Contemporary sequential segmental approach to congenital heart disease using four-dimensional magnetic resonance imaging with ferumoxytol: an illustrated editorial

The ferumoxytol-enhanced 4D MR angiography with MUSIC (Multiphase Steady State Imaging with Contrast) technique provides a single data set that captures dynamic cardiovascular anatomy and ventricular function at the same time. Homogeneous opacification of all cardiovascular structures within the imaging volume allows full sequential segmental approach to the congenital heart diseases without any blind spots. The complex systemic and pulmonary venous anatomy is particularly well captured in the MUSIC. Cinematographic display of multiplanar sectional and 3D volume images is helpful in the morphological identification of the cardiac chambers, the assessment of the dynamic nature of the ventricular outflow tracts, and the assessment of the coronary arterial origins and courses.


Introduction
The sequential segmental approach is a well-established, systematic approach to the diagnosis of congenital heart diseases (CHD) (1,2). It is particularly important in those cases having abnormal situs or abnormal segmental connections. While two-dimensional (2D) and three-dimensional (3D) imaging is traditionally used for sequential segmental approach, multiphase 3D imaging also known as four-dimensional (4D) imaging has increasingly been used for cardiovascular assessment. While 4D imaging is possible in ultrasound imaging, echocardiographic 4D imaging is limited by its inherent small field of view and abundant artifact from air and bones. 4D imaging with computed tomography (CT) requires significantly increased amount of radiation as compared to 3D imaging and its temporal resolution is limited by the gantry rotation time of the given scanner (3). In addition, CT generally produces non-uniform contrast in different chambers and vascular structures due to contrast bolus dynamics.
The contrast-enhanced magnetic resonance (MR) technique known as 4D MUSIC (Multiphase Steady State Imaging with Contrast) acquires data continuously over several minutes during uninterrupted positive pressure ventilation, offering near-perfect respiratory gating (4)(5)(6)(7)(8). When used with the contrast agent ferumoxytol (Feraheme, Covis Pharmaceuticals, Waltham, MA, USA), MUSIC produces high-definition 3D images that span the entire cardiac cycle, with immediate inline reconstruction. Ferumoxytol is an ultrasmall superparamagnetic iron oxide nanoparticle that highlights the blood pool with MR due to its high T1 relaxivity. It is proven safe with a low incidence of significant side effects when it is infused slowly with close monitoring of the vital signs (9)(10)(11). Ferumoxytol is particularly helpful in patients with a high risk for nephrogenic systemic fibrosis (NSF) linked to the use of gadolinium-based contrast agents (9)(10)(11). In patients with renal failure, ferumoxytol can not only be safe but also therapeutic for iron deficiency. To date, limited access to ferumoxytol for off-label diagnostic use, as well as its high cost, have posed obstacles to the more widespread utilization of the 4D MUSIC technique. However, the hope is that these limitations will subside and at the time of writing, a generic version of ferumoxytol (Sandoz, Basel, Switzerland) has become available in the U.S., already reducing cost for both generic and brand formulations. A Chinese formulation of ferumoxytol has recently been developed and is undergoing clinical evaluation for diagnostic use within mainland China (12). It seems highly likely that an agent with the proven advantages of ferumoxytol will ultimately earn global access.
Owing to its high T1 relaxivity and long intra-vascular half-life (approximately 15 h), ferumoxytol supports homogeneous opacification of all cardiac chambers and vascular structures for a prolonged period of 3D MR data acquisition that is typically performed with electrocardiographic (ECG) gating and respiration navigation. MUSIC images are acquired with isotropic spatial resolution for accurate 2D and 3D reformation. Maximum intensity projection (MIP) and volume rendering (VR) can be used to view images in an infinite number of imaging planes or views for both anatomical and functional assessment, without restrictions on orientation or view angle. While 4D MUSIC with ferumoxytol allows high quality dynamic 3D visualization of the beating heart, it also allows 2D cine planar reformation that is analogous to prescription of conventional 2D cine imaging planes. This property shifts the time and labor from the acquisition phase in a scan room to the post-processing phase in a reading room. Therefore, it results in shortened examination times relative to traditional approaches but with higher resolution and without repeated breath holding. Furthermore, the acquisition protocol is independent of anatomic and structural complexity, and the same protocol applies to all patients. Therefore, the total examination time for 4D MUSIC MR is potentially much shorter than the time required for conventional MR approaches that rely on sequential 2D breath-held cine and single-phase contrast-enhanced MR angiography. Step 1 Determination of the abdominal, bronchopulmonary and atrial situs, and the heart position Step 2 Identification of the cardiac chambers and arterial trunks by the morphological criteria Step 3 Assessment of the relationship between the components of each segment Atrial relationship (atrial situs): Already determined at Step1 Ventricular relationship (ventricular loop pattern) Arterial relationship (position of the aortic root relative to the pulmonary arterial trunk) Step 4 Assessment of the intersegmental connections 4-1 4-2 4-3 Systemic and pulmonary venous connections to the atria Atrioventricular connections Ventriculoarterial connections Step 5 Assessment of the associated abnormalities at each segmental level    Rotating Cartesian k-space (ROCK) MUSIC is a further development of the MUSIC technique that does not require external signals for respiratory and cardiac gating (13). Another promising technique is the free-running, five-dimensional (5D) MR approach described by Roy et al. (14). The free-running technique reconstructs 3D image sets at both multiple cardiac phases and multiple respiratory phases. At the time of writing, a current drawback of ROCK MUSIC and 5D free-running techniques is the requirement for offline and interactive image reconstruction, limiting practical widespread use. It should be noted that, although 4D and 5D techniques offer advantages over more conventional methods, highly diagnostic studies can be performed using, for example, a combination of 3D steady state free precession (SSFP) cine and dual-phase contrast enhanced MR angiography (15) or a non-contrast 3D technique such as MTC-BOOST (16). MTC-BOOST generates both a 3D bright blood set and a complementary 3D dark blood set by reconstructing magnitude-only and phase-sensitive images respectively, following an inversion magnetization preparation.
4D MUSIC MR is well suited for sequential segmental approach to complex congenital heart diseases because of its wide field of view without any blind spots, homogeneous opacification of all cardiovascular structures, and dynamic demonstration of the cardiovascular anatomy as well as function. This imaging essay illustrates the utility and major advantages of 4D MUSIC MR for the sequential segmental approach to CHD using select case examples with Supplemental Video clips. The steps of segmental approach are summarized in Table 1.

Contemporary sequential segmental approach, illustrated case examples 2.1. Determination of the visceral and atrial situs
Situs refers to the pattern of arrangement of the solid organs relative to the midline or sagittal plane of the body (17,18). To determine the situs, organ arrangement is observed at three levels; abdomen, bronchopulmonary branching and atria. While the situs at all three levels is harmonious in the majority of cases, approximately 20% of cases having abnormal situs show disharmonious situs patterns at three levels (18). Therefore, the Frontiers in Cardiovascular Medicine situs should be determined separately for the abdominal organs, the bronchopulmonary arrangement, and the atria ( Figure 1). Abdominal and bronchopulmonary situs is easy to determine by observing the liver, stomach, spleen, airways and pulmonary arterial branches at cross-sectional imaging ( Figure 1, Case 1). The atrial situs is determined by observing the shape of the atrial appendages. With some limitation, the shapes of the atrial appendages are better appreciated using volume rendered (VR) than sectional images, particularly when the VR images are displayed in cine mode ( Figure 2 Cases 1-4). When the shapes of the appendages are not clearly identifiable, the distribution of the pectinate muscles along the parietal wall of the atria is helpful (19,20). As the morphologically right atrial appendage has a wide junction with the body of the atrium, the pectinate muscles of the right atrial appendage are distributed all around the parietal aspect of the atrial wall close to the outlet or vestibule of the atrium. Because of the narrow junction of the morphologically left atrial appendage with the body of the atrium, the pectinate muscles of the left atrial appendage are identifiable in a limited part of the parietal aspect of the atrial wall. The distribution of the pectinate muscles is more easily defined in cine display of the thin MIP images than in static images (middle panels in Figure 2).

Juxtaposition of the atrial appendages
Juxtaposition of the atrial appendages on either side of the arterial trunks is uncommon and usually occurs as part and parcel of complex malformation (21, 22). Juxtaposition can involve the entire or part of the tip of the appendage for which the terms "complete" and "partial" juxtapositions have been introduced. The displaced part of the appendage is always on top of the normally positioned appendage. Usually, the appendage of the morphologically right atrium is displaced to the other side to lie on top of the appendage of the morphologically left atrium. . Juxtaposition of the left atrial appendage above the right atrial appendage including right juxtaposition in situs solitus and left juxtaposition in situs inversus is associated with exceedingly rare complex malformation (24, 25). Right juxtaposition was also reported to occur in otherwise normal heart or minor cardiac anomalies (26). When there is juxtaposition of the atrial appendages, the atrial septum shows distorted orientation, and the atrioventricular valve of the affected atrium is mildly or grossly displaced (27).

Systemic and pulmonary venous connections
Clear definition of the venous connections to the atria is particularly important in patients with heterotaxy as rerouting of the systemic and pulmonary venous circulation is required not only for biventricular but also for univentricular repair. From the imaging perspective, 3D imaging with a wide field of view is helpful for the assessment of the venous abnormalities. MR angiography is certainly advantageous over CT angiography as proper contrast enhancement of both systemic and pulmonary venous structures is a difficult task at CT angiography.
The most common is bilateral superior venae cavae with or without a bridging vein ( Figure 5, Case 4). The venous anatomy is unpredictable when there is heterotaxy ( Figures 5-7, Cases 3, 4, 7) (18,28). Interruption of the inferior vena cava with azygos or hemiazygos continuation is seen in >80% of heterotaxy cases with left isomerism, while extracardiac total anomalous pulmonary venous connection is sees in >50% of heterotaxy cases with right isomerism. The location of the superior vena cava and its connection site are important in planning cardiopulmonary bypass and establishing a bidirectional cavopulmonary anastomosis when needed. Precise depiction of the sites of the systemic and pulmonary venous connections is also very important for surgical separation of the systemic and venous returns within the atrium.
Heterotaxy with left isomerism is often associated with extrahepatic portosystemic shunt (29,30). As the portosystemic shunt results in chronic liver disease with portal hypertension and hepatic encephalopathy, its early recognition is important. 3D or 4D MR angiography is very helpful in visualization of the portal venous anatomy and collateral pathways owing to its wide

Determination of the ventricular relationship and atrioventricular connections
With rare exceptions, the ventricular mass consists of two ventricles, one morphologically right and the other morphologically left. When the two ventricles are well developed, the ventricular morphology can easily be identified by using the criteria including the overall shape of the ventricle, the trabeculation pattern, the presence or absence of the moderator band and the level of attachment of the atrioventricular valve to the septum (Figures 3-7, Cases 3-7). When one ventricle is incompletely formed and hypoplastic, these criteria may not be applicable or difficult to apply. On imaging, the relative position of the ventricles provides the accurate and most reliable clue to their morphology (27,31,32). The hypoplastic left ventricle is almost always located along the inferior diaphragmatic surface of the heart at either side of the crux cordis ( Figure 9, Case 9). The incompletely formed right ventricle, however, is almost always located anteriorly and superiorly away from the crux cordis ( Figure 10, Case 10). When there is only one ventricular chamber identifiable, the ventricular mass is described as the indeterminate ventricle. However, the solitary ventricle usually shows the classic characteristics of the morphologically right ventricle, suggesting that the severely hypoplastic left ventricle is not identifiable rather than not present. Rarely, the solitary ventricle may appear to be a common ventricular chamber because of almost complete absence of the ventricular septum. Cine display of the VR images is an easy mean for the morphological identification of the ventricles, particularly when the ventricular mass consists of a main ventricular chamber and a rudimentary ventricle (Figures 9, 10, Cases 9 and 10).
The relationship between the two ventricles is classified into Dloop (the right ventricle on the right side of the left ventricle) and L-loop (the right ventricle on the left side of the left ventricle) ventricular relationships. In the majority of cases, the right-left relationship is described by referencing the right-left coordinates of the body (Figures 3-7, Cases 3-7). Uncommonly, the rightleft relationship of the ventricles is grossly distorted with the ventricles superoinferiorly related or the atrioventricular connections twisted (33). Despite the distorted spatial orientation in these exceptional cases, however, the internal anatomic orientation of the ventricles is not changed, and the relationship between the ventricles relative to the ventricular septum is Once the atrial and ventricular relationship are determined, the atrioventricular connection is assessed. The most helpful for assessment of the atrioventricular connections is cine display of the thin MIP and VR images. In the vast majority of cases, the two atrioventricular connection axes are parallel and the type of atrioventricular connection is predictive of the relationship of the underlying ventricles. Therefore, the atrioventricular connections are usually readily appreciated in 4-chamber plane regardless of whether there are biventricular or univentricular atrioventricular connections (Figures 3-7, 9, 10, Cases 3-7 and 10). When there are unexpected spatial relationships of the cardiac chambers and arterial trunks for the given segmental connections as discussed above, the atrioventricular connection is assessed using multiplanar MIP images along each atrioventricular valve and VR images ( Figure 4B, Case 6).

Determination of the great arterial relationship and ventriculoarterial connection
The great arterial relationship is determined by describing the position of the aortic root and valve in relation to the pulmonary arterial trunk and valve. The ventriculoarterial connection is unequivocally definable when the ventricular septum is intact. When there is a ventricular septal defect underneath one or both arterial valves, the type of ventriculoarterial connection can be controversial as the ventricular septum is not uniformly oriented in relation to the arterial valves (35). Although the "50% rule" is used to define the ventriculoarterial connection when there is an   Frontiers in Cardiovascular Medicine overriding arterial valve, it is often difficult to apply in crosssectional imaging when the arterial valve may appear to arise predominantly from one ventricle in one imaging plane, while the same valve may appear to arise predominantly from the other ventricle in other imaging plane. We find the ventriculoarterial connection is more consistently definable in VR

Ventricular outflow tract obstruction
The ventricular outflow tract obstruction can be a fixed lesion but, more commonly, a dynamic lesion. The dynamic ventricular outflow tract obstruction cannot be accurately assessed using static imaging technique. It is also difficult to clearly demonstrate the exact severity of dynamic narrowing at 2D cine imaging as the region of the interest moves in and out of the imaging plane during the cardiac cycle. 4D VR imaging is particularly helpful as the dynamic nature of the obstruction can be observed throughout the cardiac cycle (Figures 9, 12, Cases 9 and 11).

Coronary arterial abnormalities
Proper identification of the origins and courses of a coronary artery or arteries are important for preoperative assessment for arterial switch operation, Ross operation and right ventricular outflow tract reconstruction. Detection of an abnormal interarterial and/or intramural course and high take-off of a coronary artery is important as it may result in sudden cardiac death. With some limitation, the coronary arterial origins and courses can be accurately assessed with cine display of MIP images ( Figure 13). It should be noted that whereas 4D MUSIC can define coronary anatomy in most case, it may not do so in all cases. Where doubt persists, coronary CT angiography should be considered.

Conclusion
MR imaging using the 4D MUSIC technique following intravenous administration of ferumoxytol provides a single data set for the assessment of dynamic cardiovascular anatomy and ventricular function at the same time. Owing to a strong T1shortening effect and a long half-life of ferumoxytol, 4D MUSIC imaging enables data acquisition with electrocardiographic and respiratory gating for a high-resolution 4D acquisition that takes several (8)(9)(10)(11)(12) minutes. Homogeneous opacification of all cardiovascular structures within the imaging volume allows full sequential segmental approach to the congenital heart diseases without any blind spots. The complex systemic and pulmonary venous anatomy is particularly well captured in 4D MUSIC imaging when compared to other conventional techniques. Cinematographic display of multiplanar sectional and 3D volume images is helpful in the morphological identification of the cardiac chambers, the assessment of the dynamic nature of the ventricular outflow tracts, and the assessment of the coronary arterial origins and courses. Because acquisition takes several minutes, the image quality relies heavily on successful mitigation of cardiac and respiratory motion artifact. To date, limited access to ferumoxytol for off-label diagnostic use, as well as its high cost, have posed obstacles to the more widespread utilization of the 4D MUSIC technique. However, the hope is that these limitations will subside as generic versions become available within and beyond the U.S.