Europace Advance Access published online on July 4, 2008
Europace, doi:10.1093/europace/eun178
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Presence of ventricular dyssynchrony and haemodynamic impact of right ventricular pacing in adults with repaired Tetralogy of Fallot and right bundle branch block
1 University Victor Segallen, 33000 Bordeaux, France; 2 CHU de Bordeaux, Bordeaux, France
Manuscript submitted 2 April 2008. Accepted after revision 10 June 2008.
* Corresponding author. Hospital Haut Leveque Service Dr Thambo, Pessac, Bordeaux, France. Tel: +11 33 5 57 65 65 65; fax: +11 33 5 57 65 65 43. E-mail address: bordacharp{at}hotmail.com
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Abstract |
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Aims: Late after surgical repair, adults with Tetralogy of Fallot (TOF) commonly present with right ventricular (RV) dysfunction and right bundle branch block (RBBB). We aimed at (i) investigating whether this prolonged RV conduction induced detrimental electromechanical dyssynchrony in both RV and left ventricle (LV) and (ii) determining the acute haemodynamic effects of pacing at different RV sites.
Methods and results: A total of 42 adults with surgically repaired TOF and RBBB were investigated by echocardiography. Intra-RV dyssynchrony (IRVD) and intra-left ventricular dyssynchrony (ILVD) were compared with measurements performed in 30 healthy matched control subjects. An acute haemodynamic study was subsequently performed in a subgroup of 10 patients with New York Heart Association functional class II or class III and echocardiographic signs of RV dysfunction. Cardiac index was measured by a thermodilution technique during spontaneous rhythm (SR) and during atrio-synchronized RV pacing at four different sites (infundibulum, apex, septal, and lateral walls). Fifty-five per cent of the patients with repaired TOF demonstrated abnormal RV and/or LV dyssynchrony. We observed an increased IRVD (37 ± 12 vs. 18 ± 8 ms; P= 0.02) and ILVD (34 ± 12 vs. 20 ± 10 ms; P= 0.04) in TOF patients when compared with control subjects. We did not observe any significant acute improvement in the cardiac output during atrio-synchronized ventricular pacing vs. SR. Similarly, RV pacing did not induce any significant reduction in the QRS duration.
Conclusion: Some TOF adults with RBBB exhibit biventricular electromechanical dyssynchrony. However, in symptomatic patients with RV dysfunction, atrio-synchronized RV pacing does not induce significant acute haemodynamic improvement.
Key Words: Tetralogy of Fallot, Pacing, Dyssynchrony
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Introduction |
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Right heart failure is an important cause of late morbidity and mortality in patients with surgically repaired Tetralogy of Fallot (TOF).1
,2 Left ventricular (LV) pacing has been proposed as a new therapeutic option for patients with severe LV dysfunction and left bundle branch block (LBBB).3–5 Similarly, the presence of right ventricular (RV) dysfunction and right bundle branch block (RBBB) in adults with surgically repaired TOF may be a reasonable target for RV pacing.6 The rationale for a favourable haemodynamic impact of RV pacing in patients with congenital heart disease is that the RV conduction delay may be associated with different detrimental levels of ventricular dyssynchrony. The aim of the present study was (i) to quantify the extent of biventricular dyssynchrony in adults with surgically repaired TOF and evidence of RBBB and (ii) to determine the acute haemodynamic impact of atrio-synchronized RV pacing at different pacing sites in adults with a history of surgically repaired TOF, RBBB, symptoms of New York Heart Association (NYHA) class 2 or class 3 heart failure, and echocardiographic evidence of RV failure. |
Methods |
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Echocardiographic study
A total of 42 consecutive patients aged >18 years with a history of surgically repaired TOF and those in sinus rhythm with electrocardiographic signs of RBBB (QRS duration
120 ms) were prospectively included for an echocardiographic evaluation. Exclusion criteria were inadequate transthoracic window for echocardiographic examination and the presence of a pacing device. Electrocardiographic and ultrasound data from these patients were compared with those obtained from 30 control subjects, matched for age and free of any history of acquired or congenital heart disease.
Echocardiography
Transthoracic echocardiography was performed by a single operator with a Vivid 7 digital ultrasound system (GE/VingMed, Horten, Norway). Imaging was performed in the left lateral position. By using continuous Doppler waveforms, the pulmonary regurgitation pressure half-time (PHT) was measured. The PHT was measured from the initial linear downslope of the pulmonary regurgitation waveform. A PHT value of <100 ms determined a severe pulmonary regurgitation.7
Tissue Doppler imaging (TDI) recordings of the base of the RV free wall, LV lateral, septal, inferior, and anterior walls were obtained from the apical two- and four-chamber views. The TDI sector was adjusted to encompass both RV and LV free walls. Gain and filter settings were adjusted as required to eliminate background noises and to allow for a clear tissue signal. Tissue Doppler imaging velocities were recorded and measured at a sweep speed of 100 mm/s using online callipers. Its data were recorded simultaneously with ECG and stored on a compact disc for later offline analysis. Optimized TDI data were analysed using EchoPac software (GE/VingMed). The systolic RV function was assessed by measuring of peak systolic TDI velocity 
1 cm towards the apex from the lateral tricuspid valve annulus in the apical four-chamber view.8
Assessment of dyssynchrony
Septal, LV lateral, LV anterior, LV inferior, and RV free-wall electromechanical delays (interval between the onset of the QRS complex and that of each segmental contraction) were measured with TDI. The intra-LV dyssynchrony was then calculated as the difference between the shortest and longest of the four segmental LV electromechanical delays. The intra-RV dyssynchrony (IRVD) was calculated as the difference between the RV free wall and the septal electromechanical delays.
Haemodynamic study
An invasive haemodynamic study was performed in a subgroup of 10 patients. The study protocol was approved by the local Ethics Committee, and informed written consent was obtained from the patients. Patients were sedated for the study. They underwent RV catheterization. Pacing leads were inserted transvenously into the right atrium and the RV. Electrocardiographic and haemodynamic measurements were performed in a random order, in spontaneous rhythm (SR), and during atrio-synchronized RV pacing applied in the VDD mode, so that atrial sensing was used to govern ventricular pacing. Different RV sites were analysed: septum, apex, infundibulum, and lateral wall. The pacing site was determined using biplane fluoroscopy in the left anterior and right anterior oblique orthogonal views. An atrioventricular delay of 70% of the intrinsic PR interval was programmed to ensure a complete ectopic ventricular capture. The cardiac output was measured by thermodilution in all patients and expressed as the average of five consecutive measurements performed after 2 min of pacing at a particular site to achieve steady state.
Data and statistical analysis
Control subjects were included in the study to estimate the range of ventricular dyssynchrony in the population with normal cardiac function and no history of cardiomyopathy. The Shapiro and Wilk test was used to verify that the distribution of the controls’ variables followed a Gaussian curve. Then, the normal range of the variables was defined as follows: the statistical alpha risk was fixed at 0.05, so that the physiological range of the parameters should be included in the ‘mean ± 2 SD’ range, which represents 95% of the control group distribution. Consequently, a TOF patient was considered to demonstrate significant ventricular dyssynchrony if he had an IRVD >34 ms (mean value + 2 SD of the control group) or an intra-LV dyssynchrony >40 ms.
Data were expressed as mean value ± SD. Comparisons between the groups were made using Student’s t-test. For all analyses, a P-value less than 0.05 was considered statistically significant.
Reproducibility
Two investigators retrospectively analysed the echocardiographic measurements blinded to clinical findings. Inter-observer and intra-observer variabilities were assessed in 30 patients (15 TOF patients and 15 controls). The intra-observer coefficient of variability of IRVD and ILVD were 6.9 and 7.4%, respectively. The inter-observer coefficient of variability and IRVD or ILVD were 9.9 and 10.8%, respectively.
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Results |
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Characteristics of the population
Forty-two patients with TOF and 30 controls were included for the echocardiographic study. The median age was 29 ± 6 years in patients vs. 26 ± 7 years in controls (P= ns). The median age at TOF repair was 5.4 ± 4.7 years. Twenty-four patients were in NYHA functional class I, 15 in class II, and 3 in class III, despite optimal medical therapy. The mean QRS duration in the TOF group was 154 ± 21 ms with an RBBB aspect vs. 88 ± 8 ms in the control group (P < 0.0001) (Table 1).
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Ten of these 42 TOF patients were included in the haemodynamic study. The median age in this subgroup was 31 ± 5 years. The median age at TOF repair was 4.9 ± 4.3 years. Seven patients were in NYHA functional class II and three in class III. The mean QRS duration was 161 ± 13 ms.
Echocardiographic study
Left and right ventricular function
The LV systolic function, estimated from the measurement of ejection fraction, was preserved in 29 patients. The LV function was moderately depressed (LV ejection fraction <55%) in the other 13 patients. The mean LV ejection fraction was 58 ± 9 vs. 68 ± 4% in the control group (P < 0.05). The systolic RV function, traduced by the systolic TDI velocity at the lateral RV wall, was significantly altered in TOF patients vs. controls (10.1 ± 2.2 vs. 15.1 ± 2 cm/s; P < 0.01) (Table 1 and Figures 1 and 2).
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Ten patients had severe pulmonary regurgitation and 32 patients had mild-to-moderate pulmonary regurgitation. The mean gradient across the pulmonary outflow tract was 19 ± 13 mmHg (P < 0.0001 vs. controls).
Intra-right ventricular dyssynchrony
The mean value of IRVD was significantly higher in the TOF group than that in the control group (37 ± 12 vs. 18 ± 8 ms; P= 0.02). Eighteen patients in the TOF group (43%) demonstrated significant IRVD (>34 ms). We did not observe any significant relation between IRVD and QRS duration (r = 0.21; P= ns).
Intra-left ventricular dyssynchrony
The mean value of intra-left ventricular dyssynchrony (ILVD) was significantly higher in the TOF group than that in the control group (34 ± 12 vs. 20 ± 10 ms; P= 0.04). Sixteen patients in the TOF group (38%) demonstrated significant ILVD (>40 ms). We did not observe any significant relation between ILVD and QRS duration (r = 0.16; P= ns).
Twenty-three TOF patients (55%) demonstrated either IRVD, ILVD, or inter-ventricular dyssynchrony (see under Methods section ‘Data and statistical analysis’ for criteria).
Haemodynamic study
In the 10 patients included in the haemodynamic study, we observed a moderately depressed LV function in 6 patients (60%), a mean LV ejection fraction of 53 ± 7%, and a systolic TDI velocity at the lateral RV wall of 9.3 ± 1.7 cm/s. Five patients (50%) had severe pulmonary regurgitation and five patients (50%) had mild-to-moderate pulmonary regurgitation. We measured a mean value of IRVD of 41 ± 8 ms (seven patients with significant dyssynchrony) and of ILVD of 37 ± 7 ms (seven patients with significant ventricular dyssynchrony) (Table 2 and Figures 3 and 4).
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Compared with sinus rhythm, QRS duration was not significantly reduced during any ventricular pacing configuration. In contrast, the QRS duration was significantly increased (P < 0.05) during apical ventricular pacing. Similarly, the cardiac index was not significantly improved by any ventricular pacing configuration. The optimal pacing configuration estimated on the basis of cardiac index was SR in four patients, lateral RV pacing in four patients, and septal RV pacing in two patients. Lateral RV pacing was significantly associated with an improvement in the cardiac index when compared with apical RV pacing. Optimal RV pacing (choice of the best ventricular pacing configuration) only provided a trend (P= 0.19) for an increase in the cardiac index when compared with spontaneous sinus rhythm. Interestingly, the changes in the QRS duration observed as a function of pacing site were significantly correlated with the changes in the cardiac index (r = 0.53; P < 0.05).
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Discussion |
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Adults with congenital heart disease may represent a new population who could benefit from electrical therapies.6
,9 In TOF patients, heart surgery during childhood often produces a right bundle branch pattern that may contribute to the development of RV dysfunction.1,10 To counteract the induced dyskinesis, ventricular resynchronization has been proposed as a potential therapy.6,11 In the present echocardiographic and acute haemodynamic studies, we have demonstrated a prevalence of 50% of abnormal ventricular dyssynchrony in patients with TOF and RBBB, but no significant increase in cardiac output with RV pacing.
The lesions in TOF patients are not restricted to the RV, and both RV and LV mechanical dyssynchrony are observed.12 The right bundle branch induces a significant delay between the electromechanical activation of the RV free wall and that of the septum, as well as between the electromechanical activation of the different LV segments. Whether the degree of dyssynchrony seen in patients with TOF is clinically relevant remains unknown. Similarly, the respective impact of RV or LV dyssynchrony remains to be determined. However, the adverse haemodynamic impact of RBBB may be profound. The asynchronous biventricular myocardial activation may trigger biventricular remodelling. This biventricular dyssynchrony may lead to both systolic and diastolic biventricular dysfunction and therefore may contribute to the development or worsening of heart failure symptoms in patients with TOF.
In patients with LV dysfunction, as well as those with TOF, the presence of prolonged QRS generally conveys poor prognosis.13,14 The impact of the RBBB on the LV activation sequence confirms previous results obtained in patients suffering from ischaemic cardiomyopathy, in whom the RBBB and the LBBB are associated with similar prevalence of LV dyssynchrony.15,16 Therefore, restoring RV and LV synchrony by cardiac resynchronization therapy may have a significant impact on patients’ symptoms and clinical course.
Whether electrical or mechanical parameters are preferable to select the TOF patient’s candidates for resynchronization will have to be assessed in large randomized studies. Our data suggest discordance between electrical and mechanical dyssynchrony. Indeed, although all included patients demonstrated a wide QRS on the surface ECG, abnormal mechanical ventricular dyssynchrony was evidenced in 55% of these patients only. Moreover, we did not observe any significant correlation between the level of RV or LV dyssynchrony and the duration of the QRS. The QRS complex represents the vectorial sum of electrical forces generated by myocardial masses over time, but regional changes represented by small vectors are inadequately displayed. There is convincing evidence that in patients with TOF, most of the fibrosis and, therefore, the electrical delay are restricted to the RV infundibulum and therefore may poorly be translated on the QRS duration.17,18 The analysis of RV dyssynchrony should probably be extended to the infundibulum and not limited to the RV cavity. In contrast, during the haemodynamic study, the changes in the QRS duration were poorly but significantly correlated with changes in the cardiac index, suggesting that, in TOF patients, the QRS duration may help for the choice of the optimal pacing sites during the implantation.
The determination of the optimal pacing site and configuration will also require randomized studies. Our data provide new insights. We could not demonstrate any significant improvement in the cardiac output with RV pacing. A previous study had suggested a positive impact of RV pacing in TOF patients.6 Right ventricular pacing sites included apex, outflow tract, and septum. The optimal RV pacing site improved cardiac output and RV dP/dt, whereas it decreased QRS duration when compared with normal sinus rhythm. The main difference between the two studies is the choice of the atrioventricular delay. Our patients were paced with an atrioventricular delay permitting a complete ventricular capture that allows us to assess completely the impact of a pacing site. In contrast, in the previous study, the atrioventricular delay was programmed to 90% of the intrinsic PR interval, favouring a high level of fusion between the spontaneous and the paced activations and therefore limiting the potential detrimental impact of RV pacing.
The biventricular nature of electromechanical alterations may explain the absence of acute haemodynamic improvement after RV pacing alone. If one can expect that RV pacing can resynchronize the RV, it does not reduce but even worsens LV dyssynchrony.19,20 The activation sequence deviates from the physiological one and is associated with a significant decline in the LV function. Although RV pacing at any site did not provide positive effect on cardiac output, our study showed that RV apical pacing was deleterious. In TOF patients requiring permanent ventricular pacing, the apex of the RV should probably be avoided and the lateral wall may be preferred. In view of the absence of improvement with RV pacing alone, alternate sites of ventricular stimulation would be desirable and may involve biventricular pacing. There is an important literature demonstrating that cardiac resynchronization therapy, achieved by biventricular pacing, is beneficial in patients with severe LV dysfunction, refractory heart failure, and LBBB.3–5 In patients with TOF, the positive impact of biventricular pacing remains to be determined.21 Multicentre prospective collaborative efforts are to be encouraged. It is, however, very likely that in some patients with TOF, heart failure is mainly linked to pulmonary regurgitation and that cardiac resynchronization therapy should probably not be considered an appropriate alternative to surgery of the pulmonary valve.
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Limitations of the study |
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There is evidence in the literatures22
,23 that in patients with repaired TOF, RBBB can arise by blocking the main truck and also by blocking a more peripheral part of the right bundle. Horowitz et al.22 have described, after surgery, three different levels of block. The level of block may have interfered with the extent of dyssynchrony and with the impact of RV pacing. Vectography or body surface mapping may have added interesting data. Moreover, a control group with patients with normal contractility and RBBB would have provided further interesting data to address the specificity of TOF patients. In our study, the analysis of IRVD was limited to the assessment of the activation of the RV cavity itself. In patients with TOF, echocardiographic measurements inside the infundibulum may provide different and additional information. The measurement of inter-ventricular dyssynchrony may have also provided additional information.
The parameter used to compare different pacing sites was the cardiac index by thermodilution. An analysis of LV dP/dt would have provided further information about the impact of the pacing site on myocardial contractility. In patients with TOF, the presence of pulmonary or tricuspid regurgitation may have interfered with the measurement of cardiac index. However, the presence of pulmonary or tricuspid regurgitation may have introduced significant potential inter-patient variability but less intra-patient variability in cardiac output determining and may not have been an important factor in the intra-patient comparison between the pacing sites. The number of included patients in the haemodynamic study was limited, and further studies on larger populations are warranted. The inclusion criteria associating echocardiographic signs of RV dysfunction with clinical symptoms of heart failure explain the limited number of patients in the present study.
Conflict of interest: none declared.
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References |
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