Effect of MitraClip on Acute and Chronic Reverse Cardiac Remodeling Assessed by CMR: The MITRA-REVERSE Study
Effect of MitraClip on Acute and Chronic Reverse Cardiac Remodeling Assessed by CMR: The MITRA-REVERSE Study
The purpose of this study is to use cardiac magnetic resonance (CMR) and echocardiography to
 define the anatomic and functional remodeling that results from MitraClip implantation. A
 total of sixty (60) patients undergoing MitraClip implantation will be enrolled across
 multiple sites. The severity of mitral regurgitation, cardiac morphology and function will be
 assessed in these patients by taking cardiac magnetic resonance imaging with an FDA approved
 contrast agent at BASELINE (within 30 days prior to MitraClip implantation), during the ACUTE
 REMODELING PHASE (pre-discharge following implantation), and during the CHRONIC REMODELING
 PHASE (6 months post-implantation).
Percutaneous mitral valve repair is expanding treatment options for patients suffering from
 symptomatic mitral regurgitation (MR). The overall objective of the procedure is to reduce
 the degree of MR, which may lead to improvement in: 1) hemodynamics, an increase in systemic
 stroke volume and decrease in left atrial (LA) pressure; 2) left ventricular (LV) and LA
 volumes (reverse remodeling); and 3) efficiency in LV mechanics (decreased wall stress and
 improved fluid kinetics in the LV). The MitraClip System is the only percutaneous therapy
 available for high surgical risk patients with significant MR (Figure 1). Two-dimensional
 Echocardiography (2-D) data from the Endovascular valve edge-to-edge study (EVEREST trial)
 showed reverse modeling of LA and LV volumes in patients with primary MR after MitraClip
 implantation. In a separate study, patients with secondary MR who were non-respondent to
 cardiac resynchronization therapy (CRT) demonstrated improvement in LA and LV volumes
 post-MitraClip implantation [3]. Two smaller studies have also demonstrated the feasibility
 of using CMR to show improvement in LA and LV volumes post-MitraClip.

 Immediate post-procedural reduction in MR or, conversely the degree of residual MR, has been
 shown to be a predictive factor of long-term improvement in MR, LV and LA reverse remodeling,
 and survival. Current assessment of MR reduction post-MitraClip relies on a combination of
 indirect hemodynamic parameters, such as LA pressure and 2-D Echo parameters, which are
 semi-quantitative at best. Therefore, a rapid and accurate quantitative method to assess the
 degree of residual MR is of great need to complement other invasive and indirect/qualitative
 echo parameters. This will not only improve the reliability and reproducibility of residual
 MR assessment post-Mitraclip, but will also provide an objective index to define successful
 procedural outcomes. The latter may potentially help in decision making for the placement of
 additional clips to further reduce MR. Of the quantitative color Doppler parameters used to
 measure the degree of MR, regurgitant volume/fraction (RV/RF) is probably the most optimal
 index. The Mitra-clip has been shown to distort data from the flow convergence (PISA) method,
 resulting in complicated and unreliable assessments of MR. Similarly, vena contracta (VC) is
 also distorted by the Mitra-Clip, which can lead to unreliable and unreproducible measures of
 MR. It has been previously shown that real-time volume color flow Doppler (RT-VCFD)
 trans-thoracic echocardiography (TTE) is useful to quantify RV/RF and comparable to CMR.
 Since 3-D transesophageal echocardiography is commonly used for Mitra-Clip assessment, the
 same principle can be applied to RT-VCFD TEE. The preliminary experience with this approach
 has shown promise.

 The attenuation of LV/LA remodeling, defined as the reduction in LV end-systolic volume and
 LA volume, is an important goal of MR reduction after Mitra-clip placement. Post Mitra-Clip
 TTE is limited by acoustic windows in at least one-third of patients, rendering 3-D TTE
 measurements of LV/LA volumes unfeasible. Contrast Echo can mitigate the drawbacks of TTE,
 but 2-D volumes are under-estimated compared to CMR. Hence, the impact of MR reduction by
 Mitra-clip on LV/LA remodeling is best determined by CMR. Furthermore, CMR will provide an
 independent reference standard to validate RV/RF measured by RT-VCFD TEE pre- and
 post-Mitra-clip placement.

 Cardiac morphology and function have primarily been assessed by echocardiography in patients
 undergoing percutaneous mitral valve repair, which has known limitations with regard to image
 quality and reproducibility. Transesophageal echocardiogram (TEE) is a standard technique for
 assessing MR and intra-procedural guidance; however, TEE quantification of MR and effective
 orifice area after MitraClip placement can be challenging in a double-orifice valve model and
 has not been well validated. While reduction in chamber size after MitraClip placement has
 been demonstrated, prior analysis has been limited by imprecise assessment of regurgitation
 severity resulting in successful remodeling and clinical improvement. Alternatively, CMR is a
 validated noninvasive technique that could be utilized to evaluate the heart and valve
 structure, function, and myocardial fibrosis without any geometric assumptions or harmful
 radiation.

 CMR enables noninvasive evaluation of cardiac anatomy, including great arteries and veins,
 and cardiac chambers. It provides excellent evaluation of both the left ventricle (LV) and
 right ventricle (RV), including ventricular size, thickness, wall motion, volumes, and
 ejection fraction (EF), without the need for geometric assumptions. Many consider CMR to be
 the gold standard for quantifying ventricular volumes and EF. In addition, CMR can better
 define valvular disease due to its ability to precisely quantify regurgitant volumes and
 fractions without limitation from acoustic windows, or highly eccentric/multiple jets.
 Feasibility and safety of CMR after MitraClip placement has previously been shown [5]. In
 order to obtain a concurrent comparison of CMR with echocardiography, a comprehensive 2D/3D
 echo with Doppler will be performed immediately before or after the CMR scan. The
 echocardiography protocol will be outlined in detail in the Echo Imaging Manual.

 Additionally, a SUBSTUDY (MITRA-REVERSE FIBROSIS) will explore newer CMR techniques, such as
 T1 mapping and extracellular volume fraction quantification, can now non-invasively quantify
 the extent of diffuse extracellular matrix expansion as a surrogate for interstitial
 fibrosis, and are supported by histological validation. The interplay between diffuse
 interstitial fibrosis, volume overload reduction (via decrease in mitral regurgitation), and
 subsequent LV reverse remodeling are not well understood. It is possible that increasing
 burden of diffuse interstitial fibrosis at baseline may prevent, blunt, or delay the reverse
 remodeling that occurs following volume overload reduction. Alternatively, volume overload
 reduction and reverse LV remodeling may lead to subsequent reduction in diffuse interstitial
 fibrosis A sub-study with gadolinium contrast administration will attempt to address these
 questions. MR patients without contraindications to gadolinium will be enrolled into the
 sub-study that includes pre- and post-gadolinium contrast imaging in order to quantifying LV
 myocardial replacement and interstitial fibrosis, as well as papillary muscle fibrosis.
 Recently, in a cohort of 48 patients with chronic MR undergoing surgical mitral valve repair,
 it has been demonstrated that the presence of LV myocardial fibrosis assessed with
 delayed-enhancement CMR was an independent predictor of increased adverse clinical outcomes.
 Similarly, in this sub-study it is intended to examine the correlation between the presence
 and extent of myocardial replacement and interstitial fibrosis to clinical response, as
 assessed by New York Heart Association (NYHA) class and Kansas City Cardiomyopathy
 Questionnaire, following a MitraClip procedure. Moreover, a new technique to quantify
 replacement fibrosis in the papillary muscles may be exploited in the gadolinium sub-study
 that could provide additional information, as the papillary muscles of the left ventricle are
 key components of the mitral valve apparatus. Papillary muscles connect the LV wall with the
 mitral leaflets and annulus, and regulate the location of the mitral leaflets. Thus, the
 geometry and function of papillary muscles contribute to mitral valve function and an
 accurate evaluation is key in understanding the pathophysiology of mitral valve disease. This
 evaluation of the papillary muscles will rely on a new procedure that is based on the use of
 a novel dark blood delayed enhancement imaging technique.
Inclusion Criteria:

 1. Males or females, 18 years of age or older.

 2. Negative pregnancy test (serum or urine β-HCG) within 24 hours of gadolinium contrast
 administration, if female and of child-bearing potential. In addition, all female
 patients of childbearing potential must agree to use a medically accepted method of
 contraception throughout the study (this applies only to patients in the gadolinium
 sub-study).

 3. Symptomatic severe mitral regurgitation (grade 3-4+).

 4. Undergoing MitraClip implantation due to increased surgical risk.

 5. Patients or legally authorized representatives who have the ability to understand the
 requirements of the study and provide written consent/assent to participate and agree
 to abide by the study requirements.

 Exclusion Criteria:

 1. The patient is enrolled in the Clinical Outcomes Assessment of the MitraClip
 Percutaneous Therapy Trial (COAPT).

 2. The patient is scheduled to undergo percutaneous coronary intervention with MitraClip
 procedure.

 3. The patient has Stage D Congestive Heart Failure or inability to lay flat for 60
 minutes.

 4. The patient has a medical condition, serious concurrent illness, or extenuating
 circumstance that would significantly decrease study compliance, including all
 prescribed follow-up.

 5. The patient has contraindications to CMR, including:

 1. Implanted defibrillator or pacemaker that is not MRI conditional

 2. Epicardial pacemaker leads, or any abandoned leads

 3. Ferromagnetic aneurysm clip

 4. Ferromagnetic halo device

 5. Cochlear implants

 6. Implanted infusion pumps

 7. Severe claustrophobia

 8. Any other conditions which represent contraindication to CMR.

 6. The patient is clinically unstable