Improving Mitral Repair for Functional Mitral Regurgitation
Phase: NA
Conditions: Cardiomyopathy, Cardiovascular Diseases, Congestive Heart Failure, Coronary Artery Disease, Heart Disease, Valvular Heart Disease, Mitral Valve Disease
Sponsor: Emory University

 
 
 
 
 
 
 
 
IMPROVING MITRAL REPAIR FOR FUNCTIONAL MITRAL 
REGURGITATION (IMPROVE-FMR) 
NCT03366649 
 
Date: June 17, 2023 
IRB00097939 

IMPROVE-FMR
Page 1
IMPROVING MITRAL REPAIR FOR FUNCTIONAL MITRAL 
REGURGITATION (IMPROVE-FMR)
Principal Investigator
Professor of Surgery
Emory University, Atlanta, GA
 
Sponsor
National Heart, Lung and Blood Institute (NHLBI)
Protocol version June 17, 2023

2
DEFINITIONS, ACRONYMS, AND ABBREVIATIONS
CCR
Center for Clinical Research
FMR
Functional mitral regurgitation
UMA
Undersizing mitral annuloplasty
IPMS
Inter papillary muscle separation
PMA
Papillary muscle approximation
LV
Left ventricle
MV
Mitral valve
LVEDI
LV End diastolic volume
LVESI
LV End systolic volume index
EF
Ejection fraction
MRF
Mitral regurgitation fraction

3
1.0
PROTOCOL SUMMARY
Title
Improving mitral repair for functional mitral regurgitation (IMPROVE-FMR) 
Precis
Functional mitral regurgitation (FMR) can have an adverse impact on the 
cardiomyopathic left ventricle, by imposing a chronic low-pressure volume 
overload. Unrepaired FMR increases the risk of congestive heart failure and 
death1, 2. Undersizing mitral annuloplasty (UMA) is the current gold standard 
for repair of FMR, but its outcomes are poor3 with 32.6% of patients 
presenting with clinically significant recurrent FMR at 1 year after the repair4, 
which increases to 58.8% of the patients at 2 years after annuloplasty5. 
Currently, we do not understand why some patients have failure of 
annuloplasty, while others do not. Lack of mechanistic insights has inhibited 
an evidence driven approach in optimizing the repairs adequately – resulting 
in plethora of new sub-valvular techniques, but very few with appropriate 
scientific justification to be tested in randomized trials.
Our team recently performed a retrospective cardiac MRI study in FMR 
patients and identified that inter-papillary muscle separation (IPMS) is a 
strong determinant of FMR severity prior to undergoing any repair6. Using 
image-derived computational biomechanical modeling, we reported that 
when IPMS is elevated, marginal chordal forces restrict parallelization of the 
leaflet edges and cause higher FMR. We built upon this observation, and 
performed an ex vivo bench study to demonstrate that IPMS is a strong 
determinant of repair success as well. In this study, we demonstrated that the 
MR volume after repair is directly correlated to the pre-operative IPMS7. We 
recently advanced this study further into a chronic swine model, and 
demonstrated that swine undergoing papillary muscle approximation (PMA) 
alone or concomitantly with undersizing mitral annuloplasty (UMA), have 
better valvular function at 3 months after surgery, compared to animals that 
receive UMA alone. Their valvular kinematics were superior, and so was their 
ventricular function.
In this observational, prospective, non-randomized study in humans with 
FMR, we seek to investigate the following:

Question 1: Does pre-operative IPMS correlate with the severity of 
FMR after UMA at 30 days, 6 months and 12 months. We will study 
this primary objective by conducting pre-operative MRI and echo in 
patients receiving UMA, and follow them to one year. Secondly, we 
will use these images from each patient as input to a computational 
biomechanical model, which will help demonstrate the chordal forces 
and stresses before repair, after repair and at the follow-up time 
points. We will recruit a total of 125 patients to this phase of the study.

4

Question 2: Does reducing IPMS with a papillary muscle 
approximation stitch reduce the FMR severity after UMA, by improving 
valve geometry and biomechanics. We will conduct a pilot study of 15 
patients with this approach and investigate their outcomes at 1 year 
after the surgery. 
Hypothesis
Elevated IPMS is a risk factor for failure of UMA and recurrence of FMR at 12 
months the repair. Reducing IPMS with a papillary muscle approximation 
stitch can reduce FMR recurrence after UMA.
Objectives
(1) Determine if pre-surgery diastolic IPMS, systolic IPMS and (diastolic-
systolic) IPMS correlates with the severity of FMR at immediate post-
op, 30 days, 6 months, and 12 months post-UMA.
(2) Does IPMS reduction with PMA performed concomitantly with UMA, 
help in reducing the severity of FMR at immediate post-op, 30 days, 6 
months, and 12 months after surgery.
Primary Endpoints
The primary endpoint of this study is to investigate if pre-operative inter-
papillary muscle separation (diastolic, systolic and diastolic-systolic) 
correlates with FMR severity at 12 months after surgery with UMA and 
UMA+PMA.
Secondary Endpoints
Survival

All-cause mortality at discharge, 6 months and 1 year
Functional Status and Hospitalizations

MACE (death, stroke, worsening heart failure (+1 NYHA Class), CHF 
hospitalization, mitral valve re-intervention at 6 months and 1 year

NYHA classification at 6 months and 1 year

6-minute walk test at 6 months and 1 year

Readmission rates at 6 months and 1 year
Physiologic
Pre-operative: 

MRI
-
MR severity
-
Interpapillary muscle dynamics
-
Left ventricular function
-
Left ventricular geometry
-
Left ventricular perfusion and motion defects
-
Left ventricular scar burden

Echo (transthoracic and transesophageal)
-
MR severity (ERO and regurgitant fraction)

5
-
Mitral valve leaflet kinematics
-
Mitral gradient and stenosis
-
Left ventricular function
-
Left ventricular geometry
-
Left atrial dimensions
-
Right ventricular size and function
-
Regional wall motion
Intra-operative:

Transesophageal Echo 
-
MR severity (ERO and regurgitant fraction)
-
Mitral valve leaflet kinematics
-
LV function
Chest closure echo:

Transesophageal Echo 
-
MR severity (ERO and regurgitant fraction)
-
Mitral valve leaflet kinematics
-
LV function
Discharge:

Transthoracic Echo
-
MR severity (ERO and regurgitant fraction)
-
Mitral valve leaflet kinematics
-
LV function
30-days:

Transthoracic Echo
-
MR severity (ERO and regurgitant fraction)
-
Mitral valve leaflet kinematics
-
LV function
6 months

Transthoracic Echo 
-
MR severity (ERO and regurgitant fraction)
-
Mitral valve leaflet kinematics
-
LV function
12 months

Cardiac MRI with contrast or Transesophageal echocardiography

Transthoracic Echo 
-
MR severity (ERO and regurgitant fraction)
-
Mitral valve leaflet kinematics
-
LV function
Population
Patients with FMR from either ischemic or non-ischemic cardiomyopathies, 
referred for surgical or transcatheter mitral valve annuloplasty with or 
without the need for revascularization. Suitability for mitral annuloplasty is 
determined by the surgeon, using some or all the criteria described here:

6

Left ventricular end diastolic diameter is less than or equal to 70mm.

Systolic tenting height is less than or equal to 12mm
Inclusion criteria

Mitral regurgitation of moderate or greater severity, as defined by the 
guidelines of the American society of echocardiography at the time of 
the study approval (via a transthoracic echo).

Cardiomyopathy of ischemic or non-ischemic origins, with or without 
the need for coronary revascularization.

Concomitant right sided valve repair or replacement (i.e. patients 
requiring concomitant tricuspid procedures).

Age ≥ 18 years

Able to sign informed consent and release of medical information 
forms, or able to assign a legal representative who can sign on the 
patient’s behalf.
Exclusion criteria

Any evidence of structural (chordal or leaflet) mitral lesions.

Prior mitral valve repair

Contraindication for cardiopulmonary bypass

Clinical signs of cardiogenic shock at the time of recruitment to the 
study.

ST segment elevation myocardial infarction within 14 days prior to 
inclusion in this study.

Congenital heart disease (except PFO or ASD)

Chronic renal insufficiency defined by Creatinine ≥ 3.0 or chronic renal 
replacement therapy, who are contraindicated for cardiac surgery

Recent history of psychiatric disease that is likely to impair compliance 
with the study protocol, in the judgement of the investigator

Pregnancy at the time of randomization

7
Study Procedures
Step 1) Obtain Emory University Institutional Review Board review and 
protocol approval to begin study.
Step 2) Study kick-off meeting, with all investigators and research staff.   Study 
protocol copies to be distributed to each team member. Data coordinators 
trained to use the study specific redcap database for data entry.
Step 3) Recruitment begins.
Patients will be recruited to three registries, with the procedures described 
as follows:
Registry # 1: Prospectively Identified Patients that will Receive Surgery after 
Recruitment and Consented to Participate in the Study
Step 4) Subjects are screened based upon medical records, external echo 
examinations, echo exams performed in the Emory cardiology clinics or cath 
labs, inclusion and exclusion criteria.
Step5) Screened patients are consented and request for release of medical 
information is signed. 
Step6) Consented patients undergo battery of baseline tests that are standard 
of care, including transthoracic echo, transesophageal echo, and cardiac MRI. 
If some patients have already completed baseline tests as part of their 
standard of care, and are identified after these are completed, we will consent 
them at this stage.
Step7) Patients undergo surgery, with pre-operative echo and closed chest 
echo. 
Step8) Blood draws and echocardiography performed at discharge and 30-
days.
Step9) Patients return for visits at 6 months and 1 year to undergo repeat of 
tests.
Step10) Patients exit study after the 1st year. If extended follow-up is 
determined to be necessary, patients will be re-consented at the 1-year visit.
Registry # 2: Retrospectively identified patients, who already underwent the 
standard of care surgery, and were identified after the procedure is 
completed, and are suitable for recruitment to the study for their post-
operative research

8
Rationale: The decision to perform mitral valve surgery could be made during 
the surgery by the surgeon, and these patients would be suitable for this 
study, but would not be consented prior to their surgery. Thus, in this registry, 
we will identify such patients for recruitment into this study, as their first 
research point isn’t until 6 months after their surgery.
Step 1) Charts will be screened for patients who underwent surgery for the 
lesion of interest at Emory, who would otherwise be eligible for this study but 
were not recruited as it was not known if they will need mitral valve surgery. 
Step 2) Patients who are still within 6 months (± 1 month) after the date of 
their surgery will be contacted after surgery and the study objective will be 
explained, verbal consent will be obtained and the date to visit Emory will be 
provided.
Step 3) Written consent will be obtained at their 6 month visit, and steps 9 
and 10 described in registry # 1 will be performed.  
Registry # 3: Retrospectively identified patients, who already underwent the 
standard of care surgery, and were identified after the procedure is 
completed, and are suitable for recruitment to the study for their post-
operative research. 
Rationale: Historical review of patients between dates 1/1/2004 to present 
who have underwent mitral valve surgery who were not previously identified 
in the study. These patients have not been consented prior to their surgery. 
The purpose is to increase the study sample size in order to gain statistical 
power for outcome analysis.  
Step 1) Charts will be screened for patients who underwent surgery between 
1/1/2004 to present for the lesion of interest at Emory, who would otherwise 
be eligible for this study but were not recruited as it was not known if they will 
need mitral valve surgery or were not recruited as they may have received the 
surgery prior to study start date. 
Sample size
140 subjects in total at Emory University.
Group 1: 125 patients to receive UMA and followed to 12 months, with 
interim imaging.
Group 2: 15 patients to receive UMA with PMA and followed to 12 months, 
with interim imaging.

9
It is expected that we will recruit ~25 patients per year. 
Group 3: patients’ medical charts will be queried between 2004 – present, 
number of subject charts are undetermined/unknown.
Risk-benefit 
determination
Neither UMA nor PMA are experimental procedures, thus the risk from the 
procedures itself is considered minimal8, 9. Surgeons at our institution have 
experience with both procedures in humans, albeit with more extensive 
experience with undersizing mitral annuloplasty and recent preliminary 
experience with papillary muscle approximation.
Proposed pre-operative and post-operative echocardiography and MRI are 
non-invasive, and thus the risk from these procedures is minimal as well. The 
data obtained from such imaging may not directly impact the patients care, 
however if any recurrence of FMR or deterioration in cardiac function is 
observed from the study imaging, the investigative team will inform the 
patient to consult their cardiologist. Thus, the patients stand to gain some 
benefit from participating in the study.
Overall, our study team determined that benefits significantly outweigh the 
risks to the patients participating in this study.
Number of sites 
enrolling participants
Emory University Hospital/Emory University Midtown Hospital/Emory St. 
Joseph’s Hospital.
Study duration
20 years.
Participant duration
1 year from the time of surgery.
2.0
OBJECTIVE
The primary objective of this protocol is to investigate if pre-operative inter-papillary muscle 
separation (IPMS) is predictive of FMR severity at 12 months after undersizing mitral 
annuloplasty (UMA) to repair functional mitral regurgitation (FMR). Furthermore, whether a cut-
off value of pre-operative inter-papillary muscle separation can be established to predict patients 
who might have failure of UMA.

10
The secondary objective of this protocol is to investigate if adding papillary muscle approximation 
(PMA) to UMA is an effective technique in reducing recurrence of FMR at 12 months’ post-
procedure.
The third objective is to use computational modeling to define the impact that IPMS has on 
chordal force imbalance, to define the mechanistic basis for repair failure. MRI and echo images 
from the patients will be used to accomplish this objective.
3.0
BACKGROUND
Functional mitral regurgitation (FMR) is a frequently diagnosed mitral valve lesion in patients 
surviving cardiomyopathies of ischemic and non-ischemic origins10-18. Volume overload from FMR 
increases the risk of congestive heart failure and death. Pharmacological management of these 
patients has been shown to be ineffective, and thus timely repair of FMR is considered to benefit 
the patient and preserve their cardiac function.
Undersizing mitral annuloplasty (UMA) is the current standard of care to repair FMR, which 
involves placing a metallic ring onto the mitral annulus, to reduce its dimensions19. This 
procedure can be performing using open heart surgical techniques or with transcatheter mitral 
valve techniques. Though UMA is considered effective, there is increasing evidence that FMR 
persists or recurs after the procedure. At 12 months, ~36% of the patients present with 
recurrence FMR, which increases to 58% at 24 months4. The mechanisms driving failure of UMA 
are unknown, and a metric for pre-operative stratification of patients to benefit from UMA is 
necessary.
Our group recently reported that in patients presenting with FMR, inter-papillary muscle 
separation (IPMS) has a strong correlation with the pre-operative severity of the regurgitation6. 
Using cardiac MRI imaging, we demonstrated that IPMS directly impacted the extent of leaflet 
tethering and mitral regurgitation, independent of the left ventricular size or volume. We used 
biomechanical modeling to demonstrate that elevated IPMS increases the forces in the marginal 
chordae, resulting in improper leaflet closure. 
In a more recent study in a bench-top ex-vivo model, we demonstrated that IPMS can also have 
an impact on mitral valve closure after undersizing mitral annuloplasty (UMA). Specifically, we 
demonstrate that when the IPMS is elevated, UMA results in a highly unphysiological leaflet 
geometry that results in persistent FMR despite the repair7. In a similar study in swine, we 
demonstrated that such an unphysiological leaflet configuration after UMA can be improved with 
papillary muscle approximation (PMA)20.
In this observational, prospective, non-randomized clinical study, we seek to test the hypothesis 
that elevated pre-operative inter-papillary muscle separation (IPMS) is a risk factor for recurrence 

11
of FMR after annuloplasty. Since high or low are subjective terms, we seek to recruit 125 patients 
undergoing undersizing mitral annuloplasty (UMA) at our institution and measure their inter-
papillary muscle separation before and after the procedure, and study their impact on 12 month 
outcomes of the repair. We will perform statistical analysis to determine a cut-off value for IPMS 
that can stratify patients at risk for UMA failure.
Using the patient specific imaging that we obtain from the 125 patients, we will perform 
comprehensive biomechanical computational modeling to demonstrate and validate that 
patients below the cut-off value of IPMS have better mitral valve force distribution, vs. those 
above the cut-off value of IPMS having poor mitral valve force distribution. This data will help 
validate the cut-off value as a viable technique to stratify patients for UMA.
In the final step of this study, we will demonstrate that those patients with higher IPMS and at 
risk of UMA failure, may benefit from a concomitant papillary muscle approximation technique. 
We will recruit 15 patients to a pilot study, in whom IPMS is above the cut off value, and perform 
papillary muscle approximation (PMS) along with undersizing mitral annuloplasty (UMA). We will 
investigate the effect of this combination approach on the outcomes at 6 months and 12 months.
4.0
CLINICAL AND SCIENTIFIC JUSTIFICATION
Failure of undersizing mitral annuloplasty (UMA) in patients with FMR is now an established fact. 
High rates of FMR recurrence after UMA have been reported in several studies, but a mechanistic 
basis for such failure is lacking. Due to the high rates of repair failure, these patients are receiving 
a mitral valve replacement (MVR), which is known to have poor durability and higher mortality. 
Thus, the clinical justification to understand the mechanisms underlying UMA failure is solid. The 
knowledge gained from this study may not directly impact these patients, but is expected to 
improve the treatment options available to other patients in the future.
The scientific justification for studying inter-papillary muscle separation (IPMS) as a determinant 
of UMA failure, stems from our previous published study. In 2014, we reported that elevated 
IPMS correlated with higher severity of FMR in humans. In a subsequent study in a bench model, 
we reported that elevated IPMS has a direct impact on valve function after UMA. Based on these 
two studies, we developed the hypothesis that a cut-off value for IPMS exists, which can 
determine who patients could have a durable repair with UMA, and which patients may require 
additional procedures. Based on this information, for those with higher IPMS we are proposing 
that papillary muscle approximation (PMA) may be a useful technique to reduce their IPMS and 
improve their suitability for UMA.
5.0
TREATMENT OPTIONS
Patients recruited to this study, are determined by their cardiologists to be suitable for correction 
of their FMR to improve their health. A transthoracic echo has been performed on them, which 

12
depicts moderate or greater severity of FMR, and thus they were referred to us for intervention. 
The patients may receive mitral valve repair or mitral valve replacement, depending on their 
choice along with advice from the physician team. Risks and benefits of both the treatment 
options will be explained to the patient. If mitral valve repair is planned in these patients, they 
will be recruited to this study. If mitral valve replacement is planned, they will not be recruited 
to this study. If mitral valve repair is planned, but intra-procedurally the physician decides that 
mitral valve replacement is more apt, they will continue in the study. If mitral valve replacement 
is planned, but intra-procedurally the physician decides that mitral valve repair is more apt, they 
will continue in the study.
6.0
STRATEGIES FOR RECRUITMENT
 Trial recruitment will be handled by the clinical research unit of the division of 
cardiothoracic surgery at Emory University. Patients will be referred to this trial from 
cardiology groups within Emory University, and from external cardiologists that do not 
have any affiliation with Emory University. 
7.0
STUDY DESIGN
7.1 Schematic of study design
7.2 Overview of study design
This is an observational, prospective, non-randomized, clinical study to investigate the 
mechanistic basis for failure of undersizing mitral annuloplasty (UMA) and the efficacy of adding 
papillary muscle approximation (PMA) as an additional technique to UMA to improve its 
outcome.
Screening: Patients with FMR will be identified in cardiology and cardiothoracic surgery clinics at 
Emory Hospital, Emory St. Joseph’s Hospital and Emory Midtown, and outside referral centers 
that refer patients to the cardiac surgery program at Emory. Existing patient medical records, 
including their imaging reports, will be used to identify patients with FMR. Through the duration 

13
of this study, we will actively inform and educate our internal and external referral cardiology 
groups about this study, so they can refer patients to our trial. Patient medical records and 
imaging examinations will be used to screen for patients. Coronary angiograms that are less than 
6 months old will be used to assess the cardiomyopathic process. 
Informed consent: Patients that successfully clear the screening process will be approached, and 
provided a thorough explanation of the study purpose, procedures, risk/benefits, alternatives 
and follow-up schedule.  If patient volunteers to participate in the study, he/she will be asked to 
sign one copy of an informed consent which will be copied. The original will be included in the 
study record, a copy will be given to the patient, and a copy scanned and uploaded to EeMR by 
OCR.  In some cases, it is possible that some patients may undergo all the standard of care 
examinations before being able to be consented for the study. In such case, the patients will be 
consented prior to surgery, explaining to them that the study team will use their medical records 
and imaging information conducted prior to the consent in this study. 
Release of medical information form: The patient will also sign the release of medical information 
form or equivalent that authorizes release of medical records, to the study investigators and 
sponsors.
Study recruitment: All consented patients will undergo the following standard-of-care 
procedures to determine their eligibility to be recruited to this study.  The study team will 
generate a unique identification code that will identify the patient throughout the course of the 
study.
Following studies will be performed as standard of care procedures for patients receiving mitral 
valve repair, whether part of this study or not:

Functional status assessment

Transthoracic echocardiogram (if >6 months)

Transesophageal echocardiogram (may use the baseline TEE in OR)

Coronary angiogram (if >6 months)

Medical history

New York Heart Association Class

Angina Class – Canadian Cardiovascular Society Classification

Medications

Physical examination

Quality of life (study purposes only)

Laboratory assessment (study purposes only)

Cardiac MRI with gadolinium enhancement

14
Inclusion/Exclusion criteria: 
Inclusion criteria:
-
Mitral regurgitation of moderate or greater severity, as defined by the guidelines of 
the American society of echocardiography (via a transthoracic echo).
-
Cardiomyopathy of ischemic or non-ischemic origins, with or without the need for 
coronary revascularization.
-
Concomitant right sided valve repair or replacement (i.e. patients requiring 
concomitant tricuspid procedures). 
-
Age ≥ 18 years
-
Able to sign informed consent and release of medical information forms
Exclusion criteria
-
Any evidence of structural (chordal or leaflet) mitral lesions.
-
Prior mitral valve repair
-
Contraindication for cardiopulmonary bypass
-
Clinical signs of cardiogenic shock at the time of randomization
-
ST segment elevation myocardial infarction within 14 days prior to inclusion in this 
study.
-
Congenital heart disease (except PFO or ASD)
-
Chronic renal insufficiency defined by Creatinine ≥ 3.0 or chronic renal replacement 
therapy, who are contraindicated for cardiac surgery
-
Recent history of psychiatric disease that is likely to impair compliance with the 
study protocol, in the judgement of the investigator
-
Pregnancy at the time of randomization
Patients will be recruited to two registries, with the procedures described as follows:
Registry # 1: Prospectively Identified Patients that will Receive Surgery after Recruitment and 
Consented to Participate in the Study
Subjects are screened based upon medical records, external echo examinations, echo exams 
performed in the Emory cardiology clinics or cath labs, inclusion and exclusion criteria. Screened 
patients are consented and request for release of medical information is signed. Consented 
patients undergo battery of baseline tests that are standard of care, including transthoracic echo, 
transesophageal echo, and cardiac MRI. If some patients have already completed baseline tests 
as part of their standard of care, and are identified after these are completed, we will consent 
them at this stage. Patients undergo surgery, with pre-operative echo and closed chest echo. 
Blood draws and echocardiography will be performed at discharge and 30-days.  Patients return 
for visits at 6 months and 1 year to undergo repeat of tests. Patients exit study after the 1st year. 

15
If extended follow-up is determined to be necessary, patients will be re-consented at the 1-year 
visit.
Registry # 2: Retrospectively identified patients, who already underwent the standard of care 
surgery, and were identified after the procedure is completed, and are suitable for recruitment 
to the study for their post-operative research
Rationale: The decision to perform mitral valve surgery could be made during the surgery by the 
surgeon, and these patients would be suitable for this study, but would not be consented prior 
to their surgery. Thus, in this registry, we will identify such patients for recruitment into this 
study, as their first research point isn’t until 6 months after their surgery.
Charts will be screened for patients who underwent surgery for the lesion of interest at Emory, 
who would otherwise be eligible for this study but were not recruited as it was not known if they 
will need mitral valve surgery. Patients who are still within 6 months (± 1 month) after the date 
of their surgery will be contacted via telephone, and the study objective will be explained, verbal 
consent will be obtained and the date to visit Emory will be provided. Written consent will be 
obtained at their 6 month visit, and steps 9 and 10 described in registry # 1 will be performed. 
Registry # 3: Retrospectively identified patients, who already underwent the standard of care 
surgery, and were identified after the procedure is completed, and are suitable for recruitment 
to the study for their post-operative research. 
Rationale: Historical review of patients between dates 1/1/2004 to present who have underwent 
mitral valve surgery who were not previously identified in the study. These patients have not 
been consented prior to their surgery. The purpose is to increase the study sample size in order 
to gain statistical power for outcome analysis.  
Medical charts will be screened for patients who underwent surgery between 1/1/2004 to 
present for the lesion of interest at Emory, who would otherwise be eligible for this study but 
were not recruited as it was not known if they will need mitral valve surgery or were not recruited 
as they may have received the surgery prior to study start date. 
Study assignment: 140 patients will be recruited in total, 1) n=125 to undersizing mitral 
annuloplasty (UMA) and 2) n=15 to undersizing mitral annuloplasty with papillary muscle 
approximation (UMA+PMA). Selection will be in a non-randomized manner. Under no 
circumstances will more than the proposed number of patients be recruited to either groups, 
without prior approval from the institutional IRB and the study sponsor.

16
Surgical procedures:
Intra-operative echo 1: On the day of the surgery, after the patients are sedated, intubated and 
anesthetized, the cardiac anesthesiologist will perform a standard of care transesophageal 
echocardiogram. 
Surgical procedures: 
Undersizing mitral annuloplasty (Figure A): Patients undergoing this procedure will receive a 
commercially available annuloplasty ring of the surgeon’s choice. Sutures are placed around the 
mitral annulus, and the metallic ring is then implanted onto the mitral annulus to reduce it in 
size. 
Undersizing mitral annuloplasty with papillary muscle approximation (Figure B): Patients 
receiving this procedure will undergo undersizing mitral annuloplasty in a manner that is identical 
to the procedure outlined above. In addition to the ring implantation, one or two 4-0 pledgeted 
sutures are used to draw the two papillary muscle tips together to reduce the IPMS. 
After the procedure is complete, the patients are revived from cardiopulmonary bypass and 
hemodynamic stability is established. 
Figure A: Undersizing mitral annuloplasty
Figure B: Papillary muscle approximation
Post-chest closure echo: Just prior to moving the patient out of the operating room, a repeat 
intra-operative standard-of-care echocardiogram will be performed to assess the valve function. 
After both procedures, the patients are revived from surgery and their post-operative care will 
follow established and standard of care protocols.  
Follow-up time points and examinations: 
Discharge: Following examinations will be performed before discharge:

Transthoracic echocardiography

17

Blood draw
30-day (+/- 7 days): Following examinations will be performed at 30-days :

Blood draw

Transthoracic echocardiography
6 months post-surgery (+/- 30 days): Following examinations will be performed at discharge at 6 
months post-surgery

Transthoracic echocardiography

Blood draw 

Quality of life questionnaire

HF questionnaire

6 minute walk test
12 months post-surgery (+/- 90 days): Following examinations will be performed at discharge at 
6 months post-surgery

Transthoracic echocardiography

Cardiac MRI with contrast or transesophageal echo (whichever is possible)

Blood draw

QoL questionnaire

Heart failure questionnaire

6MWT
Computational biomechanical modeling: Echocardiographic images, immediately after 
acquisition will be transferred to the core database established by the PI’s laboratory. These 
images obtained from the patients at the different timepoints will be used for computational 
biomechanical modeling. The 3D echocardiographic images will be segmented and a 
mathematical mesh will be developed. Idealized material properties will be assigned to the mesh 
geometry, and the strain and stress distribution on the leaflets will be quantified under different 
loading conditions.
8.0
TIMEFRAME OF MEASUREMENTS AND DATA COLLECTION
TTE
TEE
MRI
QOLq
HFq
6MWT
Blood
Screening
x
Pre-op
x
X*
X*
0
0
0
0
Intra-op
x
Chest closure
x
Discharge
x
0
30 days
x
0

18
6 months
0
0
0
0
0
12 months
0
0*
0*
0
0
0
0
x: indicates current standard of care 
0: indicates non-standard of care, paid by the study
*: indicates that both procedures could be performed, or only one of them, depending on what is 
practically possible and what the patient agrees to undergo.
TTE: trans-thoracic echo
TEE: trans-esophageal echo
MRI: magnetic resonance imaging
QOLq: quality of life questionnaire
HFq: heart failure questionnaire
6MWT: 6-minute walk test
Blood: blood collection for laboratory studies
9.0    DEFINITIONS AND MEASUREMENT OF ENDPOINTS
Primary Endpoints:
The primary endpoint of this study is to investigate if pre-operative 
inter-papillary muscle separation (diastolic, systolic and diastolic-
systolic) correlates with FMR severity at 12 months after surgery with 
UMA and UMA+PMA.
Secondary Endpoints:
Survival
All-cause mortality at discharge, 6 months and 1 year
Functional Status and Hospitalizations

MACE 
      MACE is defined as a non-weighted composite score comprised 
of the following:
-
Death
-
Stroke
-
Worsening heart failure (+1 NYHA class)
-
CHF hospitalization
-
Mitral valve re-intervention

NYHA classification 
      Functional status will be assessed by the NYHA classification 
scale. (Appendix 1)

6-minute walk test
Functional status will also be measured by a 6-minute walk test, 
which assesses the distance walked (in feet) during the pre-
specified time period. The test will be administered by a trained 
study coordinator. (Appendix 2)

Readmission rates

19
Readmission rate will be calculated for any cause within the first 
30 days and for all cause, cardiovascular and heart failure after 
30 days following surgery. Classification of readmission as heart 
failure related requires at least 2 out of the following signs and 
symptoms of acute decompensated heart failure:
- Dyspnea felt related to HF
- Treatment with intravenous diuretic, vasodilator or 
inotropic therapy
- X ray evidence of pulmonary edema or pulmonary vascular 
congestion
- Rales on physical exam
- PCWP or LVEDP > 18mm Hg
      All readmissions will be classified by the investigator and 
adjudicated by the event adjudication committee.  
Physiologic

Echocardiographic parameters
Presence and severity of mitral regurgitation will be assessed by 
measuring the effective regurgitant orifice area (EROA) by both 
the proximal isovelocity surface area and the quantitative flow 
methods. If it is not possible to assess MR using these techniques, 
MR will be assessed by tracing the jet area and normalizing by 
the left atrial area.
Mitral valve apparatus and quantification of valve area will be 
assessed by evaluating annular shape and motion, tethering 
angle and tenting area, papillary muscle position and separation, 
and calculation of mean trans-mitral stenotic gradient by mitral 
inflow continuous wave Doppler.
LV size, geometry and function will be assessed by the following 
measures: LV dimensions, ejection fraction (biplane Simpson’s 
rule), LV end-systolic volume index using the biplane volumetric 
method, LV mass, LV sphericity, radial strain, and twist.
RV size and function will be assessed by the following measures: 
tricuspid annular plane systolic excursion (TAPSE), peak systolic 
velocity, diastolic E and A velocity (by tissue doppler), and 
fractional area change.
Left atrial dimension and volume will be assessed.

20
Intracardiac pressures and hemodynamics, including pulmonary 
artery pressures and pulmonary capillary wedge pressure will be 
assessed by Doppler flow studies.
Regional Wall Motion (LV function and viability assessment) will 
be assessed at baseline and again at one year following surgery.
Inter-papillary muscle separation (IPMS) is measured as the 
distance between the centers of the antero-lateral papillary 
muscle and postero-medial papillary muscle in a short axis echo 
plane. IPMS will be measured at three locations: papillary muscle 
tips, mid-body and base. IPMS will be measured in each frame of 
the cine loop, optimized to obtain at least 20 frames per heart 
beat. IPMS is reported in diastole, systole and differences 
between diastole and systole. 

Cardiac MRI parameters
Late-Gadolinium enhanced cardiac MRI will be performed on all 
patients pre-operatively. Standard protocols will be used to 
obtain 2 and 4 chamber gated images of cardiac chambers. 
Presence and severity of mitral regurgitation will be measured as 
(total stroke volume (EDV-ESV)) – (aortic forward ejection 
(measured using flow encoded MRI imaging at the aortic valve 
annulus)). Measurements will be obtained using flow encoded 
MRI at the mitral annular plane as well.
LV size, geometry and function will be assessed by the following 
measures: LV dimensions, ejection fraction (segmenting LV from 
short axis and rotated long axis images), LV end-systolic volume 
index using the biplane volumetric method, LV mass, LV 
sphericity, strain, and twist.
Regional Wall Motion (LV function and viability assessment) will 
be assessed at baseline and again at one year following surgery.
Inter-papillary muscle separation (IPMS) is measured as the 
distance between the centers of the antero-lateral papillary 
muscle and postero-medial papillary muscle in a short axis echo 
plane. IPMS will be measured at three locations: papillary muscle 
tips, mid-body and base. IPMS will be measured in each frame of 
the cine loop, optimized to obtain at least 20 frames per heart 
beat. IPMS is reported in diastole, systole and differences 
between diastole and systole. 

21
Scar burden and localization will be measured using lade Gd 
enhancement in the myocardium, measured using Otsu’s 
method.

Quality of life questionnaires
The change in quality of life (QOL) from baseline will be 
measured, using the disease specific Minnesota Living with Heart 
Failure (MLHF) score, Duke Activity Status Index Questionnaire 
and EuroQol 5-D measures of health state preference from the 
individual and societal perspective. The Minnesota Living with 
Heart Failure Questionnaire is a disease specific instrument that 
measures the perception of the physical, psychological and social 
effects of heart failure (HF) and HF treatment on the patient. The 
Duke Activity Status Index measures a patient’s functional 
capacity.  It can be used to get a rough estimate of a patient’s 
peak oxygen uptake. The EuroQoL 5-D is a standardized 
instrument for measuring health-related quality of life. This 
questionnaire provides a simple descriptive profile that consists 
of 5 dimensions. The 5 domains are anxiety/depression, 
pain/discomfort, usual activities, self-care, and mobility. The 
instrument also has a self-assessment of health status. 
(Appendix 3).

Laboratory Tests
Blood collection will be performed using standard phlebotomy 
techniques at the time of the patients visit ±7 days of the 
targeted date. The study nurse drawing the blood will label the 
tube with the patient’s specific code.   The blood is then 
centrifuged to separate plasma and serum, and the plasma and 
serum are snap frozen. The frozen sample is then shipped to the 
core laboratory designated by the PI. The core laboratory will 
record every sample received from the study using an electronic 
tracking system, and the sample will be stored at -80C. When 
adequate number of samples (60-80) are acquired, multiple 
biomarker arrays will be run to measure the quantity of the 
biomarkers in the sample. Some examples of biomarkers include, 
Brain 
natriuretic 
peptide 
(BNP), 
MMPs, 
TIMPs 
and 
catecholamine’s etc. Samples remaining after all the tests are 
performed will be banked. 

22
10.0 DATA MANAGEMENT
A secure redcap database (www.redcap.emory.edu)  will be used to maintain enrollment records 
and patient information. Study personnel requiring access will have their own login and 
password. Access to clinical study information will be based on individual roles and 
responsibilities. The application provides hierarchical user permission for data entry, viewing and 
reporting options. Imaging data will be acquired and viewable to investigators on hospital 
application.   
Confidentiality of patient data: By removing the patient information and blinding the datasets, 
the risk of loss of patient data confidentiality is reduced. Through the entire study, secure 
networks and databases will be used to manage the data, reducing the risk of any confidentiality 
breaches. However, there is always a risk of cyber-attacks that may compromise confidential 
data, and if this study is impacted by such a cyber-attack, the patients and the sponsor will be 
intimated within 10 days of its discovery.
Quality assurance: Quality control of all data will occur automatically, based upon the rules 
described for each field in the software. Whenever a patient is registered into the system, and a 
specific field is not entered, the software will prompt for a descriptive reason for not entering 
the data and the principal investigator will receive a form describing the instance. The 
investigative team will then explore the event appropriately, and make a note of the reasons or 
rectify accordingly. 
Monitoring: The research study coordinator will perform a data audit at 6 month intervals and 
present the report to the principal investigator. Source files obtained from the patient records 
will be matched against the data entered into the study database. A minimum of patient last 
name, first name, date of birth, hospital accession number, sex, informed consent, eligibility 
criteria, date of enrollment, serious and protocol defined adverse events, mortality, heart failure 
class, 6 minute walk test and QoL questionnaire will be verified. These data will be 100% source 
verified. All other data collected will be monitored for data completeness and accuracy.
Regulatory audit: A regulatory audit will be performed at time intervals that the IRB deems 
necessary for this study protocol.   The Principal Investigator and coordinators will be available 
as necessary.  
11.0 ANALYSIS PLAN
General design issues: This is an observational, prospective, non-randomized, single center, 
multiple phase study. Enrolled patients will have clinically significant FMR with either ischemic or 
non-ischemic cardiomyopathies. 50 patients are recruited to phase 1 (all 50 receiving undersizing 
mitral annuloplasty), and 90 patients to phase 2 (75 receiving undersizing mitral annuloplasty and 
15 receiving undersizing mitral annuloplasty and papillary muscle approximation). In patients 

23
receiving undersizing mitral annuloplasty, the same rigid annuloplasty ring will be used as 
consistently as possible, and up to two sizes of downsizing will be performed as consistently as 
possible. In some patients recruited to the study, the surgeon may decide to switch to mitral 
valve replacement, or may perform a repair and deem it to be a failure and then switch to mitral 
valve replacement. In either case, the patient will continue to be part of the study, but with 
follow-up performed only at 12 months. 
Sample size estimation and statistical analysis plan: The primary objective of this study is to 
determine the correlation between pre-operative inter-papillary muscle separation and the 6 
month and 12 month post-operative FMR grade after undersizing mitral annuloplasty. Pre-
operative inter-papillary muscle separation will be measured and is a continuous variable, while 
the recurrence of FMR will be deemed binary (1: if MR greater than or equal to 2+ severity 
observed at 12 months; 0: if MR less than or equal to 2+ severity observed at 12 months). An ROC 
curve analysis will be used to determine the inflection point of inter-papillary muscle separation 
at which FMR will recur at 12 months after annuloplasty. Sample sizes are based on previously 
published data, and on ensuring the ability to detect with high probability, a clinically meaningful 
presumed benefit for patients undergoing mitral valve repair. 
Recruitment to the papillary muscle approximation arm is not based on power analysis as it is 
only a pilot study.
12.0
ADVERSE EVENT REPORTING
Considering the observational nature of this study, and lack of any experimental procedures, 
adverse event reporting will be limited only to those events that may occur from the specific 
non-standard of care lab procedures that are performed at 6 and 12 month visits. Adverse 
events at these 6 and 12 month visits are described here.
11.1 Definitions
Adverse events: An adverse event is any undesirable clinical occurrence in a study patient, that is 
related to a study intervention that is non-standard of care. Any condition that was recorded as 
pre-existing or that is associated with standard of care procedures that the patient has consented 
to is not an AE unless there is a change in the nature, severity or degree of the condition.
Serious Adverse Events (SAE): Serious adverse events are defined by FDA regulation as any 
experience that results in a fatality or is life threatening; results in significant or persistent 
disability; requires or prolongs a hospitalization; or represents other significant hazards or 
potentially serious harm to research subjects or others, in the opinion of the investigators. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 

24
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias, or convulsions that do not result in inpatient hospitalization.
Unanticipated Serious Adverse Event: An unanticipated (unexpected) serious adverse event is any 
serious adverse event that is not protocol-defined or documented in the patient consent form. 
Expedited reporting is required for serious adverse events that are unexpected.
Event Recording: The following adverse events will be captured throughout the period of trial 
participation:

Protocol-defined (as described below)

Serious unanticipated events (serious “Other” adverse events)
Causality: The investigator will assess the relationship of an adverse event to the proposed non-
standard of care lab assessments and imaging studies. Causality will be defined as follows:
Probable
Adverse events that, after careful medical evaluation, are considered with a high degree of 
certainty to be related to the proposed follow-up imaging and blood draw studies that are non 
standard of care.
The following characteristics will apply:

A reasonable temporal relationship exists between the event and the procedure, and

The event is a known reaction to the non-standard of care procedure, which can be 
explained by an alternative etiology commonly occurring in the population/individual, or

The event is not a known reaction to the proposed non-standard of care procedure but 
cannot be reasonably explained by an alternative etiology.
Possible
Adverse events that, after careful medical evaluation, do not meet the criteria for a probable 
relationship to the non-standard of care procedure, but for which a connection cannot be ruled 
out with certainty. The following characteristics will apply:

The event occurs after non-standard of care procedure, and

The event is not a known reaction to non-standard of care procedure, but cannot be 
explained by a commonly occurring alternative etiology

25
Unlikely
Adverse events that, after careful medical evaluation, do not meet the criteria for a possible or 
probable relationship to non-standard of care procedure for which a connection is unlikely. The 
following characteristics will apply:

The event does not follow a reasonable temporal sequence from administration of the 
non-standard of care procedure, or

May have been produced by environmental factors, and there is no apparent pattern of 
response to the non-standard of care procedure.
Reporting of Serious Adverse Events
All investigators conducting the clinical study supported by the NHLBI must report both expected 
(protocol-defined) and unexpected serious adverse events. All serious adverse events must be 
reported as dictated by the specific IRB policy.  Deaths unrelated to study participation will be 
reported to the IRB at the time of continuing review. Deaths related to study participation and 
associated with the non-standard of care procedures will be promptly reported to the IRB. The 
PI will notify the NHLBI program officer of any unexpected serious adverse events via e-mail 
within 24 hours of receipt of the event. 
Specific Adverse Event Definitions
Bleeding: A bleeding event is defined by any one of the following:

Transfusion of > 10 unit’s RBC within the first 24 hours following surgery

Death due to hemorrhage

Re-operation for hemorrhage or tamponade
NOTE: Hemorrhagic stroke is considered a neurological event and not as a separate bleeding 
event.
Cardiac Arrhythmias: Any documented arrhythmia that results in clinical compromise 
(e.g.,hemodynamic compromise, oliguria, pre-syncope or syncope) that requires hospitalization 
or requires a physician visit or occurs during a hospital stay. Cardiac arrhythmias are classified as 
one of two types:

Sustained ventricular arrhythmia requiring defibrillation or cardioversion

Sustained supraventricular arrhythmia requiring drug treatment or cardioversion
Pericardial Fluid Collection: Intervention or percutaneous catheter drainage. This event will be 
subdivided into those with clinical signs of tamponade (e.g. increased central venous pressure 
and decreased cardiac output) and those without signs of tamponade.
Hepatic Dysfunction: An increase in any two of the following hepatic laboratory values (total 
bilirubin, aspartate aminotransferase/AST and alanine aminotransferase/ALT) to a level greater 
than three times the upper limit of normal for the hospital, (or if hepatic dysfunction is the 
primary cause of death).

26
Major Infection: A new clinical infection accompanied by pain, fever, drainage and/or 
leukocytosis that is treated by anti-microbial agents (non-prophylactic). A positive culture from 
the infected site or organ should be present unless strong clinical evidence indicates the need for 
treatment despite negative cultures. The general categories of infection are listed below:

Localized Infection: Infection localized to any organ system or region (e.g. mediastinitis) 
without evidence of systemic involvement (see sepsis definition), ascertained by standard 
clinical methods and either associated with evidence of bacterial, viral, fungal or 
protozoal infection, and/or requiring empirical treatment.

Endocarditis: Signs, symptoms, and laboratory findings consistent with endocarditis, 
including but not limited to fever ≥ 38.0o C, positive blood cultures, new regurgitant 
murmurs or heart failure, evidence of embolic events (e.g., focal neurologic impairment, 
glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and 
peripheral cutaneous or mucocutaneous lesions (e.g., petechiae, conjunctival or splinter 
hemorrhages, Janeway lesions, Osler's nodes, and Roth spots). Echocardiographic 
evidence of a new intra-cardiac vegetation with or without other signs and symptoms 
should be considered adequate evidence to support the diagnosis of endocarditis. TEE 
should be the modality of choice for diagnosis of prosthetic valve endocarditis.

Sepsis: Evidence of systemic involvement by infection, manifested by positive blood 
cultures and/or hypotension.
Myocardial Infarction
Myocardial infarction (MI) should be classified when there is evidence of myocardial necrosis in 
a clinical setting consistent with myocardial ischemia. Under these conditions, any one of the 
following criteria meets the diagnosis for myocardial infarction:

Myocardial Infarction
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one 
value above the 99th percentile of the upper reference limit (URL) together with evidence 
of myocardial ischemia with at least one of the following:
o
Symptoms of ischemia;
o
ECG changes indicative of new ischemia (new ST-T changes or new left bundle 
branch block [LBBB]);
o
Development of pathological Q waves in the ECG;
o
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality.

Peri-CABG Myocardial Infarction
For CABG in patients with normal baseline troponin values, elevations of cardiac 
biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial 
necrosis. By convention, increases in biomarkers > 5 x 99th percentile URL plus either new 
pathological Q waves or new LBBB, or angiographically documented new graft of native 
coronary artery occlusion, or imaging evidence of new loss of viable myocardium have 
been designated as defining CABG-related MI.

27

Peri-Percutaneous Intervention (PCI) Myocardial Infarction
For PCI in patients with normal baseline troponin values, elevations of cardiac biomarkers 
above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By 
convention, increases in biomarkers > 3 x 99th percentile URL have been designated as 
defining PCI-related MI. A subtype related to a documented stent thrombosis is 
recognized. Sudden unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by presumed new ST 
elevation or new LBBB, and/or evidence of fresh thrombus by coronary angiography 
and/or autopsy, with death occurring before blood samples obtained, or at a time before 
the expected appearance of cardiac biomarkers in blood will be classified as a mortality 
due to MI.
Neurologic Dysfunction
Any new, temporary, or permanent, focal or global neurological deficit ascertained by a standard 
neurological examination (administered by a neurologist or other qualified physician and 
documented with appropriate diagnostic tests and consultation note). The examining physician 
will distinguish between a transient ischemic attack (TIA), which is fully reversible within 24 hours 
(and without evidence of infarction), and a stroke, which lasts longer than 24 hours (or less than 
24 hours if there is evidence of infarction). The Modified Rankin Scale and the NIH Stroke Scale 
must be administered at time of event (within 72 hours following the event) and 90 days 
following the event to document the presence and severity of neurological deficits.
Each neurological event must be subcategorized as:

Transient Ischemic Attack defined as an acute event that resolves completely within 24 
hours with no imaging evidence of infarction.

Ischemic or Hemorrhagic Stroke (Cerebrovascular Accident), defined as an event that 
persists beyond 24 hours or less than 24 hours associated with infarction on an imaging 
study. Hemorrhagic conversion of an ischemic stroke should be classified as ischemic.

Toxic Metabolic Encephalopathy defined as a disorder of the brain function that arises 
from abnormal systemic metabolism or exogenous substances, altering awareness and/or 
consciousness, in which there is a non-focal neurological examination and a negative 
brain image.

Other
Renal Events
Two categories of renal events will be identified:

Renal Dysfunction
Abnormal kidney function defined by > 100% rise in serum creatinine (Cr) from
baseline, and Cr > 2.0

Renal Failure
New requirement for hemodialysis related to renal dysfunction. This definition
excludes aquapheresis for volume removal alone.

28
Respiratory Failure
Impairment of respiratory function requiring re-intubation, tracheostomy or the inability to 
discontinue ventilatory support within 48 hours post-surgical intervention. This excludes 
intubation for re-operation or temporary intubation for diagnostic or therapeutic procedures.
Right Heart Failure
Symptoms and signs of persistent right ventricular dysfunction [central venous pressure (CVP) > 
18 mmHg with a cardiac index <2.0 L/min/m2 in the absence of elevated left atrial/pulmonary 
capillary wedge pressure (> 18 mmHg), tamponade, ventricular arrhythmias or pneumothorax] 
requiring RVAD implantation, inhaled nitric oxide or inotropic therapy, for a duration of > 7 day.
Arterial Non-CNS Thromboembolism
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ system due to 
thromboembolism confirmed by one or more of the following:

Standard clinical and laboratory testing

Operative findings

Autopsy findings
This definition excludes neurological events.
Venous Thromboembolic Event
Evidence of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary embolism) by 
standard clinical and laboratory testing.
Wound Dehiscence
Disruption of the apposed surfaces of a surgical incision, excluding infectious etiology, and 
requiring surgical repair.
Other An event that causes clinically relevant changes in the patient’s health, or any event that 
is life-threatening, results in a fatality, results in permanent disability, requires hospitalization, or 
prolongs an existing hospital stay.

29
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Appendix 1: 
New York Heart Association (NYHA) Classification

33

34
Appendix 2: 
-
Six minute walk test (6MWT) recording form 

35

36

37
Appendix 3:
– Minnesota Living with Heart Failure Questionnaire
– EQ-5D Health Questionnaire
– Duke Activity Status Index Questionnaire

38

39

40

41