Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re-entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF. A novel biophysical model of the canine atria was used that integrates stochastic, spontaneous subcellular Ca2+ release events (SCRE) with regional electrophysiological heterogeneity in ionic properties and a detailed three-dimensional model of atrial anatomy, microarchitecture and patchy fibrosis. Simulations highlighted the importance of the smaller inward rectifier potassium current (IK1 ) in PV cells compared to the surrounding atria, which enabled SCRE more readily to result in delayed-afterdepolarisations that induced triggered activity. There was a leftward shift in the dependence of the probability of triggered activity on sarcoplasmic reticulum Ca2+ load. This feature was accentuated in 3D tissue compared to single cells (Δ half-maximal [Ca2+ ]SR  = 58 µM vs. 22 µM). In 3D atria incorporating electrical heterogeneity, excitations preferentially emerged from the PV region. These triggered focal excitations resulted in transient re-entry in the left atrium. Addition of fibrotic patches promoted localised emergence of focal excitations and wavebreaks that had a more substantial impact on generating AF-like patterns than the PVs. Thus, a reduced IK1 , less negative resting membrane potential, and fibrosis-induced changes of the electrotonic load all contribute to the emergence of complex excitation patterns from spontaneous focal triggers. KEY POINTS: Focal excitations in the atria are most commonly associated with the pulmonary veins, but the mechanisms for this localisation are yet to be elucidated. We applied a multi-scale computational modelling approach to elucidate the mechanisms underlying such localisations. Myocytes in the pulmonary vein region of the atria have a less negative resting membrane potential and reduced time-independent potassium current; we demonstrate that both of these factors promote triggered activity in single cells and tissues. The less negative resting membrane potential also contributes to heterogeneous inactivation of the fast sodium current, which can enable re-entrant-like excitation patterns to emerge without traditional conduction block.

Shorter distance between the esophagus and the left atrium is associated with higher rates of esophageal thermal injury after radiofrequency ablation.

BACKGROUND: Esophageal thermal injury (ETI) is a known and potentially serious complication of catheter ablation for atrial fibrillation. We intended to evaluate the distance between the esophagus and the left atrium posterior wall (LAPW) and its association with esophageal thermal injury. METHODS: A retrospective analysis of 73 patients who underwent esophagogastroduodenoscopy (EGD) after LA radiofrequency catheter ablation for symptomatic atrial fibrillation and pre-ablation magnetic resonance imaging (MRI) was used to identify the minimum distance between the inner lumen of the esophagus and the ablated atrial endocardium (pre-ablation atrial esophageal distance; pre-AED) and occurrence of ETI. Parameters of ablation index (AI, Visitag Surpoint) were collected in 30 patients from the CARTO3 system and compared with assess if ablation strategies and AI further impacted risk of ETI. RESULTS: Pre-AED was significantly larger in patients without ETI than those with ETI (5.23 ± 0.96 mm vs. 4.31 ± 0.75 mm, p < .001). Pre-AED showed high accuracy for predicting ETI with the best cutoff value of 4.37 mm. AI was statistically comparable between Visitag lesion markers with and without associated esophageal late gadolinium enhancement (LGE) detected by postablation MRI in the low-power long-duration ablation group (LPLD, 25-40 W for 10-30 s, 393.16 [308.62-408.86] vs. 406.58 [364.38-451.22], p = .16) and high-power short-duration group (HPSD, 50 W for 5-10 s, 336.14 [299.66-380.11] vs. 330.54 [286.21-384.71], p = .53), respectively. CONCLUSION: Measuring the distance between the LA and the esophagus in pre-ablation LGE-MRI could be helpful in predicting ETI after LAPW ablation.

Short-term natural course of esophageal thermal injury after ablation for atrial fibrillation.

INTRODUCTION: Esophageal injury is rare but potentially a devastating complication of atrial fibrillation (AF) ablation. The goal here was to provide insight into the short-term natural history of esophageal thermal injury (ETI) after radiofrequency catheter ablation (RFCA) for AFby esophagogastroduodenoscopy (EGD). METHODS: We screened patients who underwent RFCA for AF and EGD based on esophageal late gadolinium enhancement (LGE) in postablation magnetic resonance imaging. Patients with ETI diagnosed with EGD were included. We defined severity of ETI according to Kansas City classification: type 1: erythema; type 2: ulcers (2a: superficial; 2b deep); type 3 perforation (3a: perforation; 3b: perforation with atrioesophageal fistula [AEF]). Repeated EGD was performed within 1-14 days after the last EGD if recommended and possible until any certain healing signs (visible reduction in size without deepening of ETI or complete resolution) were observed. RESULTS: ETI was observed in 62 of 378 patients who underwent EGD after RFCA. Out of these 62 patients with ETI, 21% (13) were type 1, 50% (31) were type 2a and 29% (18) were type 2b at the initial EGD. All esophageal lesions, but one type 2b lesion that developed into an AEF, showed signs of healing in repeated EGD studies within 14 days after the procedure. The one type 2b lesion developing into an AEF showed an increase in size and ulcer deepening in repeat EGD 8 days after the procedure. CONCLUSION: We found that all ETI which did not progress to AEF presented healing signs within 14 days after the procedure and that worsening ETI might be an early signal for developing esophageal perforation.

Transient recovery of epicardial and torso ST-segment ischemic signals during cardiac stress tests: A possible physiological mechanism.

BACKGROUND: Acute myocardial ischemia has several characteristic ECG findings, including clinically detectable ST-segment deviations. However, the sensitivity and specificity of diagnosis based on ST-segment changes are low. Furthermore, ST-segment deviations have been shown to be transient and spontaneously recover without any indication the ischemic event has subsided. OBJECTIVE: Assess the transient recovery of ST-segment deviations on remote recording electrodes during a partial occlusion cardiac stress test and compare them to intramyocardial ST-segment deviations. METHODS: We used a previously validated porcine experimental model of acute myocardial ischemia with controllable ischemic load and simultaneous electrical measurements within the heart wall, on the epicardial surface, and on the torso surface. Simulated cardiac stress tests were induced by occluding a coronary artery while simultaneously pacing rapidly or infusing dobutamine to stimulate cardiac function. Postexperimental imaging created anatomical models for data visualization and quantification. Markers of ischemia were identified as deviations in the potentials measured at 40% of the ST-segment. Intramural cardiac conduction speed was also determined using the inverse gradient method. We assessed changes in intramyocardial ischemic volume proportion, conduction speed, clinical presence of ischemia on remote recording arrays, and regional changes to intramyocardial ischemia. We defined the peak deviation response time as the time interval after onset of ischemia at which maximum ST-segment deviation was achieved, and ST-recovery time was the interval when ST deviation returned to below thresholded of ST elevation. RESULTS: In both epicardial and torso recordings, the peak ST-segment deviation response time was 4.9±1.1 min and the ST-recovery time was approximately 7.9±2.5 min, both well before the termination of the ischemic stress. At peak response time, conduction speed was reduced by 50% and returned to near baseline at ST-recovery. The overall ischemic volume proportion initially increased, on average, to 37% at peak response time; however, it recovered to only 30% at the ST-recovery time. By contrast, the subepicardial region of the myocardial wall showed 40% ischemic volume at peak response time and recovered much more strongly to 25% as epicardial ST-segment deviations returned to baseline. CONCLUSION: Our data show that remote ischemic signal recovery correlates with a recovery of the subepicardial myocardium, whereas subendocardial ischemic development persists.

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.

Pharmacological and simulated exercise cardiac stress tests produce different ischemic signatures in high-resolution experimental mapping studies.

OBJECTIVE: Test the hypothesis that exercise and pharmacological cardiac stressors create different electrical ischemic signatures. INTRODUCTION: Current clinical stress tests for detecting ischemia lack sensitivity and specificity. One unexplored source of the poor detection is whether pharmacological stimulation and regulated exercise produce identical cardiac stress. METHODS: We used a porcine model of acute myocardial ischemia in which animals were instrumented with transmural plunge-needle electrodes, an epicardial sock array, and torso arrays to simultaneously measure cardiac electrical signals within the heart wall, the epicardial surface, and the torso surface, respectively. Ischemic stress via simulated exercise and pharmacological stimulation were created with rapid electrical pacing and dobutamine infusion, respectively, and mimicked clinical stress tests of five 3-minute stages. Perfusion to the myocardium was regulated by a hydraulic occluder around the left anterior descending coronary artery. Ischemia was measured as deflections to the ST-segment on ECGs and electrograms. RESULTS: Across eight experiments with 30 (14 simulated exercise and 16 dobutamine) ischemic interventions, the spatial correlations between exercise and pharmacological stress diverged at stage three or four during interventions (p<0.05). We found more detectable ST-segment changes on the epicardial surface during simulated exercise than with dobutamine (p<0.05). The intramyocardial ischemia formed during simulated exercise had larger ST40 potential gradient magnitudes (p<0.05). CONCLUSION: We found significant differences on the epicardium between cardiac stress types using our experimental model, which became more pronounced at the end stages of each test. A possible mechanism for these differences was the larger ST40 potential gradient magnitudes within the myocardium during exercise. The presence of microvascular dysfunction during exercise and its absence during dobutamine stress may explain these differences.

Quantifying the spatiotemporal influence of acute myocardial ischemia on volumetric conduction velocity.

INTRODUCTION: Acute myocardial ischemia occurs when coronary perfusion to the heart is inadequate, which can perturb the highly organized electrical activation of the heart and can result in adverse cardiac events including sudden cardiac death. Ischemia is known to influence the ST and repolarization phases of the ECG, but it also has a marked effect on propagation (QRS); however, studies investigating propagation during ischemia have been limited. METHODS: We estimated conduction velocity (CV) and ischemic stress prior to and throughout 20 episodes of experimentally induced ischemia in order to quantify the progression and correlation of volumetric conduction changes during ischemia. To estimate volumetric CV, we 1) reconstructed the activation wavefront; 2) calculated the elementwise gradient to approximate propagation direction; and 3) estimated conduction speed (CS) with an inverse-gradient technique. RESULTS: We found that acute ischemia induces significant conduction slowing, reducing the global median speed by 20 cm/s. We observed a biphasic response in CS (acceleration then deceleration) early in some ischemic episodes. Furthermore, we noted a high temporal correlation between ST-segment changes and CS slowing; however, when comparing these changes over space, we found only moderate correlation (corr. = 0.60). DISCUSSION: This study is the first to report volumetric CS changes (acceleration and slowing) during episodes of acute ischemia in the whole heart. We showed that while CS changes progress in a similar time course to ischemic stress (measured by ST-segment shifts), the spatial overlap is complex and variable, showing extreme conduction slowing both in and around regions experiencing severe ischemia.

Reproducibility of clinical late gadolinium enhancement magnetic resonance imaging in detecting left atrial scar after atrial fibrillation ablation.

INTRODUCTION: Late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (MRI) can be used to detect postablation atrial scar (PAAS) but its reproducibility and reliability in clinical scans across different magnetic flux densities and scar detection methods are unknown. METHODS: Patients (n = 45) having undergone two consecutive MRIs (3 months apart) on 3T and 1.5T scanners were studied. We compared PAAS detection reproducibility using four methods of thresholding: simple thresholding, Otsu thresholding, 3.3 standard deviations (SD) above blood pool (BP) mean intensity, and image intensity ratio (IIR). We performed a texture study by dividing the left atrial wall intensity histogram into deciles and evaluated the correlation of the same decile of the two scans as well as to a randomized distribution of intensities, quantified using Dice Similarity Coefficient (DSC). RESULTS: The choice of scanner did not significantly affect the reproducibility. The scar detection performed by Otsu thresholding (DSC of 71.26 ± 8.34) resulted in a better correlation of the two scans compared with the methods of 3.3 SD above BP mean intensity (DSC of 57.78 ± 21.2, p < .001) and IIR above 1.61 (DSC of 45.76 ± 29.55, p <.001). Texture analysis showed that correlation only for voxels with intensities in deciles above the 70th percentile of wall intensity histogram was better than random distribution (p < .001). CONCLUSIONS: Our results demonstrate that clinical LGE-MRI can be reliably used for visualizing PAAS across different magnetic flux densities if the threshold is greater than 70th percentile of the wall intensity distribution. Also, atrial wall-based thresholding is better than BP-based thresholding for reproducible PAAS detection.

Blanking period after radiofrequency ablation for atrial fibrillation guided by ablation lesion maturation based on serial MR imaging.

BACKGROUND: Recent guidelines recommend a 3-month blanking period after atrial fibrillation (AF) ablations, which are based on clinical observation. Our goal was to quantify the timeline of the radiofrequency ablation lesion maturation using serial late gadolinium enhancement-magnetic resonance imaging (LGE-MRI) and to develop a blanking period estimate based on visible lesion maturation. METHODS: Inclusion criteria targeted patients who underwent AF ablation and at least four MRI scans: at baseline before ablation, within 24 hours after (acute), between 24 hours and 90 days after (subacute), and more than 90 days after ablation (chronic). Central nonenhanced (NE) and surrounding hyperenhanced (HE) area volumes were measured and normalized to chronic lesion volume. RESULTS: This study assessed 75 patients with 309 MRIs. The acute lesion was heterogeneous with a HE region surrounding a central NE region in LGE-MRI; the acute volume of the total (HE + NE) lesion was 2.62 ± 0.46 times larger than that of the chronic lesion. Acute T2-weighted imaging also showed a relatively large area of edema. Both NE and HE areas gradually receded over time and NE was not observed after 30 days. Larger initial NE volume was associated with a significantly greater chronic scar volume and this total lesion volume receded to equal the chronic lesion size at approximately 72.5 days (95% prediction interval: 57.4-92.2). CONCLUSION: On the basis of serial MRI, atrial ablation lesions are often fully mature before the typical 90-day blanking period, which could support more timely clinical decision making for arrhythmia recurrence.

Real-time magnetic resonance imaging-guided cryoablation of the pulmonary veins with acute freeze-zone and chronic lesion assessment.

AIMS: The goals of this study were to develop a method that combines cryoablation with real-time magnetic resonance imaging (MRI) guidance for pulmonary vein isolation (PVI) and to further quantify the lesion formation by imaging both acute and chronic cryolesions. METHODS AND RESULTS: Investigational MRI-compatible cryoablation devices were created by modifying cryoballoons and cryocatheters. These devices were used in canines (n = 8) and a complete series of lesions (PVI: n = 5, superior vena cava: n = 4, focal: n = 13) were made under real-time MRI guidance. Late gadolinium enhancement (LGE) magnetic resonance imaging was acquired at acute and chronic time points. Late gadolinium enhancement magnetic resonance imagings show a significant amount of acute tissue injury immediately following cryoablation which subsides over time. In the pulmonary veins, scar covered 100% of the perimeter of the ostium of the veins acutely, which subsided to 95.6 ± 4.3% after 3 months. Focal point lesions showed significantly larger acute enhancement volumes compared to the volumes estimated from gross pathology measurements (0.4392 ± 0.28 cm3 vs. 0.1657 ± 0.08 cm3, P = 0.0043). Additionally, our results with focal point ablations indicate that freeze-zone formation reached a maximum area after 120 s. CONCLUSION: This study reports on the development of an MRI-based cryoablation system and shows that with acute cryolesions there is a large area of reversible injury. Real-time MRI provides the ability to visualize the freeze-zone formation during the freeze cycle and for focal lesions reaches a maximum after 120 s suggesting that for maximizing lesion size 120 s might be the lower limit for dosing duration.

Computationally optimized ECoG stimulation with local safety constraints.

Direct stimulation of the cortical surface is used clinically for cortical mapping and modulation of local activity. Future applications of cortical modulation and brain-computer interfaces may also use cortical stimulation methods. One common method to deliver current is through electrocorticography (ECoG) stimulation in which a dense array of electrodes are placed subdurally or epidurally to stimulate the cortex. However, proximity to cortical tissue limits the amount of current that can be delivered safely. It may be desirable to deliver higher current to a specific local region of interest (ROI) while limiting current to other local areas more stringently than is guaranteed by global safety limits. Two commonly used global safety constraints bound the total injected current and individual electrode currents. However, these two sets of constraints may not be sufficient to prevent high current density locally (hot-spots). In this work, we propose an efficient approach that prevents current density hot-spots in the entire brain while optimizing ECoG stimulus patterns for targeted stimulation. Specifically, we maximize the current along a particular desired directional field in the ROI while respecting three safety constraints: one on the total injected current, one on individual electrode currents, and the third on the local current density magnitude in the brain. This third set of constraints creates a computational barrier due to the huge number of constraints needed to bound the current density at every point in the entire brain. We overcome this barrier by adopting an efficient two-step approach. In the first step, the proposed method identifies the safe brain region, which cannot contain any hot-spots solely based on the global bounds on total injected current and individual electrode currents. In the second step, the proposed algorithm iteratively adjusts the stimulus pattern to arrive at a solution that exhibits no hot-spots in the remaining brain. We report on simulations on a realistic finite element (FE) head model with five anatomical ROIs and two desired directional fields. We also report on the effect of ROI depth and desired directional field on the focality of the stimulation. Finally, we provide an analysis of optimization runtime as a function of different safety and modeling parameters. Our results suggest that optimized stimulus patterns tend to differ from those used in clinical practice.

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.

Temporal Performance of Laplacian Eigenmaps and 3D Conduction Velocity in Detecting Ischemic Stress.

BACKGROUND: Myocardial ischemia has a complex and time-varying electrocardiographic signature that is used to diagnose and stratify severity. Despite the ubiquitous clinical use of the ECG to detect ischemia, the sensitivity and specificity of ECG based detection of myocardial ischemia are still inadequate. PURPOSE: The purpose of this study was to compare, using animal models, the performance of several traditional ECG-based metrics for detecting acute ischemia against two novel metrics, the Laplacian Eigenmap (LE) parameters and a three-dimensional estimate of Conduction Velocity (CV). METHODS: LE is a machine learning technique that reduces the dimensions of simultaneously recorded time signals using a non-linear embedding followed by an singular value decomposition to represent each multichannel recording as a single trajectory on a manifold. Perturbations in the trajectories suggest the presence of myocardial ischemia. CV was computed using a tetrahedral mesh created from the electrode locations of transmural plunge needles. To validate the results, we used electrograms collected over 95 episodes of acutely induced myocardial ischemia in 15 canine and 2 porcine subjects. The LE and CV metrics were compared against traditional metrics derived from the ST segment, the T wave, the QRS of the same electrograms. The response time and robustness of each metric was quantified using parameters we defined as time to threshold (TTT) and contrast ratio (CR). RESULTS: The temporal performance of the metrics evaluated throughout the ischemic episodes showed a consistent relationship; the LE metrics changed earlier than those from the T wave, which were followed by those from the ST segment, and finally from the QRS. The CV results showed median drops in conduction velocity throughout the perfusion bed of more than 23% in canines and over 12% during half of the induced ischemia episodes in swine. The other half of the episodes in swine produced a 76% drop. CONCLUSIONS: Our results suggest that the LE metric is more sensitive to acute ischemia than traditional single parameters used in previous studies, likely because it incorporates the entire QRST across multiple electrodes in a way that captures their most salient features in a low-dimensional space. The estimates of conduction velocity suggest substantial, in some cases dramatic slowing of the spread of activation, a finding that is not surprising but has not been documented in such three-dimensional detail before. The experiments and these new metrics provide a means to both explore details of the acute ischemic response not available from humans and suggest a path to translate this knowledge into improvements in clinical scoring of ischemia.

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.

Spatial organization of acute myocardial ischemia.

INTRODUCTION: Myocardial ischemia is a pathological condition initiated by supply and demand imbalance of the blood to the heart. Previous studies suggest that ischemia originates in the subendocardium, i.e., that nontransmural ischemia is limited to the subendocardium. By contrast, we hypothesized that acute myocardial ischemia is not limited to the subendocardium and sought to document its spatial distribution in an animal preparation. The goal of these experiments was to investigate the spatial organization of ischemia and its relationship to the resulting shifts in ST segment potentials during short episodes of acute ischemia. METHODS: We conducted acute ischemia studies in open-chest canines (N=19) and swines (N=10), which entailed creating carefully controlled ischemia using demand, supply or complete occlusion ischemia protocols and recording intramyocardial and epicardial potentials. Elevation of the potentials at 40% of the ST segment between the J-point and the peak of the T-wave (ST40%) provided the metric for local ischemia. The threshold for ischemic ST segment elevations was defined as two standard deviations away from the baseline values. RESULTS: The relative frequency of occurrence of acute ischemia was higher in the subendocardium (78% for canines and 94% for swines) and the mid-wall (87% for canines and 97% for swines) in comparison with the subepicardium (30% for canines and 22% for swines). In addition, acute ischemia was seen arising throughout the myocardium (distributed pattern) in 87% of the canine and 94% of the swine episodes. Alternately, acute ischemia was seen originating only in the subendocardium (subendocardial pattern) in 13% of the canine episodes and 6% of the swine episodes (p<0.05). CONCLUSIONS: Our findings suggest that the spatial distribution of acute ischemia is a complex phenomenon arising throughout the myocardial wall and is not limited to the subendocardium.

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.

Experimental Data and Geometric Analysis Repository-EDGAR.

INTRODUCTION: The "Experimental Data and Geometric Analysis Repository", or EDGAR is an Internet-based archive of curated data that are freely distributed to the international research community for the application and validation of electrocardiographic imaging (ECGI) techniques. The EDGAR project is a collaborative effort by the Consortium for ECG Imaging (CEI, ecg-imaging.org), and focused on two specific aims. One aim is to host an online repository that provides access to a wide spectrum of data, and the second aim is to provide a standard information format for the exchange of these diverse datasets. METHODS: The EDGAR system is composed of two interrelated components: 1) a metadata model, which includes a set of descriptive parameters and information, time signals from both the cardiac source and body-surface, and extensive geometric information, including images, geometric models, and measure locations used during the data acquisition/generation; and 2) a web interface. This web interface provides efficient, search, browsing, and retrieval of data from the repository. RESULTS: An aggregation of experimental, clinical and simulation data from various centers is being made available through the EDGAR project including experimental data from animal studies provided by the University of Utah (USA), clinical data from multiple human subjects provided by the Charles University Hospital (Czech Republic), and computer simulation data provided by the Karlsruhe Institute of Technology (Germany). CONCLUSIONS: It is our hope that EDGAR will serve as a communal forum for sharing and distribution of cardiac electrophysiology data and geometric models for use in ECGI research.