Determinants of QRS duration in patients with tetralogy of Fallot after pulmonary valve replacement

Following the repair of TOF patients may be left with pulmonary regurgitation and a dilated right ventricle (RV), which in turn can lead to ventricular arrhythmias and sudden death. A prolonged QRS is a predictor of ventricular arrhythmias. However, whether subsequent pulmonary valve replacement (PVR) can reverse QRS‐prolongation is controversial. We hypothesized that changes in QRS duration following PVR are determined by preoperative QRS‐duration and RV volumes


| INTRODUCTION
Surgical repair of tetralogy of Fallot (TOF) in children is associated with excellent long-term outcomes. 1 However, a large proportion of patients develop pulmonary valve regurgitation (PR) after surgery, which can lead to right ventricular (RV) dilatation, symptoms of RV failure, and malignant arrhythmias, including sudden cardiac death. 2,3 The QRS duration is a simple marker for predicting cardiac mortality in several clinical conditions including post-TOF repair with RV failure. Intraventricular conduction delay results in abnormal electrical depolarization of the heart and mechanical ventricular dyssynchrony, which can predispose to malignant arrhythmias. QRS duration may increase by an average of 2 msec/year in TOF patients with secondary PR 3 and a QRS interval >180 msec has been reported to be predictive for sudden cardiac death in this population. [3][4][5] Pulmonary valve replacement (PVR) is recommended to improve symptoms of RV failure and reduce RV dilatation. [6][7][8] It has also been suggested that PVR may prevent or reverse QRS complex prolongation, by means of preventing volume and pressure overload allowing mechanical re-synchronization. 9 However, data to support the last hypothesis are scarce and conflicting. [9][10][11] It has been suggested that marked preoperative QRS prolongation and RV dilatation can prevent QRS stabilization or reversal of prolongation following PVR. In the present study we aimed to investigate the relationship between preoperative QRS duration and RV volume, as assessed using cardiac magnetic resonance imaging (cMRI), and changes in QRS duration post-PVR in patients with repaired TOF.

| METHOD
The study complies with the Declaration of Helsinki. The present analysis was approved by the audit board at the University Hospital of Bristol. As this analysis came under clinical audit/quality of care assessment and all data were anonymized following the governance criteria of the NHS, the IRB agreed informed consent was not required.

| Patient and public involvement
This study was done without patient and public involvement.

| Primary and secondary endpoints
The primary endpoint of the present analysis was to describe longterm changes in QRS duration following PVR in relationship to preoperative QRS duration. As secondary endpoint, we looked at the relationship between RV volumes and long-term changes in QRS duration, in a subset of patients with information on preoperative RV volumes assessed by cardiac MRI.

| Data source
This is a single-center cohort study conducted at the Bristol Heart Institute looking at repaired TOF patients undergoing their first surgical PVR. Data were retrospectively collected from medical records and the cardiac MRI database. A total of 223 TOF patients underwent first time PVR between 1995 and 2019 in our Institution.
The main indication for the first PVR intervention was symptomatic PR (exercise intolerance not explained by extracardiac causes, signs, and symptoms of heart failure or syncope attributable to arrhythmia) and/or severe right ventricle dilatation (RVEDV >150 ml/m 2 ).
Information on preoperative QRS was not available for 81 patients who were excluded from the main analysis. Information on preoperative RV volumes from cMRI examination was available for 83 patients and this subgroup was used to investigate the predicted value of RV volume on postoperative QRS duration.  Information regarding QRS duration was extracted from cardiology clinical letters in the medical records. cMRI data was used as it is considered the gold standard for quantification of RV volumes and systolic function because of its accuracy and reproducibility. 12,13 Right Ventricular volumes were indexed for body surface area. 14,15 We also reported the incidence of ventricular tachycardia (VT) before

| Relationship between preoperative RV volumes and changes in QRS duration
Preoperative cMRI RV volumes were available in a subset of 83 patients. cMRI RV volumes in the overall sample and stratified by QRS duration are reported in Table 2. Patients characteristics stratified by baseline RV volumes are reported in Table S1. We found p < .01, Figure 5), but not in those with RVEDV < 166 ml/m 2 (0.26 ± 0.33; p = .14, Figure 6). Furthermore, postoperative QRS duration tended to increase in subjects with large baseline RVESV (≥89 ml/m 2 ) (1.25 msec ± 0.43 per year; p = .01, Figure 7), but not in those with smaller RVESV (<89 ml/m 2 (0.32 ± 0.36; p = .37, Figure 8).

| DISCUSSION
The main finding of the present study was that there was no decrease Other studies confirmed a direct relation between QRS duration and late arrhythmia presentation. 21,22 Ventricular tachycardias and sudden cardiac death in TOF patients are solely determined by RV dilatation secondary to PR and therefore a timely correction of the valvular disease can dramatically improve clinical outcomes in these patients. 23 The optimal timing to perform the PVR remains controversial: when the surgery is performed later in life many patients experience irreversible damage to the RV, but, early surgery can lead to multiple re-operations over the years, which also increase global morbidity. However, in recent years, the impact of multiple surgeries has been mitigated by the novel techniques of percutaneous implantation of pulmonary valves.
Therefore early surgery should not be denied solely on the basis of the risk of future reintervention. Indeed, a recent study from Romeo et al. 24 found that a longer period between repair and PVR is associated with the progression of QRS duration after PVR, and F I G U R E 8 Graphical presentation of linear mixed model showing QRS changes after surgery in patients with preoperative right ventricular end-systolic volume index (RVESVi) < 89 ml/m 2 . Blue line represents the overall change with its 95% confidence interval. (long x axis: years from PVR). PVR, pulmonary valve replacement seems to support early intervention. Our data support this finding that it is crucial to undertake PVR before the prolongation of QRS becomes irreversible.

| LIMITATIONS
The present study has limitations similar to any retrospective study.
QRS duration information was obtained by clinical entry and letter from different clinicians over a long period of time and interobserver variability was not accounted for in the model. Secondly, the study sample was largely underpowered to investigate the effect of QRS prolongation on clinical outcomes (i.e., recurrence of VT) and therefore we can only speculate on long-term clinical consequences of prolonged QRS duration. Finally, the study population was enrolled for a long period of time and changes in patient management may have influenced the final results.

| CONCLUSION
The present analysis found that after PVR in post-TOF repair, in subjects with shorter QRS and smaller RV volumes, QRS duration remained unchanged after surgery. However, in those with prolonged QRS and dilated RV volumes, QRS tended to slowly but steadily increase after surgery. These findings provide guidance for clinicians on surveillance for patients with repaired TOF and PR. The QRS duration is a very practical and inexpensive variable to monitor, especially in primary care, and it can be used as an indication for further investigation and escalation of treatment. The present analysis supports the hypothesis of superior outcomes following the early intervention, that is, before QRS duration and RV volumes reach threshold values for nonreversibility. In particular, our analysis suggested that regardless of the presence of symptoms, patients with preoperative QRS approaching 160 msec or those with RVEDV ≥ 166 ml/m 2 or RVESV ≥ 89 ml/m 2 should be considered for intervention. Our results will need to be validated in other series.