online SAFE-T map was feasible for quantifying the diseased ventricular substrate, irrespective of the rhythm of activation, and can be used to identify the optimal ablation targets for idiopathic RVOT-VT. We found a limited region of abnormal potentials where the RVOT-VT origins were successfully ablated.

Image Integration to Guide Catheter Ablation in Scar‐Related Ventricular Tachycardia

Although multi-detector computed tomography (MDCT) and cardiac magnetic resonance (CMR) can assess the structural substrate of ventricular tachycardia (VT) in ischemic cardiomyopathy (ICM), non-ICM (NICM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), the usefulness of systematic image integration during VT ablation remains undetermined. A total of 116 consecutive patients (67 ICM; 30 NICM; 19 ARVC) underwent VT ablation with image integration (MDCT 91%; CMR 30%; both 22%). Substrate was defined as wall thinning on MDCT and late gadolinium-enhancement on CMR in ICM/NICM, and as myocardial hypo-attenuation on MDCT in ARVC. This substrate was compared to mapping and ablation results with the endpoint of complete elimination of local abnormal ventricular activity (LAVA), and the impact of image integration on procedural management was analyzed. Imaging-derived substrate identified 89% of critical VT isthmuses and 85% of LAVA, and was more efficient in identifying LAVA in ICM and ARVC than in NICM (90% and 90% vs. 72%, P < 0.0001), and when defined from CMR than MDCT (ICM: 92% vs. 88%, P = 0.026, NICM: 88% vs. 72%, P < 0.001). Image integration motivated additional mapping and epicardial access in 57% and 33% of patients. Coronary and phrenic nerve integration modified epicardial ablation strategy in 43% of patients. The impact of image integration on procedural management was higher in ARVC/NICM than in ICM (P < 0.01), and higher in case of epicardial approach (P < 0.0001). Image integration is feasible in large series of patients, provides information on VT substrate, and impacts procedural management, particularly in ARVC/NICM, and in case of epicardial approach.

Identification of Dominant Excitation Patterns and Sources of Atrial Fibrillation by Causality Analysis

Burden of atrial fibrillation (AF) can be reduced by ablation of sources of electrical impulses driving AF but driver identification is still challenging. This study presents a new methodology based on causality analysis that allows identifying the hierarchically dominant areas driving AF. Identification of dominant propagation patterns was achieved by computing causal relations between intracardiac multi-electrode catheter recordings of four paroxysmal AF patients during sinus rhythm, pacing and AF. In addition, realistic mathematical models of the atria during AF were used to validate the methodology both in the presence and absence of dominant frequency (DF) gradients. During electrical pacing, sources of propagation patterns detected by causality analysis were consistent with the location of the stimulating catheter. During AF, propagation patterns presented temporal variability, but a dominant direction accounted for significantly more propagations than other directions (49±15% vs. 14±13% or less, p<0.01). Both in patients with a DF gradient and in mathematical models, causal maps allowed the identification of sites responsible for maintenance of AF. Causal maps allowed the identification of atrial dominant sites. In particular, causality analysis resulted in stable dominant cause-effect propagation directions during AF and could serve as a guide for performing ablation procedures in AF patients.

An Implantable Pressure Sensor for Long-term Wireless Monitoring of Cardiac Function -First Study in Man

Background: Heart failure is a huge health problem. The possibility of long-term monitoring heart function more accurately in these patients has gained increasing interest. The primary aim of this study was to see if a wireless pressure sensor can be safely implanted to give accurate and reproducible long-term intracardiac pressure recordings. Another aim was to see if there are any adverse effects connected with the implant. A control group was included for comparison of clinical data. Methods: Forty patients with heart failure, 31 scheduled for open heart surgery and 9 for transcatheter aortic valve replacement (TAVR) were included to test the safety and feasibility of the Titan™ pressure sensor. The patients were randomized to the implant or control group. Findings: Initial sensor measurements showed very good correlation with reference pressure values from a fluid-filled catheter, and there was no need for calibration of the sensor. At the 6-month follow-up 11 patients had been wearing the implant for >1 year with a median time of 560 days. Ten of these had adequate sensor function. Compared to the control group there was no difference in adverse clinical events and the overall number of complications was low. Conclusions: This first study in man on a new implantable wireless hemodynamic monitor showed favorable results regarding our primary endpoints; accuracy of recordings over time and safety profile. The technology has great potential for monitoring at home since it is easy to use in the out-patient setting.

Unmasking atrial repolarization to assess alternans, spatiotemporal heterogeneity, and susceptibility to atrial fibrillation

Detection of atrial repolarization waves free of far-field signal contamination by ventricular activation would allow investigation of atrial electrophysiology and factors that influence susceptibility to atrial tachycardia and atrial fibrillation (AF). The purpose of this study was to identify means for high-resolution intracardiac recording of atrial repolarization (Ta) waves using standard clinical electrocatheters and to assess fundamental electrophysiologic properties relevant to AF risk. In alpha-chloralose anesthetized Yorkshire pigs, we studied effects of vagus nerve stimulation (VNS) on PTa and QT intervals and effects of acute atrial ischemia or administration of intrapericardial acetylcholine followed by intravenous epinephrine on susceptibility to AF. Electrocatheters with closely spaced (1-mm) electrode pairs yielded high-resolution tracings of atrial repolarization waves. These recordings permitted detection of differential effects of right or left VNS, which shortened atrial PTa interval by 30% vs. 21% (P <.01) and lengthened QT interval by 1.5% vs. 9%, respectively (P < .05). During atrial ischemia, STa segments were elevated 3.4-fold (P < .01), and the threshold for inducing AF was reduced 3.1-fold (P = .004). Ischemia amplified atrial T-wave alternans (TWAa) and spatiotemporal heterogeneity (TWHa) by 23- and 13-fold, respectively, in inverse correlation to AF threshold (r = 0.74, P <.01; r = 0.61, P = .03). TWAa and TWHa increased by 4.5- and 2-fold shortly before autonomically triggered atrial premature beats and AF. This study used standard electrocatheters to demonstrate that TWAa and TWHa analysis provides means to assess vulnerability to AF without provocative electrical stimuli. These parameters could be evaluated in the clinical electrophysiology laboratory to determine risk for this prevalent arrhythmia and efficacy of contemporary and new agents.

Entropy at the right atrium as a predictor of atrial fibrillation recurrence outcome after pulmonary vein ablation.

Atrial fibrillation (AF) recurrence rates after successful ablation procedures are still high and difficult to predict. This work studies the capability of entropy measured from intracardiac recordings as an indicator for recurrence outcome. Intra-atrial recordings from 31 AF patients were registered previously to an ablation procedure. Four electrodes were located at the right atrium (RA) and four more at the left atrium (LA). Sample entropy measurements were applied to these signals, in order to characterize different non-linear AF dynamics at the RA and LA independently. In a 3 months follow-up, 19 of them remained in sinus rhythm, whereas the other 12 turned back to AF. Entropy values can be associated to a proarrhythmic indicator as they were higher in patients with AF recurrence (1.11±0.15 vs. 0.91±0.13), in persistent patients (1.03±0.19 vs. 0.96±0.15), and at the LA with respect to the RA (1.03±0.23 vs. 0.89±0.15 for paroxysmal AF patients). Furthermore, entropy values at the RA arose as a more reliable predictor for recurrence outcome than at the LA. Results suggest that high entropy values, especially at the RA, are associated with high risk of AF recurrence. These findings show the potential of the proposed method to predict recurrences post-ablation, providing additional insights to the understanding of arrhythmia.

Isolation and characterization of embryonic stem cell-derived cardiac Purkinje cells.

The cardiac Purkinje fiber network is composed of highly specialized cardiomyocytes responsible for the synchronous excitation and contraction of the ventricles. Computational modeling, experimental animal studies, and intracardiac electrical recordings from patients with heritable and acquired forms of heart disease suggest that Purkinje cells (PCs) may also serve as critical triggers of life-threatening arrhythmias. Nonetheless, owing to the difficulty in isolating and studying this rare population of cells, the precise role of PC in arrhythmogenesis and the underlying molecular mechanisms responsible for their proarrhythmic behavior are not fully characterized. Conceptually, a stem cell-based model system might facilitate studies of PC-dependent arrhythmia mechanisms and serve as a platform to test novel therapeutics. Here, we describe the generation of murine embryonic stem cells (ESC) harboring pan-cardiomyocyte and PC-specific reporter genes. We demonstrate that the dual reporter gene strategy may be used to identify and isolate the rare ESC-derived PC (ESC-PC) from a mixed population of cardiogenic cells. ESC-PC display transcriptional signatures and functional properties, including action potentials, intracellular calcium cycling, and chronotropic behavior comparable to endogenous PC. Our results suggest that stem-cell derived PC are a feasible new platform for studies of developmental biology, disease pathogenesis, and screening for novel antiarrhythmic therapies.

Acute hemodynamic effects of single- and dual-site left ventricular pacing employing a dual cathodal coronary sinus lead.

We studied the acute hemodynamic effect of left ventricular (LV) pacing from a dual cathodal coronary sinus (CS) lead in a both single- and dual-site electrode configuration. In 17 patients who underwent implantation of a cardiac resynchronization therapy-defibrillator system with dual cathodal CS leads, LV stimulation was performed from the distal and proximal electrode separately and from both electrodes simultaneously. The acute hemodynamic response was evaluated by invasive measurement of LVdP/dtmax. Timing of LV electrical activation time measured from onset QRS to LV sense during intrinsic rhythm at both electrodes were determined from simultaneous intracardiac recordings. The latter results were compared to those of an additional group of 26 patients in whom no hemodynamic effects were evaluated. Baseline LVdP/dtmax was 897 ± 222 mm Hg/s. Single-site LV pacing resulted in a rise of LVdP/dtmax to 1,053 ± 266 mm Hg/s (+17.4%) taking the best of the two sites and 1,020 ± 254 mm Hg (+13.7%) at the worst site (P = 0.0001). In the dual-site pacing configuration LVdP/dtmax was 1,026 ± 243 mm Hg/s (+14.1%). P value for single best versus dual site was 0.005, and for dual site versus worst single site was 0.18 (n.s.). Even with a relatively small distance of 20-21 mm between stimulation electrodes, there is a significant difference in acute hemodynamic effect from the single best and worst site. Dual-site LV pacing offers no hemodynamic benefit over the best single pacing site. The short electrode distance may have been a limitation and results may not be applicable to other forms of multisite pacing.

Influence of detomidine on atrial fibrillation cycle length measured by intracardiac electrogram recording and by colour tissue Doppler imaging in horses

Shortening of atrial fibrillation cycle length (AFCL) is a marker of atrial electrical remodelling due to atrial fibrillation (AF). To investigate the effect of administration of detomidine on AFCL measured invasively from an intra-atrial electrogram (AFCLEGM) and noninvasively by tissue Doppler imaging (AFCLTDI). We hypothesised that detomidine would have no effect on AFCL but would improve the ease of TDI measurements and facilitate noninvasive AFCL determination. Prospective clinical study. Measurements were performed before and after i.v. administration of 7.5 μg/kg bwt detomidine in 33 episodes of AF in 32 horses (582 ± 64 kg bwt, 10 ± 3 years old) referred for electrical cardioversion. The AFCLEGM was measured from a right atrial intracardiac electrogram. The AFCLTDI was measured from atrial colour tissue velocity curves in 5 atrial wall regions. Mean AFCLEGM and AFCLTDI without and with sedation were compared using a repeated-measures linear mixed model with Bonferroni correction for multiple comparisons and calculation of the Bland-Altman mean bias and limits of agreement between AFCLEGM and AFCLTDI. The mean AFCL was significantly increased after sedation, but this increase was very small (mean difference +4 ms). For AFCLTDI measurements, sedation significantly improved the quality of the atrial myocardial velocity curves and the number of AF cycles that could be measured per cardiac cycle. The Bland-Altman bias between AFCLEGM without sedation and AFCLTDI with sedation ranged from -18 to +15 ms depending on wall region. Bland-Altman limits of agreement were similar between AFCLEGM without sedation and AFCLTDI without and with sedation. Therefore, noninvasive AFCLTDI measurements with sedation can be used to estimate the atrial fibrillatory rate. Sedation facilitates noninvasive AFCL measurements but causes a slight increase in AFCL. Noninvasive AFCL measurements can be used as an indicator of atrial electrical remodelling, to study AF pathophysiology and to investigate the effect of anti-arrhythmic drugs.

Atrial fibrillatory rate in the clinical context: natural course and prediction of intervention outcome.

Shortening of atrial refractory period during atrial fibrillation has been considered a hallmark of atrial electrical remodelling. The atrial fibrillatory cycle length, which is intimately related to the atrial fibrillatory rate (AFR), is generally accepted as a surrogate marker for local refractoriness. The value of using AFR to monitor the progress of atrial ablation therapy has been demonstrated and gradual slowing of AFR has consistently been observed to precede arrhythmia termination during paroxysmal or permanent atrial fibrillation ablation. Today, AFR is the key characteristic of the fibrillatory process, repeatedly validated against intracardiac recordings and extensively studied in clinical contexts. This paper provides an overview of clinical data accumulated since the method was introduced in 1998, and to present the current state of knowledge regarding ECG-derived AFR: its time course and dynamics, clinical factors affecting AFR, and available evidence of its value in the clinical context. We conclude that AFR is a promising, easily available AF characteristic that can be derived from the conventional surface ECG. It is clearly a useful tool for monitoring drug effects. Reference values for predicting intervention effect, however, are likely to be population- and context-specific and related to age, clinical types of atrial fibrillation, as well as to presence and advancement of underlying structural heart disease. Prospective studies in homogeneous patient populations are still needed to establish the clinical value of AFR.

Characteristics of ventricular fibrillation in relation to cardiac aetiology and shock success: A waveform analysis study in ICD-patients

BackgroundVentricular fibrillation (VF) waveform characteristics are associated with cardiac arrest duration and defibrillation success. Recent animal studies found that VF characteristics and shock success also depend on the presence of myocardial infarction (MI). In patients, VF induction after implantable cardioverter defibrillator (ICD) implantation offers a unique setting to study early VF characteristics: we studied the relation with cardiac disease – either presence or absence of a previous MI – and with shock success. MethodsRetrospective cohort study of ICD-patients who underwent defibrillation testing, 117 (63%) with and 69 (37%) without a previous MI. Intracardiac recordings of induced VF were analysed using Fourier analysis. ResultsIn previous MI-patients, the fundamental frequency and organisation index of the VF signal were significantly lower as compared with patients without a previous MI: 4.9Hz±0.6 vs. 5.2Hz±0.6 (p=0.005) and 56%±10 vs. 60%±9 (p=0.001), respectively. The median frequency was not different (p=0.25). We found no association between VF characteristics and ICD shock success. ConclusionsIn analogy with observations in animals, we found that a history of a previous MI was associated with slower and less organised VF. In our cohort of ICD-patients, early VF waveform characteristics were not associated with shock outcomes. Further study is warranted to determine to what extent VF characteristics are influenced by the underlying aetiology on the one hand, and time delay on the other. These findings could improve insight into the potential value of VF analysis to guide shock delivery.

Abstract 305: Pressure Overload-Induced Myocardial Hypertrophy Causes an Electrical Remodeling of CLC-3 Chloride Channels in Mouse Heart

Backgrand: Myocardial hypertrophy causes an increase in myocyte volume and constitutive activation of a volume-sensitive outwardly-rectifying anion channel (VSORAC). The underlying molecular mechanisms and function of VSORAC in the electrical remodeling during myocardial hypertrophy and heart failure remain undefined. We tested whether cardiac CLC-3 chloride channels play a role in the hypertrophy-induced electrophysiological remodeling. Methods and Results: The age-matched CLC-3 knockout (Clcn3-/-) mice and their wild-type (Clcn3+/+) littermates were subjected to minimally-invasive transverse aortic banding (MTAB). In 77% (44/57) left ventricular (LV) myocytes isolated from MTAB-Clcn3+/+ mice a large VSORAC current was activated under isotonic conditions. Hypotonic cell-swelling caused no changes in the VSORAC but hypertonic cell-shrinkage significantly inhibited it. This constitutively-activated VSORAC had an anion selectivity of I-&gt;Cl-&gt;Asp-, and was inhibited by tamoxifen, PKC activation and intracellular application of anti-CLC-3 antibody. In the age-matched MTAB-Clcn3-/- mice, a significantly smaller outwardly-rectifying current was present in only 38% (36/94, P&lt;0.05 vs MTAB-Clcn3+/+) LV myocytes. This current was neither increased by hypotonic stress nor inhibited by tamoxifen, PKC or anti-CLC-3 antibody, indicating not a VSORAC or CLC-3 current. Expression of CLC-3 protein was significantly increased in the LV tissues of MTAB-Clcn3+/+ mice but not in Sham-Clcn3+/+ and MTAB-Clcn3-/- mice. Both surface and intracardiac electrophysiological recordings revealed more atrial or ventricular arrhythmias in MTAB-Clcn3-/- mice than in MTAB- and Sham-Clcn3+/+ mice. Conclusions: Pressure-overload-induced myocardial hypertrophy causes an upregulation of CLC-3 expression and constitutive activation of CLC-3 may serve as a novel protective mechanism against the electrical remodeling during myocardial hypertrophy and heart failure.

Digital resolution enhancement of intracardiac excitation maps during atrial fibrillation.

Atrial fibrillation (AF) is often successfully treated by catheter ablation. Those cases of AF that do not readily succumb to ablation therapy would benefit from improved methods for mapping the complex spatial patterns of tissue activation that typify recalcitrant AF. To this end, the purpose of our study was to investigate the use of numerical deconvolution to improve the spatial resolution of activation maps provided by 2-D arrays of intra-cardiac recording electrodes. We simulated tissue activation patterns and their corresponding electric potential maps using a computational model of cardiac electrophysiology, and sampled the maps over a grid of locations to generate a mapping data set. Following cubic spline interpolation, followed by edge-extension and windowing, we deconvolved the data and compared the results to the model current density fields. We performed a similar analysis on voltage-sensitive dye maps obtained in isolated sheep hearts. For both the synthetic data and the voltage-sensitive dye maps, we found that deconvolution led to visually improved map resolution for arrays of 10×10 up to 30×30 electrodes placed within a few mm of the atrial surface when the activation patterns included 3-4 features that spanned the recording area. Root mean square error was also reduced by deconvolution. Deconvolution of arrays of intracardiac potentials, preceded by appropriate interpolation and edge processing, leads to potentially useful improvements in map resolution that may allow more effective assessment of the spatiotemporal dynamics of tissue excitation during AF.

Antazoline for rapid termination of atrial fibrillation during ablation of accessory pathways

To assess safety and efficacy of antazoline for termination of atrial fibrillation (AF) occurring during ablation of accessory pathways (AP). We analyzed electrophysiological mechanism of antazoline (changes in A-A interval) and the percentage of pre-excited QRS complexes before and after antazoline administration. The total dose administered and the time from the start of injection to sinus rhythm restoration were also measured. Out of consecutive 290 patients with Wolff-Parkinson-White syndrome undergoing radiofrequency (RF) ablation, 12 (4.1%) (4 females, mean age 36 ± 20 years) developed sustained AF which did not stop spontaneously within 10 min, and antazoline in 100 mg repeated boluses was administered. In all 12 patients the drug restored sinus rhythm after a mean of 425 ± 365 s (range 43-1245 s) using a mean cumulative dose of 176 ± 114 mg (range 25-400 mg). The drug slightly prolonged R-R intervals during AF (from 383 ± 106 to 410 ± 70 ms) and reduced the percentage of fully pre-excited QRS complexes (from 35% to 26%). Intracardiac recordings showed gradual increase in A-A intervals, as well as regularization and decreasing fractionation of atrial activity following drug injection (mean A-A interval of 162 ± 30 ms at baseline vs. 226 ± 26 ms shortly before sinus rhythm restoration, p < 0.001). AP was not completely blocked in any patient which enabled continuation of ablation. Antazoline safely and rapidly converts AF into sinus rhythm during ablation of AP. The drug does not block AP completely, enabling continuation of ablation. The drug converting AF into more organized atrial activity (atrial flutter/tachycardia) before sinus rhythm resumption.

0257: Genetic inactivation of Kir3.4 (GIRK4) channels improves heart rate and abolishes atrial tachyarrhythmias in a mouse model of sick-sinus syndrome

We aimed to test if genetic inactivation of the cardiac IKACh current could improve the phenotype of mice lacking L-type Cav1.3 Ca2+ channels (Cav1.3-/-), a mouse model recapitulating the sino-atrial node dysfunction and supraventricular arrhythmias typical of the “sick sinus” syndrome (SSS) in humans. SSS is an invalidating disease. The only currently available therapy consists in the implantation of an electronic pacemaker. Cav1.3-/- mice present several characteristics of the SSS, including bradycardia associated with atrial fibrillation or flutter, as well as type I and II atrioventricular conduction blocks. IKACh is involved in autonomic regulation of heart rate and in the triggering of atrial fibrillation by the parasympathetic nervous system, but its role in establishing the symptoms of SSS is unknown. We crossed IKACh-deficient mice (Kir3.4-/-), with Cav1.3-/- mice to obtain double knockout (Cav1.3-/-/Kir3.4-/-) animals. Telemetric recordings of heart rate and ECG waveforms of wild-type, Cav1.3-/-, Kir3.4-/- and Cav1.3-/-/ Kir3.4-/- mice were performed. The frequency of occurrence of episodes of atrial arrhythmias was evaluated by intracardiac recordings. Genetic inactivation of IKACh in Cav1.3-/-/Kir3.4-/- mice significantly improved the mean heart rate of Cav1.3-/- mice and completely abolished atrioventricular conduction blocks. Atrial fibrillation and flutter that were typical of Cav1.3-/- mice could not be observed or triggered in Cav1.3-/-/Kir3.4-/- mice. Inactivation of IKACh effectively improved SSS in Cav1.3-/- mice. Our study indicates that SSS patients can benefit of IKACh suppression by gene therapy or selective pharmacologic inhibitors.