Abnormal 3-D MRI Flow Patterns in Adolescents Patients With Bicuspid Aortic Valve
Condition: Congenital Heart Disease; Bicuspid Aortic Valve
MeSH terms: Heart Diseases; Heart Defects, Congenital; Bicuspid Aortic Valve Disease; Heart Valve Diseases
Study type: Observational

Summary: 
      Bicuspid aortic valve (BAV) is a form of congenital heart disease (the person is born with
      it). With BAV, the heart valves in the aorta (the blood vessel that takes blood away from the
      heart to the body) are not formed right. A person with BAV has only 2 leaflets instead of
      three and the valve leaflets are often thickened. This can result in the block of blood flow
      across the valve (aortic stenosis) and/or valve leakage (aortic valve regurgitation).

      From our experience at least 1/3 of patients with BAV will eventually develop complications.
      Many patients with BAV do not develop significant problems until well into adulthood. The
      most common problem in BAV patients is aortic dilatation and/or dissection. At this point, we
      do not know on who or why aortic dilatation or dissection occurs.It is unclear whether the
      enlargement is because of abnormal blood flow patterns, as a result of the shape of the
      bicuspid valve, or whether it is because the way the aortic valve and/or vessel is formed. In
      other words, the abnormal shape of the aortic valve may cause blood to flow in a different
      way than it normally would, causing damage to the aorta as blood leaves the heart. There may
      be a problem with the way the aortic valve connects to the aorta, which causes the aorta to
      get larger or break down over time. It is also possible that the wall of the aorta in
      patients with BAV is weaker than it would be in patients without BAV. At this point, we do
      not know. It is believed by the investigators that if we can determine why the aorta gets
      larger or tears, we can minimize the effects or prevent them altogether.

      This study will collect blood and cardiac MRI images from forty-five (45) patients at
      Children's Healthcare of Atlanta Egleston. There will be a study group (patients with BAV)
      and a control group of patients (patients scheduled for a cardiac MRI but without BAV).

      All enrolled patients will have blood drawn by nursing staff from a peripheral vein and
      collected in tubes for testing the day of their MRI scan. This test is called a plasma matrix
      metalloproteinase level. It is believed that patients who have bicuspid aortic valves and
      dilated aortas have high plasma levels of this protein. This study will compare the MRI
      images and plasma matrix protein levels of all the patients participating in the study.
    

Detailed description: 
      Introduction-Background The reported incidence of bicuspid aortic valve (BAV) based largely
      on autopsy studies varies between 0.4% to 2.25% of the population. At least a third of
      patients with a bicuspid aortic valve will eventually develop complications which include
      aortic stenosis, aortic regurgitation, infective endocarditis, aortic dilatation, aortic
      aneurysm formation, or aortic dissection. Given that in combination all other forms of
      congenital heart disease are thought to be present in 0.8% of live births, Ward has suggested
      that bicuspid aortic valves are likely to result in more morbidity and possibly mortality
      than the effects of all other congenital heart defects combined. Since many patients with
      bicuspid aortic valves do not develop significant problems until well into adulthood,
      clinicians have not focused much attention on the "normally" functioning bicuspid aortic
      valve. However, at a mean age of 17.8 years 52% of males with normally functioning aortic
      valves already have aortic dilatation, implying that associated aortic stenosis and/or
      regurgitation is not an obligate precursor.

      Previous studies have demonstrated an association between bicuspid aortic valves and
      dilatation of the aorta. Gurvitz et al. performed echocardiographic measurements of the
      aortas of children and found that those with bicuspid aortic valves had significantly larger
      aortas compared with controls, regardless of the presence of aortic stenosis or
      regurgitation. Nevertheless, the definition of clinical predictors of the risk for the
      development of aortic dilatation/dissection and an understanding of the mechanisms leading to
      aortic dilatation are lacking. Specifically, it remains unclear as yet whether such
      dilatation is secondary to abnormal flow patterns and shear stresses resulting from the
      bicuspid valve morphology or whether it is a manifestation of a distinct underlying
      structural problem with not only the aortic valve but also the aortic root including the
      ascending aorta.

      Fernandes et al. recently reviewed the echocardiograms of 1,135 children with bicuspid aortic
      valves and found that there were differences among the patients related to aortic valve
      morphology. For instance, associated moderate or greater aortic stenosis was present in 9.7%
      of patients with fusion of the intercoronary commissure of the aortic valve, vs 25.9% of
      patients with fusion of the right-coronary and non-coronary commissure, and in none of the
      patients with fusion of the left coronary and non-coronary aortic valve leaflets. Moreover,
      fusion of the right coronary and non-coronary cusps resulted in a two-fold higher risk of at
      least moderate aortic regurgitation compared with the other types of bicuspid aortic valves.
      However, this generalized division of bicuspid aortic valves into three types based on which
      commissure is fused is likely an oversimplification, and Fernandes did not report on the
      relationship between valve morphology and aortic root dilatation. However, Novaro et al.
      found that adult patients (mean age of 54 year) with fusion of the right/non-coronary
      commissure tended to have larger mid-ascending aortas compared with patients with fusion of
      the intercoronary commissure, but the difference did not reach statistical significance.
      Nevertheless, both personal clinical observations and recent publications support the
      assertion that individual bicuspid aortic valves may function quite differently from one
      another. For instance, there are bicuspid aortic valves in which there are two nearly
      symmetric leaflets whereas others may have a dominant cusp to varying degrees, resulting in a
      markedly eccentric orifice when the valve opens. In an elegant experimental model using
      excised bicuspid valves analyzed with intravascular ultrasound and high-resolution
      videography, Robicsek et al demonstrated that asymmetric bicuspid valves "induced extensive
      recirculation vortices in the ascending aorta." They found that the vortex was not "trapped"
      in the sinuses of Valsalva as it is in a normal tricuspid aortic valve, but instead is
      extended into the ascending aorta and aimed toward the right anterolateral aspect of the
      aorta (the convexity of the aorta). This correlates with published reports and our own
      personal experience in performing clinical cardiac magnetic resonance imaging (CMR) studies
      on patients with bicuspid aortic valves and aortic root dilatation in whom there is oft-noted
      asymmetry in the pattern of dilatation of the ascending aorta and resulting in an oval-shaped
      rather than a circular aortic root and ascending aorta.

      Extrapolating from the studies of Robicsek, variations present in the geometry of bicuspid
      valves are likely to result in varying degrees of turbulence even in the absence aortic valve
      stenosis. In theory, the turbulent blood flow directed at a particular segment of the aortic
      wall may result in local changes to the aortic wall leading to asymmetric aortic dilatation.
      These changes are postulated to result from receptors present on both endothelial and smooth
      muscle cells that have the ability to adapt to sheer stress by altering local gene expression
      which in turn modulates the tension between focal adhesion sites, integrins, and the
      extracellular matrix. Moreover, fibrillin-1, which is deficient in patients with dilated
      aortic roots and Marfan syndrome, has also been found to be deficient in the aortas of
      patients with bicuspid aortic valves. Similarly, Cotrufo et al. found asymmetric patterns of
      matrix protein expression and content and asymmetric patterns of elastic medial wall
      degeneration in the aortic walls of patients with bicuspid aortic valves. In addition, these
      investigators found differences between patients with bicuspid aortic valves and associated
      stenosis vs regurgitation, suggesting that focally-directed aortic turbulence may be
      influencing local gene expression and potentially explaining the asymmetric pattern of aortic
      dilatation that is often observed. Lastly, several recent studies have highlighted the
      relationship between circulating plasma MMP-2 and MMP-9 levels either in aortic dilatation in
      adult patients with thoracic or abdominal aortic aneurysms or in adults with aortic
      dilatation secondary to systemic hypertension. In addition, histologic examination of aortic
      aneurysm tissue in adult patients with bicuspid aortic valves demonstrated increased MMP-2
      expression vs. aortic aneurysms in adults with trileaflet aortic valves.

      Recently investigators have used cardiac MRI (CMR) to study flow patterns in the aorta. CMR
      is a noninvasive technique that permits 3-dimensional anatomic characterization as well as
      assessment of aortic flow. Markl et al. have used time-resolved 3-dimensional phase-contrast
      magnetic resonance imaging (3D-PCMRI) techniques to characterize aortic flow in both normal
      adults and in adults after aortic root replacement. These authors established that
      3-dimensional magnetic resonance velocity mapping was a useful technique to visualize and
      qualitatively assess the complex aortic flow patterns in both normal controls and in patients
      with aortic pathology. Similarly, Kvitting et al., who studied both adult volunteers and 2
      patients with Marfan syndrome following aortic valve sparing operations, found that the
      alterations to the normal aortic sinus architecture following surgery resulted in a loss of
      the normal vortical flow patterns seen in the aortic sinuses.

      Specific Aims

        1. Develop clinically feasible MRI imaging strategies to perform a complete evaluation of
           structure and functional dynamics of the heart, including the aortic valve, aortic root,
           and ascending aorta, as well as full volumetric 3-D ciné flow velocity encoding of the
           entire aortic root region and proximal ascending aorta.

        2. Define qualitative and quantitative metrics to characterize different types of bicuspid
           aortic valve morphology and flow patterns. These metrics will be based on structural
           information and the blood flow patterns in the aortic root, observed in MRI studies of
           patients with diagnosed bicuspid aortic valves, as compared to observation in control
           subjects with known normal aortic valves and anatomy of ascending aorta.

        3. Correlate different bicuspid aortic valve morphologies and observed characteristic flow
           patterns with the risk of development of aortic dilatation at various levels of the
           aorta, such as the aortic root, proximal ascending aorta, and distal ascending aorta.

        4. Quantify plasma concentrations of matrix metalloproteinase-2 (MMP-2) and matrix
           metalloproteinase-9 (MMP-9) levels as well as the levels of their specific tissue
           inhibitors, respectively tissue inhibitor of metalloproteinase-2 (TIMP-2) and tissue
           inhibitor of metalloproteinase-1 (TIMP-1) in controls and bicuspid aortic valve
           patients.

        5. Correlate biochemical markers of extracellular matrix degradation (both MMP and TIMP)
           with the presence or absence of aortic dilatation in both controls and in patients with
           bicuspid aortic valves.

      Study Design We will prospectively perform cardiac magnetic resonance studies on 30 patients,
      ages 10-18 years with known bicuspid aortic valves (BAV), and on 15 normal control subjects.
      The BAV patient population will consist of 15 patients with aortic root dilatation for body
      surface area as determined by published pediatric echocardiographic normal values and 15
      without aortic dilatation. Echocardiographic normals indexed for body surface area will be
      used, as there are no published normal CMR values for aortic dimensions in pediatric patients
      using cine MR techniques; however aortic measurements by echocardiography and CMR in a
      pediatric patient population have been shown to reveal no significant differences except for
      the descending aorta. Since either significant aortic stenosis or regurgitation has been
      associated with aortic dilatation, patients will be excluded if they have more than mild
      stenosis or regurgitation.

      As in previous published reports, mild aortic stenosis will be classified as a mean gradient
      across the aortic valve <17 mmHg on routine clinical echocardiography. Mild aortic
      regurgitation will be defined on routine clinical echocardiography as resulting in a left
      ventricular end-diastolic dimension <2 standard deviations below the mean for body surface
      area and the absence of pan-diastolic retrograde flow on pulsed Doppler evaluation of the
      abdominal descending aorta. Studies will be performed without sedation, but with
      breath-holding instructions as appropriate.

      Controls will consist of 15 patients with normal aortic valves and aortas who are undergoing
      clinically indicated CMR studies for reasons such as chest pain or assessment for
      cardiomyopathy and who are found to have structurally/functionally normal hearts.

      MRI Methods Cardiac magnetic resonance (CMR) studies will be performed in a GE 1.5 T MR
      system with Release 12M4 cardiovascular software. MR imaging will focus on of visualization
      in high definition of the anatomy of the aortic valve and aortic root utilizing 2-dimensional
      and 3-dimensional FIESTA cine MR sequences. Flow data will be acquired using 2-dimensional,
      or, whenever allowed within imaging time constraints, fully 3-dimensional phase velocity
      mapping sequences with full vector-encoding of velocities at 200 cm/s maximum velocity
      encoding VENC, adjusted up if velocity aliasing is observed. For 2-D flow acquisitions in
      planes across the main flow direction the in-plane directional components may be acquired at
      lower velocity encoding to achieve higher accuracy. To resolve blood flow and cardiovascular
      anatomy as a function of the cardiac phase (cine imaging), image acquisition will be
      synchronized with the vector cardiogram to reconstruct approximately 16-20 cine images
      representing the different phases of the cardiac cycle. Initial data acquisition for
      structural and velocity-encoded imaging will be performed with standard pulse sequence
      software as supplied by General Electric with the imaging device. These scans will initially
      be acquired in free-breathing mode. A series of 5-10 studies on normal volunteers will be
      conducted to optimize the protocol within those constraints, and develop guidelines for an
      prescribed add-on imaging protocol, ideally limited to not more than 20 minutes of scan time,
      for acquisition of the aortic scans. Priority solutions for respiratory motion compensation
      during the acquisition depending on the demonstrated reliability of the available options
      (free-breathing, breath-holding, respiratory k-space ordering, navigator- or belt &
      bellows-monitored respiratory gating) in these volunteer test studies, and based on the
      capability of each study subject to accommodate these options. The scans defined in this
      protocol will be added initially to the clinical protocol of all subjects in the study. In
      parallel with the protocol development and implementation by standards pulse sequence
      methods, we will pursue a collaboration effort with the MRI imaging resource center at
      Stanford University. The Stanford group has developed a highly optimized image acquisition
      method which allows fully vector-encoded 3-D respiration-ordered acquisition of an
      arbitrarily positioned rectangular 3-D imaging volume. We anticipate that this acquisition
      software, which will require running specialized pulse sequence software and off-line image
      reconstruction on one of our computer workstations, will improve the coverage and overall
      resolution of the flow-encoded data significantly. We have the required expertise and
      research software tools available from General Electric, but currently only enabled for
      research on the WCI scanner at Emory. For this project, but possibly concurrently with
      transition of software development efforts for other research projects (Noquist project) we
      will request authorization from GE to run the required research patches on the Egleston 1.5T
      GE instrument.

      Plasma MMP and TIMP quantification methods Blood samples will be taken from peripheral veins
      by nursing staff.MMP and TIMP levels will then be measured using commercially available
      sandwich enzyme-linked immunosorbent assay (ELISA) kits which have previously been validated
      for use in human tissue homogenates.Serum MMP levels will be determined using MMP-2 and MMP-9
      monoclonal antibodies.Levels of TIMP-1 and -2 will be determined using monoclonal antibodies.

      Image Processing Methods Visualization and quantitative analysis of velocity mapping data
      will be performed, initially exclusively, utilizing in-house HeartViz software developed by
      Marijn Brummer, Ph.D.The current version of the software allows fully interactive 3-D dynamic
      integrated display of structural information through texture-mapped slice display and
      time-resolved volume rendering, in conjunction with dynamic flow vector field visualization
      from multiple flow acquisitions in the same view. This software has been developed by the
      investigators during the past ten years, and has been proposed and used for evaluation of a
      variety of congenital and acquired cardiac diseases, including aortic coarctations, VSD,
      aortic dissections, and peri-atrial tumors.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        patients with bicuspid Aortic valve, normal healthy volunteers, and congential heart
        disease without bicuspid aortic valve
      
Keywords: Pediatric; Congenital Heart Disease; Imaging