Combining endocardial mapping and electrocardiographic imaging (ECGI) for improving PVC localization: A feasibility study.

INTRODUCTION: Accurate reconstruction of cardiac activation wavefronts is crucial for clinical diagnosis, management, and treatment of cardiac arrhythmias. Furthermore, reconstruction of activation profiles within the intramural myocardium has long been impossible because electrical mapping was only performed on the endocardial surface. Recent advancements in electrocardiographic imaging (ECGI) have made endocardial and epicardial activation mapping possible. We propose a novel approach to use both endocardial and epicardial mapping in a combined approach to reconstruct intramural activation times. OBJECTIVE: To implement and validate a combined epicardial/endocardial intramural activation time reconstruction technique. METHODS: We used 11 simulations of ventricular activation paced from sites throughout myocardial wall and extracted endocardial and epicardial activation maps at approximate clinical resolution. From these maps, we interpolated the activation times through the myocardium using thin-plate-spline radial basis functions. We evaluated activation time reconstruction accuracy using root-mean-squared error (RMSE) of activation times and the percent of nodes within 1 ms of the ground truth. RESULTS: Reconstructed intramural activation times showed an RMSE and percentage of nodes within 1 ms of the ground truth simulations of 3 ms and 70%, respectively. In the worst case, the RMSE and percentage of nodes were 4 ms and 60%, respectively. CONCLUSION: We showed that a simple, yet effective combination of clinical endocardial and epicardial activation maps can accurately reconstruct intramural wavefronts. Furthermore, we showed that this approach provided robust reconstructions across multiple intramural stimulation sites.

Acute noncontrast T1-weighted magnetic resonance imaging predicts chronic radiofrequency ablation lesions.

BACKGROUND: Magnetic resonance imaging (MRI) has been used to visualize radiofrequency (RF) ablation lesions but the relationship between volumes that enhance in acute MRI and the chronic lesion size is unknown. OBJECTIVES: The main goal was to use noncontrast (native) T1-weighted (T1w) MRI and late gadolinium enhancement (LGE)-MRI to visualize lesions acutely and chronically and correlate the acute area of enhancement with chronic lesion size in histology. MATERIALS AND METHODS: In a canine (n = 9) model RF ablation lesions were created in both ventricles. Native T1w MRI and LGE-MRI were acquired acutely after the ablation procedure. After 8 weeks, another set of RF ablations was performed, and the MRI study was repeated. Volume and depth of enhancement in native T1w MRI and LGE-MRI acquired after the initial ablation procedure were correlated with chronic lesion volume and depth in histology. RESULTS: Thirty-three lesions were analyzed. Native T1w MRI visualized the acute lesions but not the chronic lesions. LGE-MRI showed both acute and chronic lesions. Acute native T1w MRI volume (average of 102.1 ± 48.5 mm3 ) and depth (4.9 ± 1.2 mm) correlated well with chronic histological volume (105.9 ± 51.8 mm3 ) and depth (4.8 ± 1.3 mm) with R2 of 0.881 (P < 0.001) and 0.874 (P < 0.001), respectively. Acute LGE-MRI had a significantly higher volume of enhancement of 499.7 ± 214.4 mm3 (P < 0.001) and depth of 7.5 ± 1.8 mm ( P < 0.001) when compared with chronic histological lesion volume and depth. CONCLUSIONS: Native T1w MRI acquired acutely after RF ablation is a good predictor of chronic lesion size. Acute LGE-MRI significantly overestimates the chronic lesion size.

Higher contact force during radiofrequency ablation leads to a much larger increase in edema as compared to chronic lesion size.

INTRODUCTION: Reversible edema is a part of any radiofrequency ablation but its relationship with contact force is unknown. The goal of this study was to characterize through histology and MRI, acute and chronic ablation lesions and reversible edema with contact force. METHODS AND RESULTS: In a canine model (n = 14), chronic ventricular lesions were created with a 3.5-mm tip ThermoCool SmartTouch (Biosense Webster) catheter at 25 W or 40 W for 30 seconds. Repeat ablation was performed after 3 months to create a second set of lesions (acute). Each ablation procedure was followed by in vivo T2-weighted MRI for edema and late-gadolinium enhancement (LGE) MRI for lesion characterization. For chronic lesions, the mean scar volumes at 25 W and 40 W were 77.8 ± 34.5 mm3 (n = 24) and 139.1 ± 69.7 mm3 (n = 12), respectively. The volume of chronic lesions increased (25 W: P < 0.001, 40 W: P < 0.001) with greater contact force. For acute lesions, the mean volumes of the lesion were 286.0 ± 129.8 mm3 (n = 19) and 422.1 ± 113.1 mm3 (n = 16) for 25 W and 40 W, respectively (P < 0.001 compared to chronic scar). On T2-weighted MRI, the acute edema volume was on average 5.6-8.7 times higher than the acute lesion volume and increased with contact force (25 W: P = 0.001, 40 W: P = 0.011). CONCLUSION: With increasing contact force, there is a marginal increase in lesion size but accompanied with a significantly larger edema. The reversible edema that is much larger than the chronic lesion volume may explain some of the chronic procedure failures.

Atrial fibrillation observed on surface ECG can be atrial flutter or atrial tachycardia.

BACKGROUND: Differentiating between atrial fibrillation (AF) and atrial tachycardia (AT) or atrial flutter (AFL) on surface ECG can be challenging. The same problem arises in animal models of AF, in which atrial arrhythmias are induced by pacing or pharmacological intervention with the goal of making mechanistic determinations. Some of these induced arrhythmias can be AFL or AT, even though it might appear as AF on the body-surface ECG based on irregular R-R intervals. We hypothesize that a dominant frequency (DF) analysis of the ECG can differentiate between the two distinct arrhythmias, even when it is not evident by the presence of flutter waves or beat-to-beat regularity when looking at brief recordings. METHODS: Canine model (n = 15, 10 controls and 5 Persistent AF animals with >6 months of AF) was used to test the hypothesis. Atrial arrhythmia was induced by rapid atrial pacing. Five blinded observers evaluated the 3­lead surface ECGs recorded during atrial arrhythmia and classified the rhythm as AFL/AT or AF. The 64-electrode Constellation (Boston Scientific) catheter was used to acquire left (entire group) and right (7 of 10 controls) atrial intracardiac electrograms. For the surface ECG and the intracardiac electrograms, Welch method with a hamming window and 50% overlap was used to calculate DF of two-minute segments. Mean of standard deviations of the DF values were calculated for both ECGs and intracardiac EGMs. Ground truth came from activations maps and DF analysis derived from the intracardiac electrograms recorded in the two chambers. RESULTS: Rapid pacing induced atrial arrhythmias in all the control animals. The ECG in 8 of the 10 control cases was read as AF by at least 80% percent of observers even though the EGMs from the Constellation showed organized activation and consistent DF (STD of DF < 0.001) in all the electrodes confirming the arrhythmia as AFL in 10/10 cases. In the persistent AF group, the DF from the three lead ECGs were significantly different (Mean of STDs = 2.65 ±â€¯0.99) whereas the DF in the control animals with AFL was consistent across all ECG channels (Mean of STDs < 0.001), and the DF in the control animals ECGs was in agreement with the DF of the intracardiac electrograms. CONCLUSION: Surface ECG recordings can mimic AF even when the underlying atrial arrhythmia is AFL in control canine models. DF variation of the signals from multiple surface ECG leads can help differentiate between the AF and AFL.

Real-Time MRI-Guided Cardiac Cryo-Ablation: A Feasibility Study.

INTRODUCTION: MRI-based ablation provides an attractive capability of seeing ablation-related tissue changes in real time. Here we describe a real-time MRI-based cardiac cryo-ablation system. METHODS: Studies were performed in canine model (n = 4) using MR-compatible cryo-ablation devices built for animal use: focal cryo-catheter with 8 mm tip and 28 mm diameter cryo-balloon. The main steps of MRI-guided cardiac cryo-ablation procedure (real-time navigation, confirmation of tip-tissue contact, confirmation of vessel occlusion, real-time monitoring of a freeze zone formation, and intra-procedural assessment of lesions) were validated in a 3 Tesla clinical MRI scanner. RESULTS: The MRI compatible cryo-devices were advanced to the right atrium (RA) and right ventricle (RV) and their position was confirmed by real-time MRI. Specifically, contact between catheter tip and myocardium and occlusion of superior vena cava (SVC) by the balloon was visually validated. Focal cryo-lesions were created in the RV septum. Circumferential ablation of SVC-RA junction with no gaps was achieved using the cryo-balloon. Real-time visualization of freeze zone formation was achieved in all studies when lesions were successfully created. The ablations and presence of collateral damage were confirmed by T1-weighted and late gadolinium enhancement MRI and gross pathological examination. CONCLUSION: This study confirms the feasibility of a MRI-based cryo-ablation system in performing cardiac ablation procedures. The system allows real-time catheter navigation, confirmation of catheter tip-tissue contact, validation of vessel occlusion by cryo-balloon, real-time monitoring of a freeze zone formation, and intra-procedural assessment of ablations including collateral damage.

Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-ß1.

INTRODUCTION: Large animal models of progressive atrial fibrosis would provide an attractive platform to study relationship between structural and electrical remodeling in atrial fibrillation (AF). Here we established a new transgenic goat model of AF with cardiac specific overexpression of TGF-ß1 and investigated the changes in the cardiac structure and function leading to AF. METHODS AND RESULTS: Transgenic goats with cardiac specific overexpression of constitutively active TGF-ß1 were generated by somatic cell nuclear transfer. We examined myocardial tissue, ECGs, echocardiographic data, and AF susceptibility in transgenic and wild-type control goats. Transgenic goats exhibited significant increase in fibrosis and myocyte diameters in the atria compared to controls, but not in the ventricles. P-wave duration was significantly greater in transgenic animals starting at 12 months of age, but no significant chamber enlargement was detected, suggesting conduction slowing in the atria. Furthermore, this transgenic goat model exhibited a significant increase in AF vulnerability. Six of 8 transgenic goats (75%) were susceptible to AF induction and exhibited sustained AF (>2 minutes), whereas none of 6 controls displayed sustained AF (P < 0.01). Length of induced AF episodes was also significantly greater in the transgenic group compared to controls (687 ± 212.02 seconds vs. 2.50 ± 0.88 seconds, P < 0.0001), but no persistent or permanent AF was observed. CONCLUSION: A novel transgenic goat model with a substrate for AF was generated. In this model, cardiac overexpression of TGF-ß1 led to an increase in fibrosis and myocyte size in the atria, and to progressive P-wave prolongation. We suggest that these factors underlie increased AF susceptibility.

Diverse Fibrosis Architecture and Premature Stimulation Facilitate Initiation of Reentrant Activity Following Chronic Atrial Fibrillation.

INTRODUCTION: Patients with paroxysmal atrial fibrillation (AF) often transition between sinus rhythm and AF. For AF to initiate there must be both a trigger and a substrate that facilitates reentrant activity. This trigger is often caused by a premature atrial contraction or focal activations within the atrium. We hypothesize that specific architectures of fibrosis alter local conduction to enable AF. METHODS AND RESULTS: Control goats (n = 13) and goats in chronic AF (for an average of 6 months, n = 6) had a high-density electrode plaque placed on the LA appendage. Conduction patterns following a premature atrial contraction, caused by an electrical stimulation, were quantified to determine regions of conduction slowing. These regions were compared to architecture, either diffuse fibrosis or regions of obstructive fibrosis, and overall fibrosis levels as determined by histology from the mapped region. The chronic AF goats had more obstructive fibrosis than the controls (17.5 ± 8.0 fibers/mm(2) vs. 8.6 ± 3.0 fibers/mm(2)). Conduction velocity of the AF goats was significantly slowed compared to the control goats in the transverse direction (0.40 ± 0.04 m/s vs. 0.53 ± 0.15 m/s) but not in the longitudinal direction (0.70 ± 0.27 m/s vs. 0.76 ± 0.18 m/s). CONCLUSIONS: AF-induced atrial remodeling leads to increased obstructive fibrosis and conduction velocity slowing transverse to fiber orientation following premature stimuli. The decrease in conduction velocity causes a decrease in the cardiac wavelength, and increases the likelihood of reentry and AF onset.

Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs.

Structural remodeling in chronic atrial fibrillation (AF) occurs over weeks to months. To study the electrophysiological, structural, and functional changes that occur in chronic AF, the selection of the best animal model is critical. AF was induced by rapid atrial pacing (50-Hz stimulation every other second) in pigs (n = 4), dogs (n = 8), and goats (n = 9). Animals underwent MRIs at baseline and 6 mo to evaluate left ventricular (LV) ejection fraction (EF). Dogs were given metoprolol (50-100 mg po bid) and digoxin (0.0625-0.125 mg po bid) to limit the ventricular response rate to <180 beats/min and to mitigate the effects of heart failure. The pacing leads in pigs became entirely encapsulated and lost the ability to excite the heart, often before the onset of sustained AF. LV EF in dogs dropped from 54 ± 11% at baseline to 33 ± 7% at 6 mo (P < 0.05), whereas LV EF in goats did not drop significantly (69 ± 8% at baseline vs. 60 ± 9% at 6 mo, P = not significant). After 6 mo of AF, fibrosis levels in dog atria and ventricles increased, whereas only atrial fibrosis levels increased in goats compared with control animals. In our experience, the pig model is not appropriate for chronic rapid atrial pacing-induced AF studies. Rate-controlled chronic AF in the dog model developed HF and LV fibrosis, whereas the goat model developed only atrial fibrosis without ventricular dysfunction and fibrosis. Both the dog and goat models are representative of segments of the patient population with chronic AF.

Correlation between conduction velocity and frequency analysis in patients with atrial fibrillation using high-density charge mapping.

Spectral analysis of atrial signals has been used to identify regions of interest in atrial fibrillation (AF). However, the relationship to the atrial substrate is unclear. In this study, we compare regions with dominant frequency (DF), simultaneously determined in the left atrium (LA) by a novel noncontact mapping system using unipolar charge density signals, to the zones of slow conduction (SZ) during AF.In 19 AF patients the conduction during AF was assessed by a validated algorithm and SZ compared to the DF and the DF ratio between the DF peak and the area under the total spectrum (DFR). The results were compared in five different regions of the LA. The reproducibility of SZ location at different time measurements was higher than for DF or DFR. The SZs are mainly confined at the anterior and posterior wall of the LA. There was no statistically significant correlation between SZ and DF or DFR across the atrium.

Noncontact whole-chamber charge density mapping of the left ventricle: Preclinical evaluation in a sheep model.

BACKGROUND: Conventional contact-based electroanatomic mapping is poorly suited for rapid or dynamic ventricular arrhythmias. Whole-chamber charge density (CD) mapping could efficiently characterize complex ventricular tachyarrhythmias and yield insights into their underlying mechanisms. OBJECTIVE: The purpose of this study was to evaluate the feasibility and accuracy of noncontact whole-chamber left ventricular (LV) CD mapping and to characterize CD activation patterns during sinus rhythm, ventricular pacing, and ventricular fibrillation (VF). METHODS: Ischemic scar as defined by CD amplitude thresholds was compared to late gadolinium enhancement criteria on magnetic resonance imaging using an iterative closest point algorithm. Electrograms recorded at sites of tissue contact were compared to the nearest noncontact CD-derived electrograms to calculate signal morphology cross-correlations and time differences. Regions of consistently slow conduction were examined relative to areas of scar and to localized irregular activation (LIA) during VF. RESULTS: Areas under receiver operating characteristic curves (AUCs) of CD-defined dense and total LV scar were 0.92 ± 0.03 and 0.87 ± 0.06, with accuracies of 0.86 ± 0.03 and 0.80 ± 0.05, respectively. Morphology cross-correlation between 8677 contact and corresponding noncontact electrograms was 0.93 ± 0.10, with a mean time difference of 2.5 ± 5.6 ms. Areas of consistently slow conduction tended to occur at scar borders and exhibited spatial agreement with LIA during VF (AUC 0.90 ± 0.02). CONCLUSION: Noncontact LV CD mapping can accurately delineate ischemic scar. CD-derived ventricular electrograms correlate strongly with conventional contact-based electrograms. Regions with consistently slow conduction are often at scar borders and tend to harbor LIA during VF.

Validation of Dipole Density Mapping During Atrial Fibrillation and Sinus Rhythm in Human Left Atrium.

OBJECTIVES: This study sought to validate the accuracy of noncontact electrograms against contact electrograms in the left atrium during sinus rhythm (SR) and atrial fibrillation (AF). BACKGROUND: Noncontact mapping offers the opportunity to assess global cardiac activation in the chamber of interest. A novel noncontact mapping system, which records intracardiac voltage to derive cellular charge sources (dipole density), allows real-time mapping of AF to guide ablation. METHODS: Noncontact and contact unipolar electrogram pairs were recorded simultaneously from multiple locations. Morphology correlation and timing difference of reconstructed electrograms obtained from a noncontact catheter were compared with those from contact electrograms obtained from a contact catheter at the same endocardial locations. RESULTS: A total of 796 electrogram pairs in SR and 969 electrogram pairs in AF were compared from 20 patients with persistent AF. The median morphology correlation and timing difference (ms) in SR was 0.85 (interquartile range [IQR]: 0.71 to 0.94) and 6.4 ms (IQR: 2.6 to 17.1 ms); in AF was 0.79 (IQR: 0.69 to 0.88) and 14.4 ms (IQR: 6.7 to 26.2 ms), respectively. The correlation was stronger and the timing difference was less when the radial distance (r) from the noncontact catheter center to the endocardium was ≤ 40 versus > 40 mm; 0.87 (IQR: 0.72 to 0.94) versus 0.73 (IQR: 0.56 to 0.88) and 5.7 ms (IQR: 2.6 to 15.4 ms) versus 15.1 ms (IQR: 4.1 to 27.7 ms); p < 0.01 when in SR; 0.81 (IQR: 0.69 to 0.89) versus 0.67 (IQR: 0.45 to 0.82) and 12.3 ms (IQR: 5.9 to 21.8 ms) versus 28.3 ms (IQR: 16.2 to 36.0 ms); p < 0.01 when in AF. CONCLUSIONS: This novel noncontact dipole density mapping system provides comparable reconstructed atrial electrogram measurements in SR or AF in human left atrium when the anatomical site of interest is ≤40 mm from the mapping catheter.

Regions of High Dominant Frequency in Chronic Atrial Fibrillation Anchored to Areas of Atrial Fibrosis.

Regions within the atria with sustained rapid reentrant or focal activity have been defined as a mechanism of persistent atrial fibrillation (AF). However, the mechanism behind the anchoring of these sites and their stability over time is unknown. We tested the hypothesis that fibrosis anchors sites of high frequency activation during AF and that these sites can be non-invasively determined using cardiac T1 Mapping with MRI. A canine rapid atrial paced model of persistent AF was used (n=12, including 6 controls) for the study. Whole heart T1 Mapping was performed prior to an electrical mapping study. Spatial maps of high dominant frequency (DF) probability were constructed to determine stability of the highest DF sites. These sites were then correlated with fibrotic regions determined by T1 Mapping. The chronic AF animals had at least one site of stable, high DF for at least 22.5 (75%) of 30 minutes of AF. Regions of stable high DF bordered regions of fibrosis as determined by T1 Mapping MRI 82% of the time (p<0.05). Heterogeneous atrial remodeling, specifically fibrosis, arising from chronic AF may provide a substrate that anchors sites of high DF. Cardiac T1 Mapping with MRI may determine such sites non-invasively.

Characterization of Gadolinium Contrast Enhancement of Radiofrequency Ablation Lesions in Predicting Edema and Chronic Lesion Size.

BACKGROUND: Magnetic resonance imaging (MRI) has been used to acutely visualize radiofrequency ablation lesions, but its accuracy in predicting chronic lesion size is unknown. The main goal of this study was to characterize different areas of enhancement in late gadolinium enhancement MRI done immediately after ablation to predict acute edema and chronic lesion size. METHODS AND RESULTS: In a canine model (n=10), ventricular radiofrequency lesions were created using ThermoCool SmartTouch (Biosense Webster) catheter. All animals underwent MRI (late gadolinium enhancement and T2-weighted edema imaging) immediately after ablation and after 1, 2, 4, and 8 weeks. Edema, microvascular obstruction, and enhanced volumes were identified in MRI and normalized to chronic histological volume. Immediately after contrast administration, the microvascular obstruction region was 3.2±1.1 times larger than the chronic lesion volume in acute MRI. Even 60 minutes after contrast administration, edema was 8.7±3.31 times and the enhanced area 6.14±2.74 times the chronic lesion volume. Exponential fit to the microvascular obstruction volume was found to be the best predictor of chronic lesion volume at 26.14 minutes (95% prediction interval, 24.35-28.11 minutes) after contrast injection. The edema volume in late gadolinium enhancement correlated well with edema volume in T2-weighted MRI with an R2 of 0.99. CONCLUSION: Microvascular obstruction region on acute late gadolinium enhancement images acquired 26.1 minutes after contrast administration can accurately predict the chronic lesion volume. We also show that T1-weighted MRI images acquired immediately after contrast injection accurately shows edema resulting from radiofrequency ablation.

His bundle activates faster than ventricular myocardium during prolonged ventricular fibrillation.

BACKGROUND: The Purkinje fiber system has recently been implicated as an important driver of the rapid activation rate during long duration ventricular fibrillation (VF>2 minutes). The goal of this study is to determine whether this activity propagates to or occurs in the proximal specialized conduction system during VF as well. METHODS AND RESULTS: An 8×8 array with 300 µm spaced electrodes was placed over the His bundles of isolated, perfused rabbit hearts (n = 12). Ventricular myocardial (VM) and His activations were differentiated by calculating Laplacian recordings from unipolar signals. Activation rates of the VM and His bundle were compared and the His bundle conduction velocity was measured during perfused VF followed by 8 minutes of unperfused VF. During perfused VF the average VM activation rate of 11.04 activations/sec was significantly higher than the His bundle activation rate of 6.88 activations/sec (p<0.05). However from 3-8 minutes of unperfused VF the His system activation rate (6.16, 5.53, 5.14, 5.22, 6.00, and 4.62 activations/sec significantly faster than the rate of the VM (4.67, 3.63, 2.94, 2.24, 3.45, and 2.31 activations/sec) (p<0.05). The conduction velocity of the His system immediately decreased to 94% of the sinus rate during perfused VF then gradually decreased to 67% of sinus rhythm conduction at 8 minutes of unperfused VF. CONCLUSION: During prolonged VF the activation rate of the His bundle is faster than that of the VM. This suggests that the proximal conduction system, like the distal Purkinje system, may be an important driver during long duration VF and may be a target for interventional therapy.