| Abstract|| |
Cardiac magnetic resonance imaging (CMR) has become integrated into the routine care of individuals with congenital heart disease. Its strengths and limitations are being refined and CMR derived variables predictive of clinically important outcomes are being evaluated. This manuscript will focus on several congenital heart diseases commonly referred for CMR evaluation and review their clinical aspects, goals of the MRI evaluation, imaging protocol and current literature.
Keywords: Congenital heart disease, MRI
|How to cite this article:|
Nielsen JC, Powell AJ. Cardiovascular MRI applications in congenital heart disease. Indian J Radiol Imaging 2007;17:86-97
|How to cite this URL:|
Nielsen JC, Powell AJ. Cardiovascular MRI applications in congenital heart disease. Indian J Radiol Imaging [serial online] 2007 [cited 2020 Aug 15];17:86-97. Available from: http://www.ijri.org/text.asp?2007/17/2/86/33618
| Introduction|| |
Over the past three decades cardiac magnetic resonance imaging (CMR) has evolved from a technique with promise to one that is integrated into the clinical management of individuals with congenital heart disease (CHD). ,,, The next step of identifying CMR anatomic and physiologic data predictive of clinical outcomes is underway. , In parallel with this development, technical advances continue to improve image quality, the speed of image acquisition , and the efficiency of image analysis. This has led to expanded clinical use that together with education of trainees will help bring CMR to clinicians who care for adults and children with CHD. This article will describe the general CMR approach to CHD and review several types of CHD that are commonly referred for CMR, including a discussion of the examination goals, imaging protocols and relevant literature.
| Indication For MRI Evaluation Of CHD|| |
Given the continued expansion of CMR capabilities and the remarkable diversity of CHD, it is not practical to list individual anomalies in which the test is "indicated." In general, the clinical reasons for a CMR examination fall into one or more of the following categories: 1) when transthoracic echocardiography is incapable of providing the required diagnostic information, 2) when clinical assessment and other diagnostic tests are inconsistent, 3) as an alternative to diagnostic cardiac catheterization with its associated risks and higher cost and 4) to obtain diagnostic information for which CMR offers unique advantages. In clinical practice, CMR is typically ordered after other imaging studies have been performed and additional diagnostic information is required. [Table - 1] summarizes the primary reasons for CMR in 1119 consecutive patients evaluated at Children's Hospital Boston in 2002-2003 illustrating the wide range of cardiovascular anomalies evaluated.
| Clinical Applications|| |
General Approach . As with echocardiography and cardiac catheterization, CMR is an interactive diagnostic procedure that requires on-line review and interpretation of the data by the supervising physician. The variable nature of the anatomy and hemodynamics often require adjustment of the examination protocol. Reliance on standardized protocols and post-examination review alone in these patients may result in incomplete or even erroneous interpretation. The supervising physician needs to serially review the image quality, assess the degree of metallic device related artifact, ensure that anatomic coverage is adequate, screen for aliasing of velocity encoded cine (VEC) MRI flow data and check for motion related artifact from poor electrocardiographic (ECG)-gating or respiratory motion. Successfully troubleshooting these issues requires an understanding of CMR techniques, attention to detail, knowledge of the pathophysiology of CHD and experience to know which modifications are likely to succeed and whether additional data will be clinically useful.
Quantitative evaluation of ventricular function is achieved by obtaining a series of contiguous cine steady state free precession (SSFP) slices that cover the ventricles in the short-axis plane. This protocol is often referred to as a 'cardiac function' examination and is performed when the specific indication relates to the intracardiac anatomy, assessment of valve function or quantitative assessment of ventricular size and systolic function. Descriptions of the method of obtaining ventricular volumes and mass can be found in multiple published reports ,, as well as the specific approach used by our group.  In addition to cardiac function, VEC MRI flow measurements are routinely acquired to measure cardiac output, pulmonary-to-systemic flow ratio and for quantification of valve regurgitation. The accuracy and reproducibility of the CMR techniques for assessment of blood flow rate ,,,,,,,, and ventricular size (volume and mass) and global function ,,,,,,,, are well-documented.
For most CHD examinations, additional imaging datasets beyond cardiac function are acquired. An axial stack of contiguous cine SSFP slices covering the thorax from the hepatic inferior vena cava through the aortic arch provides a comprehensive high-resolution dynamic survey of the thoracic anatomy. Additional targeted cine SSFP stacks (often with thinner sections for improved spatial resolution) in oblique planes can then be prescribed across areas of interest to enhance interpretation. Turbo (fast) spin echo with blood suppression (TSE) can be utilized in a similar fashion and is less affected by image artifact from implanted metal devices. Although TSE provides high resolution, high contrast images, it has the disadvantage of providing only static (non-cine) images. Another useful technique to visualize the thoracic vasculature is gadolinium (Gd)-enhanced 3D magnetic resonance angiography (MRA). The major advantage of this technique is that it rapidly yields a 3D dataset, which can then be reformatted in any plane off-line. More recently, an ECG and respiratory navigator-gated 3D SSFP technique has been used to assess both intracardiac, coronary artery and vascular anatomy. This free-breathing approach acquires image data during only a portion of the cardiac cycle and tracks diaphragm position with a navigator pulse only accepting the data when the position of the diaphragm lies within a narrow user-defined window.  The result is a high-resolution 3D data set with little artifact from cardiac and respiratory motion without the administration of contrast agents [Figure - 1].
Under optimal conditions, the above general study protocol typically requires between 30 to 60 minutes to complete. The use of sensitivity encoding or other parallel imaging techniques can be used to shorten the examination time. With this general approach in mind, the following is an overview covering several types of CHD that are commonly referred for CMR evaluation. We have included a description of each anatomic lesion with an emphasis on the clinically relevant features, highlights of the published experience and specific goals for each examination.
| Tetralogy Of Fallot (TOF)|| |
Clinical Description: TOF is the most common type of cyanotic CHD with an incidence of 356 per million live births  and is the most frequent diagnosis among patients referred for CMR evaluation at Children's Hospital Boston [Table - 1]. Although TOF involves several anatomic components, the anomaly is thought to result from a single developmental anomaly-underdevelopment of the subpulmonary infundibulum (conus). , The defect is characterized by infundibular and valvar pulmonary stenosis associated with anterior, superior and leftward deviation of the infundibular (conal) septum, hypoplasia of the pulmonary valve annulus and thickened pulmonary valve leaflets. The degree of right ventricular outflow tract (RVOT) obstruction varies from mild to complete obstruction (i.e., TOF with pulmonary atresia). The size of the mediastinal pulmonary arteries varies considerably and they may be discontinuous or absent. Pulmonary blood flow may come from a patent ductus arteriosus and collateral vessels arising from the aorta or its branches. The ventricular septal defect (VSD) in TOF is located between the mal-aligned conal septum superiorly and the muscular septum inferiorly (termed conoventricular septal defect ).  The VSD is usually large but it can rarely be restrictive.  In 5-6% of patients with TOF, a major coronary artery crosses the RVOT.  Most commonly, the anterior descending coronary artery originates from the right coronary artery and traverses the infundibular free wall before reaching the anterior interventricular groove. Preoperative identification of a major coronary artery crossing the RVOT is important to avoid inadvertent damage to the coronary artery during surgical relief of RVOT obstruction.
Surgical repair of TOF is usually performed during the first year of life, often during the first six months.  A typical repair includes patch closure of the VSD and relief of the RVOT obstruction using a combination of resection of obstructive muscle bundles and an overlay patch. When the pulmonary valve annulus is significantly hypoplastic, the RVOT patch is extended across the pulmonary valve annulus into the main pulmonary artery, damaging the valve and rendering it incompetent. In patients with TOF and pulmonary atresia or when a major coronary artery crosses the RVOT, a conduit-either a homograft or a prosthetic tube-is used to connect the RVOT and the pulmonary arteries. The results of surgical repair of TOF have improved dramatically since the introduction of open-heart surgery. Early mortality is currently less than 2% and the 20-year survival nears 90%. ,, The majority of these patients, however, have residual hemodynamic abnormalities, primarily due to (right ventricular) RV volume load from chronic pulmonary regurgitation. Other sequelae include RV hypertension from RVOT or pulmonary arterial obstruction(s), RV dysfunction, tricuspid regurgitation, left ventricular (LV) volume load from a residual VSD and aortic dilatation. Conduction abnormalities and arrhythmias also contribute to late morbidity and mortality in this growing patient population. ,,,,,,
MRI Evaluation: Unlike infants in whom echocardiography generally provides all the necessary diagnostic information for surgical repair, , CMR assumes an increasing role in adolescents and adults with TOF in whom the acoustic windows are frequently limited.  CMR is useful in both pre- and postoperative assessment of TOF but the focus of the examination is different.
PreOperative MRI: In most patients with unrepaired TOF, the central question for the CMR examination is to delineate all sources of pulmonary blood flow-pulmonary arteries, aorto-pulmonary collaterals and the ductus arteriosus. Gd-enhanced 3D MRA is ideally suited to image these vessels [Figure - 2]. Compared with conventional X-ray angiography, MRA has been shown to be highly accurate in depicting all sources of pulmonary blood supply in patients with complex pulmonary stenosis or atresia, including infants with multiple small aorto-pulmonary collaterals. 
Cine SSFP is used to assess ventricular dimensions and function, the VSD, the RVOT as well as dynamic flow imaging of valve function. When the origins and proximal course of the coronary arteries are not known from other imaging studies, they should be imaged either by a gradient-echo sequence designed for coronary imaging or by a fast spin-echo sequence. Particular attention is paid to excluding a major coronary artery crossing the RVOT.Post-Operative MRI : CMR has been used extensively for assessment of post-operative TOF in adolescents and adults. , Quantitative assessment of biventricular dimensions and function is a key element of CMR evaluation in patients with repaired TOF. The degree of RV dysfunction is an important determinant of clinical status late after TOF and is also closely associated with LV dysfunction, likely through ventricular-ventricular interaction.  Recently, an RV end-diastolic volume of greater than 7 standard deviations above the mean in normals (172 ml/m 2 in females and 185 ml/m 2 in males) and an LV ejection fraction of less than 55% have been shown to predict adverse clinical outcomes including worsening heart failure status, development of ventricular tachycardia and sudden death.  Many studies have shown that the degree of pulmonary regurgitation measured by VEC MRI is associated with the degree of RV dilation. ,,, As a result of the ventriculotomy, repaired TOF patients often have an aneurysm in the RVOT [Figure - 3], which impacts RV size and function.  Evidence of fibrosis in this region can be detected by performing post-gadolinium myocardial delayed enhancement (MDE).  The clinical significance of positive MDE in patients with repaired TOF awaits further study. Taken together with clinical assessment, exercise testing and electrophysiological data, information derived from CMR is increasingly being used to guide management decisions such as the timing of pulmonary valve replacement.
The goals of the CMR examination in repaired TOF, therefore, include (1) quantitative assessment of ventricular size and function; (2) assessment of the right ventricular outflow tract for residual stenosis, aneurysm and fibrosis; (3) quantification of pulmonary and tricuspid regurgitation; (4) evaluation of the pulmonary arteries, aorta and aortopulmonary collaterals. In addition to the general cardiac function examination, these goals are met with the following protocol:
- Cine SSFP sections profiling to the RVOT in long-axis, pulmonary arteries in an axial plane and the aortic root and ascending aorta in long-axis and cross-sectional planes.
- Gd-enhanced 3-D MRA.
- VEC MRI to measure main pulmonary artery, branch pulmonary artery, ascending aorta and atrioventricular (AV) valve flow.
- MDE for evaluation of fibrosis and/or scar tissue.
| Transposition Of The Great Arteries (TGA)|| |
Clinical Description : TGA is defined as discordant connections between the ventricles and the great arteries - the aorta arises from the RV and the pulmonary artery arises from the LV. There are several anatomical types of TGA, depending on the viscero-atrial situs, ventricular looping and atrioventricular alignment.  The most common type of TGA is in viscero-atrial situs solitus, concordant atrioventricular alignment, ventricular D-loop and dextro-malposition of the aortic valve relative to the pulmonary valve, termed D-loop TGA . The incidence of D-loop TGA is estimated at 303 per million live births.  The principal physiological abnormality in D-loop TGA is that systemic venous blood is directed to the aorta and oxygenated pulmonary venous blood is directed to the lungs, resulting in profound hypoxemia. Consequently, survival is dependent on communications that allow mixing of blood between the systemic and pulmonary circulations (ductus arteriosus, atrial septal defect and/or VSD). Associated anomalies include VSD, aortic coarctation, interrupted aortic arch, pulmonary stenosis, RV hypoplasia and juxtaposition of the atrial appendages. 
Surgical management of D-loop TGA in the 1960's and 1970's consisted mostly of an atrial switch procedure-the Senning or Mustard operations. In both procedures, the systemic and pulmonary venous blood returns are redirected within the atria so that the pulmonary venous blood reaches the tricuspid valve, RV and aorta, whereas the systemic venous blood reaches the mitral valve, LV and pulmonary arteries [Figure - 4]. The main technical difference between these procedures is that in the Mustard operation, pericardium is used to redirect the blood flow and in the Senning operation native atrial tissue is used.  Although atrial switch procedures have allowed patients to survive thus far into their fourth decade, the incidence of complications including RV (systemic ventricle) failure, sinus node dysfunction, atrial arrhythmias, obstruction of the systemic and/or pulmonary venous pathways and baffle leaks, increase over time. ,, Beginning in the late 1970's and rapidly gaining popularity in the 1980's, the arterial switch operation (ASO) largely replaced the atrial switch procedures. , The ASO directly addresses the anatomic abnormality by repositioning the great arteries above their physiologically correct ventricle and relocating the coronaries to the neo-aortic root (native pulmonary root). The advantages of the ASO over the atrial switch procedures include establishment of the LV as the systemic ventricle and avoidance of extensive suture lines in the atria. Recent data on late outcome of the ASO continues to show excellent overall survival with low morbidity. ,,,,, The Rastelli operation is another surgical option for patients with an associated subvalvar and valvar pulmonary stenosis and a VSD. It consists of patch closure of the VSD so that LV outflow is directed to the aortic valve and placement of a conduit between the RV and the pulmonary arteries.
MRI Evaluation: CMR is seldom requested for pre-operative assessment of infants with D-loop TGA because echocardiography usually provides all necessary diagnostic information.  In post-operative TGA, CMR assumes an increasing role due to its ability to non-invasively evaluate most clinically relevant issues. ,,,,,,,,,
Post-operative atrial switch : The goals of CMR evaluation of post-operative atrial switch include (1) quantitative evaluation of the size and function of the systemic RV,  (2) imaging of the systemic and pulmonary venous pathways for obstruction and baffle leaks, (3) assessment of tricuspid valve regurgitation, (4) evaluation of the left and right ventricular outflow tracts for obstruction and (5) detection of aortopulmonary collateral vessels. The presence of post-gadolinium MDE can be used to detect myocardial fibrosis and the response of the systemic RV to pharmacological stress (dobutamine) or to exercise can be tested by CMR; , however, the clinical utility of this information awaits further study. In addition to the general cardiac function examination, the examination goals can be achieved with the following protocol:
- Cine SSFP in an axial plane from the level of the diaphragm to the transverse arch to provide dynamic imaging of the venous pathways, qualitative assessment of ventricular function, AV valve regurgitation and visualization of the outflow tracts.
- Targeted oblique cine SSFP of the superior vena cava and inferior vena cava pathways in their long-axis plane.
- Gd-enhanced 3-D MRA.
- VEC MRI to measure main pulmonary artery, ascending aorta and AV valve flow; additional VEC MRI acquisitions as needed to evaluate specific areas suspected for obstruction or baffle leaks. 
- MDE for evaluation of fibrosis and/or scar tissue.
Post-operative arterial switch: The long-term concerns in patients after the ASO relate primarily to the technical challenges of the operation - transfer of the coronary arteries from the native aortic root to the neo-aortic root (native pulmonary root) and the transfer of the pulmonary arteries anterior to the ascending aorta [Figure - 5]. Patients may be left with or develop coronary artery stenosis or compression, ventricular outflow and pulmonary artery obstruction, ventricular dysfunction, aortic root dilation, aortic valve regurgitation or a left-to-right shunt from a VSD or aorto-pulmonary collaterals. The goals of CMR evaluation of post-operative arterial switch include (1) evaluation of global and regional LV and RV size and function; (2) evaluation of the left and right ventricular outflow tracts for obstruction; (3) qualitative estimation of RV systolic pressure based on the configuration of the interventricular septum; (4) imaging of the great vessels with emphasis on evaluation of the pulmonary arteries for stenosis and the aortic root for dilatation; and (5) detection of aorto-pulmonary collaterals. In addition to the general cardiac function examination, these goals are achieved with the following protocol:
- Targeted cine SSFP in a 4-chamber or axial plane covering the intracardiac anatomy and in oblique planes profiling the outflow tracts.
- Gd-enhanced 3-D MRA.
- VEC MRI to measure main pulmonary artery, ascending aorta and AV valve flow.
- MDE for evaluation of fibrosis and/or scar tissue.
| Coarctation of The Aorta|| |
Clinical Description : Coarctation of the aorta is a discrete narrowing most commonly located just distal to the left subclavian artery, at the site of insertion of the ductus arteriosus. It is thought to arise either from an abnormal flow pattern through the arch during development or from extension of ductal tissue into the aortic wall which contracts post-natally. Hypoplasia and elongation of the distal transverse arch is a frequent association. Coarctation may be present alone or in combination with other anatomic lesions including bicuspid aortic valve, aortic stenosis (valvar or subvalvar), mitral valve abnormalities, atrial septal defect, VSD, persistent patent ductus arteriosus and conotruncal anomalies. ,
Therapeutic options for coarctation include surgical repair and percutaneous balloon angioplasty, sometimes with stent placement. Currently, resection of the coarctation with an end-to-end anastomosis and augmentation of the transverse arch if needed, is the most widely practiced surgical repair and has the lowest incidence of recurrent obstruction. Other approaches have included subclavian flap aortoplasty, patch augmentation and conduit interposition. These latter techniques have fallen out of favor as post-operative complications, such as aneurysm formation at the site of the prosthetic patch and recurrent arch obstruction, have become increasingly recognized. , Coarctation in infants is treated surgically in the majority of centers because of the lower risk of residual obstruction, recurrence and technique-related complications compared with percutaneous interventions.  For isolated coarctation, the surgical mortality approaches zero.  In the event of recurrent coarctation following surgical repair, balloon angioplasty with or without stent placement is often the first line of therapy. Coarctation in older children or adults is increasingly being treated primarily by percutaneous interventions, which thus far have shown a low risk of re-obstruction and aneurysm formation. ,
MRI Evaluation . The use of CMR to image anomalies of the aortic arch dates back to the early 1980's.  While those studies provided mostly static anatomical information, the advent of new imaging sequences has greatly expanded the capabilities of CMR to include comprehensive anatomic and functional evaluation. In a retrospective study of 84 adult patients following intervention for coarctation of the aorta, Therrien and colleagues showed that the combination of clinical assessment and CMR on every patient was more "cost-effective" for detecting complications than combinations that relied on echocardiography or chest radiography as imaging modalities. 
Much of the anatomic information in coarctation can be gleaned from the Gd-enhanced 3D MRA ,, including the anatomy of the aorta, imaging of collateral vessels and cross-sectional measurements of the aorta in various locations [Figure - 6]. TSE with blood suppression provides high-resolution, high-contrast imaging of the aortic wall [Figure - 7], which may be particularly important in cases with discrete coarctation comprised of a thin "shelf" that protrudes into the aortic lumen. This technique is also useful in patients with stents as it is less susceptible to metallic artifact. Gradient-echo sequences show signal voids from turbulent jets, which may help localize the site of obstruction.
Evaluation of the hemodynamic significance of coarctation is an important element of the CMR examination. Several investigations compared the anatomic features and the extent of collateral blood flow with coarctation diameter measured by X-ray angiography, , blood pressure measurements by sphygmomanometry  and Doppler assessment of flow velocity.  Riquelme and colleagues  showed a correlation coefficient of 0.99 between gradient echo cine MRI measurement of coarctation diameter and angiography. Other groups have focused on the percent increase in descending aorta flow from collateral vessels to assess coarctation severity. Steffens et al  reported that the percent increase in flow correlated with the diameter of the coarctated segment (r=0.94), with arm-to-leg blood pressure difference (r=0.84) and with Doppler gradient (r=0.76). More recently, Araoz and colleagues demonstrated that the percent increase in descending aorta flow in 19 patients with repaired coarctation more accurately reflected the degree of narrowing than arm-to-leg blood pressure measurements.  We have developed a CMR-based model to predict the probability of hemodynamically significant coarctation defined as a pressure gradient ≥20 mm Hg measured by catheterization.  The combination of the smallest cross-sectional area of the aorta (measured from the Gd-enhanced 3D MRA) and the heart rate-adjusted mean deceleration of flow in the descending aorta (measured by VEC MRI distal to the coarctation) predicted coarctation severity group with 95% sensitivity, 82% specificity, 90% positive and negative predictive values and an area under the receiver-operator characteristics curve of 0.94.
The objectives of the CMR evaluation of suspected or repaired aortic coarctation include (1) anatomic evaluation of the aorta including the proximal brachiocephalic arteries and the descending aorta to the level of the renal arteries; (2) imaging of blood flow throughout the thoracic aorta to detect high-velocity flow jets suggestive of stenosis; (3) detection of collateral vessels that bypass the coarctation site; (4) assessment of LV mass, volumes and function; (5) detection of any associated lesions; and (6) an estimate of the hemodynamic significance of any narrowing. In addition to the general cardiac function examination, these goals are achieved by the following protocol:
- Targeted cine SSFP profiling the ascending aorta and arch in its long-axis.
- Gradient-echo cine profiling areas of potential narrowing to visualize turbulence related flow jet.
- Turbo spin-echo profiling the arch in its long-axis.
- Gd-enhanced 3D MRA.
- VEC MRI to measure main pulmonary artery, ascending and descending aorta and AV valve flow.
| Single Ventricle|| |
Clinical Description : The broad diagnosis of "single ventricle" encompasses a variety of congenital heart lesions, which have functionally one ventricle. Grouping these lesions into a single category has some merit with respect to the CMR approach in that the palliative surgical therapy is similar in most lesions as are the clinically important imaging issues: evaluation of the pulmonary arteries and veins, valve function, ventricular function, ventricular outflow, the aorta and patency of the surgically placed venous pathways (Glenn or Fontan). Variations of the Fontan operation all have in common the diversion of the systemic venous blood directly to the pulmonary arteries. Early approaches entailed bypassing an atretic tricuspid valve with a right atrium to right ventricle conduit or direct anastomosis of the superior aspect of the right atrium to the branch pulmonary arteries (atriopulmonary type Fontan) [Figure - 8]; later modifications utilized a superior cavopulmonary anastomosis to route superior vena cava flow to the pulmonary arteries along with a baffle or conduit to route inferior vena cava flow to the pulmonary arteries.
MRI Evaluation: Several reports have utilized CMR as an investigational tool to study blood flow dynamics within the Fontan pathways and to delineate the distribution of inferior and superior caval flow to each lung. ,,, Myocardial tagging has proved an important investigational tool in the evaluation of myocardial mechanics in patients with functional single ventricle and Fontan circulation, demonstrating asynchrony and impaired regional wall motion.  The clinical utility of CMR in patients with the Fontan circulation increases as these patients grow and their acoustic windows become more restricted. An important limitation of CMR in patients with Fontan circulation is the frequent presence of metallic implants (e.g. coils, stents, occluding devices) that produce image artifacts.  The goals of the CMR examination in patients with the Fontan circulation include (1) assessment of the pathways from the systemic veins to the pulmonary arteries for obstruction and thrombus; (2) detection of Fontan baffle fenestration or leaks; (3) evaluation of the pulmonary veins for compression; (4) ventricular volumes, mass and function; (5) imaging of the systemic ventricular outflow tract for obstruction; (6) quantitation of valve regurgitation; (7) imaging the aorta for obstruction or aneurysm; and (8) detection of aorto-pulmonary, systemic venous or systemic-to-pulmonary venous collateral vessels. In addition to the general cardiac function examination, these goals are achieved by the following protocol:
- Targeted axial and oblique cine SSFP profiling the Fontan pathway and outflow tract.
- Gd-enhanced 3D MRA.
- VEC MRI to measure ascending aorta, Fontan pathway (±branch pulmonary arteries) and AV valve flow.
- MDE for evaluation of fibrosis and/or scar tissue.
| Conclusion|| |
CMR is a powerful non-invasive diagnostic tool capable of contributing significantly to the management of adults and children with congenital heart disease. Future advances are needed to define reliable normative data in the youngest subjects based on current sequences (cine SSFP); establish standardize protocols that facilitate cross-institutional comparison of CMR data; and further identify CMR-derived data that predicts clinically important outcomes.
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Andrew J Powell
Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8]
[Table - 1]