The utility of cardiopulmonary exercise testing (CPET) to define the risks of arrhythmia and sudden death in postoperative patients with congenital heart disease (CHD) remains uncertain. As part of the US Melody valve trial, prospective standardized CPET, along with echocardiography, cardiac magnetic resonance imaging, and cardiac catheterization, were performed in 170 CHD patients with right ventricular outflow tract conduit dysfunction before Melody valve implantation. Ventricular premature complexes (VPC) occurred in 75 patients (44%) and were common during all phases of CPET (13% baseline, 24% exercise, and 23% recovery). Although no subjects had sustained arrhythmias, 2 had nonsustained ventricular tachycardia and 3 had nonsustained supraventricular tachycardia during recovery. There were no statistically significant differences between patients with or without VPCs in echocardiographic, cardiac magnetic resonance imaging, or catheterization measures of cardiac function. However, clinical parameters of age, New York Heart Association functional class ≥II, and ≥3 cardiac surgical procedures were correlated with VPCs. Persistent ventricular ectopy during all exercise stages was present in 11 patients (6.5%), including 3 of the 4 patients who died during follow-up. In conclusion, VPCs were common during CPET, although they were not correlated with various measures of hemodynamic impairment; conversely, increased age, functional class, and number of surgeries were correlated with an increased prevalence of VPCs. CPET appears to be of minimal risk for sustained arrhythmia provocation in CHD patients with right ventricular outflow tract conduits and various degrees of advanced subpulmonary ventricular dysfunction.
For the past 50 years, right ventricular outflow tract (RVOT) anomalies, such as tetralogy of Fallot, transposition of the great vessels, and pulmonary atresia, have been successfully managed during infancy through surgical methods. However, an increasing prevalence of arrhythmias, sometimes resulting in death, has been observed in these patients with increasing age and impaired functional status. In patients with RVOT conduit dysfunction, the degrees of pulmonary stenosis and insufficiency have also been associated with ventricular arrhythmias and sudden death. Recently, several studies have reported usefulness of preoperative cardiopulmonary exercise testing (CPET) to predict the long-term prognosis in adults with congenital heart disease (CHD). However, the prevalence and potential risk of significant arrhythmias during CPET in patients with CHD with significant impairment of hemodynamics has not been systematically evaluated. Therefore, the purposes of this study were to characterize the type and prevalence of arrhythmias during CPET in patients with significant RVOT conduit dysfunction and to evaluate the relation between arrhythmias and echocardiographic, cardiac magnetic resonance imaging (MRI), and cardiac catheterization–derived parameters of hemodynamic function.
Methods
This study was an aspect of the US Melody valve trial, a nonrandomized prospective study assessing short-term effect of the Melody valve in patients with RVOT conduit dysfunction. Patients were included or excluded from the study based on specific criteria. Preimplantation CPET, echocardiography, cardiac MRI, and cardiac catheterization were performed at the following centers: Boston Children’s Hospital, Miami Children’s Hospital, Nationwide Children’s Hospital, Seattle Children’s Hospital, and Children’s Hospital New York. Data analysis and interpretation were performed at the University of California, Irvine. Pediatric cardiologists at each implanting institution and University of California, Irvine reviewed individual reports after each test was completed.
The study was conducted under an investigational device exemption (No. G050186), and all versions of and amendments to the protocol were approved by the Food and Drug Administration, the Center for Devices and Radiological Health, and the Institutional Review Board at each institution. The trial is registered at ClinicalTrials.gov (identifier: NCT00740870 ).
Patients (n = 170) who underwent a Melody valve implantation between January 2007 and January 2010 were investigated with a standardized CPET protocol. CPET was performed on a mechanically braked cycle ergometer. Equipment was calibrated to manufacturers’ specifications, and testing was performed with standard protocols previously used in subjects with CHD. Subjects pedaled in an unloaded state for 3 minutes. Workload was then increased continuously with a slope chosen to achieve each subject’s predicted maximal work rate after 10 to 12 minutes of cycling. Predicted maximum heart rate was estimated using the Astrand formula (220 − age). A 12-lead electrocardiogram was recorded throughout the CPET protocol to analyze cardiac rhythm, with recordings performed during baseline, exercise, and recovery phases. Leads II, aVF, and V 5 were also monitored continuously on an oscilloscope. The postexercise electrocardiogram was monitored and recorded every minute for at least 5 minutes. Details of the CPET protocol have been previously reported.
Conduit mean gradients were determined by tracing the border of continuous-wave spectral Doppler recordings and integrating the area under the curve. Pulmonary regurgitation was assessed using color and pulse-wave Doppler interrogation in the RVOT proximal to the conduit, main pulmonary artery, and proximal branch pulmonary artery and was categorized as none, trace, mild, moderate, or severe, based on regurgitant jet width relative to conduit width and the extent of pulmonary artery diastolic flow reversal.
Short-axis cine images were obtained using a steady-state free precession technique, covering both ventricles from the apex to the base. Flow measurements were obtained by selecting a plane through the main pulmonary artery and performing a breath-through, velocity-encoded, phase-contrast acquisition. Ventricular mass and volumes were calculated by manually tracing the epicardial and endocardial contours without separate exclusion of trabeculae not continuous with the mural surface on each slice.
Patients who met entry criteria underwent cardiac catheterization using general endotracheal anesthesia. The peak-to-peak right ventricle (RV)-to-pulmonary artery gradient was calculated as the difference in systolic pressure between RV body and main pulmonary artery distal to the conduit. Angiography was performed in the RV, conduit, and aortic root.
Statistical analysis was performed using commercially available software (Excel 2011 for Mac; Microsoft, Redmond, Washington). Comparison of proportions (e.g., incidence of arrhythmias) was done using the Marascuilo procedure and Fisher’s exact test. Odds ratios comparing quantitative parameters of cardiac function between patients with and without ventricular premature complexes (VPCs) were calculated through a binomial regression using SPSS Statistics (v20; IBM, Armonk, New York). For comparison of individual parameters, we used the mean ± SD. Group comparisons were calculated on the base mean plus or minus the 95% confidence interval. For all analyses, a value of p <0.05 was considered statistically significant.
Institutional review boards at each institution approved the study, and written informed consent was obtained from patients or their parents before the baseline CPET. The Melody trial was funded by Medtronic Inc. The investigators are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results
A total of 193 patients were initially recruited in this study and 170 completed the CPET protocol ( Table 1 ). Mean age at the time of the study was 21.2 ± 1.3 years (range 7 to 53), with a mean of 2.7 ± 1.1 previous cardiac surgeries. The average left ventricular ejection fraction was 57 ± 11% compared with an average RV ejection fraction of 42 ± 14%. Moderate-to-severe pulmonary and/or tricuspid regurgitation were present in 57% and 22%, respectively. Cardiac function parameters are detailed in Table 2 . The average QRS duration was 141.2 ± 2.8 ms.
| Parameter | Prevalence (n = 170) |
|---|---|
| Age (years) | 21.2 (7–53) |
| Weight (kg) | 64.4 (30.1–146.7) |
| Body mass index (kg/m 2 ) | 23.9 (14.1–44.2) |
| Male | 87 (63.5%) |
| New York Heart Association functional classification | |
| I | 25 (15.2%) |
| II | 112 (67.9%) |
| III | 27 (16.4%) |
| IV | 1 (0.6%) |
| Number of surgeries | 2.7 ± 1.1 |
| Open | 2.2 ± 1.7 |
| Closed | 0.5 ± 0.7 |
| Implanted cardiac rhythm device | 14 (8.2%) |
| Implantable cardioverter-defibrillator | 2 (1.2%) |
| Pacemaker | 12 (7.1%) |
| Diagnoses | |
| Tetralogy of Fallot | 83 (48.8%) |
| Aortic stenosis | 35 (20.6%) |
| Truncus arteriosus | 17 (10.0%) |
| Transposition of the great arteries | 17 (10.0%) |
| Double outlet right ventricle | 10 (5.9%) |
| Isolated pulmonary stenosis | 4 (2.4%) |
| Coarctation of the aorta | 2 (1.2%) |
| Variable | No VPCs (n = 95) | VPCs (n = 75) | p | OR | 95% CI |
|---|---|---|---|---|---|
| Age (years) | 19.4 ± 0.9 | 24.3 ± 1.1 | 0.007 | 1.058 | 1.015–1.103 |
| Prior cardiac surgeries | 2.4 ± 0.1 | 3.0 ± 0.1 | 0.023 | 2.418 | 1.128–5.180 |
| QRS duration (milliseconds) | 130.8 ± 3.4 | 141.3 ± 4.2 | 0.21 | 1.006 | 0.996–1.017 |
| Echocardiographic parameters | |||||
| At least moderate pulmonary regurgitation | 71 (75%) | 50 (67%) | 0.93 | 1.04 | 0.455–2.365 |
| Mean right ventricular outflow tract gradient (mm Hg) | 35.9 ± 1.5 | 30.3 ± 1.7 | 0.58 | 0.99 | 0.968–1.019 |
| Left ventricular fractional shortening (%) | 34.5 ± 0.7 | 32.4 ± 1.0 | 0.11 | 0.960 | 0.913–1.009 |
| MRI parameters | |||||
| Ratio of right ventricular to left ventricular end-diastolic volume index | 1.7 ± 0.1 | 1.9 ± 0.1 | 0.06 | 1.627 | 0.979–2.703 |
| Left ventricular ejection fraction (%) | 56.9 ± 1.1 | 56.6 ± 1.4 | 0.91 | 1.002 | 0.968–1.038 |
| Right ventricular ejection fraction (%) | 42.2 ± 1.3 | 41.5 ± 1.9 | 0.46 | 0.989 | 0.961–1.018 |
| Catheterization parameters | |||||
| Right ventricular systolic pressure (mm Hg) | 64.2 ± 2.0 | 68.2 ± 2.1 | 0.19 | 1.010 | 0.995–1.026 |
| Right ventricular end-diastolic pressure (mm Hg) | 11.8 ± 0.4 | 12.9 ± 0.5 | 0.47 | 1.026 | 0.958–1.099 |
| Right ventricular to left ventricular pressure ratio | 0.7 ± 0.1 | 0.7 ± 0.1 | 0.71 | 1.346 | 0.280–6.458 |
| Right ventricular to pulmonary artery gradient (mm Hg) | 35.7 ± 1.7 | 34.6 ± 1.9 | 0.72 | 1.003 | 0.985–1.022 |
All 170 exercise tests were completed successfully; there were no sustained arrhythmias that prompted the exercise tests to be terminated prematurely. VPCs were common (n = 75, 44%) either during baseline (n = 22, 13%), exercise (n = 40, 24%), or recovery (n = 39, 23%); 11 patients (7%) had VPCs during all 3 stages. Nonsustained ventricular tachycardia (n = 2, 1%) occurred during exercise (4 beat run) in 1 patient and recovery (3 beat run) in another. Premature atrial contractions (n = 15, 9%) were less common and were noted during baseline (n = 7, 4%), exercise (n = 8, 5%), or recovery (n = 10, 6%) stages of CPET. Nonsustained atrial tachycardia and atrial flutter, each <3 seconds, occurred in 1 patient each during the baseline period. Nonsustained supraventricular tachycardia occurred in 3 patients (2%) during the recovery stage of the CPET protocol—2 episodes were <3 seconds and the other lasted for 11 seconds. The prevalence of ventricular ectopy and arrhythmias is summarized in Table 3 . All patients were asymptomatic during these arrhythmias.
| Variable | Prevalence (n = 170) | 95% CI |
|---|---|---|
| Ventricular premature complexes | 75 (44.1%) | 36.7%–51.6% |
| Baseline | 22 (12.9%) | 7.9%–18.0% |
| Exercise | 40 (23.5%) | 17.2%–29.9% |
| Recovery | 39 (22.9%) | 16.6%–29.3% |
| All stages of cardiopulmonary exercise testing | 11 (6.5%) | 2.8%–10.2% |
| Ventricular tachycardia | 2 (1.2%) | −0.4%–2.8% |
| Atrial premature complexes | 15 (8.8%) | 4.6%–13.1% |
| Baseline | 7 (4.1%) | 1.1%–7.1% |
| Exercise | 8 (4.7%) | 1.5%–7.9% |
| Recovery | 10 (5.9%) | 2.3%–9.4% |
| Atrial tachycardia | 1 (0.6%) | −0.6%–1.7% |
| Atrial fibrillation | 1 (0.6%) | −0.6%–1.7% |
| Supraventricular tachycardia | 3 (1.8%) | −0.2%–3.7% |
| Anti-arrhythmic therapy | 41 (24.1%) | 17.7%–30.5% |
| β-Blocker | 21 (12.4%) | 7.4%–17.3% |
| K + -Channel blocker | 4 (2.4%) | 0.1%–4.6% |
| Digoxin | 21 (12.4%) | 7.4%–17.3% |
| Ventricular premature complexes by anatomic diagnoses | ||
| Transposition of the great arteries | 11 (64.7%) | 62.9%–66.5% |
| Double outlet right ventricle | 6 (60.0%) | 58.3%–61.7% |
| Isolated pulmonary stenosis | 2 (50.0%) | 48.4%–51.6% |
| Coarctation of the aorta | 1 (50.0%) | 48.4%–51.6% |
| Tetralogy of Fallot | 38 (45.8%) | 44.3%–47.3% |
| Aortic stenosis | 12 (34.3%) | 33.0%–35.6% |
| Truncus arteriosus | 5 (29.4%) | 28.2%–30.6% |
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