Effect of MitraClip on Acute and Chronic Reverse Cardiac Remodeling Assessed by CMR: The MITRA-REVERSE Study

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