Lead I R‐wave amplitude to distinguish ventricular arrhythmias with lead V3 transition originating from the left versus right ventricular outflow tract

Abstract Background The electrophysiology algorithm for localizing left or right origins of outflow tract ventricular arrhythmias (OT‐VAs) with lead V3 transition still needs further investigation in clinical practice. Hypothesis Lead I R‐wave amplitude is effective in distinguishing the left or right origin of OT‐VAs with lead V3 transition. Methods We measured lead I R‐wave amplitude in 82 OT‐VA patients with lead V3 transition and a positive complex in lead I who underwent successful catheter ablation from the right ventricular outflow tract (RVOT) and left ventricular outflow tract (LVOT). The optimal R‐wave threshold was identified, compared with the V2S/V3R index, transitional zone (TZ) index, and V2 transition ratio, and validated in a prospective cohort study. Results Lead I R‐wave amplitude for LVOT origins was significantly higher than that for RVOT origins (0.55 ± 0.13 vs. 0.32 ± 0.15 mV; p < .001). The area under the curve (AUC) for lead I R‐wave amplitude as assessed by receiver operating characteristic (ROC) analysis was 0.926, with a cutoff value of ≥0.45 predicting LVOT origin with 92.9% sensitivity and 88.2% specificity, superior to the V2S/V3R index, TZ index, and V2 transition ratio. VAs in the LVOT group mainly originated from the right coronary cusp (RCC) and left and right coronary cusp junction (L‐RCC). In the prospective study, lead I R‐wave amplitude identified the LVOT origin with 92.3% accuracy. Conclusion Lead I R‐wave amplitude provides a useful and simple criterion to identify RCC or L‐RCC origin in OT‐VAs with lead V3 transition.


| INTRODUCTION
Outflow tract ventricular arrhythmias (OT-VAs) are the most common subgroup of idiopathic ventricular arrhythmias (VAs), with a high cure rate achieved by radiofrequency (RF) catheter ablation. [1][2][3][4] The majority (approximately 70%) of idiopathic VAs originate from the right ventricular outflow tract (RVOT). 5 Less commonly, 10%-15% of cases arise from the left ventricular outflow tract (LVOT) and surrounding regions. 6 VAs originating from the RVOT generally manifest a left bundle branch block (LBBB) electrocardiography (ECG) with R/S-wave precordial transition at or after lead V 3 , while those originating from the LVOT manifest an earlier transition at or before lead V 3 . 7 Although several criteria for ECG precordial leads have been proposed to differentiate the left from right origin, localizing the origin site of VAs with lead V 3 transition can still be challenging. [8][9][10][11][12][13][14] Lead I is a left-sided lead, and the LVOT lies posterior and rightward relative to the RVOT. 15 A negative complex in lead I typically suggests a site of origin (SOO) in the anterior RVOT, left coronary cusp (LCC), or adjacent left ventricle (LV) summit. 16,17 As the structure shifts more rightward, the QRS complex in lead I appears more positive. VAs originating from the LCC and LV summit commonly transit at lead V 1 or V 2 . 18 Thus, VAs with lead V 3 transition and a positive complex in lead I, which usually originate from the RVOT, right coronary cusp (RCC), and the left and right coronary cusp junction (L-RCC), need focused attention. We hypothesized that the R-wave amplitude in lead I would be useful for differentiating the SOO. 19 2 | METHODS After excluding patients with structural abnormalities or ischemic heart disease (n = 32) or arrhythmogenic right ventricular cardiomyopathy (n = 1), paced rhythm (n = 16), failed ablation (n = 31), incomplete records (n = 51), precordial transition (from R/S < 1 to R/S ≥ 1) at lead V 1 or V 2 (n = 62), or transitional lead later than V 3 (n = 44), we obtained ECG measurements from 109 cases of OT-VAs with lead V 3 transition. VAs with an R/S < 1 morphology in lead I (n = 27) were not included for analysis. Antiarrhythmic drugs were discontinued at least five half-lives before the ablation. All patients gave informed consent for the procedure. This study complied with the Declaration of Helsinki and was approved by the Institutional Review Board of the Second Hospital of Hebei Medical University.

| Electrophysiological study
A standard ten-pole diagnostic catheter was positioned in the coronary sinus and a standard quadripolar diagnostic catheter was placed in the right ventricle through the femoral vein. Mapping and ablation were performed with an 8-Fr, 3.5 mm-tip irrigated THERMOCOOL or SMARTTOUCH Catheter (Biosense-Webster, Diamond Bar, California, USA) via the right femoral vein (for the RVOT) or the right femoral artery (for the LVOT).

| Mapping and ablation
The CARTO three-dimensional (3D) electromagnetic mapping system (Biosense-Webster) and standard fluoroscopy were used to localize the SOO of the VAs. An electroanatomic shell of the RVOT was created via the right femoral vein. Activation mapping was performed during frequently spontaneous premature ventricular contractions (PVCs) or ventricular tachycardia (VT). In cases with infrequent ectopy, isoproterenol was injected (1-20 μg/min) to promote triggered activity and manifest PVCs/VT. The target site for ablation was the earliest activation site (EAS), preceding QRS onset by at least 20 ms, along with a QS pattern in the unipolar electrogram. If the ablation in the RVOT was unsuccessful or no satisfactory RVOT sites were identified, we created the electroanatomic shell of the LVOT and mapped the LVOT sites via a retrograde aortic approach (Figure 1 The target site for catheter ablation was evaluated using the 3D electroanatomic mapping system (Figure 1(E)) with standard fluoroscopy. If the target site was localized at the aortic sinus, the 3D shell of each cusp was accurately reconstructed with the CARTO system. To confirm the catheter position within or between the cusps of the aortic sinus, we injected a contrast agent through the irrigated catheter followed by angiography of the aortic sinus with a pigtail catheter ( Figure 1(F)-(G)). In addition, selective angiography of the coronary artery or aorta was performed to assess the safe distance between the ablation site and these structures.

| ECG measurement
Standard 12-lead ECG electrode placement was used. The electrodes for the chest and limb leads were carefully placed by an experienced technician. The 12-lead ECG morphologies of all patients during sinus rhythm (SR) and PVCs/VT were measured by two observers (who were blinded to the SOO) using electronic calipers on the recording system (the LEAD-9000 Electrophysiology Management System, Jinjiang Electronic Science and Technology Co., Ltd, Sichuan, China). The lead gain was uniform with a paper speed of 100 mm/s. Amplitudes were measured using the vertical caliper tool and ratios were manually calculated. The mean value of two measurements was used for analysis. During both SR and PVCs/VT, the following measurements were obtained: (1) R-and S-wave amplitudes in leads I, II, III, aVR, aVL, and V 1 to V 3 ; (2) R-and S-wave duration in leads I, II, III, aVR, aVL, and V 1 to V 3 ; (3) Total QRS duration; (4) R amplitude ratio in leads III to II (III/II ratio), and Q amplitude ratio in leads aVL to aVR (aVL/aVR ratio); (5) V 2 S/V 3 R index, transitional zone (TZ) index, and V 2 transition ratio. The T-P segment was considered the isoelectric baseline for measurement of R-and S-wave amplitude. In cases with an RS pattern in lead I, R-wave amplitude was defined as the difference between the highest and lowest point amplitude of the QRS complex. The total QRS duration was measured from the site of earliest initial deflection from the isoelectric line in any lead to the time of latest activation in any lead. The Rwave duration was measured from the site of earliest initial deflection from the isoelectric line to the time at which the R-wave intersected the isoelectric line. We standardized the SR measurements by measuring the largest R-and S-waves over a 10-s window at 25-mm/s sweep speed to minimize respiratory variation. The V 2 S/V 3 R index was calculated by computing the S-wave amplitude in lead V 2 divided by the R-wave amplitude in lead V 3 during the VAs. 10 The TZ index was calculated as follows: TZ score of the PVCs/VT minus the TZ score of the SR. 9 The TZ score was graded with 0.5-point increments according to the site of the R-wave transition (e.g., TZ The V 2 transition ratio was calculated as the percentage R-wave during VT (R/R + S) VT divided by the percentage R-wave in SR (R/R + S) SR . 14

| Prospective analysis
To evaluate the reliability of lead I R-wave amplitude, the measurement was repeatedly conducted in a prospective cohort of 39 patients with the same inclusion criteria between October 2019 and April 2020.

| Statistical analysis
Continuous variables are expressed as mean ± 1 SD. Normally distributed continuous variables were compared using the Student t test, and  software (SPSS Inc., Chicago, IL) was used for statistical analysis. A twotailed p value <.05 was considered significant.

| Patient baseline and ECG characteristics
The baseline patient characteristics and electrocardiographic characteristics are given in Table 1 p < .05). Other parameters including the TZ index and V 2 transition ratio did not show significant differences between these two groups.

| Predicted accuracy of lead I R-wave amplitude and other indices
The entire area under the curve (AUC) produced by ROC curve analysis is shown in Table 1. Among the ECG measurements and other indices, lead I R-wave amplitude exhibited the largest AUC of 0.926 (Figure 2(A)). The optimal cut-off value for predicting LVOT origin was 0.45, yielding 92.9% sensitivity and 88.2% specificity (Figure 2(B)). The AUC of the aVL/aVR ratio, III /II ratio and Q amplitude in aVL were 0.832, 0.782 and 0.798, and the cut-off value was 0.66, 0.86, and 0.67, respectively. The accuracy of the R-wave amplitude in lead I and other indices reported previously were calculated and are compared in Figure 2(A).

| Anatomic considerations and R-wave amplitude in lead I
The aortic root occupies the central location within the heart. The  In this study, the Q-wave amplitude in lead aVL and ratio of leads aVL to aVR are also significantly larger in the RVOT than in the LVOT.
Lead aVR/III and aVL/II have rightward and leftward vectors as additional horizontal approximations, respectively. 18 Although lead I reflects the horizontal dimension better than leads aVL/II or aVR/III, corroborating lead I R-wave amplitude with these indices to localize the SOO may also help to increase the accuracy.

| LIMITATIONS
In this study, several insufficiencies should be taken into consideration before attempting to apply the results. Cases with structural heart disease that affect cardiac anatomy were excluded. Other factors like BMI that have a potential influence on the attitudinal orientation of the heart did not produce significant differences between the LVOT and RVOT groups in this retrospective study.
However, we did not obtain cross-sectional cardiac images to exclude inter-individual variables. This may explain a few cases that did not match our criteria. Additionally, we used the location of the successful catheter ablation as the VA's site of origin. It is possible that the ablation lesions extended into adjacent structures and that VAs from the LVOT could be abolished via the RVOT.
Finally, due to the unreliability of pace mapping for VAs originating from the aortic sinus, 24 our study may be not suitable for pace mapping cases.

| CONCLUSION
Lead I R-wave amplitude provides a simple and useful criterion to distinguish LVOT from RVOT origin in VAs with lead V 3 transition and a positive complex in lead I. OT-VAs with lead V 3 transition and greater R-wave amplitude (≥0.45 mV) may originate from the RCC or L-RCC.
VAs with lead V 3 transition and smaller R-wave amplitude suggest an origin site in the RVOT.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

DATA AVAILABILITY STATEMENT
The datasets generated and/or analyzed during the current study are available from the corresponding author, Suyun Liu, upon reasonable request.