Long-term outcome after repair of tetralogy of Fallot (TOF) is related to chronic pulmonary insufficiency (PI), right ventricular (RV) dilation, and deteriorating ventricular function. Pulmonary valve incompetence increases in severity over time and has been linked to deterioration of exercise capacity and RV function. RV diastolic dysfunction, RV fibrosis, and eventual left ventricular (LV) dysfunction also influence outcomes in these patients.

Traditionally, restrictive diastolic RV physiology has been characterized by the echocardiographic presence of end-diastolic antegrade flow in the main pulmonary artery (MPA) after atrial contraction. Restrictive diastolic RV physiology has been identified in survivors of TOF repair. Its presence has been considered potentially beneficial in patients late after repair, although the literature is inconsistent. In adults 15 to 35 years after repair, Gatzoulis et al. showed that those with restrictive right ventricles had smaller cardiothoracic ratios on chest x-ray and better exercise performance than those without restrictive RV physiology. Eroglu et al. concluded that RV restriction, at midterm follow-up after transannular patch repair of TOF, was more often associated with a smaller right ventricle and less prolongation of the QRS complex on electrocardiography. Yet Lu et al. recently showed that patients with repaired TOF with larger RV end-diastolic volumes had more evidence of restrictive physiology, a feature also noted recently in a Toronto cohort. Finally, Helbing et al. showed no significant difference in RV size, PI, or RV ejection fraction (EF) for young (mean age, 12 ± 3 years) patients with repaired TOF with restrictive and nonrestrictive RV physiology, and they also found that exercise function was diminished in patients with TOF with restrictive physiology.

Using cardiac magnetic resonance (CMR) imaging, the gold standard for RV assessment, the ranges of biventricular sizes and systolic function in patients with repaired TOF have been defined. In the present era, clinical decision making for patients with repaired TOF, especially regarding the appropriate timing of pulmonary valve replacement, remains challenging. Caregivers seek to avoid the irreversible ventricular dysfunction from chronic PI and volume overload, described in retrospective studies by Therrien et al. , in which RV volume thresholds (end-diastolic volume indexed to body surface area, 170 mL/m ² ; end-systolic volume indexed to body surface area, 85 mL/m ² ) predicted poor RV remodeling and recovery of RV function after pulmonary valve replacement.

Before these volumetric thresholds are attained, regional myocardial deformation may be altered and can be prospectively evaluated from echocardiography-derived speckle-tracking analysis to measure myocardial strain and provide direct information about the contractile performance of the right ventricle. Regional RV myocardial mechanics have been previously described in healthy children and in patients with congenital heart disease, with recent studies exploring regional myocardial mechanics in patients after repair of TOF. We sought to prospectively characterize and compare the clinical status and regional myocardial mechanics of young patients with restrictive versus nonrestrictive RV physiology after TOF repair at our institution, using the complementary modalities of CMR imaging and echocardiography.

Methods

Study Population

This was a prospective study with approval from the Children’s Hospital of Wisconsin Institutional Review Board. Informed consent and child assent were obtained from consecutively recruited patients with repaired TOF receiving care in the Herma Heart Center at the Children’s Hospital of Wisconsin from February 2008 to August 2009. Patients with a documented primary diagnosis of TOF were identified by review of clinic schedules and approached for enrollment in the study at the time of their clinic visits or while waiting for clinical testing. Patients were considered eligible if they were 8 to 40 years of age, had repaired TOF, and had at least mild residual PI on echocardiography. Furthermore, they were deemed eligible for study participation only if their cardiologists planned collection of all clinical data within 3 months of their clinic visits; these clinically indicated studies included assessment of New York Heart Association (NYHA) classification from clinic visit, brain natriuretic peptide (BNP) level, transthoracic echocardiography, CMR imaging, and Bruce-protocol exercise treadmill testing. Patients were excluded if they had (1) TOF with atrioventricular septal defect, (2) any major developmental disability that might limit their ability to complete required testing (e.g., DiGeorge syndrome), or (3) relative contraindications to CMR imaging (e.g., pregnancy, pacemaker, defibrillator). Of 76 patients with TOF (age range, 8–40 years) seen during this time period at Children’s Hospital of Wisconsin, 35 were eligible, and 29 successfully completed the protocol (with the remaining six having incomplete data collection within the 3-month time frame).

Clinical Evaluation

Pertinent medical history (e.g., original diagnoses, past palliations, cardiac catheter interventions, operative repairs, current medications, symptoms) as well as physical examination findings from the recent clinic visit were extracted from the medical record. Each individual’s NYHA classification was designated, by two independent cardiologists, on review of reported symptoms described in the recent clinic visit note. BNP level was obtained at the time of CMR imaging as an additional means of evaluating clinical status.

Exercise Stress Testing

All study subjects underwent Bruce-protocol exercise testing on a treadmill ergometer with incremental increases in speed and grade to voluntary exhaustion. Blood pressure and heart rate were obtained every minute. A 12-lead electrocardiogram was obtained every 3 min or at times of arrhythmia occurrence. Oxygen consumption was determined (SensorMedics, Inc., Yorba Linda, CA) and computer recorded on a breath-by-breath basis. Maximal oxygen consumption (V o ₂ max) was expressed as absolute (liters per minute), relative (milliliters per kilogram per minute), and percentage of predicted. Maximal effort was considered if the peak heart rate exceeded 90% predicted, if a plateau occurred in oxygen consumption in the absence of a rise with increasing work, or if the respiratory quotient was >1.10. Postexercise monitoring included 12-lead electrocardiography and blood pressure monitoring through 5 min of recovery.

CMR Imaging

CMR imaging was performed per institutional protocol using a Siemens 1.5-T Symphony magnetic resonance scanner (Siemens Medical Solutions USA, Inc., Malvern, PA). Ventricular dimensions and function were assessed from electrocardiographically gated, breath-held steady-state free precession (TrueFISP; Siemens Medical Solutions USA, Inc.) cine CMR pulse sequences for the ventricular short-axis plane (matrix size, 192 × 192 or better; repetition time, 45–75 msec; echo train length, 1–2 msec; slice thickness, 6–8 mm). Steady-state free precession (TrueFISP) or gradient-echo (FLASH; Siemens Medical Solutions USA, Inc.) cine imaging was obtained for the RV outflow tract (sagittal and coronal planes) and the branch pulmonary arteries (axial plane). Through-plane flow assessment of MPA was obtained, using velocity-encoded retrospectively electrocardiographically gated, free-breathing phase-contrast CMR imaging (repetition time, 46 msec; echo train length, 3.9 msec; slice thickness, 5 mm) by prescribing a plane perpendicular to MPA flow. CMR data analyses were performed offline using a commercially available software package (Mass & Flow Analysis Package; MEDIS Medical Imaging Systems, Leiden, The Netherlands). RV and LV volumes, masses, and EFs were measured as described by Alfakih et al. Data were then normalized to each study subject’s body surface area to allow comparisons among patients.

Echocardiography

Echocardiography was performed using a Sequoia ultrasound system (Siemens Medical Solutions USA, Inc.). Standard electrocardiographically triggered digital capture occurred, and two-dimensional, color flow, and Doppler flow assessments were done per institutional protocol. The peak RV outflow tract gradient was measured offline from a continuous-wave Doppler recording using syngo Ultrasound Workplace (Siemens Medical Solutions USA Inc.). RV and LV diastolic function was measured offline using Doppler (peak E and peak A velocities and the E/A ratio) and Doppler tissue imaging of the tricuspid and mitral lateral annuli, according to methods described previously. Figure 1 shows key Doppler tissue imaging measurements. Finally, restrictive RV physiology was confirmed with spectral Doppler tracings showing consistent (at least three heartbeats) antegrade end-diastolic flow into the MPA with atrial contraction by standard methods described by Redington et al. ( Figure 2 ). Because these were clinical echocardiographic examinations, respiratory monitoring was not standard procedure, and patients were simply breathing comfortably. Thus, consistency of this MPA flow pattern was important to enable accurate classification of restrictive RV physiology, because this pattern has been described as a normal finding during inspiration in normal controls. We did not use the stricter definition of Vukomanovic et al. that requires antegrade flow into the MPA of >30 cm/sec for five heartbeats. Patients were assigned to one of two groups, those with restrictive RV physiology and those with nonrestrictive physiology, for later analyses.

Diastolic indices, measured from the annular velocities, include peak early diastolic annular velocity (E _a ) and peak diastolic annular velocity with atrial contraction (A _a ). Systolic indices include peak systolic annular velocity (S _a ) and systolic acceleration (Ac). Time intervals that can be calculated include the early diastolic annular deceleration time (DT), isovolumic contraction (IC), and isovolumic relaxation (IR) time intervals.

Antegrade end-diastolic flow seen in the MPA with atrial contraction ( arrows ) is indicative of restrictive RV physiology, whereas nonrestrictive RV physiology lacks this flow pattern.

Myocardial Mechanics

Velocity Vector Imaging technology (Siemens Medical Solutions USA, Inc.), based on speckle-tracking, was used to analyze global and regional RV myocardial motion. These analyses were performed on high-quality, digitally acquired two-dimensional echocardiographic images of the right ventricle (single-beat acoustic capture from the apical four-chamber view with a frame rate of 70–120 frames/cardiac cycle). Digital clips that clearly visualized the RV endocardium were chosen, from which the subendocardial border was manually traced and automatically tracked by syngo Velocity Vector Imaging technology, according to methods described by Kutty et al. , with the frame of reference located at the RV apex. Tracings were independently reviewed by a second reader to optimize accuracy in tracking the endocardial border. Measurement of regional peak longitudinal tissue velocities in systole and diastole, peak longitudinal systolic RV strain, peak longitudinal systolic and diastolic RV strain rates, peak longitudinal displacement of the RV free wall, and times to these peak parameters were performed for the RV free wall segments ( Figure 3 ). Because the interventricular septum is shared with the left ventricle, this research focused on the RV free wall segments.

(A) Using Velocity Vector Imaging technology (Siemens Medical Solutions USA, Inc.), the measurement of peak diastolic velocity ( arrow ) for the right basal segment of the right ventricle is shown for a postoperative TOF patient with restrictive RV physiology. (B) Measurement of corresponding peak diastolic strain for the right basal RV segment is shown ( arrow ).

Statistical Analyses

Medians and ranges are given for continuous demographic variables and frequencies and percentages for categorical variables. Pearson’s correlation coefficients were calculated between two continuous variables. Continuous data were compared for the groups with restrictive versus nonrestrictive RV physiology after TOF repair using Wilcoxon-Mann-Whitney tests if the data were skewed and t tests otherwise. Fisher’s exact tests were used to compare categorical variables between the two groups. Given the large number of comparisons made, P values < .005 were considered significant. This is not an adjustment for a specific number of tests, interrelated or otherwise, but rather a realization that a P value < .05 is too generous a level, but a full Bonferroni adjustment (for >100 comparisons) would be far too stringent and lead to many false-negatives, given the sample size. A P value < .05 shows an interesting trend, possibly worthy of additional study in future research. SAS version 9.1 (SAS Institute Inc., Cary, NC) was used for statistical analyses.