Right Ventricular Mechanics and QRS Duration in Patients With Repaired Tetralogy of Fallot
Implications of Infundibular Disease
Background— Patients after repair of tetralogy of Fallot (ToF) frequently have right ventricular (RV) dysfunction and prolonged QRS duration (QRSd) and thus could be candidates for cardiac resynchronization therapy. We aimed to assess the relationship between QRSd and the timing of RV wall motion, including the RV outflow tract (RVOT), in these patients.
Methods and Results— Sixty-seven repaired ToF patients (median age, 34 years; interquartile range, 24 to 43 years) and 35 age-matched control subjects were studied by echocardiography and cardiovascular magnetic resonance (n=55 of 67 ToF patients). Time intervals of the RV cardiac cycle were measured from Doppler recordings. Long-axis M-mode recordings were acquired from the right ventricular (RV) free wall and RV outflow tract (RVOT), and the delay in onset of long-axis shortening was measured. ToF patients showed minor abnormalities of the RV cardiac cycle unrelated to QRSd. RV ejection time was prolonged and correspondingly filling time was reduced compared with control subjects (22.3±2.6 versus 20.0±2.9 s/min, P<0.0001; 29.0±3.8 versus 32.7±3.5 s/min, P<0.0001). Total isovolumic time was normal in ToF patients (8.7±4.0 versus 7.4±2.9 s/min; P=NS). QRSd correlated with the delay in RV free wall motion (r=0.55, P<0.0001) and more so with the delay in RVOT shortening (r=0.82, P<0.0001). QRSd also correlated with measures of RVOT abnormality such as long-axis RVOT excursion and akinetic area length (r=−0.46, P=0.004; r=0.33, P=0.01).
Conclusions— QRSd in postoperative ToF patients reflects mainly abnormalities of the RVOT rather than the RV body itself. Thus, prevention and treatment of mechanical asynchrony and malignant arrhythmia should focus on the RV infundibulum. Indications for cardiac resynchronization therapy after ToF repair warrant further investigation.
Received January 5, 2007; accepted July 26, 2007.
Patients with repaired tetralogy of Fallot (ToF) frequently have right bundle-branch block with greatly prolonged QRS duration (QRSd), usually attributed to the effects of cardiac surgery.1 This electric abnormality has been recognized not only as a risk factor for sudden cardiac death in these patients2 but also as a contributor to right ventricular (RV) dysfunction.2,3 Many studies have demonstrated interrelations between left bundle-branch block and left ventricular (LV) dysfunction, particularly in patients with dilated cardiomyopathy, which may be improved by cardiac resynchronization therapy (CRT).4–10 However, the corresponding interrelations between RV dysfunction and abnormal RV activation have received little attention, although CRT has recently been considered in patients with repaired ToF.11,12 In the present study, therefore, we aimed to investigate the effects of right bundle-branch block on the timing of RV wall motion in patients with repaired ToF. In this way, we hoped to gain information about the mechanism of prolongation of the QRS complex in these patients and to define more rigorous criteria for using CRT. Furthermore, because the RV differs from the LV in having an infundibulum, which is universally involved in surgical repair of ToF, we paid particular attention to the electromechanical interaction of this structure.
Clinical Perspective p 1539
We performed a prospective echocardiographic study on 67 consecutive patients with repaired ToF who were seen in the Adult Congenital Heart Disease Unit of the Royal Brompton Hospital (London, England) between March 2003 and November 2005. Comprehensive echocardiographic evaluation included long-axis M-mode and tissue Doppler imaging. Control subjects matched for age and free of any history of acquired or congenital heart disease also were studied prospectively according to the same echocardiographic protocol. Only patients in sinus rhythm at the time of the echocardiographic assessment were considered for the study.
Transthoracic echocardiography was performed in all subjects by a single experienced operator using a standardized transthoracic approach with a Philips Sonos 7500 echocardiograph (Philips Medical Systems, Eindhoven, The Netherlands) interfaced with a multifrequency MHz transducer.
With the subject in the left semilateral position, aortic, pulmonary, and transtricuspid pulsed-wave Doppler recordings were obtained from the apical 5-chamber, parasternal short-axis, and apical 4-chamber view, respectively, with the sample volume at the tips of the respective valve leaflets. Long-axis M-mode and tissue Doppler recordings of LV lateral wall, ventricular septum, and RV free wall were obtained from the apical 4-chamber view with the sample volume positioned at the left and septal angles of the mitral valve ring and the right angle of the tricuspid valve ring as described previously.13 In 37 ToF patients and 25 control subjects, additional RV outflow tract (RVOT) recordings were obtained from the apical RVOT view with the cursor placed at the level of the pulmonary valve annulus (Figure 1). All recordings were made simultaneously with an ECG and a phonocardiogram and were stored digitally for offline analysis with Medcon software (Medcon Telemedicine Technology, Whippany, NJ).
The timing of the RV cardiac cycle was measured from pulmonary and tricuspid valve pulsed-wave Doppler recordings (Figure 2). RV ejection time (ET) was measured as the interval from the onset to the end of forward flow across the pulmonary valve. Because the pulmonic component of the second heart sound (P2) was not always clear on the phonocardiogram, RV isovolumic relaxation time (IVRT) was measured as the algebraic difference between the interval from the first high-frequency vibration of the aortic component of the second heart sound (A2) to the onset of flow across the tricuspid valve and the interval from A2 to the end of pulmonary ejection (Figure 2). RV filling time (FT) was measured from the transtricuspid flow recording as the interval from the onset of the E wave to the end of the A wave. RV isovolumic contraction time (ICT) was calculated as follows: ICT=RR interval−(ET+FT+IVRT). All time intervals were multiplied by heart rate and expressed as seconds per minute because these values are independent of heart rate.14 Total isovolumic time (t-IVT) is the time of the cardiac cycle when the ventricle is neither filling nor ejecting. It is expressed in seconds per minute and was calculated as follows: t-IVT=60−(t-ET+t-FT), where t-ET and t-FT represent total ET and FT, respectively. The aortic velocity time integral was calculated from the aortic valve Doppler tracings.
Mechanical asynchrony was assessed from the different long-axis M-mode and tissue Doppler tracings by measuring electromechanical delay in each of the 4 segments. Electromechanical delay was measured from the long-axis M-mode recordings as the interval from the q wave of the ECG to the onset of systolic shortening (q-Os)15 and from the tissue Doppler recordings as the interval from the q wave to the onset of systolic shortening velocity (q-Os)′. The interval from the q wave to peak systolic shortening rate also was measured in each of the 4 segments (q-S′; Figure 1).
Ventricular long-axis function was recorded from the M-mode tracings of the LV lateral wall, ventricular septum, RV free wall, and RVOT. Total systolic long-axis excursion was measured in the respective segments as described previously16 and shown in (Figure 1).
Standard 12-lead ECGs were acquired for all patients at a paper speed of 25 mm/s. QRSd was measured manually as previously described.1 ECGs were evaluated by a single investigator blinded to the results of echocardiographic measurements.
Cardiovascular Magnetic Resonance
The majority of ToF patients (n=55 of 67) had a cardiovascular magnetic resonance (CMR) scan performed on the day of echocardiography, according to our follow-up protocol. The scans were performed with a 1.5-T Siemens Sonata system (Siemens Erlangen, Erlangen, Germany) and analyzed by a single blinded investigator. A short-axis contiguous stack of steady-state free-procession cine images (7-mm slices) from the atrioventricular ring to the apex was acquired, as described previously.17,18 The short-axis stack was quantified by planimetry by Simpson’s method to determine ventricular volumes and function with semiautomated software (CMR Tools, Cardiovascular Imaging Solutions, London, United Kingdom). Trabecular ridges and bands were excluded from blood pool measurements. The reproducibility for this population has been documented previously.19 The following measurements were obtained from the short-axis stack: RV end-diastolic volume index, RV end-systolic volume index, and RV and LV ejection fractions. The degree of pulmonary regurgitation was quantified by nonbreathhold phase-velocity mapping in a plane transecting the pulmonary trunk.20 From cine imaging, the maximum length of the RVOT akinetic area was measured as previously described.18
Data are expressed as mean±SD or median (interquartile range) as appropriate. Comparisons between groups were made with Student t test after testing for normality with the Kolmogorov-Smirnov method. Univariate and multiple linear regression analyses were used to assess associations between variables and potential confounders. The relationship between continuous variables and New York Heart Association functional class was analyzed by Spearman’s rank correlation coefficient. For all analyses, a value of P<0.05 was considered statistically significant. Statistical analysis was performed with StatView for Windows, version 5.0 (SAS Institute Inc, Cary, NC).
Two investigators who were blinded to the clinical and CMR findings analyzed the echocardiographic measurements. Interobserver and intraobserver variabilities were assessed in 30 patients (20 ToF patients, 10 control subjects). Duplicate measurements were made of the time intervals of the RV cardiac cycle and all long-axis M-mode and tissue Doppler measurements. The reproducibility data of our CMR measurements have been reported previously.19 Detailed data on reproducibility of echocardiographic and CMR measurements are listed in Table 1.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Sixty-seven patients with ToF fulfilled inclusion criteria and were studied 27±8 years after repair, along with 35 healthy control subjects (Table 2). Surgical technique was clearly documented in 52 ToF patients, whereas the exact technique of RVOT reconstruction remained unclear in 15 patients because operation notes were no longer available.
Time Intervals of the RV Cardiac Cycle
Data on the timing of the RV cardiac cycle are summarized in Table 3. RV isovolumic contraction and relaxation times did not differ significantly from normal control subjects, so the same applied to total isovolumic time. RV ET was prolonged in ToF patients, whether or not QRSd was increased by a mean of ≈2 to 3 s/min, and RV FT was reduced correspondingly. Prolongation of RV ET was not related to QRSd but was correlated with peak RVOT pressure drop (r=0.40, P=0.001): ET (s/min)=20.7+0.07×RVOT peak pressure drop (mm Hg).
Segmental Electromechanical Delay
The extent of any segmental delay in LV and RV wall motion is given in Table 4. Data for all M-mode and tissue Doppler measurements are given.
LV and Interventricular Septum
The timing of LV and septal long-axis motion was normal in ToF patients when the interval from the q wave to the onset of shortening was measured by the M-mode and tissue Doppler method and was unrelated to QRSd (Table 4). Delay in LV and septal long-axis motion was suggested by tissue Doppler measurement of the timing of peak systolic shortening rate. This delay also was unrelated to QRSd (Table 4).
Within the RV, a consistent delay was present in the onset of RV free wall motion demonstrated by M-mode recording in all patients with ToF and in those with prolonged QRSd by tissue Doppler (Table 4). When timing of peak systolic shortening rate was considered, tissue Doppler demonstrated this to be early in ToF patients with QRSd below the median of 155 ms but to be effectively normal in those with QRSd ≥155 ms (Table 4).
RV Outflow Tract
The most striking disturbances in timing of shortening were shown in the RVOT. M-mode echocardiography showed the onset of shortening to be delayed compared with normal by ≈20 ms when QRSd was <155 ms and by a further 55 ms with QRSd ≥155 ms. Both these values were highly significant (both P<0.0001; Table 4). Tissue Doppler demonstrated the time of onset of systolic myocardial acceleration to be effectively normal when QRSd was <155 ms but to be delayed by 40 ms when QRSd was >155 ms (P<0.0001; Table 4). Measurement of the time to peak systolic shortening rate by tissue Doppler showed a similar delay only when QRSd was >155 ms (Table 4).
Correlates of QRSd
QRSd correlated with delay in the onset of motion of the RV free wall as determined by M-mode echocardiography (r=0.55, P<0.0001). However, a stronger correlation was found between QRSd and delay in the onset of RVOT motion as determined by M-mode recordings (r=0.82, P<0.0001; Figure 3). Multiple regression analysis demonstrated that the interval from the q wave to the onset of RV free wall motion as measured by M-mode echocardiography contributed no further information to the prediction of QRSd once the interval from the q wave to the onset of RVOT shortening was taken into account (Figure 3). Furthermore, the M-mode delay in the onset of RVOT motion was increased to more than the upper 95% confidence limit of normal in all patients in whom QRSd was >165 ms.
Through the use of tissue Doppler imaging, comparable data on the relationship between QRSd and RV mechanics could be obtained. On linear regression analysis, the interval from the q wave to the onset of RVOT shortening was more closely related to QRSd than the interval from the q wave to the onset of shortening of the RV free wall (r=0.72, P<0.0001; and r=0.46, P=0.0001, respectively). Similarly, measurement of the interval from the q wave to the peak shortening rate showed that this interval of the RVOT was more closely related to QRSd (r=0.58, P<0.0001) than that of the RV free wall (r=0.46, P<0.0001).
Surgical Technique, QRSd, and Shortening Delay of the RVOT
The technique of RVOT reconstruction was clearly documented in 52 patients (78%) for whom operation notes were still available (Table 2). A total of 32 patients had transannular patch enlargement of the RVOT at repair. In an additional 10 patients, an RVOT patch was inserted in combination with pulmonary valvotomy (n=6) or conduit implantation (n=4). In the remaining 10 of the 52 patients with operation notes available, no RVOT patch was used at repair.
QRSd was not statistically different between patients who underwent RVOT patch enlargement compared with those without a patch (146.9±26.4 versus 142.9±25.9 ms). However, the onset of RVOT contraction tended to be later in patients with an RVOT patch compared with those without (145.9±40.8 versus 113.2±34.0 ms; P=0.06; Figure 4).
Global RV Function, QRSd, and RVOT Abnormalities
QRSd correlated with indexed RV volumes and inversely with RV ejection fraction (RV end-diastolic volume index: r=0.42, P=0.0017; RV end-systolic volume index: r=0.42, P=0.0017; RV ejection fraction, −0.51, P=0.0001; Table 4). QRSd also correlated with measures of RVOT abnormality such as RVOT systolic long-axis excursion and akinetic area length (r=−0.46, P=0.004; and r=0.33, P=0.01) but, in contrast, not with long-axis function of the RV free wall (r=−0.1, P=NS) (Table 4). The size of the akinetic area was related not only to QRSd but also, as expected, to RV ejection fraction (r=−0.51, P=0.0001), whereas RV ejection fraction and RVOT long-axis function were not related (r=0.13, P=NS).
Shortening Delay of the RVOT, Global Hemodynamics, and Clinical Status
On univariate regression analysis, shortening delay of the RVOT was significantly correlated with an increase in RV volumes (both RV end-diastolic and end-systolic volume indexes) and a reduction in RV ejection fraction and the aortic velocity time integral (r=0.48, r=0.55, r=0.58, r=0.47; P<0.01 for all). A significant correlation with New York Heart Association functional class also was found on linear regression analysis (r=0.43, P<0.01).
The present study demonstrates that RV mechanical asynchrony is prevalent in patients with repaired ToF and relates to QRSd. However, prolonged QRSd reflects mainly abnormalities of the RVOT and not of the RV body itself. Associations between QRSd and morphological and functional abnormalities of the RVOT underscore the importance of this region in determining the late pathophysiology of repaired ToF.
The RV Cardiac Cycle
Because mechanical asynchrony is prevalent mainly in the RVOT, repaired ToF patients have only mild abnormalities in the timing of the RV cardiac cycle. RV isovolumic times are normal. ET is slightly prolonged, and FT is correspondingly reduced. Prolongation of ET is not related to QRSd but to the degree of RVOT obstruction, a relationship first described in pulmonary valve stenosis by Leatham and Weitzman.21
Total isovolumic time, the time when the ventricle neither ejects nor fills (ie, wasted time), has been shown to be prolonged in patients with left bundle-branch block and cardiomyopathy.22 Prolongation in total isovolumic time in these patients reflects LV mechanical asynchrony. Successful CRT shortens LV total isovolumic time and correspondingly prolongs FT with an improvement in cardiac output and exercise tolerance.22–24 Because RV total isovolumic time is not prolonged in ToF patients with right bundle-branch block, the improvement in cardiac output in repaired ToF patients reported in the first pilot study on CRT11 cannot be explained on this basis.
QRSd is associated with some delay in shortening of the RV free wall but much more so of the RVOT. Significant delay outside the normal range was present in all patients with QRSd >165 ms (Table 4 and Figure 3). This finding suggests that QRS prolongation is related mainly to RVOT disease resulting from previous surgical repair and fibrosis.18
In contrast to a previous study, we could not demonstrate asynchronous shortening of the LV lateral wall and septum in our group of ToF patients when measuring the delay in onset of segmental shortening using M-mode echocardiography and tissue Doppler imaging (Table 4).25 However, when measuring the interval from the q wave to the maximal systolic shortening rate, we found results comparable to those of Abd el Rahman and coworkers25 (Table 4), who measured electromechanical delay by tissue Doppler as the interval between the q wave and maximum strain. These intervals, which relate to a time point within systole (maximum strain or maximal systolic shortening), do not reflect only electromechanical delay but also any prolongation of myocardial contraction influenced by heart rate, systolic loading conditions, or impaired myocardial function.
Long-axis M-mode echocardiography appeared more discriminating than tissue Doppler imaging in assessing mechanical asynchrony. We speculate that this may reflect the greater repetition rate of this method compared with tissue Doppler. Furthermore, bold tissue Doppler tracings sometimes render ambiguous the exact definition of systolic time points, especially that of maximal systolic shortening velocity (see Figure 1).
In contrast to a study by Geva et al26 using both CMR and contrast acoustic quantification echocardiography, we did not demonstrate the presence of RV peristalsis in our group of healthy control subjects (Table 4). This discrepancy probably reflects the different methods used. Using long-axis echocardiography, we analyzed the timing of contraction of fibers orientated longitudinally from the vortex of the heart to the atrioventricular and arterial orifices in adults, whereas Geva and colleagues measured circumferential contraction of the RV sinus and the infundibulum in children.
Mechanical asynchrony of the RVOT tended to be more pronounced in patients who had undergone RVOT patch insertion. Modifications in surgical strategy over the last 2 decades that aim to preserve pulmonary valve and RVOT function and to avoid or minimize the use of RVOT patches might thus reduce damage to the RVOT and hence reduce asynchronous contraction.
Echocardiography of the RVOT
In the RVOT of normal subjects and of patients with ToF, subendocardial and subepicardial muscle fibers are orientated longitudinally running parallel to the outlet axis.27 Reconstruction of the RVOT at ToF repair often involves longitudinal incision into the RVOT with dissection of circumferential fibers. Therefore, assessment of long-axis movement seemed superior to measurement of circumferential shortening of the RVOT28 because the continuity of longitudinal fibers is better preserved.
Previous studies involving CMR imaging have described functional impairment, fibrosis, akinesis, and aneurysm formation of the reconstructed RVOT after ToF repair and discuss the potential importance of these findings for adverse outcomes, including arrhythmia.18,29,30 Our study directly relates RVOT pathology to QRS prolongation. The latter is an established risk factor for ventricular tachycardia and sudden cardiac death in postoperative ToF patients.1,2 Our data are therefore consistent with previous reports suggesting that these malignant arrhythmias arise in the diseased RVOT and with early electrophysiological data that also support this thesis.31–33
Furthermore, pulmonary valve replacement in patients with repaired ToF and pulmonary regurgitation causes a reduction in QRSd that most likely is a result of the fact that slow-conducting and partly fibrotic tissue is resected at the same time.34,35 A decrease in the incidence of ventricular tachycardia has been noted when pulmonary valve replacement is combined with electrophysiological mapping and cryoablation.35 We would speculate, therefore, that routine electrical “isolation” of the RVOT at the time of pulmonary valve replacement might reduce the risk of ventricular tachycardia and sudden death in this patient population. Furthermore, CRT should be reserved for patients with documented and persisting mechanical asynchrony of the body of the RV after target lesion surgery and should not be considered an alternative to reoperation. Whether pacing of the RVOT may counteract its delay in shortening and is technically feasible in the fibrotic or patched RVOT late after repair and what, if any, effect this might have on RV ejection and cardiac output in selected ToF patients remain to be elucidated.
We cannot exclude the possibility that the patient population enrolled in this study was biased toward more symptomatic patients and those with more significant residual lesions. Nevertheless, our study cohort reflects the current adult population of postoperative ToF patients with a wide scatter of QRSd.
The long time interval between initial surgery and follow-up unfortunately meant that operation notes were no longer available for 22% of patients studied. Furthermore, surgical techniques varied during this period, so the cardiac and surgical data of our patient group are complex.
RV mechanical asynchrony is prevalent in patients with repaired ToF and relates to QRSd. QRSd, in turn, reflects mainly abnormalities of the RVOT and not of the RV body itself. Our data underscore the pathological importance of the infundibulum as a likely source of malignant arrhythmia and suggest that RV disease in repaired ToF patients is primarily an infundibular disease. Thus, prevention and treatment of mechanical asynchrony and malignant arrhythmia should focus on the RV infundibulum. Indications for CRT after ToF repair warrant further investigation.
Sources of Funding
This work was supported by the Royal Brompton Adult Congenital Heart Centre and Centre for Pulmonary Hypertension. Dr Uebing and Dr Gatzoulis have received support from the Clinical Research Committee and the Waring Trust, both at the Royal Brompton Hospital, and from the British Heart Foundation. Dr Babu-Narayan was supported by the British Heart Foundation. Dr Diller was supported in part by an educational grant from Actelion, United Kingdom.
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Long-term broadening of the QRS complex of right bundle-branch block type is common after total repair of the tetralogy of Fallot. It is clinically significant in that it is a marker of sudden death in these patients. In the present study, we have shown a close association between the extent of QRS broadening and delay in the onset of contraction of the infundibulum (right ventricular outflow tract) but not with that of the body of the right ventricle. These findings probably reflect the common involvement of the infundibulum in reparative surgery for tetralogy of Fallot. They also suggest that right ventricular outflow tract pathology may underlie malignant arrhythmias, so repaired tetralogy of Fallot should potentially be regarded at least in part as an infundibular disease. In contrast, the findings militate against the idea that QRS broadening on its own should be taken as an indication for treating right ventricular disease with cardiac resynchronization therapy in these patients. Perhaps an analogy can be made between “rogue” potentials arising from islets of myocardial cells in the pulmonary veins leading to atrial arrhythmias and those in the scarred infundibulum after total repair of tetralogy of Fallot. These data suggest that the risk assessment for and the prevention and treatment of malignant arrhythmia should focus on this region.