Background
Tetralogy of Fallot (TOF) - consisting of ventricular septal defect (VSD), pulmonary stenosis (PS), over-riding aortic root, and right ventricular hypertrophy (RVH) - is one of the most frequent complex congenital heart defects, accounting for 9-14% of all congenital heart defects [
1]. Since the development of more sophisticated and comprehensive cardiovascular surgical techniques over the last 20 years, long-term survival is expected. Therefore, the physiological sequelae of these surgical procedures, aimed at increasing flow to the pulmonary circulation, are often encountered in adolescents and adults. Following repair, patients with TOF frequently present with pulmonary regurgitation (PR) and/or residual or recurrent pulmonary artery stenosis (PS). Cardiovascular magnetic resonance (CMR) is routinely used to follow patients after TOF repair to monitor for changes in right ventricular (RV) size and function related to PR [
2‐
5].
Four-dimensional (4D) flow-sensitive velocity mapping (VM) CMR [
6] is increasingly being used for the visualization of complex flow patterns, which may prove helpful in determining functional outcomes following surgery for complex congenital heart disease [
7]. In addition to providing insights into qualitative changes in flow patterns, 4D VM-CMR can also be used to quantify flow through any vessel of interest
a posteriori, including in patients with TOF [
8]
A limitation of 4D VM-CMR, especially when applying Cartesian encoding, is the compromise between length of acquisition, volume coverage, and spatial resolution. To keep scan times to tolerable durations, the imaging volume is typically limited to a moderately thick slab and spatial resolution has to be sacrificed. To overcome limitations of Cartesian 4D-VM CMR, radial undersampling provides large volume coverage with high spatial resolution in reasonable scan times. Radial acquisitions are also advantageous, relative to Cartesian acquisitions, because of their reduced susceptibility to motion artifacts [
9]. The purpose of this study was to demonstrate the feasibility of implementing a true three-dimensional (3D) radially-undersampled 4D VM-CMR technique for the analysis of right heart flow patterns and quantification of pulmonary artery flow in normal volunteers and subjects with TOF.
Discussion
The findings of this study confirm that 4D VM-CMR with PC VIPR lends itself well to qualitative and quantitative analysis of the flow features of the entire right heart circulation. Similar to what has been recently reported by Geiger,
et al. [
16], we demonstrated similarities and differences in right heart flow patterns in normal healthy volunteers and in a broad age and size range of patients with palliated and repaired Tetralogy of Fallot. An important advantage of PC VIPR for evaluation of intra-cardiac flow patterns, relative to other approaches to 4D velocity flow mapping, is the volumetric chest coverage and isotropic spatial resolution (1.02-1.25 mm
3) at clinically acceptable acquisition times on the order of 9-17 minutes. This provides a systematic approach for comprehensive hemodynamic evaluations of the heart and thoracic vasculature because all areas of potential interest are included within the imaging volume. By doing so, multi-planar reformations can be generated in all directions comprising perfectly co-registered morphologic and functional information without compromises in spatial resolution or additional scan times. Of note, the scan times for the PC VIPR acquisitions in this study (9-17 minutes) were similar to previously reported Cartesian approaches used for intra-cardiac flow pattern assessment with considerably worse (up to 9-times) spatial resolution [
14].
Flow patterns in the RA and RV of normal volunteers were uniform and well organized, following patterns that have been described previously [
7,
14]. Of note, diastolic flow in the IVC was greater than systolic flow in two normal volunteers. Although the reasons for this cannot be determined definitively, these findings are not entirely unexpected. Appleton ,
et al. found that 10% of healthy subjects had greater diastolic than systolic forward velocity integrals in the SVC during at least one phase of respiration [
17]. Flow in the vena cavae is known to change with differences in respiration and changes in intrathoracic and intraperitoneal pressures, with the IVC being more susceptible to these fluctuations than the SVC [
18]. As expected, RA and RV flow patterns in patients with rTOF were dramatically different from those in normal volunteers. Diastolic flow in the RV was markedly abnormal in 10/11 rTOF patients, while systolic flow remained normal in 9/11 rTOF patients. The major inflow through the tricuspid valve in the repaired rTOF patients was directed toward the RV apex, usually as a result of concomitant pulmonary regurgitation. These findings agree with previous studies that evaluated impaired diastolic function in patients with repaired TOF [
19‐
22]. In addition, impaired RV filling may help explain symptoms related to exercise these patients.
The alterations in filling of, and flow within, the RA are not unexpected in view of previous studies documenting alterations of RA function after repair of TOF [
23,
24]. These findings strongly suggest that the contribution of altered intracardiac flow patterns on morphodynamic coupling of diseases that affect the right heart circulation may have been underestimated thus far. We believe it reasonable to hypothesize that the extent of altered hemodynamics may precede morphological changes in the RV. 4D VM-CMR with comprehensive visualization of acquired flow fields may therefore have the potential to improve the characterization of the disease status. Clearly, such speculation cannot be based on the presented data and larger, longitudinal studies are warranted to further investigate the hemodynamics in RV failure. However, the results of this study demonstrate that PC VIPR is a promising potential diagnostic tool to achieve this goal.
The changes in flow patterns in the pulmonary arteries is concordant with the findings of Geiger,
et al. who also reported the presence of abnormal vortices in the pulmonary arteries of patients with rTOF [
16]. Although we did not measure the size of the pulmonary arteries, changes in MPA, RPA, and LPA size may contribute to the development of increased helices and vortices in dilated or post-stenotic segments. This phenomenon is commonly seen in aortic aneurysms [
6,
25,
26]. Another factor in the development in vortices may be the increased pulmonary vascular resistance and elevated pulmonary arterial pressures. Reiter,
et al. [
27] reported that vortices develop in the MPA in patients with pulmonary arterial hypertension (PAH) secondary to flow separation between the boundary layer adjacent to the vessel wall, which is susceptible to the formation of vortical flow. The reduced acceleration time in the MPA in the rTOF subjects is also concordant with the findings of Reiter,
et al. in subjects with PAH [
27].
Although quantification of flow was not validated in this study, a benefit of using 4D VM-CMR techniques in complex CHD is that it is possible to a posteriori quantify flow volumes through any region of interest. This is particularly valuable in patients with complex congenital heart disease that frequently have multiple vessels through which flow quantification is required. To prospectively prescribe 2D velocity mapping acquisitions requires careful planning and a separate magnetic resonance angiography acquisition while the patient is on the scanner. Using 4D VM-CMR has the potential to simplify the acquisition of flow data and lead to decreased time for image acquisition.
Recently, 4D VM-CMR has been used to estimate wall shear stress
in vivo[
15,
25,
28,
29]. Our observation of increased wall shear stress in the main PA of patients with rTOF is concordant with findings reported by E. Bedard, et al. on the histological abnormalities present in the pulmonary trunk of patients with TOF [
30]. These authors reported an increased prevalence of medionecrosis, fibrosis, cyst-like formation, and abnormal elastic tissue configuration in the pulmonary trunks of patients with TOF. Presumably, these alterations in pulmonary trunk composition contribute to alterations in its mechanical properties. Although not the focus of this study, 4D VM-CMR could be use to quantify wall shear stress in the ascending aorta [
15,
25,
28,
29] as well to monitor for changes in the mechanical properties of the ascending aorta known to exist in patients with TOF [
31]. Although still controversial, changes in wall shear stress have been implicated in the development and growth of aneurysms - with high wall shear stress associated with initiation [
32] and low wall shear stress correlated with growth of [
33] cerebral aneurysms. Analysis of the changes in the mechanical properties of the PA with 4D VM-CMR could potentially provide a means of further understanding PA-RV coupling leading to RV failure in patients with TOF as well as the changes that occur in aorta stiffness and aorta aneurysm development.
A major limitation of this study is that only a small number of rTOF subjects were examined and there was variability in types of repair that were performed. As a result, it is not possible to determine the relationship between the type of repair and its impact on RA and RV flow. The effects of type of repair will be the subject of subsequent investigation and could potentially provide insight into the relative advantages of different repairs on long term prognosis. Another potential drawback of this study is that the normal volunteers and patients were not age-matched, with normal volunteers having a greater mean age than the rTOF subjects, although it is unlikely that this would contribute to the relative differences in the observed alterations in right heart flow patterns. An additional limitation of this study is that we did not perform 4D VM-CMR with a Cartesian acquisition. Therefore, although we would assume that it is beneficial to have greater 3D spatial coverage with higher spatial resolution, it is not possible to confirm these theoretical benefits from the results of this study.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
CJF conceived the original study and assisted with study design, data acquisition, analysis, and manuscript preparation.
SS assisted with analysis and manuscript preparation.
MLS assisted with study design, data acquisition, analysis, and manuscript preparation.
SBR assisted study design, data acquisition and manuscript preparation.
EN performed data analysis and assisted with manuscript preparation.
BRL performed data analysis and assisted with manuscript preparation.
OW assisted with study design, analysis, and manuscript preparation. AF assisted with study design, data acquisition, analysis, and manuscript preparation.
All authors read and approved the final manuscript.