Abstract
Background
The underlying mechanisms contributing to global right ventricular (RV) dysfunction in patients with repaired tetralogy of Fallot (TOF) are incompletely understood. We therefore sought to quantify regional RV abnormalities and to determine the relationship of these to global RV function and exercise capacity.
Methods and Results
Clinical and cardiac magnetic resonance (CMR) data from 62 consecutive patients with repaired TOF were analyzed (median age at follow-up 23 years [limits 9–67]). Using CMR data, 3-dimensional RV endocardial surface models were reconstructed from segmented contours and a correspondence between end-diastole and end-systole was computed using a novel algorithm. Regional RV abnormalities were quantified and expressed as segmental ejection fraction (EF), spatial extent of dyskinetic area, displacement of dyskinetic area, and score of extent of late gadolinium enhancement (LGE). Regional abnormalities of function and hyperenhancement were greatest in the RV outflow tract (RVOT). These regional RVOT abnormalities correlated with global RV EF: RVOT EF r= 0.64, p<0.0001; RVOT dyskinetic area r= −0.51, p<0.0001; RVOT displacement of dyskinetic area r= −0.49, p<0.0001; and RVOT LGE score r= −0.33, p= 0.01. Peak oxygen consumption during exercise correlated best with RVOT EF (r= 0.56, p= 0.0002) as compared with the remainder of the RV (r= 0.35, p= 0.03). The only CMR variable independently predictive of aerobic capacity was RVOT EF (p= 0.02).
Conclusion
Greater extent of regional abnormalities in the RVOT adversely affects global RV function and exercise capacity after TOF repair. These regional measures may have important implications for patient management, including RVOT reconstruction, at the time of pulmonary valve replacement.
Keywords: tetralogy of Fallot; heart defect, congenital; magnetic resonance imaging
Right ventricular (RV) dysfunction often complicates the clinical course of patients with repaired tetralogy of Fallot (TOF) and is associated with increased morbidity and mortality.1, 2 Although the RV is usually capable of initially adapting to the abnormal loading conditions after TOF repair, global RV dysfunction ultimately results from failure of compensatory mechanisms to accommodate the chronic volume and/or pressure loads.3, 4 While the sequence of events leading to ventricular dysfunction has been studied in detail in conditions affecting the left ventricle (LV),5 the pathophysiology of RV dysfunction in late survivors of TOF repair remains incompletely understood. Investigators have long suspected that scar tissue and/or patch material in the right ventricular outflow tract (RVOT) can adversely affect RV mechanics after TOF repair. Using cardiac magnetic resonance (CMR), two recent reports have demonstrated an association between late gadolinium enhancement (LGE) in the RV and global systolic dysfunction.6, 7 Another study found worse global RV dysfunction in patients with RVOT aneurysms compared with those without aneurysms.8 These studies, however, utilized predominantly qualitative measures of LGE and regional RV wall motion abnormalities. The degree to which regional abnormalities can affect global RV function and whether these adversely affect exercise capacity, ventricular arrhythmia, and heart failure, independent of global RV dysfunction, remain unknown. The goal of this study, therefore, was to quantify regional RV abnormalities by CMR and to determine their relationship to global RV function and exercise capacity.
METHODS
Subjects
Patients were included in the study if they fulfilled the following criteria: 1) had a diagnosis of TOF repair; 2) completed a standardized CMR examination protocol at our laboratory between 2002 and 2005; and 3) had a contemporary clinical evaluation. Patients were excluded if the technical quality of the CMR data was inadequate for quantitative analysis or if they had pulmonary valve replacement before the CMR study. The study was approved by the Scientific Review Committee of the Department of Cardiology and by the Children's Hospital Boston Committee on Clinical Investigation.
Patient Data
The following information was abstracted from medical records: date of birth, gender, anatomic diagnoses, date, age, and type of each surgical procedure, date and age at CMR, and date and age at most recent clinical evaluation. The most recent clinical evaluations were reviewed through March 2008. Results of contemporary cardiopulmonary exercise tests were recorded. Rhythm and conduction abnormalities were identified from a 15-lead electrocardiogram (ECG), Holter results, and electrophysiology studies. Symptoms of heart failure (New York Heart Association [NYHA] functional class) and cardiovascular interventions were documented.
Cardiac Magnetic Resonance
The details of the CMR protocol utilized in our laboratory for assessment of patients with repaired TOF have been published.9 Briefly, studies were performed with a commercially available 1.5 Tesla scanner. Ventricular dimensions and function were assessed using ECG-gated steady-state free precession cine MR pulse sequence during brief periods of breath-holding in the following planes: ventricular 2-chamber (vertical long-axis), 4chamber (horizontal long-axis), and short-axis planes (perpendicular to the ventricular long-axis plane based on the previous 4-chamber images) with 12–14 equidistant slices completely covering both ventricles. Flow measurements were performed in the proximal main pulmonary artery using a retrospectively gated velocity-encoded cine MRI pulse sequence during free breathing.
LGE imaging was performed in the ventricular short- and long-axis planes 10–20 minutes after injection of 0.2 mmol/kg gadopentetate dimeglumine (Magnevist, Berlex Laboratories, NJ) through a peripheral venous cannula. Imaging was performed with a commercially available inversion recovery prepared, ECG-triggered, fast gradient recalled echo pulse sequence.10 Inversion time was optimized for suppression of signal from the RV myocardium, as described by Desai et al.11
A single investigator (RMW) who was blinded to patient clinical outcomes analyzed the CMR data using commercially available software packages (MASS version 4.0 and FLOW version 2.0, Medis, Leiden, The Netherlands). Left and right ventricular end-diastolic (maximal) and end-systolic (minimal) volumes, mass at end-diastole, stroke volumes, and ejection fraction (EF) were measured, as described by Alfakih et al.12
Quantitative Analysis of Regional RV Function
Using a validated triangulation algorithm,13 three-dimensional (3D) models of the RV endocardial surfaces at end-diastole and end-systole for each patient were reconstructed from the aforementioned steady-state free precession short-axis cine images. The impact of long-axis “through plane” motion from base-to-apex was incorporated into the model using the long-axis cine images, as previously described.14 Analyses of regional wall motion abnormalities and LGE were restricted to the RV free wall. The reconstructed RV free wall comprised an average of 550 triangles with an average triangle size of ~23 mm2.
Analysis of segmental ejection fraction
For segmental analysis, the RV was divided into 3 longitudinal and 3 vertical regions for a total of 9 segments as described by Klein et al. (Figure 1).15 Segmental EFs were calculated for segments 1 through 9 from the reconstructed segmental 3D datasets at end-diastole and end-systole. To assess the accuracy of the calculated segmental EFs, quantification of global RV EF using the sum of the 3D reconstructed segments was compared in each patient with the standard method of EF calculation.
Figure 1.
Segments of the right ventricle. The 3 longitudinal regions were termed basal, mid-ventricular, and apical. The apical region was defined as the segment inferior to the moderator band. The portion of the RV between the right atrioventricular groove and the moderator band was equally divided into basal and mid-ventricular segments. To delineate the 3 vertical regions, the angle between the superior and inferior septal insertion points and the center of the LV was defined and was divided into equal thirds to comprise the superior, anterior and inferior regions of the RV free wall.
Analysis of regional RV free wall displacement
Using custom software developed by one of the investigators (IH), the magnitude and direction of RV free wall systolic motion was calculated by establishing a correspondence between the surfaces at end-diastole and end-systole. For each triangle on the end-diastolic surface, a vector was defined along the local normal and its intersection with the end-systolic surface was found. The length of the vector between the original triangle center and the intersection point determined the displacement of that triangle. The direction and extent of systolic displacement was subsequently analyzed for each triangle in the RV wall. The direction of systolic displacement was considered inward (negative) if motion was towards the center of the LV and was considered outward (positive) if it was away from it. Positive triangular displacement was labeled dyskinesis (Figure 2A).
Figure 2.
Three-dimensional surface models of the RV free wall. A. Displacement map showing dyskinesis of the RVOT (red). B. Late gadolinium enhancement map showing extensive enhancement of the RVOT (yellow and orange).
Two quantitative measures were derived using this 3D model of RV free wall motion: 1) the area-weighted spatial extent of dyskinesis defined as the ratio of the dyskinetic area to total RV free wall area, termed dyskinetic area; and 2) the area-weighted magnitude of dyskinesis (in mm) defined as the total displacement of all dyskinetic segments indexed to the total RV free wall area (i.e., A1·D1 + A2·D2 …+ A n·Dn/total RV free wall area, where A is the triangle area, D the dyskinetic displacement and n is the number of triangles in the RV free wall), termed displacement of dyskinetic area.
Quantification of late gadolinium enhancement
Using LGE images of the ventricles in short-and long-axis planes, enhanced areas in the RV free wall were manually segmented by a single investigator (RMW) who was unaware of patient outcome. The segments of enhanced pixels were represented in the 3D coordinate system on the reconstructed RV endocardial surface and converted to voxels by accounting for the slice thickness of the image (Figure 2B). For each enhanced voxel, a corresponding triangle on the 3D reconstructed surface was found and the number of enhanced voxels in each triangle was recorded. An enhancement score was derived and is defined as the area-weighted voxel count per triangle (i.e., A1·C1 + A2·C2 …+ An·Cn/total RV free wall area, where A is the triangle area, C is the number of enhanced voxels in a triangle, and n is the number of triangles in the RV free wall). Presence of LGE in the interventricular septum and LV free wall was noted.
Outcomes
The primary clinical outcome was defined as peak oxygen consumption measured by exercise test and expressed as an absolute value (ml/kg/min) and as percent predicted for age-and gender-adjusted normal population. Subnormal exercise capacity was defined as <85% predicted as recommended by the American Thoracic Society/American College of Chest Physicians and by Albouaini et al.16, 17 Secondary outcomes included sustained ventricular tachycardia (defined as ventricular tachycardia lasting ≥ 30 seconds and/or tachyarrhythmia requiring cardioversion) and heart failure symptoms (defined as NYHA class ≥ II).
Statistical Analysis
Demographic, clinical, and laboratory characteristics were compared for subjects who had impaired exercise tolerance and those who had normal exercise capacity using the Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables. Continuous variables were correlated using the Spearman correlation coefficient. Multivariable linear regression was used to evaluate: (1) independent relationships between measures of regional RV abnormalities and global RV systolic function, and (2) independent relationships between CMR variables and exercise capacity (peak oxygen consumption). Statistical data were analyzed using a commercially available software package (SAS version 9.1.3, SAS Institute, Cary, North Carolina).
Statement of Responsibility
The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
RESULTS
Subjects
Of the 256 patients with repaired TOF who underwent CMR examination in our laboratory during the study period, 62 satisfied the study criteria. Reasons for exclusion were absent or incomplete LGE dataset, prior placement of prosthetic pulmonary valve, and image artifacts related to metallic implants. Table 1 summarizes the demographic, clinical, ECG, and exercise characteristics of the study patients. There were no deaths in this cohort. During follow-up, 19 patients underwent pulmonary valve replacement and 4 patients had an automatic cardiac defibrillator implanted due to sustained ventricular tachycardia. Table 2 summarizes the CMR data for all patients and compares patients with abnormal to those with normal exercise capacity.
Table 1.
Clinical characteristics of the 62 study patients
| Gender | 34 males (55%) |
| Median age at TOF repair | 1.2 years (0.02 – 46.4) |
| Median age at CMR | 19.7 years (4.2 – 67.2) |
| Median age at last follow-up | 22.9 years (9.3 – 67.2) |
| Median time from TOF repair to last follow-up | 22.0 years (7.7 – 41.6) |
| Median time from CMR to last follow-up | 3.0 years (0 – 5.2) |
| Type of TOF repair | |
| Transannular patch | n = 30 (48%) |
| Non-transannular patch | n = 10 (16%) |
| RV-PA Conduit | n = 13 (21%) |
| Details unknown | n = 9 (15%) |
| Exercise test (n= 38) | |
| Median peak oxygen consumption | 26 cc/kg/min (11 – 52) |
| Median % predicted peak oxygen consumption | 71% (44 – 121) |
| Sustained ventricular tachycardia | n = 5 |
| Median QRS duration (n=55) | 149 ms (100–206) |
| NYHA class at last follow-up (n=56) | |
| I | n = 42 (75%) |
| II | n = 11 (20%) |
| III | n = 3 (5%) |
| IV | n = 0 |
CMR = cardiac magnetic resonance; PA = pulmonary artery; RV = right ventricle; TOF = tetralogy of Fallot
Table 2.
Cardiac magnetic resonance data
| Variables* | All Patients (n = 62) | Subnormal Exercise Capacity (n=28) | Normal Exercise Capacity (n=10) | P Value** |
|---|---|---|---|---|
| Global RV Variables | ||||
| RV EDVi (ml/m2) | 139 (77 – 372) | 167 (82 – 372) | 121 (77 – 167) | 0.03 |
| RV EDV Z-score | 4 (0 – 20) | 6 (0 – 20) | 3 (0 – 7) | 0.05 |
| RV ESVi (ml/m2) | 67 (22 – 282) | 74 (41 – 282) | 45 (22 – 79) | 0.005 |
| RVSV (ml/m2) | 74 (36 – 189) | 75 (41 – 171) | 75 (51 – 143) | NS |
| RV EF (%) | 50 (24 – 71) | 51 (24 – 62) | 56 (43 – 71) | 0.012 |
| RV mass (g) | 70 (23 – 167) | 70 (23 – 167) | 51 (26 – 78) | 0.067 |
| RV mass:volume ratio | 0.29 (0.17 – 0.49) | 0.27 (0.17 – 0.49) | 0.31 (0.25 – 0.49) | NS |
| Pulmonary regurgitation (%) | 34 (3 – 67) | 39 (3 – 59) | 35 (20 – 43) | NS |
| Regional RV Variables | ||||
| RVOT EF (%) | 41 (14 – 74) | 39 (14 – 56) | 52 (35 – 66) | 0.004 |
| Dyskinetic area of the RV (%) | 4 (0 – 15) | 6 (0 – 14) | 1 (0 – 4) | 0.014 |
| Dyskinetic area of the RVOT (%) | 10 (0 – 29) | 11 (0 – 29) | 7 (0 – 28) | NS |
| Displacement of dyskinetic area of the RV | 0.06 (0 – 0.38) | 0.08 (0 – 0.28) | 0.01 (0–0.05) | 0.009 |
| Displacement of dyskinetic area of RVOT | 0.14 (0 – 0.75) | 0.15 (0 – 0.73) | 0.04 (0 – 0.75) | NS |
| Enhancement score (all RV segments) | 0.74 (0 – 4.29) | 0.74 (0 – 3.19) | 0.49 (0 – 1.18) | NS |
| Enhancement score of RVOT | 1.15 (0 – 7.49) | 0.96 (0 – 7.19) | 1.0 (0 – 2.48) | NS |
| LV Variables | ||||
| LV EDVi (ml/m2) | 84 (59 – 176) | 87 (62 – 176) | 78 (59 – 105) | NS |
| LV ESVi (ml/m2) | 34 (17 – 73) | 34 (19 – 73) | 25 (17 – 45) | 0.065 |
| LV EF (%) | 59 (34 – 75) | 61 (34 – 72) | 65 (54 – 71) | NS |
| LV mass (g) | 102 (30 – 206) | 109 (39 – 206) | 81 (35 – 127) | 0.034 |
| LV mass:volume ratio | 0.73 (0.51 – 1.17) | 0.72 (0.51 – 1.02) | 0.69 (0.56 – 0.83) | NS |
Data reported as median value (limits)
Wilcoxon rank sum test
Abbreviations: EDV(i)= end-diastolic volume (index); EF= ejection fraction; ESV(i)= end-systolic volume (index); LV= left ventricle; NS= not significant; PR= pulmonary regurgitation; RVOT= right ventricular outflow tract; RV= right ventricle
Validation of Regional RV EF Calculation
There was close correlation (r= 0.83, p <0.0001) and agreement (mean bias 3.2%, limits of agreement −7.0 to +13.4%) between RV EF calculated from summation of RV surface-reconstructed segmental volumes and the standard method (Figure 3).
Figure 3.
Comparison between global RV ejection fractions calculated by standard technique (EF1) and by reconstructed 3D RV segments (EF2). A. Scatterplot of EF1 versus EF 2.
B. Bland-Altman plot.
Effect of Regional Dysfunction on Global RV Systolic Function
Regional EF, percent dyskinetic area, displacement of dyskinetic area, and enhancement score in the 9 RV segments are shown in Table 3. The proportion of patients with regional wall motion abnormalities and LGE in each of the RV free wall segments are shown in Figure 4. There was good agreement between RV free wall dyskinesis and LGE (p= 0.002). Except for small, localized areas of LGE in the superior and inferior septal-free wall junctions and at the site of the ventricular septal defect patch, no significant areas of enhancement were seen in the LV. These areas were not included in further analyses.
Table 3.
Measures of regional RV dysfunction and late gadolinium enhancement
| Variable* | EF (%) | Dyskinetic Area | (%) Displacement of Dyskinetic Area | Enhancement score |
|---|---|---|---|---|
| Global RV | 50 (24 – 71) | 5 (0 – 18) | 0.10 (0 – 0.46) | 0.96 (0 – 4.29) |
| Segment 1 | 44 (−6 – 100) | 12 (0 – 55) | 0.15 (0 – 1.17) | 1.81 (0 – 16.27 |
| Segment 2 | 49 (22 – 81) | 5 (0 – 95) | 0.04 (0 – 2.93) | 0 (0 – 9.94) |
| Segment 3 | 63 (24 – 88) | 0 (0 – 15) | 0 (0 – 0.63) | 0 (0 – 0.10) |
| Segment 4 | 31 (−6 – 73) | 0 (0 – 30) | 0 (0 – 0.69) | 0.01 (0 – 17.39) |
| Segment 5 | 25 (−0.2 – 48) | 0 (0 – 45) | 0 (0 – 0.63) | 0.01 (0 – 7.23) |
| Segment 6 | 58 (30 – 92) | 0 (0 – 0) | 0 (0 – 0) | 0 (0 – 0) |
| Segment 7 | 70 (−20 – 100) | 0 (0 – 50) | 0 (0 – 1.34) | 0 (0 – 0.28) |
| Segment 8 | 57 (15 – 95) | 0 (0– 5) | 0 (0 – 0.05) | 0 (0 – 0.23) |
| Segment 9 | 74 (22 – 97) | 0 (0 – 23) | 0 (0 – 0.12) | 0 (0 – 0) |
Data reported as median value (limits)
Figure 4.
Segmental distribution of regional RV abnormalities. A. Percent of patients with regional dyskinesis in each segment. B. Percent of patients with LGE in each segment.
Quantitative measures of regional RV free wall dyskinesis—area-weighted spatial extent of dyskinetic area and displacement of dyskinetic area—inversely correlated with global RV systolic function. Specifically, a larger area of RV free wall dyskinesis was associated with a lower global RV EF (r= −0.54, p< 0.0001; Figure 5A) and a greater extent of dyskinetic displacement was similarly associated with lower global RV EF (r= −0.46, p< 0.0002; Figure 5B). Furthermore, a higher LGE score correlated with a lower global RV EF (r= −0.34, p <0.0001). Multivariable linear regression adjusting for potential confounders, including ventricular volume, LV function, and pulmonary regurgitation, demonstrated independent contributions of dyskinetic area (p=0.03, regression coefficient −21.3, standard error 9.8) and displacement of dyskinetic area (p=0.003, regression coefficient −62.9, standard error 20.6) to global RV EF.
Figure 5.
Correlations between global RV ejection fraction and area-weighted spatial extent of dyskinetic area (A) and area-weighted magnitude of RV dyskinesis (B).
Given that the majority of segmental dyskinesis and LGE concentrated in segments that correspond to the RVOT (segments 1, 2, and 4; Figure 4), further analyses evaluated relationships between measures of regional dysfunction involving the RVOT, as compared with the remainder of the RV, on global RV systolic function. The following measures of regional abnormalities in the RVOT were moderately correlated with lower global RV function: spatial extent of dyskinetic area (r= −0.51, p <0.0001), magnitude of dyskinesis (r= −0.49, p <0.0001), and LGE score (r= −0.33, p=0.01). In comparison, correlations between the RV sinus and global RV EF for the aforementioned variables were weaker or absent (dyskinetic area r= −0.39, p=0.002; magnitude of dyskinesis r= −0.38, p= 0.003; LGE score r= 0.05, p= 0.971).
Effects of Regional RV Dysfunction on Exercise Capacity
Peak oxygen consumption on exercise testing was more strongly correlated with RVOT EF (r= 0.56, p= 0.0002) as compared with the remainder of the RV (r= 0.35, p= 0.03). Furthermore, patients with subnormal exercise capacity had a greater degree of global and regional RV dysfunction (Table 2). On univariable analysis, subnormal exercise capacity was more closely associated with RVOT EF (p= 0.004) as compared with global RV EF (p= 0.012). By linear regression analysis with step-wise selection to evaluate independent predictors of exercise capacity (peak oxygen consumption) and adjusting for CMR parameters of global and regional RV dysfunction, the only significant CMR variable was RVOT EF (p= 0.02, regression coefficient 0.29, standard error 0.12).
Effects of Regional RV Dysfunction on Ventricular Tachycardia and Heart Failure Symptoms
By univariable analysis, lower RVOT EF was associated with sustained ventricular tachycardia (p= 0.045), whereas global RV EF was not (p= 0.06). Additionally, sustained ventricular tachycardia was associated with other RV measures, including higher RV end-diastolic (p= 0.011) and end-systolic (p= 0.014) volumes, higher RV end-diastolic volume Z-score (p=0.007), and RV stroke volume (p= 0.013).
Compared with patients without heart failure symptoms, those with NYHA class ≥ II had larger RV end-diastolic (p= 0.025) and end-systolic (p= 0.003) volumes, higher RV end-diastolic volume Z-score (p=0.008), higher RV mass (p= 0.023), lower global RV EF (p= 0.01), and a higher LGE score (p= 0.036). Among the parameters of regional RV dysfunction, patients with NYHA class ≥ II had a higher RVOT enhancement score as compared with those without symptoms (p= 0.044).
DISCUSSION
This study used newly developed quantitative methods to analyze the effects of regional RV wall motion abnormalities and late gadolinium enhancement on global RV systolic function and clinical status in patients with repaired TOF. In addition to demonstrating that regional RV abnormalities contribute to RV dysfunction independent of RV size, degree of pulmonary regurgitation, and other confounding factors, we have also found that measures of regional dysfunction are associated with decreased exercise capacity, sustained ventricular tachycardia, and symptoms of heart failure.
Previous studies on regional RV wall motion abnormalities after TOF repair are difficult to compare because these studies predominantly relied on qualitative methods to assess wall motion, did not precisely localize the abnormal regions within the RV free wall, did not systematically examine the association between markers of fibrosis (e.g., LGE) and regional wall motion abnormalities, and/or did not investigate the influence of regional RV dysfunction on clinical outcomes. Although the presence of aneurysms in the RVOT after TOF repair has long been recognized based on x-ray ventriculography, echocardiography, CMR, and computed tomography, little has been known about the hemodynamic effects of these aneurysms on global RV function despite widespread clinical suspicion of an adverse influence.18, 19 Indeed, much of the research on this issue has concentrated on the association between RVOT aneurysms and ventricular tachyarrhythmias.20 21 More recently, Davlouros and colleagues have shown that patients with an RVOT aneurysm or akinesis detected by CMR had a lower global RV EF. In contrast to the present study, however, the presence of an aneurysm or akinesis was based on visual inspection, was not quantified, and was subject to through-plane motion artifacts.
The importance of fibrosis and/or non-viable tissue such as patch material in the RVOT was highlighted by Oosterhof et al.6 and Babu-Narayan et al.7 Our study also found that in addition to the immediate area of the RVOT, LGE frequently extended to the anterior RV free wall and neighboring segments (Figure 4B) and that the presence of LGE was associated with regional RV dysfunction. Notably, unlike the findings of Babu-Narayan et al., who reported LGE in the LV of 53% of their patients, we have not encountered significant areas of LGE in the LV in our cohort. This discrepancy is likely related to the frequent use of trans-apical LV vent during surgery in their patients as well as differences in myocardial preservation techniques.7
Clinical Implications
Current management strategies in late survivors of TOF repair aim to restore pulmonary valve competency either by surgical or transcatheter approaches and to control arrhythmias.4, 22–25 Several studies have demonstrated either lack of improvement or even decline in RV function as well as inconsistent electrophysiological responses after pulmonary valve implantation; however, the reasons for the unpredictable results have not been fully elucidated.25–31 Given the association between RVOT dyskinesis/fibrosis and global RV dysfunction demonstrated in this study, it is reasonable to speculate that, when left untreated, these abnormalities will likely continue to adversely affect RV function as well as functional capacity. The clinical importance of subnormal exercise tolerance in adults with congenital heart disease is highlighted by the study of Diller et al., which evaluated a large cohort comprised predominantly of patients with repaired TOF and showed that decreased peak oxygen consumption on exercise test predicts hospitalization or death.32 Our data provide evidence that one of the possible mechanisms for exercise intolerance late after TOF repair relates to abnormalities of RVOT function.
Although most surgical reports on pulmonary valve replacement describe either limited resection of a localized, discrete aneurysm in the RVOT or no specific measures to address dyskinetic or fibrotic RV wall segments,27–31, 33 we found that fibrosis and dyskinesis often extend beyond the superior aspect of the RVOT (the site of pulmonary valve implantation) into adjacent segments (Figures 2 and 4), suggesting that more extensive remodeling of the RV might be necessary for optimal functional recovery. The clinical benefit of this approach has been demonstrated in patients with LV aneurysms treated by surgical ventricular remodeling.34 Of note, a recent computational modeling study based on in-vivo CMR data from patients with repaired TOF has demonstrated that compared with limited RVOT resection, aggressive exclusion of fibrotic/dyskinetic segments in the RV free wall led to reduced local stress/strain conditions and may lead to improved functional recovery of the RV.35 Our institution has an ongoing prospective clinical trial designed to evaluate whether extensive RV remodeling at the time of pulmonary valve replacement lead to improved functional recovery and/or reduced arrhythmia propensity.
Limitations
This cohort does not represent the entire spectrum of patients with repaired TOF, at least in part due to exclusion of patients with pacemakers and implantable defibrillators and the selective use of CMR in infants and young children. However, the patient characteristics in this cohort are similar to those published by other centers.22, 33, 36 In addition, the study design was predominantly cross-sectional with a relatively short follow-up interval from CMR to latest clinical evaluation (median 3 years). Therefore, a more complete realization of the prognostic value of regional RV abnormalities may require longer follow-up. Since exercise data were available in only 38 of 62 patients, there may not have been adequate power to detect differences in CMR variables based on exercise capacity. Similarly, the study might have been underpowered to detect more nuanced associations between measures of regional abnormalities and clinical outcomes, and milder abnormalities such as hypokinesis were not examined. In addition, we performed comparisons on 20 CMR variables, thus increasing the possibility of type I error due to multiple comparisons. Finally, although our software for analysis of regional RV function is not commercially available, the methodology has been validated previously and adds little more than a few minutes of additional processing time to a clinical CMR study.13
Conclusions
A greater extent of regional abnormalities in the RVOT adversely affects global RV function and exercise capacity after TOF repair. These findings support further refinement of treatment strategies designed to address these regional abnormalities, ideally based on a patient-specific approach.
Clinical Relevance.
It has long been known that right ventricular (RV) dysfunction often complicates the clinical course of patients with repaired tetralogy of Fallot (TOF) and is associated with increased morbidity and mortality. For many years investigators have suspected that scar tissue and/or patch material in the right ventricular outflow tract (RVOT) can adversely affect RV mechanics after TOF repair, but the degree to which regional abnormalities can affect global RV function has remained largely unknown. In addition, it is unclear whether regional abnormalities adversely affect exercise capacity, ventricular arrhythmia, and heart failure independent of global RV dysfunction. This article reports the use of newly developed cardiac MRI-based quantitative methods to analyze the effects of regional RV wall motion abnormalities and late gadolinium enhancement on global RV systolic function and clinical status in 62 patients with repaired TOF. In addition to showing that regional RV abnormalities contribute to RV dysfunction independent of RV size, degree of pulmonary regurgitation, and other confounding factors, the study also demonstrates that quantitative measures of regional dysfunction are associated with decreased exercise capacity, sustained ventricular tachycardia, and symptoms of heart failure. Furthermore, the study found that fibrosis and dyskinesis often extend beyond the superior aspect of the RVOT (the site of pulmonary valve implantation) into adjacent segments. These observations suggest that in patients with substantial areas of patch and scar tissue associated with regional wall motion abnormalities of the RVOT and adjacent areas, pulmonary valve insertion alone ± local patch resection may be insufficient and that extensive remodeling of the RV might be necessary for optimal functional recovery.
Acknowledgments
Funding Sources: This work was supported in part by the National Institutes of Health (NIH/NHLBI 1P50 HL074734-01; Drs. Geva, Haber, and Powell).
Idith Haber: Research Grant: National Institutes of Health (NIH/NHLBI 1P50 HL074734-01, Amount: ≥$10,000
Andrew J. Powell: Research Grant: National Institutes of Health (NIH/NHLBI 1P50 HL074734-01, Amount: ≥$10,000
Tal Geva: Research Grant: National Institutes of Health (NIH/NHLBI 1P50 HL074734-01, Amount: ≥$10,000
Footnotes
Author Disclosures Rachel M. Wald: No disclosures
Ron Wald: No disclosures
Anne Marie Valente: No disclosures
Conflict of Interest Disclosures: None
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