High-resolution noncontact charge-density mapping of endocardial activation

Abstract

Background: Spatial resolution in cardiac activation maps based on voltage measurement is limited by far-field interference. Precise characterization of electrical sources would resolve this limitation; however, practical charge-based cardiac mapping has not been achieved.

Methods: A prototype algorithm, developed from first principles of electrostatic field theory, derives charge density (CD) as a spatial representation of the true sources of the cardiac field. The algorithm processes multiple, simultaneous, noncontact voltage measurements within the cardiac chamber to inversely derive the global distribution of CD sources across the endocardial surface.

Results: Comparison of CD to an established computer-simulated model of atrial conduction demonstrated feasibility in terms of spatial, temporal, and morphologic metrics. Inverse reconstruction matched simulation with median spatial errors of 1.73 mm and 2.41 mm for CD and voltage, respectively. Median temporal error was less than 0.96 ms and morphologic correlation was greater than 0.90 for both CD and voltage. Activation patterns observed in human atrial flutter reproduced those established through contact maps, with a 4-fold improvement in resolution noted for CD over voltage. Global activation maps (charge density-based) are reported in atrial fibrillation with confirmed reduction of far-field interference. Arrhythmia cycle-length slowing and termination achieved through ablation of critical points demonstrated in the maps indicates both mechanistic and pathophysiological relevance.

Conclusion: Global maps of cardiac activation based on CD enable classification of conduction patterns and localized nonpulmonary vein therapeutic targets in atrial fibrillation. The measurement capabilities of the approach have roles spanning deep phenotyping to therapeutic application.

Trial registration: ClinicalTrials.gov NCT01875614.

Funding: The National Institute for Health Research (NIHR) Translational Research Program at Royal Papworth Hospital and Acutus Medical.

Keywords: Arrhythmias; Cardiology; Cardiovascular disease.

Conflict of interest statement

Conflict of interest: GB is Chief Technology Officer, MZ is Principal Scientist, XS is Senior Principal Scientist, and DC is Senior Technical Fellow at Acutus Medical and each holds stock options. LD is co-founder and holds stock and CS is a co-founder of Acutus Medical with an equity interest. The work described in this study is protected by US Patents 7,841,986; 8,417,313; 8,512,255; 8,700,119; 8,918,158; 9,167,982; 9,192,318; 9,308,350; 9,504,395; 9,610,024; 9,757,044; 9,789,286; and D782,686. Additional patents are pending in the US and worldwide.

Figures

Figure 1. Spatiotemporal relationships among charge density, voltage, and action potential.

(A) The cardiac voltage field arises as a spatially broad summation of local, dipolar charge sources generated by the action of cellular ion channels throughout the myocardium. Charge density (CD; coulombs/cm) represents the magnitude of these sources with reduced contribution from far-field sources. (B) Depiction of a CD waveform overlaid on a corresponding voltage-based EGM that represents the sharper, narrower nature of CD and a 4-fold improvement in temporal resolution over voltage. (C) Area of depolarization shown on a CD map at a specific instant of time, with the red region depicting the associated negative phase of CD. The area-spanning space is correlated with the temporal duration of the negative phase of the CD waveform and with phase 2 of the action potential. (D) Spatial distribution of depolarization area for a CD map displayed beside the corresponding voltage-based map that demonstrates a 4-fold improvement in spatial resolution of CD over voltage. Spatial maps display the magnitude of all points at one fiducial instant of time (t0) corresponding to the yellow time cursor in the waveform in panel E. Propagation is ascertained by animation of the maps from each sample instant through time. PA, posterior-anterior. (E) Temporal CD waveform overlaid on the corresponding voltage-based waveform that demonstrates an average 4-fold improvement in temporal resolution of CD over voltage. Temporal waveforms display the magnitude of one point at all instants of time. The lower-magnitude, fractionated morphology represents localized irregular activation (LIA; see Figure 6A), which is the dominant conduction pattern in AF and for which the resolution of CD is improved the most over voltage. The larger-magnitude, organized morphology represents localized rotational activation (LRA; see Figure 6A), which is a nondominant, regionally organized conduction pattern in AF and for which the resolution of CD is improved over voltage, but less so than noted for LIA. LIPV, LSPV, RIPV, RSPV are left and right inferior and superior pulmonary veins, respectively; MV, mitral valve.

Figure 2. Four computational steps were completed to evaluate the accuracy of the CD inverse algorithm in a biologically realistic simulation.

Step 1 is simulation of action potential propagation. Step 2 is calculation of a priori known CD, ground-truth potentials, and actual activation times. Step 3 is inverse reconstruction of CD, forward reconstruction of potentials, and postprocessed activation times. Step 4 is comparative evaluation of forward-reconstructed potentials and activation times with ground-truth potentials and activation times.

Figure 3. Performance comparisons and spatiotemporal accuracy of reconstructed CD and voltage in a biologically realistic simulation.

(A) Box-and-whisker plot of Xcorr distribution from 6,000 pairs of voltage waveforms. (B) Box-and-whisker plot of Tdiff distribution from 6,000 pairs of voltage waveforms. (C) Box-and-whisker plot of AURC distributions from 3,929 time frames comparing spatiotemporal overlap of CD and voltage activation times versus actual activation times. Paired t and Mann-Whitney (M-W) tests indicated that activation times were similar (P < 0.0001 and P < 0.003, respectively). (D) Box-and-whisker plot of D2O distributions from 30 focal simulations. (E) Box-and-whisker plot of D2O distributions for inverse-reconstructed CD and forward-reconstructed voltage. CD was more accurate in localizing the site of focal origin than voltage (P < 0.08). In all plots, boxes span from quartiles Q1 to Q3 and whiskers span from the 10th to 90th percentiles of the population. The red cross denotes the mean value and the blue horizontal bar denotes the median value. The dashed lines delineate the minimum acceptable correlation value of 0.7, or the maximum acceptable time shift of 6 ms, or the maximum acceptable D2O of 5 mm.

Figure 4. System, mapping catheter, and anatomic reconstruction used in clinical studies of human atria.

(A) The system consists of a console, workstation, and interface unit. Localization and electrical reference electrodes are connected to the system through the patient interface. The AcQMap catheter, ECG electrodes, and auxiliary catheters are connected to the console front panel. Commercially available ablation catheters and generators can be connected through an ablation interface. (B) AcQMap mapping catheter has a 10-F shaft, integral handle (not shown), and deployable distal 25-mm spheroid apparatus that has 6 splines, each populated with 8 ultrasound transducers for anatomy reconstruction and 8 unipolar electrodes for mapping. (C) Radiographic (28° left anterior oblique [LAO]) view of the AcQMap catheter in the left atrium. (D) Ultrasound reconstruction of the left atrium is based on the transit time of sonic reflections between the endocardial surface and the transducers on the catheter splines. Distances calculated from the transit times result in 3D points that represent locations on the endocardial surface and are dynamically triangulated into a surface mesh. Rotation, advancement, and retraction of the catheter during point collection achieves a complete reconstruction throughout the entire chamber, usually over 90–180 seconds (Supplemental Video 1). Postprocessing is performed to establish the final anatomy that is used for navigation and mapping.

Figure 5. Initial clinical validation in typical cavotricuspid-isthmus–dependent atrial flutter.

Example of typical, counter-clockwise flutter in the right atrium. In the upper panel, the propagation-history color bands are set to display a fixed propagation-history map of the entire cycle length, shown in anterior-posterior (AP) and left-anterior-oblique (LAO) views. Signals can be visualized from any position on the map (labeled on the anatomical mesh) and at any instant of time due to the global, simultaneous calculation of the inverse solution. The duration of propagation history can be adjusted by the operator and is demarcated by the translucent-gray region in the lower panel. The yellow time cursor at the right edge of the history window corresponds to the leading edge of the red color band on the map, shown reaching the roof from the septum. The other color bands, located progressively clockwise, represent the location of the wavefront at earlier instants of time. The span of the color bands, across space, and the associated duration of the translucent-gray region, across time, were set equal to the flutter-cycle length (CL, 255 ms). Accordingly, waveforms sampled from 8 evenly spaced locations around the entire right atrium reproduce the expected morphology and timing of propagation, while the map reveals the activation sequence progressing inferiorly from the roof on the lateral wall (LAT), medially on the isthmus (CTI), and superiorly on the septum (SEP). IVC, inferior vena cava; RAA, right atrial appendage; SVC, superior vena cava; TV, tricuspid valve.

Figure 6. Conduction patterns identified in propagation history maps and localization of activation patterns of atrial fibrillation.

(A) Three discrete identified conduction patterns, including focal activation, with radial conduction from a single location ≥ 3 times per 5-second duration of AF; localized rotational activation (LRA), with ≥ 270 degrees of conduction around a fixed, confined zone; and localized irregular activation (LIA), with repetitive, multidirectional entry, exit, and pivoting conduction through and around a fixed, confined zone (see Supplemental Videos 4–6). (B) Spatial plot of conduction patterns and locations identified in a subset of 10 patients recruited into the DDRAMATIC SVT trial. Conduction patterns were identified at patient-specific locations throughout the atrial body (regions 1–12), with one or more patterns arising from the same location.

Figure 7. Case example of atrial fibrillation termination through targeted ablation.

(A) Anterior-posterior (AP) view of left atrium with no classifiable activation patterns noted on anterior surface. (B) Posterior-anterior (PA) view of left atrium showing a single localized rotational activation (LRA) posterior and inferior to the left inferior pulmonary vein (LIPV). (C) Isolation of the right pulmonary veins (yellow dots) indicating the planned ablation line. No alterations, as indicated by the red dots, were made to the ablation line. (D) Incorporation of the LRA within the isolation line of the left pulmonary veins based on proximity of the central point of the LRA to the planned line that was altered to pass through the central point of the LRA. The yellow dots indicate the original planned line and the red dots the executed ablation line. While ablating within the identified area of interest, the AF terminated to sinus rhythm. The isolation line was completed, with block verified in sinus rhythm. (E) Calculated CD signals are displayed at locations 1-6 on the 3D anatomy displayed in panels A and B. The position of the yellow cursor, in time, correlates with the position of the leading edge of the red color band in the display of propagation history. CD signals 1–3 show predominantly positive (R-wave) unipolar CD morphology representing the resting state. CD signal number 4 shows a predominant QS morphology, with the yellow line crossing zero at the same instant that the red color band is reaching its location on the map. CD signal number 5 shows that depolarization occurred at that location at an earlier time in the propagation history. The duration of propagation history is displayed by the translucent-gray rectangle positioned behind the yellow time cursor and, in this example, the duration was set by the user to 112 ms (see Supplemental Videos 5 and 7).