- Email: [email protected]
Standard peak-to-peak bipolar voltage amplitude criteria underestimate myocardial scar during substrate mapping with a novel microelectrode catheter
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Standard peak-to-peak bipolar voltage amplitude criteria underestimate myocardial scar during substrate mapping with a novel microelectrode catheter Q5
Q1
Adam Lee, MBBS, MMed (Clin Epi), Tomos E. Walters, MBBS, PhD, Christina Alhede, MD, PhD, Eric Vittinghoff, PhD, Richard Sievers, BS, Edward P. Gerstenfeld, MD From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California. BACKGROUND Ventricular bipolar voltage values ,0.5 and ,1.0/ 1.5 mV (epi- and endocardium) correlating with dense scar and border zone, respectively, were established using a 3.5-mm tip catheter. Novel microelectrode catheters promise improved mapping resolution; however, whether standard voltage criteria apply to catheters with smaller electrode size and interelectrode distance remains unclear. OBJECTIVE The purpose of this study was to determine whether traditional bipolar voltage criteria for scar apply during substrate mapping with a microelectrode catheter. METHODS Paired bipolar and microbipolar voltage values were acquired from control swine (n 5 2) using the microelectrode catheter and assessed for systemic differences. In a postinfarction swine model (n 5 6), scar characteristics were compared between the bipolar maps and microbipolar maps using both standard and adjusted voltage criteria derived from the control animals.
[left ventricular (LV) endo]; 0.88 mV vs 0.98 mV [epi]), median values were significantly greater when acquired by microbipolar electrodes (3.60 vs 6.76 mV, P 5 .002 [LV endo]; 2.61 vs 2.72 mV, P 5 .02 [epi]). Microbipolar values were systematically larger by 2.0! and 1.4! in the LV endocardium and epicardium, respectively. Application of standard voltage values to microbipolar maps in postinfarct swine underestimated scar area by approximately 41% in the LV endocardium (13.7 vs 33.4 cm2, P 5 .004). CONCLUSION Bipolar voltage values acquired from microelectrodes are systemically larger than those acquired from standard catheters. New reference values should be established for these novel catheters. KEYWORDS Electroanatomic mapping; High-density mapping; Microelectrode catheter; Myocardial infarction; Ventricular arrhythmia; Voltage mapping
RESULTS In control swine, although 5th percentile values for bipolar and microbipolar voltage were similar (1.12 vs 1.22 mV
(Heart Rhythm 2019;-:1–9) All rights reserved.
Introduction
hemodynamically tolerated in patients with impaired cardiac function.2 An important aspect of a substrate ablation strategy involves acquisition of a voltage map of the relevant endocardial and/or epicardial surfaces of the targeted ventricle. The voltage map allows visualization of endocardial/epicardial scar and the surrounding border zone that harbors critical components of the VT circuitry and helps guide ablation.3 However, standardized bipolar values for low voltage (defined as ,0.5/1.5 mV and ,0.5/1.0 mV for dense scar/ border zone in the left ventricular [LV] endocardium and epicardium, respectively) were established using standard ablation catheters with relatively large tip electrodes (3.5 or 4.0 mm) and relatively large tip-to-ring interelectrode distances. Newer mapping catheters with multiple small electrodes and tighter interelectrode distances hold the promise
Substrate mapping is a cornerstone of contemporary catheterbased therapies for the treatment of scar-related ventricular tachyarrhythmias (VTs) in patients with cardiomyopathies.1 Although entrainment and activation mapping allow delineation and targeting of specific components of clinical VTs, such techniques are limited because many VTs are not
The animals for this study were funded by an investigator-initiated research grant to Dr Gerstenfeld from Biosense-Webster. All other authors have reported that they have no conflicts relevant to the contents of this paper Q2 Q3 to disclose. Address reprint requests and correspondence: Dr. Edward P. Gerstenfeld, Division of Cardiology, Department of Medicine, University of California San Francisco, MU-East 4th Floor, 500 Parnassus Avenue, San Francisco, CA 94143. E-mail address: [email protected].
1547-5271/$-see front matter © 2019 Heart Rhythm Society. All rights reserved.
©
2019 Heart Rhythm Society.
https://doi.org/10.1016/j.hrthm.2019.10.013
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2 of faster mapping and greater mapping resolution; however, whether the previously established values for low voltage/ scar apply to maps acquired with these modern catheters is not clear. In this study, we compared standard bipolar and microelectrode voltage maps acquired with a novel mapping/ablation catheter that includes both a standard tip-to-ring configuration (3.5-mm tip, 1-mm tip-to-ring interelectrode distance) in addition to 3 microelectrodes embedded circumferentially within the distal tip surface. We aimed to determine (1) whether electrogram (EGM) voltage acquired by a standard bipole (bipolar) differs from that acquired by a microelectrode bipole (microbipolar); (2) the relationship between these values if such a difference exists; and (3) differences in scar area as determined by low-voltage areas between voltage maps acquired by the standard bipole vs the microelectrode bipole.
Methods A novel mapping catheter comprises three 0.167-mm2 electrodes (1.755-mm interelectrode distance) embedded circumferentially within a standard 3.5-mm tip catheter (Qdot Micro, Biosense Webster, Diamond Bar, CA) (Figure 1). Eight swine were included in this study. Two swine served as control animals and underwent LV endocardial and epicardial mapping to determine the relationship between bipolar and microbipolar voltage in normal swine hearts. Derived values were then applied to 6 additional swine (39–45 kg)
after creation of an anteroseptal myocardial infarction to determine differences in scar or low-voltage areas on electroanatomic (EA) mapping. The protocol was approved and monitored by the Laboratory Animal Resource Center at the University of California, San Francisco, California, according to the American Heart Association Guidelines for Animal Research.
Chronic infarct model Six swine underwent experimental myocardial infarction in order to create a model of postinfarct cardiomyopathy. Amiodarone 400 mg daily was administered for 3–7 days before experimental infarction. All swine underwent intubation and general anesthesia with intramuscular acepromazine (0.4 mg/kg) and ketamine (25 mg/kg) for induction, followed by maintenance inhalational isoflurane (1%–5%). All swine were mechanically ventilated with 100% oxygen. Femoral venous and arterial access was obtained using the modified Seldinger technique. The left coronary artery was engaged with an 8F hockey-stick guide catheter, and the left anterior descending artery was wired with an 0.014-inch angioplasty wire. Transient balloon occlusion (using a 3.0- to 3.5-mm over-the-wire compliant angioplasty balloon) was performed for 90–120 minutes immediately distal to the first diagonal branch. Adequate occlusion was confirmed by the presence of anterolateral ST elevation on the 12-lead electrocardiogram and by confirmation of anterior segment akinesis on intracardiac echocardiography. If
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Figure 1 Microbipolar catheter with three 0.167-mm2 microelectrodes (0.1755-mm center-to-center interelectrode distance) embedded circumferentially on the distal end of a standard 3.5-mm tip electrode. The standard bipole consists of the 3.5-mm tip electrode and 1-mm ring electrode separated by a 1-mm interelectrode distance. FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Lee et al
ventricular fibrillation occurred during arterial occlusion, lidocaine 100 mg was administered intravenously once and external defibrillation performed promptly as required. The animals recovered and survived for 4–6 weeks postinfarction.
EA mapping Terminal mapping studies were performed in the 6 infarct swine 4–6 weeks postinfarction. The control swine underwent terminal mapping studies when they had reached a weight comparable to that of the postinfarct animals (68–82 kg). The procedure was performed with the animals under general anesthesia as described for the infarct studies. Femoral venous and arterial access was obtained using the modified Seldinger technique. Epicardial access was obtained using the micropuncture needle-in-needle technique under fluoroscopic guidance without complication.4 The catheter was advanced to the epicardial space via an 8.5F, 40-cm Agilis EPI Steerable sheath (Abbott, Lake Bluff, IL). A 10,000-unit heparin bolus was administered after successful epicardial access was obtained, and additional heparin boluses were intermittently administered throughout the procedure. The LV endocardium was accessed with the mapping catheter via the retrograde aortic approach after completion of the epicardial map. Detailed point-by-point mapping of the LV endocardial and epicardial surfaces was performed using the novel mapping catheter. Point acquisition was performed manually,
3 with use of the CONFIDENSE mapping module (CARTO, Biosense Webster). Acquired points were taken at sites with at least 5g of contact force and were evenly distributed throughout the relevant surfaces. Paired peak-to-peak bipolar voltage amplitudes were acquired at each point between the standard tip-to-ring electrodes (bipolar) as well as between the 3 possible pairs of the microelectrodes (microbipolar) embedded within the catheter tip. Bipolar and microbipolar voltage amplitudes were automatically measured and exported by the CARTO3 software (Figure 2A). At each point, the mapping software displays the largest value among the 3 microelectrode pairs as the microbipolar voltage for that point. Bipolar signals were filtered at 30–400 Hz. Acquired points were manually assessed for appropriate EGM annotation, and erroneous measurements or noise were discarded. Paired bipolar and microbipolar voltage amplitude values were compared in the control animals. In the 6 postinfarct swine, surface areas of low voltage (initially defined as ,1.5 mV and ,1.0 mV in the LV endocardium and epicardium, respectively) as well as areas representing “dense scar” (,0.5 mV) were contoured manually using the mapping software, excluding areas within 1 cm of valve annuli, using a fill threshold of 15.
Gross anatomic pathology Two postinfarct swine underwent analysis of macroscopic scar on gross pathology. The remaining 4 could not be
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Underestimation of Scar by Microelectrode Catheters
Figure 2 A: Bipolar (tip to ring; blue arrow) and microbipolar electrogram (EGM) peak-to-peak voltage amplitude for a single acquired point. The microbipolar value is automatically determined by the largest measured peak-to-peak amplitude measured among the 3 microelectrode pairs (in this case, microbipolar 31; orange arrow). B, C: Bipolar/microbipolar EGMs from normal and scarred myocardium in the left ventricular (LV) endocardium (B) and epicardium (C). FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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4 accurately quantified because they were used for another study incorporating catheter ablation that obscured the scar border. After the terminal mapping study was completed, 2,3,5-triphenyl-2H-tetrazolium chloride solution was administered intravenously to enhance macroscopic scar visualization and facilitate cardiac arrest. The hearts were excised and fixed in formalin for 10–14 days. The hearts were subsequently sectioned into 5-mm short-axis slices (Figure 3A). Each short-axis slice was photographed and then imported digitally into and analyzed with image processing software (ImageJ, Rasband WS, US National Institutes of Health, Bethesda, MD). For each slice, the endo- and epicardial contours of macroscopic scar was traced and scar surface areas calculated as L ! 5 mm, where L is the traced length of scar measured at the endo- or epicardial surface (Figure 3B). As some portion of the scar was nontransmural, we defined the epicardial tracing length to include all segments with underlying scar even if the immediate underlying epicardial myocardium appeared healthy. The total LV endo- or epicardial scar surface area was thus calculated by summating the individual surface areas calculated from each short-axis slice.
Statistical analysis Continuous variables are presented as median with interquartile range. Between-group comparisons were performed using a generalized linear model with log-transformed outcomes as appropriate. A 2-sided a-level ,0.05 was considered statistically significant. Associations between continuous variables were assessed with the Spearman correlation test. Systematic differences between bipolar and microbipolar voltage amplitude were assessed in the 2 control pigs
semiquantitatively using Bland-Altman analysis. Any differences were then applied to the standard thresholds for low voltage (,1.5/1.0 mV for scar border zone in the LV endocardium/epicardium and ,0.5 mV for dense scar) on the microbipolar maps of the infarct animals (adjusted voltage maps).
Results EGM distribution A total of 5470 LV endocardial and 7250 epicardial points were acquired from the 6 infarct swine in total, and 658 LV endocardial and 965 epicardial points were acquired from control animals. In control animals, the median standard bipolar and microbipolar voltage values were 3.60 and 6.76 mV, respectively, in the LV endocardium (P 5 .002), and in the epicardium were 2.61 and 2.72 mV, respectively (P 5 .02). The 5th percentile bipolar and microbipolar thresholds were 1.12 mV and 1.22 mV, respectively, in the LV endocardium, whereas the values in the epicardium were 0.88 and 0.98 mV, respectively (Table 1 and Figure 4). There was strong correlation between bipolar and microbipolar peak-to-peak voltage amplitude in the infarct animals (LV endocardium: r 5 0.735, P ,.001; epicardium: r 5 0.775, P ,.001), and weak-to-moderate correlation in the control animals (LV endocardium: r 5 0.374, P ,.001; epicardium: r 5 0.590, P ,.001).
Bipolar vs microbipolar voltage amplitude In the control swine, microbipolar peak-to-peak voltage amplitudes were found to be systematically larger than bipolar voltage amplitudes in both the LV endocardium and
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Figure 3 A: Heart sectioned into 5-mm short-axis slices. B: Calculation of left ventricular (LV) endocardial/epicardial surface area per slice: endocardial/ epicardial contour length (blue and green line, respectively) ! 5 mm. The epicardial contour included all LV segments with underlying scar even if the immediately adjacent myocardium was healthy (to incorporate nontransmural scar). FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Lee et al Table 1
5
Bipolar and microbipolar peak-to-peak voltage amplitude distributions in control swine LV endocardium (n 5 658)
Bipolar Microbipolar
Epicardium (n 5 965)
Median (IQR)
5th percentile
Median (IQR)
5th percentile
3.60 (2.61–5.25) 6.76 (3.86–9.70)
,1.12 ,1.22
2.61 (1.60–4.29) 2.72 (1.60–4.83)
,0.88 ,0.93
IQR 5 interquartile range; LV 5 left ventricle.
epicardium. Visual inspection of the Bland-Altman plots demonstrated the relationship of microbipolar/standard bipolar voltage to be a fixed ratio (2! for LV endocardium and 1.4! for epicardium) rather than a fixed absolute difference (Figure 5). “Adjusted” voltage amplitude thresholds for scar border zone and dense scar were calculated by multiplying the standard threshold values by these numbers. In the LV endocardium, dense scar and scar border zone was defined as ,1.0 mV and ,3.0 mV, respectively, on the microbipolar maps, and in the epicardium as ,0.7 mV and ,1.4 mV, respectively.
by standard and adjusted thresholds in each individual infarct animal are outlined in Table 2.
Gross pathology In the 2 infarct animals in which gross pathology was assessed, the scar surface area seemed numerically to best approximate the area of dense scar on the adjusted microbipolar voltage maps (Table 2), although formal statistical assessment of this relationship was not feasible with 2 animals.
Discussion Low-voltage areas on EA mapping In the infarct swine, the mean area of LV endocardial scar on the “unadjusted” microbipolar voltage maps defined using standard criteria (,1.5 mV) was 41% lower than that of the bipolar voltage maps (13.7 6 14.4 cm2 vs 33.4 6 14.5 cm2; P 5 .004). The mean area of epicardial scar on the unadjusted microbipolar voltage maps (,1.0 mV) was numerically lower than that of the bipolar voltage maps, although this did not achieve statistical significance (13.8 6 10.1 cm2 vs 25.4 6 23.9 cm2; P 5 .17). Scar surface areas when reassessed using adjusted microbipolar threshold values (,3.0 mV and ,1.4 mV for the LV endocardium and epicardium, respectively) better approximated those of the standard bipolar voltage maps (LV endocardium mean area: 31.9 6 18.5 cm2 vs 33.4 6 14.5 cm2, P 5 .69; epicardium: 22.0 6 16.2 cm2 vs 25.4 6 23.9 cm2, P 5 .46). Figure 6 shows an example set of LV endocardial and epicardial bipolar and microbipolar (unadjusted and adjusted) voltage maps in a swine. Representative EGMs are shown in Figures 2B and 2C. Low-voltage areas as defined
The main findings of this study are as follows. (1) Standard bipolar peak-to-peak voltage amplitude underestimates scar area by w40% when applied to an EA map acquired by microelectrodes. (2) Although the 5th percentile peak-to-peak voltage amplitudes are similar between those acquired by a traditional tip-to-ring bipole and the novel microelectrode bipoles, in our swine, EGMs acquired by the latter are, on average, 2.0! and 1.4! larger than EGMs acquired by the former in the LV endocardium and epicardium, respectively. (3) Adjustment of low voltage threshold values by a fixed ratio may adjust for differences in the area of scar delineated by microelectrode catheters. Substrate ablation for unmappable arrhythmias has become an integral component of contemporary VT management.2 An initial step involves approximating areas of scar as represented by low-voltage areas delineated on an EA map in sinus rhythm, as these areas are most likely to harbor the critical components of VT circuitry that need to be targeted for ablation.3 Reference values for “scar,” both in the
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Underestimation of Scar by Microelectrode Catheters
Figure 4 Cumulative frequency graphs demonstrating despite similar 5th percentile thresholds for both bipolar and microbipolar voltage values. There is a greater positive skew of the microbipolar voltages, predominantly in the left ventricular (LV) endocardium. FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Figure 5 Bland-Altman plot demonstrating a fixed ratio relationship between paired microbipolar and bipolar voltage amplitudes: 1.4! for the epicardium and Q4 2.0! for the left ventricular (LV) endocardium.
endocardium and epicardium, have been established by researchers at the University of Pennsylvania, with bipolar voltage peak-to-peak amplitude values of ,1.5 mV and ,1.0 mV defining scar in the LV endocardium and epicardium, respectively.5,6 Any values below the 5th percentile of all sampled points in a small cohort of patients without macroscopic scar or structural heart disease were deemed abnormal. Point-by-point acquisition was performed manually using a standard mapping catheter of that era with a 4or 3.5-mm tip electrode and 2-mm tip-to-ring interelectrode distance. Despite the statistical (rather than pathologic) derivation, these standard values have stood the test of time and are the default reference ranges used universally in contemporary cases of scar-mediated VT.7
More recently, the advent of high-resolution multipolar mapping catheters holds the promise of not only faster but improved mapping resolution. Multiple electrodes in conjunction with automated acquisition algorithms allow rapid acquisition of EA maps with higher point density, whereas smaller electrode dimensions and tighter interelectrode distances allow for greater fidelity signals and a higher resolution “window” into the underlying substrate. Because electrode size and configuration can affect EGM characteristics including voltage,8 whether the standard bipolar voltage thresholds for scar should be applied to maps derived from these novel mapping catheters is unclear. Bipolar voltage, although often used as a surrogate for myocardial scar, conceptually reflects the magnitude and
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6
Figure 6 A–C: Left ventricular endocardial low-voltage zones as determined by standard thresholds (,1.5/,0.5 mV for scar border zone/dense scar) on bipolar and microbipolar maps (A, B) compared to adjusted microbipolar thresholds (C) (,3.0/,1.0 mV for scar border zone/dense scar). D–F: Epicardial lowvoltage zones as determined by standard thresholds (,1.0/,0.5 mV) on bipolar/microbipolar maps (D, E) compared to adjusted microbipolar thresholds (F) (,1.4/,0.7 mV). FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Table 2
Underestimation of Scar by Microelectrode Catheters
7
Percent scar determined from bipolar electrodes, microbipolar electrodes, and pathology Bipolar
Swine
Unadjusted microbipolar
Adjusted microbipolar
Gross pathology
Area (cm2)
1
NA Endo Total scar Dense scar Epi Total scar Dense scar
31.5 14.5
5.9 0
23.4 1.2
22.4 6.7
7.6 0.5
15.4 4
2
NA Endo Total scar Dense scar Epi Total scar Dense scar
42.9 14.9
7.2 0.1
29.7 5.2
28.9 19.4
26.9 13.7
34.5 22.4
3
NA Endo Total scar Dense scar Epi Total scar Dense scar
54.6 38.3
41.2 18.4
64.8 45.6
71.1 33.5
25.2 10.2
48.2 18.7
12.1 0.6
0.3 0
8.5 0
4.8 0.3
2.1 0.3
4.1 0.8
4 Endo Total scar Dense scar Epi Total scar Dense scar
NA
5
10.3 Endo Total scar Dense scar Epi Total scar Dense scar
26.2 8.6
15 2.4
31.8 10.3
11.9 2.7
7.7 0.8
12.9 3.5
2.9
6
9.1 Endo Total scar Dense scar Epi Total scar Dense scar
32.9 14.8
12.3 2.9
32.9 11.3
13.3 7.6
13.1 5.7
16.6 10.3
4.5
Low-voltage area in individual postinfarct swine as defined by standard thresholds (,1.5/,0.5 mV for scar border zone/dense scar in the left ventricular [LV] endocardium, ,1.0/,0.5 mV in the epicardium) on bipolar and unadjusted microbipolar voltage maps and adjusted thresholds (,3.0/,1.0 mV in the LV endocardium and ,1.4/,0.7 mV in the epicardium) on adjusted microbipolar voltage maps with comparative areas of macroscopic scar determined on gross pathology in 2 animals.
direction of wavefront activation between 2 electrodes. Whereas “scarred myocardium” results in attenuated voltage by virtue of fibrous replacement of electrically active myocardial cell mass, many other factors can influence bipolar voltage, including catheter electrode configurations (electrode size, interelectrode distance), and aspects of the catheter/tissue interface, including the relative orientation of the recording bipole to wavefront activation and tissue contact.8 Additionally, the displayed voltage on an EA map may be affected by point density due to data interpolation. Multiple studies have consistently shown larger bipolar EGM voltage amplitude during mapping using catheters
with smaller electrodes,9–12 although the lowest 5th percentile values remain consistent with those acquired with the standard catheter configuration.10–12 This suggests that such a statistical method of determining scar on EA mapping based on standard catheters may not be appropriate for these novel catheters.
Previous studies Tanaka et al11 compared a high-density 64-electrode minibasket catheter (IntellaMap Orion, Boston Scientific, Marlborough, MA) to a linear quadripolar catheter during
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mapping of the LV in a swine model of postinfarct cardiomyopathy and compared total scar areas to those acquired by magnetic resonance imaging (MRI). They derived a 5th percentile cutoff (1.54 mV) similar to that in previous studies. Although no statistical difference was found, numerically the surface area derived by the linear catheter was larger (20.9 cm2 vs 17.8/17.5 cm2 for the basket catheter/MRI).11 Tschabrunn et al12 compared the use of a contemporary multipolar mapping catheter (PentaRay, Biosense Webster) to a contemporary mapping/ablation catheter (SmartTouch ThermoCool, Biosense Webster) in a swine model of postinfarct cardiomyopathy. Using 3 control animals, they demonstrated 5th percentile values were similar between the 2 catheters (1.62 and 1.48 mV for the SmartTouch ThermoCool and PentaRay catheters, respectively). However, in postinfarct animals, the area of scar delineated by bipolar voltage ,1.5 mV was 22.5% smaller when acquired with the PentaRay than with the standard catheter (21.7 vs 28.0 cm2; P 5 .003).12 Although these studies support the hypothesis that high-resolution mapping catheters delineate smaller areas of “low voltage” using standard voltage thresholds (,1.5 mV), whether these differences arise from properties intrinsic to the catheter or are due to differences in map point density as a result of multipolar mapping is unclear. In our study, every acquired point is associated with a paired bipolar and microbipolar voltage value, thus implying such differences are due to the properties of the recording electrodes alone as the point acquisition and density between both maps are identical. However, we cannot exclude the possibility that the presence of the tip electrode (upon which the microelectrodes are embedded) affects the EGM recordings from the microelectrode pairs by affecting local current. Notwithstanding properties intrinsic to the smaller electrode size, a factor that may contribute to greater microelectrode bipole voltage in the Qdot catheter specifically is the presence of 3 microbipolar vectors compared to only 1 standard bipolar vector. Because the value is determined by the largest of the 3 microbipoles, there is a greater chance that any one microbipole pair is oriented more orthogonally to the direction of wavefront activation than the standard tipto-ring vector. High-resolutionmapping cathetersallshare thesameproperties of smaller electrode sizes and tighter interelectrode distances. However, Tung et al13 found measured EGM amplitude to increase with greater interelectrode distances when measured using a linear duodecapolar catheter in which the electrode sizes were fixed. That most studies of highresolution catheters, including our own, demonstrate greater EGM voltage amplitudes suggests that other factors (smaller electrode size, greater number of microbipolar vectors) dominate the attenuating effect of the smaller interelectrode distance. Leshem et al10 also examined the Qdot catheter in a postinfarction swine model. They similarly found that although the 5th percentiles of voltage amplitude were similar between bipolar voltage acquired with the standard tip-to-ring bipole and the microelectrodes, the distribution of overall bipolar voltage was greater with the former and the area of low
voltage defined by standard parameters (,1.5 mV) was smaller. Our study builds on this finding by demonstrating a fixed ratio relationship between paired bipolar and microbipolar points, which allows the possibility of “correcting” the apparent scar area on voltage maps acquired with this highresolution mapping catheter. The Qdot catheter has similarities to the MiFi (Boston Scientific), another microelectrode catheter. This catheter has three w1-mm-diameter microelectrodes embedded radially within the distal electrode approximately 1.3 or 2.0 mm proximal to the tip (either 4.5-mm irrigated or 8-mm nonirrigated). A study examining the use of a preproduction model of this catheter with 4 microelectrodes embedded within an 8-mm nonirrigated tip demonstrated greater EGM voltage amplitudes when measured between the microelectrodes compared to those measured between the 8-mm tip and ring,14 a finding consistent with our study. However, this is difficult to reconcile with results from the same group using a similar catheter (but with only 3 microelectrodes) in which they found measured EGM amplitudes to be greater with the 8-mm tip-to-ring configuration compared to those measured by all 3 pairs of microelectrodes.15 Despite this finding, the preponderance of evidence suggests that EGM voltage amplitudes are greater when measured between smaller electrodes with smaller interelectrode differences,9–12,14 possibly due to a smaller “antenna” effect such that the recorded signal averages less of the surrounding far-field signal.
Study limitations This was a small animal study. It is possible that the ratio that we calculated for scar adjustment on microbipolar maps is not generalizable to human subjects undergoing mapping with this catheter. A future study in human subjects would be needed to determine this possibility. Although our data are consistent with those of previous studies demonstrating the somewhat counterintuitive finding that catheters with smaller electrodes record larger voltage values, our study is not able to offer insights into the mechanism of this phenomenon. Additionally, the inability to measure recorded microbipolar voltage values in the absence of the standard tip electrode limits the extrapolation of our findings to other microelectrode catheters in which the microelectrodes are embedded in a different configuration (eg, the MiFi catheter). Examination of gross pathology was performed in only 2 animals, so any comparison to mapping-derived metrics is descriptive. However, the accuracy of correlating pathologic to EA-derived scar is questionable because the former is measured ex vivo in a contracted/rigor mortis heart whereas the latter is acquired in vivo with stretching due catheter contact during diastole. In this regard, the robust and validated bipolar threshold values acquired by a standard tip-to-ring catheter may serve as a better “gold standard” for scar. Finally, the definition of epicardial scar in our study as measured using EA mapping and pathology included areas in which the scar was nontransmural. This has limitations
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with regard to the significance of recorded EGM voltages, as previous studies have demonstrated a lack of correlation of endocardial voltage amplitude with imaging-proven scar on MRI in certain situations.16 Advanced imaging techniques such as cardiac MRI may serve as a better anatomic reference for scar, although this was not performed in our study. Scar characteristics including isolated potentials were not assessed in this study. We noted significant artifact/noise on microelectrode channels during manipulation of the shaft of these preliminary catheters that precluded the ability to assess for true isolated signals or fractionated EGMs.
Conclusion In a swine model of myocardial infarction, peak-to-peak bipolar voltage amplitude as sampled by a novel microelectrode catheter resulted in, on average, 2.0! and 1.4! greater voltage values than that obtained by a standard tip-to-ring bipolar (3.5-mm tip with 1-mm interelectrode distance) on the LV endocardium and epicardium, respectively. Although definitions of low voltage/scar using 5th percentile thresholds may not be appropriate for such catheter or electrode configurations, appropriate scar areas may be determined by applying a corrective ratio. Although high-resolution mapping catheters hold the promise of increased mapping resolution, appropriate voltage reference ranges for scar need to be established in humans before widespread clinical use.
References 1. Santangeli P, Marchlinski FE. Substrate mapping for unstable ventricular tachycardia. Heart Rhythm 2016;13:569–583. 2. Stevenson WG, Wilber DJ, Natale A, et al. Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction. Circulation 2008;118:2773–2782.
9 3. Hsia HH, Lin D, Sauer WH, Callans DJ, Marchlinski FE. Anatomic characterization of endocardial substrate for hemodynamically stable reentrant ventricular tachycardia: identification of endocardial conducting channels. Heart Rhythm 2006;3:503–512. 4. Gunda S, Reddy M, Pillarisetti J, et al. Differences in complication rates between large bore needle and a long micropuncture needle during epicardial access: time to change clinical practice? Circ Arrhythm Electrophysiol 2015;8:890–895. 5. Cano O, Hutchinson M, Lin D, et al. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol 2009;54:799–808. 6. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–1296. 7. Tung R, Ellenbogen KA. Emergence of multielectrode mapping. Circ Arrhythm Electrophysiol 2016;9:e004281. 8. Anter E, Josephson ME. Bipolar voltage amplitude: what does it really mean? Heart Rhythm 2016;13:326–327. 9. Berte B, Relan J, Sacher F, et al. Impact of electrode type on mapping of scarrelated VT. J Cardiovasc Electrophysiol 2015;26:1213–1223. 10. Leshem E, Tschabrunn CM, Jang J, et al. High-resolution mapping of ventricular scar: evaluation of a novel integrated multielectrode mapping and ablation catheter. JACC Clin Electrophysiol 2017;3:220–231. 11. Tanaka Y, Genet M, Chuan Lee L, Martin AJ, Sievers R, Gerstenfeld EP. Utility of high-resolution electroanatomic mapping of the left ventricle using a multispline basket catheter in a swine model of chronic myocardial infarction. Heart Rhythm 2015;12:144–154. 12. Tschabrunn CM, Roujol S, Dorman NC, Nezafat R, Josephson ME, Anter E. High-resolution mapping of ventricular scar. Circ Arrhythm Electrophysiol 2016;9:e003841. 13. Tung R, Kim S, Yagishita D, et al. Scar voltage threshold determination using ex vivo magnetic resonance imaging integration in a porcine infarct model: influence of interelectrode distances and three-dimensional spatial effects of scar. Heart Rhythm 2016;13:1993–2002. 14. Price A, Leshen Z, Hansen J, et al. Novel ablation catheter technology that improves mapping resolution and monitoring of lesion maturation. J Innov Card Rhythm Manag 2012;3:599–609. 15. Avitall B, Horbal P, Vance D, Koblish J. Determinants of atrial lesion maturation during radio frequency ablation using localized tissue electrograms. J Innov Card Rhythm Manag 2014;5:1574–1585. 16. Josephson ME, Anter E. Substrate mapping for ventricular tachycardia: assumptions and misconceptions. JACC Clin Electrophysiol 2015; 1:341–352.
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Standard peak-to-peak bipolar voltage amplitude criteria underestimate myocardial scar during substrate mapping with a novel microelectrode catheter Q5
Q1
Adam Lee, MBBS, MMed (Clin Epi), Tomos E. Walters, MBBS, PhD, Christina Alhede, MD, PhD, Eric Vittinghoff, PhD, Richard Sievers, BS, Edward P. Gerstenfeld, MD From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California. BACKGROUND Ventricular bipolar voltage values ,0.5 and ,1.0/ 1.5 mV (epi- and endocardium) correlating with dense scar and border zone, respectively, were established using a 3.5-mm tip catheter. Novel microelectrode catheters promise improved mapping resolution; however, whether standard voltage criteria apply to catheters with smaller electrode size and interelectrode distance remains unclear. OBJECTIVE The purpose of this study was to determine whether traditional bipolar voltage criteria for scar apply during substrate mapping with a microelectrode catheter. METHODS Paired bipolar and microbipolar voltage values were acquired from control swine (n 5 2) using the microelectrode catheter and assessed for systemic differences. In a postinfarction swine model (n 5 6), scar characteristics were compared between the bipolar maps and microbipolar maps using both standard and adjusted voltage criteria derived from the control animals.
[left ventricular (LV) endo]; 0.88 mV vs 0.98 mV [epi]), median values were significantly greater when acquired by microbipolar electrodes (3.60 vs 6.76 mV, P 5 .002 [LV endo]; 2.61 vs 2.72 mV, P 5 .02 [epi]). Microbipolar values were systematically larger by 2.0! and 1.4! in the LV endocardium and epicardium, respectively. Application of standard voltage values to microbipolar maps in postinfarct swine underestimated scar area by approximately 41% in the LV endocardium (13.7 vs 33.4 cm2, P 5 .004). CONCLUSION Bipolar voltage values acquired from microelectrodes are systemically larger than those acquired from standard catheters. New reference values should be established for these novel catheters. KEYWORDS Electroanatomic mapping; High-density mapping; Microelectrode catheter; Myocardial infarction; Ventricular arrhythmia; Voltage mapping
RESULTS In control swine, although 5th percentile values for bipolar and microbipolar voltage were similar (1.12 vs 1.22 mV
(Heart Rhythm 2019;-:1–9) All rights reserved.
Introduction
hemodynamically tolerated in patients with impaired cardiac function.2 An important aspect of a substrate ablation strategy involves acquisition of a voltage map of the relevant endocardial and/or epicardial surfaces of the targeted ventricle. The voltage map allows visualization of endocardial/epicardial scar and the surrounding border zone that harbors critical components of the VT circuitry and helps guide ablation.3 However, standardized bipolar values for low voltage (defined as ,0.5/1.5 mV and ,0.5/1.0 mV for dense scar/ border zone in the left ventricular [LV] endocardium and epicardium, respectively) were established using standard ablation catheters with relatively large tip electrodes (3.5 or 4.0 mm) and relatively large tip-to-ring interelectrode distances. Newer mapping catheters with multiple small electrodes and tighter interelectrode distances hold the promise
Substrate mapping is a cornerstone of contemporary catheterbased therapies for the treatment of scar-related ventricular tachyarrhythmias (VTs) in patients with cardiomyopathies.1 Although entrainment and activation mapping allow delineation and targeting of specific components of clinical VTs, such techniques are limited because many VTs are not
The animals for this study were funded by an investigator-initiated research grant to Dr Gerstenfeld from Biosense-Webster. All other authors have reported that they have no conflicts relevant to the contents of this paper Q2 Q3 to disclose. Address reprint requests and correspondence: Dr. Edward P. Gerstenfeld, Division of Cardiology, Department of Medicine, University of California San Francisco, MU-East 4th Floor, 500 Parnassus Avenue, San Francisco, CA 94143. E-mail address: [email protected].
1547-5271/$-see front matter © 2019 Heart Rhythm Society. All rights reserved.
©
2019 Heart Rhythm Society.
https://doi.org/10.1016/j.hrthm.2019.10.013
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2 of faster mapping and greater mapping resolution; however, whether the previously established values for low voltage/ scar apply to maps acquired with these modern catheters is not clear. In this study, we compared standard bipolar and microelectrode voltage maps acquired with a novel mapping/ablation catheter that includes both a standard tip-to-ring configuration (3.5-mm tip, 1-mm tip-to-ring interelectrode distance) in addition to 3 microelectrodes embedded circumferentially within the distal tip surface. We aimed to determine (1) whether electrogram (EGM) voltage acquired by a standard bipole (bipolar) differs from that acquired by a microelectrode bipole (microbipolar); (2) the relationship between these values if such a difference exists; and (3) differences in scar area as determined by low-voltage areas between voltage maps acquired by the standard bipole vs the microelectrode bipole.
Methods A novel mapping catheter comprises three 0.167-mm2 electrodes (1.755-mm interelectrode distance) embedded circumferentially within a standard 3.5-mm tip catheter (Qdot Micro, Biosense Webster, Diamond Bar, CA) (Figure 1). Eight swine were included in this study. Two swine served as control animals and underwent LV endocardial and epicardial mapping to determine the relationship between bipolar and microbipolar voltage in normal swine hearts. Derived values were then applied to 6 additional swine (39–45 kg)
after creation of an anteroseptal myocardial infarction to determine differences in scar or low-voltage areas on electroanatomic (EA) mapping. The protocol was approved and monitored by the Laboratory Animal Resource Center at the University of California, San Francisco, California, according to the American Heart Association Guidelines for Animal Research.
Chronic infarct model Six swine underwent experimental myocardial infarction in order to create a model of postinfarct cardiomyopathy. Amiodarone 400 mg daily was administered for 3–7 days before experimental infarction. All swine underwent intubation and general anesthesia with intramuscular acepromazine (0.4 mg/kg) and ketamine (25 mg/kg) for induction, followed by maintenance inhalational isoflurane (1%–5%). All swine were mechanically ventilated with 100% oxygen. Femoral venous and arterial access was obtained using the modified Seldinger technique. The left coronary artery was engaged with an 8F hockey-stick guide catheter, and the left anterior descending artery was wired with an 0.014-inch angioplasty wire. Transient balloon occlusion (using a 3.0- to 3.5-mm over-the-wire compliant angioplasty balloon) was performed for 90–120 minutes immediately distal to the first diagonal branch. Adequate occlusion was confirmed by the presence of anterolateral ST elevation on the 12-lead electrocardiogram and by confirmation of anterior segment akinesis on intracardiac echocardiography. If
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Figure 1 Microbipolar catheter with three 0.167-mm2 microelectrodes (0.1755-mm center-to-center interelectrode distance) embedded circumferentially on the distal end of a standard 3.5-mm tip electrode. The standard bipole consists of the 3.5-mm tip electrode and 1-mm ring electrode separated by a 1-mm interelectrode distance. FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Lee et al
ventricular fibrillation occurred during arterial occlusion, lidocaine 100 mg was administered intravenously once and external defibrillation performed promptly as required. The animals recovered and survived for 4–6 weeks postinfarction.
EA mapping Terminal mapping studies were performed in the 6 infarct swine 4–6 weeks postinfarction. The control swine underwent terminal mapping studies when they had reached a weight comparable to that of the postinfarct animals (68–82 kg). The procedure was performed with the animals under general anesthesia as described for the infarct studies. Femoral venous and arterial access was obtained using the modified Seldinger technique. Epicardial access was obtained using the micropuncture needle-in-needle technique under fluoroscopic guidance without complication.4 The catheter was advanced to the epicardial space via an 8.5F, 40-cm Agilis EPI Steerable sheath (Abbott, Lake Bluff, IL). A 10,000-unit heparin bolus was administered after successful epicardial access was obtained, and additional heparin boluses were intermittently administered throughout the procedure. The LV endocardium was accessed with the mapping catheter via the retrograde aortic approach after completion of the epicardial map. Detailed point-by-point mapping of the LV endocardial and epicardial surfaces was performed using the novel mapping catheter. Point acquisition was performed manually,
3 with use of the CONFIDENSE mapping module (CARTO, Biosense Webster). Acquired points were taken at sites with at least 5g of contact force and were evenly distributed throughout the relevant surfaces. Paired peak-to-peak bipolar voltage amplitudes were acquired at each point between the standard tip-to-ring electrodes (bipolar) as well as between the 3 possible pairs of the microelectrodes (microbipolar) embedded within the catheter tip. Bipolar and microbipolar voltage amplitudes were automatically measured and exported by the CARTO3 software (Figure 2A). At each point, the mapping software displays the largest value among the 3 microelectrode pairs as the microbipolar voltage for that point. Bipolar signals were filtered at 30–400 Hz. Acquired points were manually assessed for appropriate EGM annotation, and erroneous measurements or noise were discarded. Paired bipolar and microbipolar voltage amplitude values were compared in the control animals. In the 6 postinfarct swine, surface areas of low voltage (initially defined as ,1.5 mV and ,1.0 mV in the LV endocardium and epicardium, respectively) as well as areas representing “dense scar” (,0.5 mV) were contoured manually using the mapping software, excluding areas within 1 cm of valve annuli, using a fill threshold of 15.
Gross anatomic pathology Two postinfarct swine underwent analysis of macroscopic scar on gross pathology. The remaining 4 could not be
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Figure 2 A: Bipolar (tip to ring; blue arrow) and microbipolar electrogram (EGM) peak-to-peak voltage amplitude for a single acquired point. The microbipolar value is automatically determined by the largest measured peak-to-peak amplitude measured among the 3 microelectrode pairs (in this case, microbipolar 31; orange arrow). B, C: Bipolar/microbipolar EGMs from normal and scarred myocardium in the left ventricular (LV) endocardium (B) and epicardium (C). FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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4 accurately quantified because they were used for another study incorporating catheter ablation that obscured the scar border. After the terminal mapping study was completed, 2,3,5-triphenyl-2H-tetrazolium chloride solution was administered intravenously to enhance macroscopic scar visualization and facilitate cardiac arrest. The hearts were excised and fixed in formalin for 10–14 days. The hearts were subsequently sectioned into 5-mm short-axis slices (Figure 3A). Each short-axis slice was photographed and then imported digitally into and analyzed with image processing software (ImageJ, Rasband WS, US National Institutes of Health, Bethesda, MD). For each slice, the endo- and epicardial contours of macroscopic scar was traced and scar surface areas calculated as L ! 5 mm, where L is the traced length of scar measured at the endo- or epicardial surface (Figure 3B). As some portion of the scar was nontransmural, we defined the epicardial tracing length to include all segments with underlying scar even if the immediate underlying epicardial myocardium appeared healthy. The total LV endo- or epicardial scar surface area was thus calculated by summating the individual surface areas calculated from each short-axis slice.
Statistical analysis Continuous variables are presented as median with interquartile range. Between-group comparisons were performed using a generalized linear model with log-transformed outcomes as appropriate. A 2-sided a-level ,0.05 was considered statistically significant. Associations between continuous variables were assessed with the Spearman correlation test. Systematic differences between bipolar and microbipolar voltage amplitude were assessed in the 2 control pigs
semiquantitatively using Bland-Altman analysis. Any differences were then applied to the standard thresholds for low voltage (,1.5/1.0 mV for scar border zone in the LV endocardium/epicardium and ,0.5 mV for dense scar) on the microbipolar maps of the infarct animals (adjusted voltage maps).
Results EGM distribution A total of 5470 LV endocardial and 7250 epicardial points were acquired from the 6 infarct swine in total, and 658 LV endocardial and 965 epicardial points were acquired from control animals. In control animals, the median standard bipolar and microbipolar voltage values were 3.60 and 6.76 mV, respectively, in the LV endocardium (P 5 .002), and in the epicardium were 2.61 and 2.72 mV, respectively (P 5 .02). The 5th percentile bipolar and microbipolar thresholds were 1.12 mV and 1.22 mV, respectively, in the LV endocardium, whereas the values in the epicardium were 0.88 and 0.98 mV, respectively (Table 1 and Figure 4). There was strong correlation between bipolar and microbipolar peak-to-peak voltage amplitude in the infarct animals (LV endocardium: r 5 0.735, P ,.001; epicardium: r 5 0.775, P ,.001), and weak-to-moderate correlation in the control animals (LV endocardium: r 5 0.374, P ,.001; epicardium: r 5 0.590, P ,.001).
Bipolar vs microbipolar voltage amplitude In the control swine, microbipolar peak-to-peak voltage amplitudes were found to be systematically larger than bipolar voltage amplitudes in both the LV endocardium and
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Figure 3 A: Heart sectioned into 5-mm short-axis slices. B: Calculation of left ventricular (LV) endocardial/epicardial surface area per slice: endocardial/ epicardial contour length (blue and green line, respectively) ! 5 mm. The epicardial contour included all LV segments with underlying scar even if the immediately adjacent myocardium was healthy (to incorporate nontransmural scar). FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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5
Bipolar and microbipolar peak-to-peak voltage amplitude distributions in control swine LV endocardium (n 5 658)
Bipolar Microbipolar
Epicardium (n 5 965)
Median (IQR)
5th percentile
Median (IQR)
5th percentile
3.60 (2.61–5.25) 6.76 (3.86–9.70)
,1.12 ,1.22
2.61 (1.60–4.29) 2.72 (1.60–4.83)
,0.88 ,0.93
IQR 5 interquartile range; LV 5 left ventricle.
epicardium. Visual inspection of the Bland-Altman plots demonstrated the relationship of microbipolar/standard bipolar voltage to be a fixed ratio (2! for LV endocardium and 1.4! for epicardium) rather than a fixed absolute difference (Figure 5). “Adjusted” voltage amplitude thresholds for scar border zone and dense scar were calculated by multiplying the standard threshold values by these numbers. In the LV endocardium, dense scar and scar border zone was defined as ,1.0 mV and ,3.0 mV, respectively, on the microbipolar maps, and in the epicardium as ,0.7 mV and ,1.4 mV, respectively.
by standard and adjusted thresholds in each individual infarct animal are outlined in Table 2.
Gross pathology In the 2 infarct animals in which gross pathology was assessed, the scar surface area seemed numerically to best approximate the area of dense scar on the adjusted microbipolar voltage maps (Table 2), although formal statistical assessment of this relationship was not feasible with 2 animals.
Discussion Low-voltage areas on EA mapping In the infarct swine, the mean area of LV endocardial scar on the “unadjusted” microbipolar voltage maps defined using standard criteria (,1.5 mV) was 41% lower than that of the bipolar voltage maps (13.7 6 14.4 cm2 vs 33.4 6 14.5 cm2; P 5 .004). The mean area of epicardial scar on the unadjusted microbipolar voltage maps (,1.0 mV) was numerically lower than that of the bipolar voltage maps, although this did not achieve statistical significance (13.8 6 10.1 cm2 vs 25.4 6 23.9 cm2; P 5 .17). Scar surface areas when reassessed using adjusted microbipolar threshold values (,3.0 mV and ,1.4 mV for the LV endocardium and epicardium, respectively) better approximated those of the standard bipolar voltage maps (LV endocardium mean area: 31.9 6 18.5 cm2 vs 33.4 6 14.5 cm2, P 5 .69; epicardium: 22.0 6 16.2 cm2 vs 25.4 6 23.9 cm2, P 5 .46). Figure 6 shows an example set of LV endocardial and epicardial bipolar and microbipolar (unadjusted and adjusted) voltage maps in a swine. Representative EGMs are shown in Figures 2B and 2C. Low-voltage areas as defined
The main findings of this study are as follows. (1) Standard bipolar peak-to-peak voltage amplitude underestimates scar area by w40% when applied to an EA map acquired by microelectrodes. (2) Although the 5th percentile peak-to-peak voltage amplitudes are similar between those acquired by a traditional tip-to-ring bipole and the novel microelectrode bipoles, in our swine, EGMs acquired by the latter are, on average, 2.0! and 1.4! larger than EGMs acquired by the former in the LV endocardium and epicardium, respectively. (3) Adjustment of low voltage threshold values by a fixed ratio may adjust for differences in the area of scar delineated by microelectrode catheters. Substrate ablation for unmappable arrhythmias has become an integral component of contemporary VT management.2 An initial step involves approximating areas of scar as represented by low-voltage areas delineated on an EA map in sinus rhythm, as these areas are most likely to harbor the critical components of VT circuitry that need to be targeted for ablation.3 Reference values for “scar,” both in the
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Figure 4 Cumulative frequency graphs demonstrating despite similar 5th percentile thresholds for both bipolar and microbipolar voltage values. There is a greater positive skew of the microbipolar voltages, predominantly in the left ventricular (LV) endocardium. FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Figure 5 Bland-Altman plot demonstrating a fixed ratio relationship between paired microbipolar and bipolar voltage amplitudes: 1.4! for the epicardium and Q4 2.0! for the left ventricular (LV) endocardium.
endocardium and epicardium, have been established by researchers at the University of Pennsylvania, with bipolar voltage peak-to-peak amplitude values of ,1.5 mV and ,1.0 mV defining scar in the LV endocardium and epicardium, respectively.5,6 Any values below the 5th percentile of all sampled points in a small cohort of patients without macroscopic scar or structural heart disease were deemed abnormal. Point-by-point acquisition was performed manually using a standard mapping catheter of that era with a 4or 3.5-mm tip electrode and 2-mm tip-to-ring interelectrode distance. Despite the statistical (rather than pathologic) derivation, these standard values have stood the test of time and are the default reference ranges used universally in contemporary cases of scar-mediated VT.7
More recently, the advent of high-resolution multipolar mapping catheters holds the promise of not only faster but improved mapping resolution. Multiple electrodes in conjunction with automated acquisition algorithms allow rapid acquisition of EA maps with higher point density, whereas smaller electrode dimensions and tighter interelectrode distances allow for greater fidelity signals and a higher resolution “window” into the underlying substrate. Because electrode size and configuration can affect EGM characteristics including voltage,8 whether the standard bipolar voltage thresholds for scar should be applied to maps derived from these novel mapping catheters is unclear. Bipolar voltage, although often used as a surrogate for myocardial scar, conceptually reflects the magnitude and
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Figure 6 A–C: Left ventricular endocardial low-voltage zones as determined by standard thresholds (,1.5/,0.5 mV for scar border zone/dense scar) on bipolar and microbipolar maps (A, B) compared to adjusted microbipolar thresholds (C) (,3.0/,1.0 mV for scar border zone/dense scar). D–F: Epicardial lowvoltage zones as determined by standard thresholds (,1.0/,0.5 mV) on bipolar/microbipolar maps (D, E) compared to adjusted microbipolar thresholds (F) (,1.4/,0.7 mV). FLA 5.6.0 DTD HRTHM8174_proof 29 October 2019 2:33 pm ce
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Table 2
Underestimation of Scar by Microelectrode Catheters
7
Percent scar determined from bipolar electrodes, microbipolar electrodes, and pathology Bipolar
Swine
Unadjusted microbipolar
Adjusted microbipolar
Gross pathology
Area (cm2)
1
NA Endo Total scar Dense scar Epi Total scar Dense scar
31.5 14.5
5.9 0
23.4 1.2
22.4 6.7
7.6 0.5
15.4 4
2
NA Endo Total scar Dense scar Epi Total scar Dense scar
42.9 14.9
7.2 0.1
29.7 5.2
28.9 19.4
26.9 13.7
34.5 22.4
3
NA Endo Total scar Dense scar Epi Total scar Dense scar
54.6 38.3
41.2 18.4
64.8 45.6
71.1 33.5
25.2 10.2
48.2 18.7
12.1 0.6
0.3 0
8.5 0
4.8 0.3
2.1 0.3
4.1 0.8
4 Endo Total scar Dense scar Epi Total scar Dense scar
NA
5
10.3 Endo Total scar Dense scar Epi Total scar Dense scar
26.2 8.6
15 2.4
31.8 10.3
11.9 2.7
7.7 0.8
12.9 3.5
2.9
6
9.1 Endo Total scar Dense scar Epi Total scar Dense scar
32.9 14.8
12.3 2.9
32.9 11.3
13.3 7.6
13.1 5.7
16.6 10.3
4.5
Low-voltage area in individual postinfarct swine as defined by standard thresholds (,1.5/,0.5 mV for scar border zone/dense scar in the left ventricular [LV] endocardium, ,1.0/,0.5 mV in the epicardium) on bipolar and unadjusted microbipolar voltage maps and adjusted thresholds (,3.0/,1.0 mV in the LV endocardium and ,1.4/,0.7 mV in the epicardium) on adjusted microbipolar voltage maps with comparative areas of macroscopic scar determined on gross pathology in 2 animals.
direction of wavefront activation between 2 electrodes. Whereas “scarred myocardium” results in attenuated voltage by virtue of fibrous replacement of electrically active myocardial cell mass, many other factors can influence bipolar voltage, including catheter electrode configurations (electrode size, interelectrode distance), and aspects of the catheter/tissue interface, including the relative orientation of the recording bipole to wavefront activation and tissue contact.8 Additionally, the displayed voltage on an EA map may be affected by point density due to data interpolation. Multiple studies have consistently shown larger bipolar EGM voltage amplitude during mapping using catheters
with smaller electrodes,9–12 although the lowest 5th percentile values remain consistent with those acquired with the standard catheter configuration.10–12 This suggests that such a statistical method of determining scar on EA mapping based on standard catheters may not be appropriate for these novel catheters.
Previous studies Tanaka et al11 compared a high-density 64-electrode minibasket catheter (IntellaMap Orion, Boston Scientific, Marlborough, MA) to a linear quadripolar catheter during
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mapping of the LV in a swine model of postinfarct cardiomyopathy and compared total scar areas to those acquired by magnetic resonance imaging (MRI). They derived a 5th percentile cutoff (1.54 mV) similar to that in previous studies. Although no statistical difference was found, numerically the surface area derived by the linear catheter was larger (20.9 cm2 vs 17.8/17.5 cm2 for the basket catheter/MRI).11 Tschabrunn et al12 compared the use of a contemporary multipolar mapping catheter (PentaRay, Biosense Webster) to a contemporary mapping/ablation catheter (SmartTouch ThermoCool, Biosense Webster) in a swine model of postinfarct cardiomyopathy. Using 3 control animals, they demonstrated 5th percentile values were similar between the 2 catheters (1.62 and 1.48 mV for the SmartTouch ThermoCool and PentaRay catheters, respectively). However, in postinfarct animals, the area of scar delineated by bipolar voltage ,1.5 mV was 22.5% smaller when acquired with the PentaRay than with the standard catheter (21.7 vs 28.0 cm2; P 5 .003).12 Although these studies support the hypothesis that high-resolution mapping catheters delineate smaller areas of “low voltage” using standard voltage thresholds (,1.5 mV), whether these differences arise from properties intrinsic to the catheter or are due to differences in map point density as a result of multipolar mapping is unclear. In our study, every acquired point is associated with a paired bipolar and microbipolar voltage value, thus implying such differences are due to the properties of the recording electrodes alone as the point acquisition and density between both maps are identical. However, we cannot exclude the possibility that the presence of the tip electrode (upon which the microelectrodes are embedded) affects the EGM recordings from the microelectrode pairs by affecting local current. Notwithstanding properties intrinsic to the smaller electrode size, a factor that may contribute to greater microelectrode bipole voltage in the Qdot catheter specifically is the presence of 3 microbipolar vectors compared to only 1 standard bipolar vector. Because the value is determined by the largest of the 3 microbipoles, there is a greater chance that any one microbipole pair is oriented more orthogonally to the direction of wavefront activation than the standard tipto-ring vector. High-resolutionmapping cathetersallshare thesameproperties of smaller electrode sizes and tighter interelectrode distances. However, Tung et al13 found measured EGM amplitude to increase with greater interelectrode distances when measured using a linear duodecapolar catheter in which the electrode sizes were fixed. That most studies of highresolution catheters, including our own, demonstrate greater EGM voltage amplitudes suggests that other factors (smaller electrode size, greater number of microbipolar vectors) dominate the attenuating effect of the smaller interelectrode distance. Leshem et al10 also examined the Qdot catheter in a postinfarction swine model. They similarly found that although the 5th percentiles of voltage amplitude were similar between bipolar voltage acquired with the standard tip-to-ring bipole and the microelectrodes, the distribution of overall bipolar voltage was greater with the former and the area of low
voltage defined by standard parameters (,1.5 mV) was smaller. Our study builds on this finding by demonstrating a fixed ratio relationship between paired bipolar and microbipolar points, which allows the possibility of “correcting” the apparent scar area on voltage maps acquired with this highresolution mapping catheter. The Qdot catheter has similarities to the MiFi (Boston Scientific), another microelectrode catheter. This catheter has three w1-mm-diameter microelectrodes embedded radially within the distal electrode approximately 1.3 or 2.0 mm proximal to the tip (either 4.5-mm irrigated or 8-mm nonirrigated). A study examining the use of a preproduction model of this catheter with 4 microelectrodes embedded within an 8-mm nonirrigated tip demonstrated greater EGM voltage amplitudes when measured between the microelectrodes compared to those measured between the 8-mm tip and ring,14 a finding consistent with our study. However, this is difficult to reconcile with results from the same group using a similar catheter (but with only 3 microelectrodes) in which they found measured EGM amplitudes to be greater with the 8-mm tip-to-ring configuration compared to those measured by all 3 pairs of microelectrodes.15 Despite this finding, the preponderance of evidence suggests that EGM voltage amplitudes are greater when measured between smaller electrodes with smaller interelectrode differences,9–12,14 possibly due to a smaller “antenna” effect such that the recorded signal averages less of the surrounding far-field signal.
Study limitations This was a small animal study. It is possible that the ratio that we calculated for scar adjustment on microbipolar maps is not generalizable to human subjects undergoing mapping with this catheter. A future study in human subjects would be needed to determine this possibility. Although our data are consistent with those of previous studies demonstrating the somewhat counterintuitive finding that catheters with smaller electrodes record larger voltage values, our study is not able to offer insights into the mechanism of this phenomenon. Additionally, the inability to measure recorded microbipolar voltage values in the absence of the standard tip electrode limits the extrapolation of our findings to other microelectrode catheters in which the microelectrodes are embedded in a different configuration (eg, the MiFi catheter). Examination of gross pathology was performed in only 2 animals, so any comparison to mapping-derived metrics is descriptive. However, the accuracy of correlating pathologic to EA-derived scar is questionable because the former is measured ex vivo in a contracted/rigor mortis heart whereas the latter is acquired in vivo with stretching due catheter contact during diastole. In this regard, the robust and validated bipolar threshold values acquired by a standard tip-to-ring catheter may serve as a better “gold standard” for scar. Finally, the definition of epicardial scar in our study as measured using EA mapping and pathology included areas in which the scar was nontransmural. This has limitations
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Underestimation of Scar by Microelectrode Catheters
with regard to the significance of recorded EGM voltages, as previous studies have demonstrated a lack of correlation of endocardial voltage amplitude with imaging-proven scar on MRI in certain situations.16 Advanced imaging techniques such as cardiac MRI may serve as a better anatomic reference for scar, although this was not performed in our study. Scar characteristics including isolated potentials were not assessed in this study. We noted significant artifact/noise on microelectrode channels during manipulation of the shaft of these preliminary catheters that precluded the ability to assess for true isolated signals or fractionated EGMs.
Conclusion In a swine model of myocardial infarction, peak-to-peak bipolar voltage amplitude as sampled by a novel microelectrode catheter resulted in, on average, 2.0! and 1.4! greater voltage values than that obtained by a standard tip-to-ring bipolar (3.5-mm tip with 1-mm interelectrode distance) on the LV endocardium and epicardium, respectively. Although definitions of low voltage/scar using 5th percentile thresholds may not be appropriate for such catheter or electrode configurations, appropriate scar areas may be determined by applying a corrective ratio. Although high-resolution mapping catheters hold the promise of increased mapping resolution, appropriate voltage reference ranges for scar need to be established in humans before widespread clinical use.
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9 3. Hsia HH, Lin D, Sauer WH, Callans DJ, Marchlinski FE. Anatomic characterization of endocardial substrate for hemodynamically stable reentrant ventricular tachycardia: identification of endocardial conducting channels. Heart Rhythm 2006;3:503–512. 4. Gunda S, Reddy M, Pillarisetti J, et al. Differences in complication rates between large bore needle and a long micropuncture needle during epicardial access: time to change clinical practice? Circ Arrhythm Electrophysiol 2015;8:890–895. 5. Cano O, Hutchinson M, Lin D, et al. Electroanatomic substrate and ablation outcome for suspected epicardial ventricular tachycardia in left ventricular nonischemic cardiomyopathy. J Am Coll Cardiol 2009;54:799–808. 6. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–1296. 7. Tung R, Ellenbogen KA. Emergence of multielectrode mapping. Circ Arrhythm Electrophysiol 2016;9:e004281. 8. Anter E, Josephson ME. Bipolar voltage amplitude: what does it really mean? Heart Rhythm 2016;13:326–327. 9. Berte B, Relan J, Sacher F, et al. Impact of electrode type on mapping of scarrelated VT. J Cardiovasc Electrophysiol 2015;26:1213–1223. 10. Leshem E, Tschabrunn CM, Jang J, et al. High-resolution mapping of ventricular scar: evaluation of a novel integrated multielectrode mapping and ablation catheter. JACC Clin Electrophysiol 2017;3:220–231. 11. Tanaka Y, Genet M, Chuan Lee L, Martin AJ, Sievers R, Gerstenfeld EP. Utility of high-resolution electroanatomic mapping of the left ventricle using a multispline basket catheter in a swine model of chronic myocardial infarction. Heart Rhythm 2015;12:144–154. 12. Tschabrunn CM, Roujol S, Dorman NC, Nezafat R, Josephson ME, Anter E. High-resolution mapping of ventricular scar. Circ Arrhythm Electrophysiol 2016;9:e003841. 13. Tung R, Kim S, Yagishita D, et al. Scar voltage threshold determination using ex vivo magnetic resonance imaging integration in a porcine infarct model: influence of interelectrode distances and three-dimensional spatial effects of scar. Heart Rhythm 2016;13:1993–2002. 14. Price A, Leshen Z, Hansen J, et al. Novel ablation catheter technology that improves mapping resolution and monitoring of lesion maturation. J Innov Card Rhythm Manag 2012;3:599–609. 15. Avitall B, Horbal P, Vance D, Koblish J. Determinants of atrial lesion maturation during radio frequency ablation using localized tissue electrograms. J Innov Card Rhythm Manag 2014;5:1574–1585. 16. Josephson ME, Anter E. Substrate mapping for ventricular tachycardia: assumptions and misconceptions. JACC Clin Electrophysiol 2015; 1:341–352.
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