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I diopathic ventricular tachycardia and prematureventricular complexes (PVCs) arising from theventricular outflow tracts (OTs) are the most
common type of ventricular arrhythmias in theabsence of structural heart disease. Catheter ablationhas been demonstrated to be a curative therapy, with>80% success rates (1). An accurate method to predictthe site of successful ablation can guide and facilitatethe procedural strategy for mapping and ablation.However, the accuracy of 12-lead electrocardio-graphic localization can be affected and therebylimited by body surface anatomy, cardiac anatomy,rotation, and variability in electrocardiogram (ECG)lead placement (2).
Several electrocardiographic criteria have beenproposed to differentiate and localize the site oforigin of outflow tract PVCs (3–10). Although multipleelectrocardiographic criteria have been shown tohave diagnostic accuracy, the vast majority incorpo-rate the precordial transition into the localization al-gorithm. Because the right ventricular outflow tract(RVOT) and left ventricular outflow tract (LVOT) havean anteroposterior anatomic relationship, we soughtto prospectively evaluate the value of a dedicatedelectrocardiographic posterior lead to localize the siteof PVC origin between the RVOT and LVOT for cath-eter ablation. The prospective study was conductedin 2 phases: 1) derivation cohort for optimal cutoffdetermination; and 2) validation cohort with com-parison to 2 other published criteria.
METHODS
Consecutive patients referred for ablation of idio-pathic OT PVCs at 2 academic centers between2013 and 2015 were prospectively assessed. StandardV5 and V6 leads were placed on the back of the patient,with V5 located at the inferior tip of left scapular (V8)and V6 just left of the spine at the same level (V9)(Figure 1). This method was chosen to obviate the needfor additional leads beyond the standard 12-lead sys-tem because the incremental clinical value of V5 andV6 for outflow tract PVCs is low. Patients with struc-tural heart disease, permanent pacing, and bundlebranch block (BBB) were excluded. The institutionalreview boards at both participating centers approvedreview of this data.
Diagnostic catheterization and ablation were per-formed via the right femoral venous approach formapping of the RVOT and retrograde aortic approachwas used for mapping of the LVOT. Systemic hep-arinization was administered (goal: 250 to 300 s)during LVOT mapping and ablation. Isoproterenolwas administered intravenously if spontaneous PVCs
were not present in the baseline state orunder conscious sedation. Ablation was per-formed with standard activation mappingusing electroanatomic mapping systems(CARTO, Biosense Webster, Diamond Bar,California, or NAVX, St. Jude Medical, Min-neapolis, Minnesota). Irrigated catheterswere used for ablation (ThermoCool, Bio-sense Webster, Diamond Bar, California, orCoolFlex, St. Jude Medical, Minneapolis,Minnesota). The flow rate was 17 to 30 ml/min and applications were applied for 60 s(power: 30 to 50 W; temperature limit: 42�C).The location of the PVC was defined by thesuccessful site where radiofrequency appli-cation permanently suppressed ventricularectopy during the procedure. The RVOT wassubcategorized into 6 sections: 1) anteriorfree wall; 2) free wall; 3) posterior free wall;4) posteroseptal; 5) septal; 6) anteroseptal;
and 7) pulmonary artery. The LVOT was sub-categorized into: 1) right coronary cusp (RCC); 2) RCC-left coronary cusp (LCC) junction (RCC/LCC); 3) LCC;4) aorto-mitral continuity region; and 5) coronaryvenous system (great cardiac vein [GCV]-interventricular vein [AIV] junction).
ELECTROCARDIOGRAPHIC ANALYSIS: V4/V8 RATIO. Inall patients, the 12-lead ECG (V1 and V2 in the fourthintercostal space) was recorded during sinus rhythmand PVCs and measurements were made using theelectronic caliper of the recording system (PruckaCardiolab, GE Healthcare, Waukesha, Wisconsin, andEP LabSystem, Bard, Lowell, Massachusetts) at asweep speed of 100 mm/s with uniform lead gain.Amplitudes were measured using the vertical calipertool and ratios were manually calculated. The T-Psegment was used as the isoelectric baseline forR and S amplitude measurement. R-wave durationwas measure from the first deflection from baselineback to the return to baseline (T-P segment).
The following measurements were made for allpatients during both sinus rhythm and the PVC:
1. R-wave duration in V1
2. R-wave amplitude in V1 to V4
3. Precordial transition defined as the lead with R>S4. R and S wave amplitude of V2
5. R-wave amplitude of V8 and V9, if there was noR-wave present on V8 or V9, this was considered tobe zero
6. Ratio of PVC R-wave V4/V8
7. Ratio of sinus rhythm R-wave V4/V8
8. V4/V8 Index defined as the normalized ratio of PVCV4/V8 divided by sinus rhythm V4/V8 (Figure 1)
FIGURE 1 Posterior Lead Positioning, Measurement of V4/V8 Ratio and Index With Anatomic Basis for Anteroposterior Ratio
LVOT ¼ left ventricular outflow tract; PVC ¼ premature ventricular complex; RVOT ¼ right ventricular outflow tract.
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R-waves were measured from the isoelectric line asthe reference for both amplitude and duration. In theprospective validation cohort, the V4/V8 ratio andV4/V8 index were compared with the V2 transitionratio (cutoff $0.6) (6) and the V2S/V3R ratio(cutoff #1.5) (8). Sensitivity and specificity of eachtest was calculated and analysis was performed usingreceiver operator characteristic curves.
PROSPECTIVE DERIVATION AND VALIDATION. Theplanning of this prospective study involved 2 phases:1) prospective derivation of optimal cutpoints(n ¼ 134) and 2) prospective validation study (n ¼ 40).All cases included in both phases had placement ofthe posterior leads prior to mapping and ablation. Ourcentral hypothesis was that PVCs arising from theLVOT exhibit a higher V4/V8 ratio compared withRVOT origin because of earlier R-wave precordialtransition (V4) with the predominant vector movingaway from posterior lead (V8). Additionally, we hy-pothesized that comparing this ratio with the intrinsicsinus rhythm as a normalized index would improvediagnostic accuracy, as originally described byBetensky et al. As proof-of-concept, we pace-mapped
from different outflow tract regions to assess if agradient of R-wave loss in V8 was seen from right toleft in the first 5 patients (Figure 2).
STATISTICAL ANALYSIS. Continuous variable arepresented as mean standard deviation. Continuousvariables were compared with Student t test. Receiveroperator curves were used for sensitivity and speci-ficity analysis to calculate area under the curve(AUC). A p value <0.05 was considered statisticallysignificant.
RESULTS
DERIVATION COHORT. A total of 134 patientsunderwent ablation of PVCs with 2 modified posteriorleads (V5 and V6). The mean age was 45 � 15 years,and 37% were male. The mean ejection fractionwas 62 � 7% with a PVC burden of 24 � 12%.The PVC had a left bundle morphology in 88% ofcases. Thirty-three had left-sided sites of successfulablation (aorto-mitral continuity [AMC] region: 14;GCV-AIV: 8; RCC: 4; RCC/LCC junction: 3; LCC: 4) and101 had successful ablation from within the RVOT.
FIGURE 2 Morphologies seen During Pacemapping From RVOT to LVOT
With more leftward and posterior progression anatomically, a gradient of decreasing
R-wave is seen in posterior lead V5 (V8). AMC ¼ aorto-mitral continuity; GCV-AIV ¼ great
cardiac vein-interventricular vein junction; LCC ¼ left coronary cusp; RCC ¼ right coronary
cusp.
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The locations of the successful ablation sites areshown in Table 1. A mean 5 � 4 radiofrequency ap-plications were delivered in each patient to eliminatethe PVC. One patient (right BBB morphology) hadacute failure resulting from the proximity of thecoronary artery to the GCV earliest site of activation(V4/V8 ratio: 7.44; V4/V8 index: 3.66).
Increasing values for mean V4/V8 ratios wereobserved from anterior to posterior locations withanterior RVOT sites exhibiting a ratio of 0.65, post-eroseptal RVOT 2.29, RCC 7.77, and LCC 8.27. Asimilar increasing trend of mean V4/V8 index wasobserved, with anterior RVOT showing the lowestindex of 0.33, posteroseptal RVOT 1.03, RCC 2.32, andLCC 3.95. A summary of the V4/V8 ratios and V4/V8
indices normalized to sinus rhythm is shown inTable 2.
Overall, PVCs successfully ablated from the leftside had a statistically significantly higher V4/V8 ratiocompared with right-sided PVCs (11.7 � 10.6 vs. 2.3 �2.4, p < 0.001). At a cutoff >3, the V4/V8 ratio had asensitivity of 88% with a specificity of 77% (AUC: 0.89[0.83 to 0.94]) (Figure 3). When normalized to sinusrhythm, PVCs successfully ablated from the left sidehad a statistically significantly higher V4/V8 indexcompared with right-sided PVCs (4.7 � 3.5 vs. 0.9 �0.7, p < 0.001). At a cutoff >2.28, the V4/V8 indexhad a sensitivity of 67% with a specificity of 98%(AUC: 0.85 [0.78 to 0.91]). Discrimination with theV9 lead was not as strong as the V8 lead and thereforeV9 was not subsequently used. When using theV9 lead, the AUC for V4/V9 ratio was 0.86 (0.70 to0.92) with a sensitivity of 76% and specificity of 84%at a cutoff of >6.29.
PROSPECTIVE VALIDATION COHORT. Forty patientsunderwent ablation of PVCs with modified posteriorleads. The mean age was 44 � 16 years, and 35%were male. The mean ejection fraction was 61 � 8%with a PVC burden of 23 � 12%. The PVC had a leftbundle morphology in 100% of cases, and 48%(n ¼ 19) had a V3 transition. Twelve had left-sidedsites of successful ablation (LV RCC: 5; RCC/LCCjunction: 3; LCC: 4) and 28 had successful ablationfrom within the RVOT. The locations of the successfulablation sites are shown in Table 1. A mean of 5 � 4radiofrequency applications were delivered in eachpatient to eliminate the PVC. One patient had acutefailure because of the proximity of the coronaryartery to the AIV’s earliest site of activation leftbundle branch morphology PVC (V4/V8 ratio: 4.62).At the cutoff >3, the V4/V8 ratio had a sensitivityof 75% with a specificity of 82% (positivepredictive value [PPV]: 64%; negative predictive
value [NPV]: 89%) for left-sided locations. Whennormalized to sinus rhythm, the cutoff >2.28 for theV4/V8 index had a sensitivity of 67%, specificity of96%, PPV of 89%, and NPV of 87% for left-sided lo-cations. The V2 transition had a sensitivity of 67%,specificity of 67%, PPV 47%, and NPV 82% at acutoff $0.6 for left-sided PVCs. The V2S/V3R ratiohad a sensitivity of 36%, specificity of 71%, PPV33%, and NPV 74% at a cutoff of #1.5 (Table 3). Anexample of an LVOT PVC ablated from the rightside of the RCC/LCC commissure that was correctlypredicted only by the V4/V8 ratio and index is shown(Figure 4).
When analyzing 19 patients with a V3 precordialtransition, the sensitivity of V4/V8 and the V4/V8 in-dex was 67% and 67%, whereas the V2 transition andV2S/V3R had sensitivity of 50% and 40%, respectively.The specificity of V4/V8 and the V4/V8 index was 81%and 100%, whereas the V2 transition and V2S/V3R hadspecificity of 54% and 62%, respectively. The V4/V8
index had a positive predictive value of 100% andboth V4/V8 ratio and V4/V8 index had a negativepredictive value of 87% (Table 3). An example of anRVOT PVC with V3 transition that was correctly
TABLE 1 Baseline Characteristics of Patients in the Prospective Derivation
Aorto-mitral continuity region 14.15 � 18.76 4.21 � 3.92
Coronary venous system (GCV-AIV) 15.18 � 8.44 6.31 � 3.41
Values are mean � SD.
See Table 1 for abbreviations.
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predicted only by the V4/V8 ratio and index is shown(Figure 5).
DISCUSSION
The major findings of the present prospective studyare as follows.
1. A posterior modification of positioning lead V5 toV8 allows for the calculation of a novel ante-roposterior ratio, which improves the diagnosticaccuracy for differentiating left from right ven-tricular OT locations.
2. Normalizing the V4/V8 ratio to the patient’s sinusrhythm results in improved specificity and positivepredictive value for left-sided sites.
The cardiac anatomic orientation within thechest necessitates the relationship of “right” and“left” structures to be more accurately defined as“anterior” and “posterior,” respectively. Although theearly precordial R-wave amplitude of V1 and V2 duringPVCs arising from the aortic root is due to a leftwardorigin with respect to the right precordial leads, animportant contribution of the R-wave amplitude maybe attributed to a posterior to anterior vector.
As the RVOT rotates and wraps around the centralaorta, the portion of the RVOT adjacent to the pul-monary valves is leftward of the aortic root. Forthis reason, a dedicated lead on the back to comparethe relative amplitudes with vector analysis in ananteroposterior dimension has anatomic merit. Wechose the modification of placing V5 posteriorly toV8 because it does not require additional electrocar-diographic leads, simplifying its application inany clinical setting. More important, precordial tran-sition is typically most discriminatory at V3, making V5
and V6 relatively expendable for diagnostic localiza-tion. Igarashi et al. recently evaluating the localizationof PVCs with an 18-lead ECG, which included back andright-sided leads (11). In this study, an anteroposteriorratio was not evaluated and the most accurate pre-dictor was right-sided V5R.
Several criteria have been clinically useful todifferentiate right and left OTVT. Ouyang et al. re-ported a greater R-wave duration and R/S-waveamplitude ratio in leads V1 or V2 in LVOT origin (12).Distinctive morphologic patterns have been reportedto be specific for the LCC/RCC junction (3,13). Tanneret al. reported that outflow tract VTs with V3 transi-tions may arise from six distinct anatomic sites (14).The proportion of patients (48%) with V3 transition intheir validation group was higher than other pub-lished studies. More important, the V4/V8 index hasthe highest specificity (100%) in cases with a left BBB
FIGURE 3 Receiver Operator Characteristic Curves From V4/V8 Ratio and V4/V8 Index
Scatter plots for RVOT and LVOT sites are shown by V4/V8 ratio (A, C) and V4/V8 index (B, D). AUC ¼ area under the curve; other abbreviations
as in Figure 1.
TABLE 3 Test Characteristics
Sensitivity Specificity PPV NPV
Predictive of left-sided location in the prospective cohort
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pattern with V3 transition, which is clinically mostchallenging to differentiate right from left locations.
The reproducibility of electrode placement be-tween technicians and various clinic and proceduralsettings is limited. Further, variable chest–heart re-lationships resulting from cardiac orientation androtation limits the generalizability of any ECGcriteria. One logical method to mitigate these varia-tions requires interpretation of normalized or“indexed” precordial transition with respect to thesinus rhythm transition. Betensky et al. (6) demon-strated this concept in a series of patients withretrospective and prospective evaluation, showingthat the V2 transition ratio outperformed traditionalcriteria. For the same reason, we report that the
FIGURE 4 Case Example of LVOT PVC With Inaccurate Prediction Using Other ECG Criteria (V2 Transition Ratio and V2S/V3R)
Both V4/V8 ratio and V4/V8 index accurately predicted the successful ablation site on the right side of the RCC/LCC junction in the aortic root.
ECG ¼ electrocardiogram; LAO ¼ left anterior oblique; other abbreviations as in Figure 2.
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V4/V8 index has greater specificity and positive pre-dictive value than a single PVC value in isolation.Although this does require an additional step inanalysis, the rationale for this correction allows foreach subject to serve as their own control whencalculating an ECG parameter and the present datafurther support this notion.
The strength of the present study is the prospec-tive comparison with other validated criteria. Wefound that this anteroposterior ratio of V4/V8 out-performed previously validated criteria with ademonstrated diagnostic accuracy >90%. The major-ity of the published ECG criteria to localize PVCorigin have not been prospectively evaluated, withthe exception of Betensky et al. (6) and Ito et al. (9).To our knowledge, this is the largest prospective(n ¼ 174) examination of ECG criteria for differenti-ating left from right OT ventricular arrhythmias. Ahighly specific ECG criterion for left-sided successfulablation sites has several clinical advantages. First,mapping of the OT regions is conventionally per-formed from right to left. Unnecessary ablation andmapping can be avoided if left-sided origin is
suggested, because perforations are most commonlyseen in the RVOT. Additionally, non-RVOT sites oforigin have been reported to have greater associationwith PVC-induced cardiomyopathy (15,16) as well asrisk for sudden death (10). The identification of thesesubsets from a modified 12-lead ECG even in the clinicsetting can be helpful for patient consultation andprocedural planning.
STUDY LIMITATIONS. We chose the inferior pointof the scapula as a reference point for localizationfor posterior lead placement for reproducibility. Aswith anterior electrode placement, the relative anat-omy of an individual cardiac position in relation tothe scapula has inherent variability with variationsin body habitus. It is not clear how anatomic varia-tions and obesity affect the anteroposterior ratio,but we believe that the indexing to sinus rhythmhelps overcome part of these limitations. Further,this anteroposterior vectoral approach is leastconfounded if V4 and V8 are situated at the exactsame craniocaudal level. A more inferior displace-ment of 1 lead relative to the other could alter
FIGURE 5 Case Example of RVOT PVC With Inaccurate Prediction Using Other ECG Criteria (V2 Transition Ratio and V2S/V3R)
Both V4/V8 ratio and V4/V8 index accurately predicted the successful ablation site in the posteroseptal RVOT. Abbreviatons as in Figures 1 and 4.
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R-wave amplitude that is not indicative of theanteroposterior relationship. Because of improvedreceiver operating characteristic curves and testcharacteristics in lead V8 compared with V9, we didnot report the details and characteristics of V9
lead data. Further, the value of alternate posteriorECG site locations was not tested in this study,but we believe that the utility of a single lead relativeto the scapula is useful for ease of clinicalimplementation.
PVCs with a right BBB pattern pose less of adiagnostic dilemma, but these cases were onlyincluded as proof of concept in the derivation study.Last, ablation may be successful from multiple lo-cations because of the close relationship of the RVOTand LVOT, particularly in the posterior RVOT rela-tive to the RCC, which both provide access to thehighest portion of the interventricular septum. Theclassification of such sites has an element of arbi-trariness and likely reflects the same region oforigin. This may explain the relatively larger stan-dard deviation seen in cases successfully ablatedfrom the RCC. Preferential exits can occur across theseptum from the site of origin and also account forwide standard deviations because the 12-lead ECG
only reflects the exit site (17). Because simultaneousmapping from both outflow tracts was not requiredbefore ablation, it is possible that earlier sites ofactivation relative to the ablation site may have beenfound in other regions. For this reason, we chose aclinically practical definition to serve as the PVClocation gold standard, where the PVC was perma-nently suppressed by ablation, rather than activationtiming.
CONCLUSIONS
A simple modification of precordial lead V5 posteri-orly to V8 may provide incremental diagnostic valuefor localizing PVCs arising from the outflow tracts. Inaddition to this novel anteroposterior ratio, normal-izing PVC localization criteria to the sinus rhythmresults in the highest specificity when compared withother validated criteria.
ADDRESS FOR CORRESPONDENCE: Dr. RoderickTung, The University of Chicago Medicine, Center forArrhythmia Care, 5841 South Maryland Avenue, MC6080, Chicago, Illinois 60637. E-mail: [email protected].
appreciate the limitations of current precordial lead
placement for localizing outflow tract PVCs that have an
anatomic anterior to posterior orientation. To understand
that the V4/V8 ratio outperformed previously published
criteria in the largest prospective analysis of PVC
localization to date.
TRANSLATIONAL OUTLOOK 1: The present study
suggests that enhancement of ECG localization can be
achieved by creating an anteroposterior ratio using a
standard 12-lead ECG with placement of V5 on the back
under the scapula.
TRANSLATIONAL OUTLOOK 2: Improved
identification of left-sided successful sites of ablation
may improve preprocedural consultation, planning,
and identifying patient subsets that may be at
higher risk.
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KEY WORDS ablation,electrocardiography, leads, posterior,premature ventricular contraction
