Fu Siong Ng

Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes

Optical mapping has become an increasingly important tool to study cardiac electrophysiology in the past 20 years. Multiple methods are used to process and analyze cardiac optical mapping data, and no consensus currently exists regarding the optimum methods. The specific methods chosen to process optical mapping data are important because inappropriate data processing can affect the content of the data and thus alter the conclusions of the studies. Details of the different steps in processing optical imaging data, including image segmentation, spatial filtering, temporal filtering, and baseline drift removal, are provided in this review. We also provide descriptions of the common analyses performed on data obtained from cardiac optical imaging, including activation mapping, action potential duration mapping, repolarization mapping, conduction velocity measurements, and optical action potential upstroke analysis. Optical mapping is often used to study complex arrhythmias, and we also discuss dominant frequency analysis and phase mapping techniques used for the analysis of cardiac fibrillation.

Techniques for automated local activation time annotation and conduction velocity estimation in cardiac mapping

Measurements of cardiac conduction velocity provide valuable functional and structural insight into the initiation and perpetuation of cardiac arrhythmias, in both a clinical and laboratory context. The interpretation of activation wavefronts and their propagation can identify mechanistic properties of a broad range of electrophysiological pathologies. However, the sparsity, distribution and uncertainty of recorded data make accurate conduction velocity calculation difficult. A wide range of mathematical approaches have been proposed for addressing this challenge, often targeted towards specific data modalities, species or recording environments. Many of these algorithms require identification of activation times from electrogram recordings which themselves may have complex morphology or low signal-to-noise ratio. This paper surveys algorithms designed for identifying local activation times and computing conduction direction and speed. Their suitability for use in different recording contexts and applications is assessed.

Spatial Resolution Requirements for Accurate Identification of Drivers of Atrial Fibrillation

Background— Recent studies have demonstrated conflicting mechanisms underlying atrial fibrillation (AF), with the spatial resolution of data often cited as a potential reason for the disagreement. The purpose of this study was to investigate whether the variation in spatial resolution of mapping may lead to misinterpretation of the underlying mechanism in persistent AF. Methods and Results— Simulations of rotors and focal sources were performed to estimate the minimum number of recording points required to correctly identify the underlying AF mechanism. The effects of different data types (action potentials and unipolar or bipolar electrograms) and rotor stability on resolution requirements were investigated. We also determined the ability of clinically used endocardial catheters to identify AF mechanisms using clinically recorded and simulated data. The spatial resolution required for correct identification of rotors and focal sources is a linear function of spatial wavelength (the distance between wavefronts) of the arrhythmia. Rotor localization errors are larger for electrogram data than for action potential data. Stationary rotors are more reliably identified compared with meandering trajectories, for any given spatial resolution. All clinical high-resolution multipolar catheters are of sufficient resolution to accurately detect and track rotors when placed over the rotor core although the low-resolution basket catheter is prone to false detections and may incorrectly identify rotors that are not present. Conclusions— The spatial resolution of AF data can significantly affect the interpretation of the underlying AF mechanism. Therefore, the interpretation of human AF data must be taken in the context of the spatial resolution of the recordings.

Transmural APD gradient synchronizes repolarization in the human left ventricular wall

AIMS The duration and morphology of the T wave predict risk for ventricular fibrillation. A transmural gradient in action potential duration (APD) in the ventricular wall has been suggested to underlie the T wave in humans. We hypothesize that the transmural gradient in APD compensates for the normal endocardium-to-epicardium activation sequence and synchronizes repolarization in the human ventricular wall. METHODS AND RESULTS We made left ventricular wedge preparations from 10 human donor hearts and measured transmural activation and repolarization patterns by optical mapping, while simultaneously recording a pseudo-ECG. We also studied the relation between local timings of repolarization with the T wave in silico. During endocardial pacing (1 Hz), APD was longer at the subendocardium than at the subepicardium (360 ± 17 vs. 317 ± 20 ms, P < 0.05). The transmural activation time was 32 ± 4 ms and resulted in final repolarization of the subepicardium at 349 ± 18 ms. The overall transmural dispersion in repolarization time was smaller than that of APD. During epicardial pacing, the dispersion in repolarization time increased, whereas that of APD remained similar. The morphology of the T wave did not differ between endocardial and epicardial stimulation. Simulations explained the constant T wave morphology without transmural APD gradients. CONCLUSION The intrinsic transmural difference in APD compensates for the normal cardiac activation sequence, resulting in more homogeneous repolarization of the left ventricular wall. Our data suggest that the transmural repolarization differences do not fully explain the genesis of the T wave.

Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia-reperfusion-induced ventricular arrhythmias.

Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective If current inhibitor, to assess the effects of heart rate reduction (HRR) during ischaemia–reperfusion on reperfusion ventricular arrhythmias and assessed potential anti-arrhythmic mechanisms by optical mapping. Five groups of rat hearts were subjected to regional ischaemia by left anterior descending artery occlusion for 8 min followed by 10 min of reperfusion: (1) Control n = 10; (2) 1 μM of ivabradine perfusion n = 10; (3) 1 μM of ivabradine + 5 Hz atrial pacing throughout ischaemia–reperfusion n = 5; (4) 1 μM of ivabradine + 5 Hz pacing only at reperfusion; (5) 100 μM of ivabradine was used as a 1 ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n = 5; 5 Hz pacing n = 5) were subjected to global ischaemia whilst transmembrane voltage transients were recorded. Epicardial activation was mapped, and the rate of development of ischaemia-induced electrophysiological changes was assessed. HRR observed in the ivabradine group during both ischaemia (195 ± 11 bpm vs. control 272 ± 14 bpm, p < 0.05) and at reperfusion (168 ± 13 bpm vs. 276 ± 14 bpm, p < 0.05) was associated with reduced reperfusion ventricular fibrillation (VF) incidence (20% vs. 90%, p < 0.05). Pacing throughout ischaemia–reperfusion abolished the protective effects of ivabradine (100% VF), whereas pacing at reperfusion only partially attenuated this effect (40% VF). Ivabradine, given as a bolus at reperfusion, did not significantly affect VF incidence (80% VF). Optical mapping experiments showed a delay to ischaemia-induced conduction slowing (time to 50% conduction slowing: 10.2 ± 1.3 min vs. 5.1 ± 0.7 min, p < 0.05) and to loss of electrical excitability in ivabradine-perfused hearts (27.7 ± 4.3 min vs. 14.5 ± 0.6 min, p < 0.05). Ivabradine administered throughout ischaemia and reperfusion reduced reperfusion VF incidence through HRR. Heart rate during ischaemia is a major determinant of reperfusion arrhythmias. Heart rate at reperfusion alone was not a determinant of reperfusion VF, as neither a bolus of ivabradine nor pacing immediately prior to reperfusion significantly altered reperfusion VF incidence. This anti-arrhythmic effect of heart rate reduction during ischaemia may reflect slower development of ischaemia-induced electrophysiological changes.

Adverse Remodeling of the Electrophysiological Response to Ischemia-Reperfusion in Human Heart Failure Is Associated with Remodeling of Metabolic Gene Expression

Background—Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia–reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia–reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. Methods and Results—We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia–reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. Conclusions—We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia–reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes.

Visualizing Localized Reentry With Ultra–High Density Mapping in Iatrogenic Atrial Tachycardia: Beware Pseudo-Reentry

Background— The activation pattern of localized reentry (LR) in atrial tachycardia remains incompletely understood. We used the ultra–high density Rhythmia mapping system to study activation patterns in LR. Methods and Results— LR was suggested by small rotatory activations (carousels) containing the full spectrum of the color-coded map. Twenty-three left-sided atrial tachycardias were mapped in 15 patients (age: 64±11 years). 16 253±9192 points were displayed per map, collected over 26±14 minutes. A total of 50 carousels were identified (median 2; quartiles 1–3 per map), although this represented LR in only n=7 out of 50 (14%): here, rotation occurred around a small area of scar (<0.03 mV; 12±6 mm diameter). In LR, electrograms along the carousel encompassed the full tachycardia cycle length, and surrounding activation moved away from the carousel in all directions. Ablating fractionated electrograms (117±18 ms; 44±13% of tachycardia cycle length) within the carousel interrupted the tachycardia in every LR case. All remaining carousels were pseudo-reentrant (n=43/50 [86%]) occurring in areas of wavefront collision (n=21; median 0.5; quartiles 0–2 per map) or as artifact because of annotation of noise or interpolation in areas of incomplete mapping (n=22; median 1, quartiles 0–2 per map). Pseudo-reentrant carousels were incorrectly ablated in 5 cases having been misinterpreted as LR. Conclusions— The activation pattern of LR is of small stable rotational activations (carousels), and this drove 30% (7/23) of our postablation atrial tachycardias. However, this appearance is most often pseudo-reentrant and must be differentiated by interpretation of electrograms in the candidate circuit and activation in the wider surrounding region.

A Prospective Study of Ripple Mapping in Atrial Tachycardias A Novel Approach to Interpreting Activation in Low-Voltage Areas

Background—Post ablation atrial tachycardias are characterized by low-voltage signals that challenge current mapping methods. Ripple mapping (RM) displays every electrogram deflection as a bar moving from the cardiac surface, resulting in the impression of propagating wavefronts when a series of bars move consecutively. RM displays fractionated signals in their entirety thereby helping to identify propagating activation in low-voltage areas from nonconducting tissue. We prospectively used RM to study tachycardia activation in the previously ablated left atrium. Methods and Results—Patients referred for atrial tachycardia ablation underwent dense electroanatomic point collection using CARTO3v4. RM was played over a bipolar voltage map and used to determine the voltage “activation threshold” that differentiated functional low voltage from nonconducting areas for each map. Ablation was guided by RM, but operators could perform entrainment or review the isochronal activation map for diagnostic uncertainty. Twenty patients were studied. Median RM determined activation threshold was 0.3 mV (0.19–0.33), with nonconducting tissue covering 33±9% of the mapped surface. All tachycardias crossed an isthmus (median, 0.52 mV, 13 mm) bordered by nonconducting tissue (70%) or had a breakout source (median, 0.35 mV) moving away from nonconducting tissue (30%). In reentrant circuits (14/20) the path length was measured (87–202 mm), with 9 of 14 also supporting a bystander circuit (path lengths, 147–234 mm). In breakout tachycardias, splitting of wavefronts resulted in 2 to 4 incomplete circuits. RM-guided ablation interrupted the tachycardia in 19 of 20 cases with the first ablation set. Conclusions—RM helps to define activation through low-voltage regions and aids ablation of atrial tachycardias.

An automated algorithm for determining conduction velocity, wavefront direction and origin of focal cardiac arrhythmias using a multipolar catheter.

Determining locations of focal arrhythmia sources and quantifying myocardial conduction velocity (CV) are two major challenges in clinical catheter ablation cases. CV, wave-front direction and focal source location can be estimated from multipolar catheter data, but currently available methods are time-consuming, limited to specific electrode configurations, and can be inaccurate. We developed automated algorithms to rapidly identify CV from multipolar catheter data with any arrangement of electrodes, whilst providing estimates of wavefront direction and focal source position, which can guide the catheter towards a focal arrhythmic source. We validated our methods using simulations on realistic human left atrial geometry. We subsequently applied them to clinically-acquired intracardiac electrogram data, where CV and wavefront direction were accurately determined in all cases, whilst focal source locations were correctly identified in 2/3 cases. Our novel automated algorithms can potentially be used to guide ablation of focal arrhythmias in real-time in cardiac catheter laboratories.

Mitochondrial depolarization and electrophysiological changes during ischemia in the rabbit and human heart

Instability of the inner mitochondrial membrane potential (ΔΨm) has been implicated in electrical dysfunction, including arrhythmogenesis during ischemia-reperfusion. Monitoring ΔΨm has led to conflicting results, where depolarization has been reported as sporadic and as a propagating wave. The present study was designed to resolve the aforementioned difference and determine the unknown relationship between ΔΨm and electrophysiology. We developed a novel imaging modality for simultaneous optical mapping of ΔΨm and transmembrane potential (Vm). Optical mapping was performed using potentiometric dyes on preparations from 4 mouse hearts, 14 rabbit hearts, and 7 human hearts. Our data showed that during ischemia, ΔΨm depolarization is sporadic and changes asynchronously with electrophysiological changes. Spatially, ΔΨm depolarization was associated with action potential duration shortening but not conduction slowing. Analysis of focal activity indicated that ΔΨm is not different within the myocardium where the focus originates compared with normal ventricular tissue. Overall, our data suggest that during ischemia, mitochondria maintain their function at the expense of sarcolemmal electrophysiology, but ΔΨm depolarization does not have a direct association to ischemia-induced arrhythmias.