Author + information
- Received November 2, 2017
- Revision received January 25, 2018
- Accepted February 1, 2018
- Published online June 18, 2018.
- Gijsbert F.L. Kapel, MDa,
- Charlotte Brouwer, MDa,
- Zakaria Jalal, MDb,c,
- Frédéric Sacher, MD, PhDb,
- Jeroen Venlet, MDa,
- Martin J. Schalij, MD, PhDa,
- Jean-Benoît Thambo, MD, PhDc,
- Monique R.M. Jongbloed, MD, PhDa,
- Nico A. Blom, MD, PhDa,
- Marta de Riva, MDa and
- Katja Zeppenfeld, MD, PhDa,∗ ()
- aDepartment of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
- bElectrophysiology and Heart Modeling Institute, Bordeaux University Hospital, Bordeaux, France
- cDepartment of Paediatric and Adult Congenital Cardiology, Bordeaux University Hospital, Bordeaux, France
- ↵∗Address for correspondence:
Dr. Katja Zeppenfeld, Department of Cardiology, Leiden University Medical Centre, C5-P, PO Box 9600, 2300 RC Leiden, the Netherlands.
Objectives This study sought to evaluate the influence of slow conducting anatomic isthmuses (SCAI) as dominant ventricular tachycardia (VT) substrate on QRS duration.
Background QRS prolongation has been associated with VT in repaired tetralogy of Fallot.
Methods Seventy-eight repaired tetralogy of Fallot patients (age 37 ± 15 years, 52 male, QRS duration 153 ± 29 ms, 67 right bundle branch blocks [RBBB]) underwent programmed stimulation and electroanatomic activation mapping during sinus rhythm. Right ventricular (RV) surface, RV activation pattern, RV activation time, conduction velocity at AI, and remote RV sites were determined.
Results Twenty-four patients were inducible for VT (VT+); SCAI was present in 22 of 24 VT+ but only in 2 of 54 patients without inducible VT (VT−). Conduction velocity through AI was slower in VT+ patients (median of 0.3 [0.3 to 0.4] vs. 0.7 [0.6 to 0.9] m/s; p < 0.01) but conduction velocity in the remote RV did not differ between groups. In non-RBBB, QRS duration was similar in VT+ patients (n = 6) and VT− patients (n = 5), but RV activation within SCAI exceeded QRS offset in VT+ patients (37 ± 20 ms vs. –5 ± 9 ms, p < 0.01). In RBBB, both QRS duration and RV activation time were longer in VT+ patients (n = 18, 17 of 18 QRS > 150 ms) compared with VT− patients (n = 49, 27 of 49 QRS > 150 ms) (173 ± 22 ms vs. 156 ± 20 ms; p < 0.01; 141 ± 22 ms vs. 129 ± 21 ms; p = 0.04). In VT+ patients, QRS prolongation >150 ms (n = 17) was due to SCAI or blocked isthmus in 15 patients (88%) and 1 (6%). In contrast, in VT− patients, QRS prolongation >150 ms (n = 27) was due to enlarged RV or blocked isthmus in 10 patients (37%) and 8 (30%), but due to SCAI in only 1 (4%). After exclusion of a severely enlarged RV, a QRS duration >150 ms was highly predictive for SCAI/blocked AI (OR: 17; 95% CI: 3.3 to 84; p < 0.01).
Conclusions A narrow QRS interval does not exclude VT-related SCAI. In the presence of RBBB, SCAI further prolongs QRS duration. QRS duration >150 ms is highly suspicious for SCAI or isthmus block distinguishable by electroanatomic mapping.
As a result of earlier repair and evolving surgical techniques, the majority of patients with repaired tetralogy of Fallot (rTOF) survive to adulthood (1–3), but they may remain at risk of sudden cardiac death (SCD) due to ventricular arrhythmias (VA) (4,5). Monomorphic ventricular tachycardia (VT) is the most common arrhythmia subtype affecting >14% of patients and accounting for >80% of appropriate implantable cardioverter-defibrillator therapies (6,7). Over the last decades, efforts have been made to noninvasively identify rTOF patients at risk for VT. Although no single risk factor has shown sufficient independent predictive value for the presence of an arrhythmic substrate in an individual patient, a prolonged QRS duration >180 ms has consistently been associated with VT and SCD (8–10). In contemporary cohorts, a lower QRS cutoff value to identify a patient at risk has been suggested and attributed to advances in surgical approaches (11,12). The modern transatrial-transpulmonary surgical approach with smaller transannular patches may not only prevent severe pulmonary valve regurgitation and right ventricular (RV) dilatation, but also right bundle branch damage. Accordingly, contemporary rTOF patients may have less RV dilatation, different RV activation patterns, and even a narrow post-operative QRS interval (13). QRS prolongation was initially thought to be the combined effect of a surgically created right bundle branch block (RBBB) and progressive, RV dilatation with global conduction delay, the latter creating a substrate for VT (9). However, invasive electroanatomic mapping studies have demonstrated that the dominant substrate for VT are slow conducting anatomic isthmuses (SCAI) confined to the right ventricular outflow tract (RVOT) (14). We hypothesize that the interplay between a post-operative RBBB and conduction delay in SCAI determines the RV activation pattern and QRS prolongation. The objective of this study is to evaluate, with the use of invasive electroanatomic mapping, whether QRS prolongation is due to localized conduction delay across SCAI, rather than due to global conduction delay.
The cohort consisted of 83 consecutive rTOF patients with either documented sustained VT, or considered at risk for VT and/or with indication for reoperation who underwent electrophysiological evaluation and RV electroanatomic mapping (EAM) between 2005 and 2013 at Leiden University Medical Center (n = 53) and Bordeaux University Hospital (n = 30). Patients were considered at risk for VT if ≥1 of the following risk factors was present: syncope, nonsustained VT on Holter monitor, QRS duration ≥180 ms, late repair (≥5 years), at least moderately depressed RV or left ventricular (LV) function or presence of a transannular patch (9,10,15–19). The Dutch Central Committee on Human-Related Research permits use of anonymous data without prior approval of an institutional review board, if the data are obtained for patient care and if the data do not contain identifiers that could be traced back to the individual patient. All patients were treated according to our standard clinical protocol and provided informed consent (14).
Patient records were reviewed for date and type of repair, device implantation, and documented VA. Nonpaced 12-lead electrocardiograms (ECG) recorded at 25 mm/s were assessed for QRS duration and intraventricular conduction disturbances. In 53 of 83 patients, QRS duration was also measured using LEADS (Leiden ECG Analysis and Decomposition Software) (Leiden University Medical Center, Leiden, the Netherlands) (see the Online Methods) (20). Holter recordings were reviewed for nonsustained VT. RV and LV cardiac function was assessed by cardiac magnetic resonance (CMR) and/or echocardiography. A mildly reduced or good RV function (RV ejection fraction >40%) with a tricuspid plane systolic excursion ≥14 mm and LV ejection fraction ≥40% were classified as preserved RV and LV function, respectively (21). Cardiac volumes were determined by CMR and indexed for body surface area. RV end-diastolic volume index ≥180 ml/m2 was considered severely enlarged (22).
EAM and electrophysiological evaluation
Programmed electrical stimulation (PES) was performed (see the Online Methods). Sustained VT was defined as lasting ≥30 s or causing hemodynamic compromise requiring termination. A detailed 3-dimensional EAM of the RV was constructed during sinus rhythm (SR) using a nonfluoroscopic mapping system (Carto3 and CartoXP, Biosense Webster, Irvine, California). The endocardial RV surface was measured using dedicated tools of the Carto system. EAM RV surface was compared with CMR-derived volume. All mapping points were reviewed offline for correct annotation of the local activation time, defined as the sharp bipolar electrogram coinciding with the fast down-stroke of the unipolar electrogram. All activation maps were displayed as isochronal maps and as propagation maps (Online Videos 1 and 2) to determine RV activation pattern. The site(s) of earliest and latest RV activation were identified and the total RV activation time was calculated. Earliest onset and latest offset of the QRS complex in any lead were annotated on Carto to assess QRS duration. QRS duration, total right ventricular activation time (RVAT), and intervals between onset of QRS and onset of RV activation, and between offset of QRS and offset of RV activation were measured using electronic calipers (sweep speed 200 mm/s) (Figure 1).
AI characteristics and its relation to VT
The identification of anatomic isthmuses (AI) in rTOF has been described in detail in the Online Methods (23). Isthmus 1 is located between the tricuspid annulus (TA) and the RVOT patch/RV incision; isthmus 2 between the RV incision and the pulmonary valve (PV). Isthmuses 3 and 4 are located at the infundibular septum, with isthmus 3 between PV and the ventricular septal defect (VSD) patch, and isthmus 4 between the VSD patch and TA (23). The electroanatomic characteristics of each identified AI were assessed. The fill threshold for EAM of the AI was set at ≤10 mm and care was taken to delineate the length of the isthmus by recording the first normal voltage electrograms at isthmus entrance and exit sites (14). Isthmus length is the distance between entrance and exit sites and the conduction time through the isthmus is the difference between the local activation time at isthmus entrance and exit. The isthmus conduction velocity (CV) was calculated (isthmus length/conduction time). CV was measured in the direction of the RV propagation wave front during SR. In selected patients, we have performed differential pacing close to the AI to differentiate between slow conduction and block. SCAI was defined as isthmus with low bipolar voltage electrograms (<1.5 mV) and a CV <0.50 m/s (14). Based on the first quartile of CV distribution in normal control subjects, a CV ≥0.50 m/s and ≤0.63 m/s was considered borderline CV (14). An AI was classified as having a pre-existing conduction block if either no excitable tissue between its anatomic boundaries could be identified or double potentials could be recorded along the AI and in addition the RV activation sequence during SR was consistent with propagation toward the isthmus from both sites. Septal block was defined as a pre-existing conduction block at isthmus 3 in case of perimembranous VSD (absence of isthmus 4) or as a pre-existing conduction block at both isthmus 3 and 4 in case of muscular VSD. Whether an induced VT was dependent on a SCAI was determined by pace-mapping (≥11/12 pace match) and/or concealed entrainment and/or diastolic activation during VT with VT termination by radiofrequency delivery (23). To compare CV within and remote from AI, the CV was calculated for 3 additional RV areas: RV septum, RV free wall, and low RVOT free wall (see the Online Methods).
Continuous data are presented as mean ± SD or median (interquartile range [IQR]) according to distribution. Categorical data are reported as percentages or frequencies. The difference in QRS duration measured with LEADS on 12-lead ECG and using the Carto system was assessed by paired Student’s t-test. Patients with and without VT were compared using IQR, Mann-Whitney U, and chi-square tests where appropriate, including subgroups. Associations among QRS duration, RV volumes on CMR, and RV area on EAM were assessed by Pearson correlation. The relation between: 1) QRS duration and RVAT; and 2) QRS duration and RV activation after QRS offset was illustrated with a scatterplot for all patients and patients with and without RBBB, dots were marked for VT inducibility. QRS duration of RBBB patients were illustrated with an aligned scatterplot, according to VT profile. In addition, in these patients, the unadjusted odds ratio (OR) of QRS duration of >150 ms was calculated for AI properties using logistic regression. SPSS version 22.0 for Windows (IBM, Armonk, New York) was used. A value of p < 0.05 was considered significant.
Eighty-three patients underwent electrophysiological evaluation. Five patients with an incomplete RV map or maps acquired during ventricular pacing were excluded. One patient had undergone a prior VT ablation in another center. Subsequently, the study population consisted of 78 patients (age 37 ± 15 years, 67% male) who were repaired at a median age of 5.0 years (IQR: 2.1 to 8.5 years). Eleven patients (14%) had documented sustained VT. QRS duration was 153 ± 29 ms. Sixty-seven patients (86%) had a broad QRS interval (>120 ms), all RBBB configuration, and 11 patients had a narrow QRS interval. Thirteen patients (17%) had QRS duration ≥180 ms. All but 2 patients had a preserved LV function and 47 (60%) a preserved RV function. Baseline characteristics are provided in Table 1.
EAM and electrophysiological evaluation
RV activation time during SR was 130 ± 24 ms. QRS duration did not differ when measured on pre-procedural 12-lead ECG or on Carto (OR: −1.8 ms; 95% confidence interval [CI]: –4.0 to 0.4 ms; p = 0.11). The electroanatomic RV surface was 249 ± 66 cm2 and showed a significant correlation with the RV end-diastolic volume derived from CMR (r = 0.68, p < 0.001) (Online Figure 1). A RV end-diastolic volume index of >180 ml/m2 (severely dilated RV) corresponded to a RV surface of >293 cm2 observed in 15 patients (19%). For the entire population, neither the RV surface nor the RV volume correlated to QRS duration (r = 0.14, p = 0.22; r = 0.07, p = 0.55, respectively) (Online Figure 2).
AI characteristics and its relation to VT
All patients had at least 1 AI and 24 (31%) at least 1 SCAI, which was SCAI 3 in the majority (21 of 24). One of the 21 patients with SCAI 3 had normal conduction through isthmus 4, compensating for septal conduction delay, and 1 patient had only septal SCAI 4. Accordingly, 21 of 24 patients with any SCAI showed slow conduction at the infundibular septum. In 9 patients, a pre-existing block of an AI was observed, which was septal isthmus 3 in all. Thirteen patients had at least 1 AI with borderline CV, which was also isthmus 3 in all.
Twenty-four patients (31%) (including all 11 patients with spontaneous VT) were inducible for a total of 34 VT (median VT cycle length: 247 ms; IQR: 230 to 287 ms). In 22 patients (92%) with 32 VT, SCAI was the substrate for all clinical and induced VT (see the Online Results), which was a septal SCAI (3 or 4) in 19 of 22 patients (86%). There was no difference in AI CV between the 11 patients with spontaneous and inducible VT (median: 0.27 m/s; IQR: 0.20 to 0.32 m/s) and the 13 patients with only inducible VT (median: 0.34 m/s; IQR: 0.29 to 0.42 m/s; p = 0.16). In contrast, SCAI was found in only 2 of 54 patients (4%) without documented or induced VT. Slow conduction was not observed remotely from the AI. The electroanatomic CV for the RV septum, RV free wall, and RVOT free wall were 1.3 ± 0.3 m/s, 1.3 ± 0.3 m/s, and 0.9 ± 0.2 m/s, respectively, and did not differ between patients with or without VT. Fourteen of the 22 patients with SCAI-related VT underwent successful ablation, defined as noninducibility of any VT and transection of the SCAI. Two patients had no VT, but did have SCAI 3 and underwent successful ablation defined as bidirectional block of the SCAI. All 68 patients without SCAI (52 at baseline, 16 after ablation) remained free from VT during follow-up (39 ± 24 months). Detailed acute and long-term ablation outcome are added to the Online Results.
QRS duration, RV activation time and pattern according to VT inducibility
For the entire population, QRS duration did not differ significantly between patients with and without VT (157 ± 35 ms vs. 151 ± 25 ms, p = 0.411). However, the RVAT was significantly longer in patients with VT (142 ± 23 ms vs. 125 ± 23 ms in non-VT patients, p = 0.005) (Table 2).
A subgroup analysis was performed according to presence or absence of RBBB:
1. In patients with narrow QRS interval (non-RBBB), QRS duration was similar in patients with and without VT (108 ± 11 ms and 101 ± 11 ms, p = 0.429), whereas the RVAT was longer in patients with VT (143 ± 30 ms vs. 91 ± 12 ms in patients without VT, p = 0.017). In all patients, the earliest RV activation during SR was observed simultaneously at the distal septum and at the anterior RV free wall followed by rapid propagation of activation wave fronts toward the lateral and septal RVOT. The onset of RV activation coincided or was close to the QRS onset (3 ± 12) in patients with and without VT (p = 0.931). However, QRS offset and RV activation offset coincided only in those without VT. In non-RBBB patients with VT, the latest RV activation exceeded QRS offset by 37 ± 20 ms (Figures 2D and 2E, Online Figure 3) and was located at the exit site of the VT-related SCAI in all patients. These small late activated areas with low bipolar voltages did not contribute to the 12-lead surface ECG as demonstrated in Figure 3. RV size and RV CV remote from the AI was similar between non-RBBB patients with and without VT (Table 3).
2. In patients with RBBB, both QRS duration and RVAT were longer in patients with VT as compared to patients without VT (173 ± 22 and 141 ± 22 vs. 156 ± 20 and 129 ± 21, p = 0.004 and p = 0.036, respectively). Of interest, only 6 of 18 with VT had a QRS duration ≥180 ms, but all but 1 had a QRS duration >150 ms. In contrast, only 27 (55%) of the 49 RBBB patients without VT had QRS duration >150 ms. In all RBBB patients, earliest RV activation was observed in a broad area at the mid-to-basal RV septum, but not at the RV free wall. In patients without VT and normal conducting AI, activation propagated in different wave fronts: from the RV septum through the septal AI and AI 1, across the inferior wall and across the RV free wall, with fusion of wave fronts typically at the basal lateral TA being the latest RV activated area (Figure 4, Online Video 1). In patients with VT and septal activation delay or delay in AI 1, the latest activated RV area shifted toward the lateral RVOT (Figure 4, Online Video 2). The prolongation of the pathway for total RV activation resulted both in increase in RVAT and QRS duration. Of note, the same activation pattern and prolongation of RV activation and QRS duration was observed in 8 patients without VT and a pre-existing septal isthmus block (excluding the septal isthmus as substrate for VT). In RBBB patients, the onset of the RV activation was recorded 26 ± 12 ms after the onset of the QRS both in patients with and without VT (p = 0.305). Furthermore, QRS offset and RV activation offset coincided (−3 ± 8 ms, p = 0.524) in patients with and without VT (Figure 2F and Online Figure 3). As in patients with narrow QRS, CV of the RV remote from AI and the RV endocardial surface did not differ between patients with and without VT (Table 3).
Interplay among QRS duration, RV size, SCAI, and VT in patients with RBBB
Of the 18 patients with RBBB and VT, 17 had a QRS duration >150 ms, 16 had SCAI, but only 4 had severely dilated RV (Figure 5). Accordingly, in patients with RBBB and VT, SCAI was the most prevalent mechanism for QRS prolongation. The only patient with RBBB, VT, and QRS duration <150 ms had SCAI 3–related VT. However, the second fast conducting septal isthmus 4 prevented septal activation delay and QRS prolongation.
In contrast, of the 49 RBBB patients without VT, only 27 had QRS duration >150 ms. Of these 27 patients, the majority (n = 16; 59%) had a severely enlarged RV without SCAI (n = 10; 37%) and/or a pre-existing blocked septal isthmus (n = 8; 30%) as mechanisms for QRS prolongation (Figure 5). In contrast, none of the 22 patients without VT and QRS duration ≤150 ms had either a severely dilated RV or a blocked septal isthmus. These data suggest that in contemporary rTOF, a QRS duration between120 and 150 ms is solely due to the post-operative RBBB.
The presence of RBBB with QRS duration >150 ms was strongly associated with the presence of a slow conducting or blocked isthmus (OR: 13.8; 95% CI: 2.9 to 66.2; p = 0.001). After exclusion of patients with severely enlarged RV (n = 14), the OR of a QRS duration >150 ms for slow conducting or blocked AI was 16.6 (95% CI: 3.3 to 84; p = 0.001).
To the best of our knowledge, this is the first study using detailed 3-dimensional RV EAM to assess the relation among QRS duration, RV size, and RV activation during SR and the substrate for re-entry VT in patients with rTOF. We could demonstrate that rTOF patients with a narrow QRS can be at risk for life-threatening VT related to SCAI. Rapid activation through the distal specific conduction system with fusion of wave fronts at the infundibulum can mask slow conduction in septal AI. In these patients, the surface ECG does not contribute to substrate identification. In contrast, in rTOF patients with a pre-existing RBBB at any level, VT-related SCAI further prolong the pathway for total RV activation resulting in QRS duration >150 ms. A similar QRS prolongation in rTOF patients with RBBB but without SCAI can be observed in those with a severely dilated RV or with pre-existing septal isthmus block. After exclusion of severe RV dilatation, QRS duration >150 ms is highly predictive for conduction delay at the infundibular septum as potential substrate for VT. To further distinguish between conduction delay within an AI as substrate for VT and conduction block requires EAM.
VA and SCD in rTOF
Monomorphic ventricular tachycardia (MVT) is the most commonly documented arrhythmia subtype in rTOF (6,7,14). Considering the typically short cycle length, MVT may lead to SCD even if the biventricular function is preserved (4,5,24). EAM studies have demonstrated that the dominant underlying mechanism of MVT is macro-re-entry using SCAI located in the RVOT (14,23). In the present cohort, SCAI was the substrate for all clinical and induced VT in 22 of 24 patients.
QRS prolongation as risk factor for VT and SCD
A prolonged QRS duration has consistently been associated with both MVT and SCD in rTOF (8–10). In a large series of 182 patients, all 13 patients with (near-missed) SCD had QRS ≥180 ms, which was observed in only 5.3% of patients without an event. Of importance, all 9 SCD survivors underwent PES and were inducible for monomorphic fast re-entry VT, suggesting that MVT had caused the event and that QRS prolongation may predict the substrate for re-entry VT (9). PES performed in 134 unselected rTOF patients confirmed the association between QRS duration ≥180 ms and MVT. A QRS duration ≥180 ms was 35% sensitive and 97% specific for inducibility of any MVT and 100% sensitive and 96% specific for inducibility of the clinical VT (8). A subsequent multicenter study demonstrated that QRS duration ≥180 ms was the strongest independent predictor for VT with a remarkable hazard ratio of 41.9 (95% CI: 14.7 to 119.4) (10). In more recent cohorts, the reported sensitivity of QRS duration ≥180 ms for death or VT was much lower (28% to 53%) and a cutoff value of 170 ms has been suggested (sensitivity 53%, specificity 86%) (11,12). Similarly, in our cohort, QRS duration ≥180 ms was observed in only 6 of 24 patients (25%) with VT and in 7 of 54 (13%) without VT.
A modern transpulmonary approach may prevent a post-operative RBBB. As a consequence, an important number of contemporary rTOF patients have a narrow QRS interval without RBBB, which may influence the predictive value of a prolonged QRS for VT/SCD if patients with and without RBBB are not separated. We could only demonstrate a significant difference in QRS duration between patients with and without VT after excluding the 11 rTOF patients (14%) with a narrow QRS interval. Of importance, the use of smaller transannular patches may reduce PV regurgitation and RV dilatation. As a result, contemporary patients, with post-operative RBBB may still have less additional QRS prolongation, as the delayed myocardial activation of a severely dilated RV is avoided. Accordingly, in contemporary rTOF patients with a post-operative RBBB, the optimal QRS cutoff for risk stratification needs to be redefined.
RV activation in rTOF patients with narrow QRS interval
All patients with narrow QRS interval showed early simultaneous RV activation at the anterior wall and the septum via distal ramifications of the conduction system with further propagation toward the anterolateral RVOT and the infundibular septum (25). In the 6 patients with narrow QRS interval and isthmus-related VT, fusion of activation wave fronts during SR was typically observed at the infundibular septum. Late activation after QRS offset was restricted to a small area with low bipolar voltages, therefore not contributing to the surface QRS. Such late potentials are also often observed in patients with scar-related VT of other etiologies. Of importance, in our series, a narrow QRS interval did not exclude a substrate for life-threatening VT. Although not performed in this study, signal-averaged electrocardiography (SAECG) may detect late activated infundibular regions with low voltages. Previous studies that have assessed the association between SAECG and VA were either performed in heterogeneous groups of patients with congenital heart disease or have looked at any VA, including premature ventricular complexes and nonsustained VT as outcome parameter, with conflicting results (26,27). One prior study conducted in 66 rTOF patients undergoing repair via a RV ventriculotomy with subsequent RBBB could demonstrate that patients who developed sustained VT (n = 12; 18%) had a longer filtered QRS interval on SAECG compared with those without VT (179 ± 18 ms vs. 165 ± 17 ms, p = 0.01) (28). Of interest, both additional SAECG criteria (the high-frequency and low-amplitude signal duration, and the root mean square of the mean voltage in the terminal portion of filtered QRS), consistent with late activation of low amplitude regions, did not differ between groups. The predictive value of SAECG for sustained VT in contemporary rTOF patients with a narrow QRS interval has never been evaluated. Of interest, 2 patients with a narrow QRS interval had a severely dilated RV, suggesting that in patients with rapid conduction through the specific conduction system rather than primary myocardial activation, RV size does not significantly contribute to QRS duration.
RV activation in rTOF patients with RBBB
In patients with RBBB, rapid conduction via the specific conduction system is interrupted and RV activation depends on slower myocardial impulse propagation. RBBB after surgery can be present at 3 levels: the proximal right fascicle; the distal ramification after infundibular resection; or the peripheral conduction system secondary to the right ventriculotomy (29). Of interest, a vertical ventriculotomy alone can result in an RBBB pattern with QRS prolongation by an average of 39 ms (13). Irrespective of the level of block, the basal lateral RV and RVOT are activated late (29). In our patients with RBBB and no additional area of conduction delay, the earliest RV activation during SR was always observed at the septum, and excitation wave fronts were merging at the basal lateral TA. In patients with septal conduction delay due to SCAI or isthmus block, the pathway of impulse propagation was prolonged with a shift of latest activation toward the lateral RVOT. This latest area had preserved voltage and contributed to prolongation of both the RVAT and QRS duration. This is in contrast to other forms of structural heart disease with scar-related VT, where slow conduction within the scar results in late potentials of low amplitude inscribing after QRS offset.
QRS duration: Global versus localized delay
In our series, all RBBB patients had normal CV remote from the anatomically defined isthmuses (i.e., normal global CV). Despite normal global CV, severe RV dilation can also prolong the pathway for myocardial impulse propagation, leading to an increase in QRS duration. Fourteen of 44 RBBB patients with QRS >150 ms had a severely enlarged RV. In 8 of 14, QRS prolongation was solely due to longer RV activation time of the dilated RV, in 6 of 14 patients, SCAI or isthmus block further contributed to QRS prolongation. These data support the findings that local rather global myocardial conduction delay or block contributes to QRS prolongation in the majority of patients.
The localized conduction delay or isthmus block resulted in a shift of latest activation toward the RVOT. The observed shift in latest activation provides a potential explanation for prior findings on RV dyssynchrony showing that QRS duration was strongly associated with the delay in RVOT shortening, which was more pronounced if QRS duration was ≥155 ms. The delay increased to more than the upper 95% in all patients with a QRS duration >165 ms (30).
The link between QRS duration and VT in rTOF
According to our data, in the absence of a severely enlarged RV, QRS duration >150 ms is highly suspicious for the presence of SCAI as potential substrate for VT. This finding provides an important link between prolonged QRS interval and VT substrate in rTOF patients with RBBB. In only 1 patient of our cohort, the VT substrate, that is, the SCAI, did not influence QRS duration because of the presence of a second and normal conducting septal isthmus. A QRS duration >150 ms can also be observed in patients with pre-existing isthmus block. Information on isthmus block can be sometimes derived from the operation records, for example, description of an absent infundibular septum. If not conclusive, EAM is required to distinguish slow conduction as substrate for VT from a pre-existing block. It would be interesting to assess in future studies, if noninvasive methods such as ECG imaging are able to identify presence and properties of septal and nonseptal AI with sufficient spatial resolution, to overcome the need for invasive EAM.
This study is limited by the cross-sectional design. In the current study, rTOF patients who were considered at risk for VT or who presented with spontaneous VT underwent PES with RV mapping. The results can therefore not be applied to the general rTOF population. In 5 patients with RBBB, we could not identify the mechanism of QRS duration >150 ms. As electroanatomic CV was measured only at the endocardium and not at the epicardium, additional epicardial and transmural conduction delay cannot be excluded. Electroanatomically determined CV can only be a surrogate for the complex 3-dimensional activation. However, the suggested cutoff value of <0.5 m/s is supported by the following: 1) the range of RV electroanatomically determined CV (range 0.52 to 1.89 m/s) found in a control group of patients with structural normal hearts (14); 2) a CV remote from the AI or in AI not related to VT of >0.5 m/s in our population; and 3) the consistent finding that all VT-related AI had an electroanatomically determined CV of <0.5 m/s. Differentiating between conduction block and long conduction delay can be difficult. Long conduction delay cannot be excluded if conduction time through the isthmus equals the conduction time required to activate the isthmus from the other site. However, none of the patients with electroanatomic conduction block had spontaneous VT or was inducible for VT during long-term follow-up. In addition, a large RV was pre-defined based on 1 RV end-diastolic volume index cutoff value.
In rTOF with pre-existing RBBB, the increased QRS duration is frequently due to localized conduction delay across the AI rather than the global delay. These SCAI prolong the pathway for RV activation and QRS duration, providing an important causal link between the QRS width and the substrate for VT. After exclusion of severe RV dilatation, a QRS duration >150 ms is highly predictive for SCAI and may justify EAM to distinguish between a slow conducting and blocked AI. A narrow QRS interval in rTOF patients does not exclude SCAI and the risk for VT.
COMPETENCY IN MEDICAL KNOWLEDGE 1: The dominant substrate for VT in rTOF are SCAI. In rTOF patients with RBBB, SCAI increase RV activation time and QRS duration. In rTOF patients with a narrow QRS interval, SCAI does not influence QRS duration.
COMPETENCY IN MEDICAL KNOWLEDGE 2: In rTOF patients with RBBB, a QRS duration >150 ms is highly suggestive for presence of SCAI or blocked isthmus, in particular in patients without severe RV dilatation. EAM can distinguish SCAI from isthmus block and may become an important tool for VT substrate identification.
COMPETENCY IN MEDICAL KNOWLEDGE 3: In rTOF patients with a narrow QRS interval, a VT substrate cannot be excluded.
TRANSLATIONAL OUTLOOK: Data are based on a cross-sectional study in a selected group of rTOF patients with documented sustained VT, considered at risk for VT, and/or with indication for reoperation. Further studies in the contemporary rTOF population are desirable.
The Department of Cardiology Leiden has received unrestricted research and fellowship grants from Edward Lifesciences, Boston Scientific, Medtronic and Biotronik. The Electrophysiology and Heart Modeling Institute has received financial support from the French government (grant ANR-10-IAHU-04). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- anatomic isthmus
- confidence interval
- cardiac magnetic resonance
- conduction velocity
- electroanatomic map
- interquartile range
- left ventricle
- monomorphic ventricular tachycardia
- odds ratio
- pulmonary valve
- programmed electrical stimulation
- right bundle branch block
- repaired tetralogy of Fallot
- right ventricle
- total right ventricular activation time
- right ventricular outflow tract
- signal-averaged electrocardiography
- slow conducting anatomic isthmus
- sudden cardiac death
- sinus rhythm
- tricuspid annulus
- ventricular arrhythmia
- ventricular septal defect
- ventricular tachycardia
- Received November 2, 2017.
- Revision received January 25, 2018.
- Accepted February 1, 2018.
- 2018 American College of Cardiology Foundation
- Khairy P.,
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