Author + information
- Received November 28, 2010
- Revision received January 12, 2011
- Accepted January 19, 2011
- Published online May 1, 2011.
- Matthew A. Harris, MD⁎,†,⁎ (, )
- Kevin K. Whitehead, MD, PhD⁎,†,
- Matthew J. Gillespie, MD⁎,†,
- Timothy Y. Liu, BS†,
- Michael T. Cosulich, BS†,
- David C. Shin, BA†,
- Elizabeth Goldmuntz, MD⁎,†,
- Paul M. Weinberg, MD⁎,† and
- Mark A. Fogel, MD⁎,†
- ↵⁎Reprint requests and correspondence:
Dr. Matthew A. Harris, Department of Pediatrics and Radiology, Divisions of Pediatric Cardiology and Cardiac MRI, Children's Hospital of Philadelphia of the University of Pennsylvania School of Medicine, Office 8NW-48, 34th and Civic Center Boulevard, Philadelphia, Pennsylvania 19104
Objectives We sought to investigate whether differential branch pulmonary artery (BPA) regurgitation correlates with differences in BPA anatomy and physiology.
Background Patients with repaired conotruncal anomalies such as Tetralogy of Fallot frequently have residual BPA stenosis or BPA size differences. Previous reports have demonstrated an increased left pulmonary artery (LPA) regurgitant fraction (RF) in these patients.
Methods We retrospectively reviewed 76 consecutive cardiac magnetic resonance (CMR) studies for BPA size and phase-contrast magnetic resonance data, including 13 consecutive patients who underwent both CMR and catheterization.
Results Thirty of the 76 patients had either BPA stenosis or significant size discrepancy. Whereas previous studies had shown an increased RF in the LPA, patients with BPA stenosis or size discrepancy showed no significant difference between right and left BPA RF (30% vs. 30%, p = 0.985). However, there was a significantly increased RF of the larger versus smaller BPA (39% vs. 21%, p < 0.001), resulting in an insignificant deviation from normal fractional flow distribution (RPA 63% vs. LPA 37%; normal net fractional flow distribution RPA 55% vs. LPA 45%). Retrospective review of patients who underwent both CMR and catheterization provides support for the preceding findings and validates differential BPA RF as strongly correlating with differential pulmonary vascular resistance (PVR) (r = 0.8364, p < 0.001).
Conclusions BPA RF is a function of the relative PVR and the presence of BPA stenosis or size discrepancy. Contrary to prior reports, the LPA RF is only elevated in patients with relatively equal sized BPAs. In the setting of BPA stenosis or size discrepancy the larger BPA has a relatively increased RF and PVR. Therefore, the differential RF is an important tool for screening patients with unilateral stenosis for contralateral increases in PVR that cannot be identified with net flows alone. This can affect the indication and timing for BPA intervention.
- differential branch pulmonary regurgitation
- pulmonary vascular disease
- right ventricular dilation
- tetralogy of Fallot
Tetralogy of Fallot and other conotruncal anomalies are common forms of complex congenital heart diseases (1,2). In many cases, repairing these defects involves reconstruction of the right ventricular (RV) outflow tract and ventricular septal defect closure, with the aim of establishing separate and unobstructed pulmonary and systemic circulations (3,4). Many post-operative patients have some degree of pulmonary insufficiency. In addition, residual branch pulmonary artery (BPA) stenosis, hypoplasia, or dilation is common after repair (5,6). The combination of BPA stenosis and pulmonary insufficiency can produce RV enlargement and hypertension and underdevelopment of the BPAs (7–9). Indications for treatment of BPA stenosis include: 1) relief of RV hypertension (10–13); 2) promoting growth of the stenotic artery by increasing its pulmonary blood flow (PBF) (11–13); and 3) prevention of contralateral BPA hypertension (11,12,14,15).
There have been few studies investigating the causes of differential BPA regurgitant flows after repair of conotruncal anomalies (16–18). Kang et al. (16) found that the left pulmonary artery (LPA) has increased BPA regurgitation. However, this study did not distinguish between patients with and without residual BPA stenosis. Our group reported that patients with conotruncal anomalies without residual BPA stenosis have increased LPA regurgitation (17), and we speculated in that study that the differential BPA regurgitant fraction (RF) can be used as a method of estimating the relative right and left pulmonary vascular resistance (PVR) in these patients. The current investigation continues our original work; we investigated the impact of residual BPA stenosis on the flow dynamics in the BPAs and correlated these findings with hemodynamic catheterization data.
We hypothesized that differential regurgitation patterns vary among patients with BPA stenosis or size discrepancy compared with patients with relatively equal-sized BPAs. In patients without BPA stenosis or size discrepancy, differences in RF relate to differences in the relative PVR. In contrast, in patients with BPA stenosis or size discrepancy, differences in RF relate to the presence of BPA stenosis, size discrepancy, and relative PVR. This fundamental difference has clinical significance. Patients with a stenotic BPA coexisting with contralateral elevated PVR can have normal fractional net flows to each lung because of the opposing effects of these factors. These patients may benefit from BPA intervention to relieve stenosis, even though their fractional net flows suggest that the stenosis is insignificant.
We retrospectively reviewed 76 consecutive cardiac magnetic resonance (CMR) studies of post-operative conotruncal anomalies in patients who underwent phase-contrast magnetic resonance (PCMR) imaging of the proximal BPA from November 2003 through December 2006. Patients were referred for CMR as part of their routine clinical care or they were recruited and enrolled in a prospective research study investigating the impact of genotype on clinical outcome after surgery for conotruncal anomalies.
We also retrospectively reviewed 13 consecutive patients who underwent both PCMR and cardiac catheterization over the same time interval after repair of a conotruncal anomaly. For the PCMR/cardiac catheterization data comparison, inclusion criteria required that the PCMR and cardiac catheterization studies were performed within 1 year of each other without a BPA intervention in the interim. All magnetic resonance (MR) studies included in both retrospective reviews had significant BPA regurgitation defined as at least a 10% RF in one of the BPAs (16). Patients with endovascular stents in the RV outflow tract or BPAs (n = 2) and repeat studies (n = 2) were excluded. Patients with pulmonary venous pathology were also excluded (n = 2). One patient had unilateral pulmonary vein hypoplasia, and the other had unrepaired partial anomalous pulmonary venous connection.
All CMR studies were performed on either a 1.5-T Siemens Sonanta (Siemens, Erlangen, Germany) or Avanto (Siemens) system. Generally children younger than 9 years are sedated, and the acquisition is performed while the patient is spontaneously breathing. Older children generally can undergo magnetic resonance imaging without sedation, and the acquisition occurs during end-expiration. Studies were post-processed on a satellite workstation and analyzed by one of 2 cardiologists (M.A.H., M.A.F.). PCMR and ventricular volume data were analyzed using ARGUS software (Siemens). MR studies were reviewed for determination of the BPA size, PCMR flow data, and ventricular volume data.
BPA size assessment
The sizes of the proximal BPAs were measured in 2 dimensions, and the cross-sectional area (CSA) was calculated from the linear measurements. In patients with proximal narrowing of a BPA, measurement of its distal segment was obtained immediately before the origin of the upper lobe branch.
We defined BPA stenosis as the proximal CSA of a BPA at its origin being less than one-half of its respective distal measurement immediately proximal to the origin of the upper lobe branch. We defined BPA size discrepancy when the CSA of one BPA was less than one-third of the total CSA of both BPAs (measured at the origin of the BPAs). Patients with either BPA stenosis or size discrepancy were placed in group A, and patients without BPA stenosis or size discrepancy were placed in group B.
Phase-contrast magnetic resonance
PCMR acquisition was applied at the main pulmonary artery and BPAs and at the aortic valve for flow quantification (19,20). PCMR data analysis involved contouring regions of interest throughout all phases of the cardiac cycle. Forward, regurgitant, and net flows were then automatically calculated from the resulting time-volume curves. The RF through a region of interest is defined as follows: RF (%) = (reverse flow/forward flow) × 100. Fractional BPA PBF is calculated as follows: fractional BPA PBF (%) = (net BPA flow/net total PBF) × 100.
Cardiac catheterization data analysis
Cardiac catheterization data were reviewed for determination of the mean BPA pressure distal to any stenosis and wedge pressures of each lung. From these data combined with the fractional PBF distribution data quantified by PCMR, the right and left PVRs were calculated. The reciprocal of the total PVR is equal to the sum of the reciprocals of each BPA unilateral PVR. Consequently, the unilateral PVR is defined as follows: (mean distal BPA pressure − wedge pressure)/BPA net flow indexed to body surface area.
Because the normal range for total PVR is 1 to 3 Woods units (Wu) (21), a unilateral PVR of greater than 6 Wu is abnormally elevated.
Standard descriptive statistics (i.e., mean ± SD) were used to describe the patient demographics. The paired t test was used to compare the size and flow data between the groups. To determine the effects of PVR on the relative RF of each BPA, the Pearson correlation was conducted. A value of p < 0.05 was taken to be significant.
Approval by the Institutional Review Board of the Children's Hospital of Philadelphia was obtained for this retrospective review.
Seventy-six CMR studies were reviewed for determination of BPA size and flow data (Table 1). There were 46 males and 30 females. The mean age at the time of MR imaging was 12.6 ± 6.9 years (range 0.1 to 35.5 years). Diagnoses included tetralogy of Fallot (n = 64 [84%]), truncus arteriosus (n = 6), transposition of the great arteries (n = 5), and double outlet right ventricle (n = 1).
BPA stenosis and size discrepancy analysis
Thirty of the 76 patients (39%) had either the proximal CSA of a BPA measuring less than one-half of its respective distal measurement (BPA stenosis) or the proximal CSA of one BPA was less than one-third of the total proximal CSA of both BPAs (BPA size discrepancy). These patients were placed in group A.
Nineteen of the 30 group A patients (63%) had stenosis of at least 1 of their BPAs. Of the 30 group A patients, 11 had LPA stenosis (37%), 4 had right pulmonary artery (RPA) stenosis (13%), and 4 had bilateral stenosis (13%). All 4 patients with bilateral stenosis had more stenosis of the LPA compared with that of the RPA.
Twenty-two of the 30 group A patients (73%) had proximal BPA size discrepancy. There were 11 patients (37%) who had BPA size discrepancy without stenosis of the contralateral BPA. Among the 22 patients with size discrepancy, 14 patients had dilated RPAs (47%) and 8 patients had dilated LPAs (27%) (Fig. 1B). Nine of the 30 patients (30%) had stenosis of 1 BPA and relative dilation of the contralateral BPA, with resultant size discrepancy.
Forty-six of the 76 patients (61%) did not have either stenosis or significant size discrepancy of the BPAs (group B).
BPA size and flow correlation
In Group A patients, we found a moderate correlation between relative BPA size and both forward (R2 = 0.4007, p < 0.001) and reverse (R2 = 0.3661, p < 0.001) flow, whereas there was no significant correlation between relative BPA size and net flow (p = 0.11). In contrast, group B patients did not show a correlation between relative BPA size and forward, reverse, or net flow (Figs. 1A and 1B).
Differential RF analysis
There was a significant increase in RF of the LPA versus the RPA (36% vs. 30%, p = 0.020; n = 76) when all patients were considered. This was due to the LPA and RPA RFs of group B patients (39% vs. 31%, p < 0.001; n = 46). Group A patients did not show a significant difference in LPA versus RPA RF (30% vs. 30%, p = 0.985; n = 30).
There was a significant increase in the larger versus smaller BPA RF when all patients were considered (38% vs. 29%, p < 0.001; n = 76). This was due to group A patients (39% vs. 21%, p < 0.001; n = 30). Group B patients did not demonstrate a significant difference in BPA RF of the larger versus smaller BPA (36% vs. 34%, p = 0.217; n = 46) (Table 1).
Differential BPA regurgitation was more common in group A. Twelve of the 30 group A patients (40%) compared with 7 of the 46 group B patients (15%) had a >20% difference in RF between the BPAs.
Differential BPA RF and PVR
Thirteen patients underwent CMR and cardiac catheterization within 97.0 ± 112.5 days (range 0 to 302 days), without a BPA intervention in the interim.
There was a significant positive correlation between the difference in RPA and LPA RF compared with the difference in PVR of the right and left lungs (r = 0.8364, p < 0.001) (Fig. 2). Four of the thirteen patients (31%) who underwent catheterization had increased differential regurgitation (RF difference >20%), with a lower RF in the smaller BPA, associated with at least one-third of the total BPA flow directed toward the smaller branch (35% to 45%). All four patients had elevated PVR in the larger branch (8.1 to 11 Wu). Three of the 4 patients had unilateral stenosis of the smaller BPA and underwent stent implantation at the time of the catheterization (Fig. 3). The fourth patient had hypoplasia without discrete stenosis of the smaller BPA.
We demonstrated the significance of measuring BPA RFs in patients after repair of conotruncal anomalies. Previous studies (16–18) had shown that differential BPA regurgitation occurs in these patients. However, to date, no study has clearly demonstrated the relationship of differential BPA regurgitation to BPA anatomy or PVR. Most importantly, we used these data to demonstrate the practical clinical advantage of measuring BPA RFs rather than measuring fractional net flows alone.
Generally speaking, the purpose of identifying BPA stenosis is to determine which patients may undergo catheter or surgical intervention and expect to have an improved net fractional flow distribution that mirrors that of normal people. Ordinarily, the method for identifying discrete BPA stenosis requires identifying a decrease in the CSA of the proximal BPA relative to the region distal to the stenosis in combination with diminished fractional flow to the stenotic artery (11–13). Patients with BPA stenosis can be identified indirectly by undergoing nuclear perfusion scintigraphy. Nuclear perfusion scintigraphy uses ionizing radiation to measure differences in enhancement of the two lungs after injection of a radioisotope, thereby providing the fractional flow distribution to each lung.
However, this approach is insufficient in patients with pulmonary regurgitation. It is important to realize that the net flow to a given lung depends on both the forward and reverse flows for that lung. For example, consider a patient with LPA stenosis and pulmonary regurgitation for which the RPA RF is 50% and the LPA has no regurgitation. If the RPA to LPA forward flow ratio is 70:30, then the net flow ratio would appear to be essentially normal and measure 54:46. In this case, obtaining the net flow ratio with nuclear perfusion scintigraphy without directly imaging the BPAs can lead to the erroneous conclusion that there is no LPA stenosis. For this reason, CMR is a much more useful tool for assessing BPA flows compared with nuclear perfusion scintigraphy. CMR provides precise anatomic definition of the BPAs, in addition to measuring the forward and reverse flows directed toward and away from each branch. CMR identifies patients with varying degrees of stenosis and dilation of the BPAs, while also providing the PBF measurements to each branch. In contrast, nuclear perfusion scintigraphy does not provide anatomic data and requires the use of ionizing radiation, which is especially important to consider in pediatric and female patients, who are more radiosensitive (22,23).
Ideally, after repair of conotruncal anomalies, patients will not have residual BPA stenosis, hypoplasia, or dilation. Group B patients (n = 46 [61%]) had the preferable post-operative result. They had no significant stenosis (proximal to distal ratio <50%) or discrepant sizes (one BPA CSA <33% of the total BPA CSA), and their net fractional flow distribution reflected that of normal people (RPA:LPA = 57:43; p < 0.001).
Group A patients (n = 30 [39%]) represented a less desirable, although frequent, outcome after repair of conotruncal anomalies. They have BPA stenosis, size discrepancy, or some combination of these elements. We demonstrated that analyzing group A patients on the basis of comparing the RPA with LPA flows will not completely identify important and statistically significant results. For example, the differential BPA RF between the RPA and LPA in group A patients was not significant (RPA 30%; LPA 30%; p = 0.985). Therefore, we also analyzed our data by searching for differences between the smaller or stenotic artery versus the larger contralateral artery.
This study confirmed our earlier findings that after repair of conotruncal anomalies, patients without BPA stenosis or size discrepancy (group B) had increased regurgitation in the LPA compared with the RPA (39% vs. 31%, p < 0.001) (17). Moreover, we showed that patients with stenosis or size discrepancy had significantly lower RFs in the smaller or stenotic artery compared with the contralateral larger artery (RF 21% vs. 39%, p < 0.001). Considering the data in this way illustrates that differential regurgitation is more severe in the BPA contralateral to the stenotic or smaller artery in patients with significant stenosis or size discrepancy, regardless of whether the smaller artery is the LPA or the RPA. Other studies (16,18) also measured an overall increase in LPA RF compared with the RPA, but their studies did not comprehensively investigate differences in the pattern of regurgitation between patients with and without angiographic evidence of discrete stenosis or discrepant BPA sizes. Furthermore, our study demonstrated a strong positive correlation between differential regurgitation and differential PVR (r = 0.84, p < 0.001). Accordingly, PCMR serves as a tool for identifying relative differences in the PVR of the two lungs. This finding is logical. Differential BPA regurgitation should be proportional to differential PVR. For this reason, patients with relatively equal-sized BPAs (group B) would be expected to have an increased LPA RF (39% vs. 31%, p < 0.001) and decreased LPA net flow (42% vs. 58%, p < 0.001), as we observed. Consequently, in the absence of BPA stenosis or size discrepancy, relative PVR largely dictates both relative flow and relative RF. Similarly, patients with BPA stenosis or size discrepancy (group A) should also demonstrate a correlation with differential BPA RF and PVR. However, the correlation should depend on which artery is smaller or stenotic. The enlarged, contralateral artery would be expected to have a relatively higher RF because it has relatively increased PVR. Finally, we demonstrated that in group A patients, there is a moderate correlation between BPA size and both forward and reverse flows but not net flow. This underscores that using net flows alone can mislead physician perception of the significance of BPA anatomic pathology. In summary, our findings highlight the importance of interpreting the net PBFs together with the differential BPA RFs because these patients may have significant differences between the right and left PVRs. Abnormalities of the pulmonary vascular bed in patients with conotruncal anomalies can be congenital or acquired (24), and patients with stenosis or size discrepancy associated with significant differential BPA regurgitation may be developing relatively elevated PVR in the larger contralateral artery. Interventional catheterization for BPA stenosis is important to consider in patients after repair of conotruncal anomalies (25), and the prevention of contralateral BPA hypertension is an indication for intervention independent of the net PBF distribution (11,12,14,15). In light of our data, in combination with the fact that echocardiographic windows are frequently limited in post-operative patients with tetralogy of Fallot, relying on net flows derived from pulmonary scintigraphy without directly imaging the BPAs may lead to an underappreciation of the presence of BPA pathology.
Limitations of this study include the inherent biases of its retrospective design. Nevertheless, our comparison of the MR imaging and catheter data without a BPA intervention between the 2 studies is compelling because the statistical correlation is very strong and the resultant data are consistent. Future studies should prospectively measure PCMR BPA RFs concurrently with catheter pressure measurements for PVR. These data will become more readily available with the emergence of combined MR imaging and catheterization laboratories positioned adjacent to one another, where these data can be measured under the same anesthetic procedure.
This investigation focused on the impact of PVR and BPA size on differential BPA regurgitation. However, other factors affecting pulmonary regurgitation such as main pulmonary artery and RV diastolic compliance, pulmonary valve competence, and diastolic filling time were not addressed (26). In addition, this investigation analyzed differential BPA regurgitation in terms of differential RFs similar to previous studies on this topic. However, an alternative approach would be to consider the data from the perspective of differential regurgitant volumes because some have advocated that the regurgitant volume more accurately reflects RV preload (27).
BPA RF is a function of the relative PVR and the presence of BPA stenosis or size discrepancy. Contrary to prior reports, the LPA RF was only elevated in patients with relatively equal-sized BPAs. In the setting of BPA stenosis or size discrepancy, net flows will not identify unilateral increases in PVR. Therefore, measuring the differential RF is an important tool for screening patients for unilateral increases in PVR, which can affect the indication and timing for repair of BPA stenosis.
This research was supported by a grant from the National Heart, Lung, and Blood Institute (P50 HL74731) to Drs. Fogel and Goldmuntz. All authors report that they have no relationships to disclose. Drs. Fogel and Whitehead are joint senior authors of this work.
- Abbreviations and Acronyms
- branch pulmonary artery
- cardiac magnetic resonance
- cross-sectional area
- left pulmonary artery
- phase-contrast magnetic resonance
- pulmonary vascular resistance
- pulmonary blood flow
- regurgitant fraction
- right pulmonary artery
- right ventricular
- Received November 28, 2010.
- Revision received January 12, 2011.
- Accepted January 19, 2011.
- American College of Cardiology Foundation
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