The Right Ventricular Pulmonary Circulation Continuum in Mitral Valve Disease
Conditions: Mitral Regurgitation, Pulmonary Hypertension
Sponsor: Imperial College London

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RIPCOM 1 
 
 
 
 
The right ventricular pulmonary circulation in mitral valve disease study 1 
 
 
 
Version 3 31/12/2016 
IRAS ID 199676 
 
 
 
 
MAIN SPONSOR: Imperial College London 
FUNDERS: Applications to Heart Research UK, Rosetrees Trust and British Heart Foundation pending 
STUDY COORDINATION CENTRE: Department of Cardiothoracic Surgery, Hammersmith Hospital 
NRES reference: 199676 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
Mr Prakash Punjabi 
31/12/16 
 
Dr Jonathan Afoke 
31/12/16 
 
Dr Simon Gibbs 
31/12/16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Management Group 
 
Chief Investigator: Mr Prakash Punjabi 
 
Co-investigators: Dr Jonathan Afoke, Dr Simon Gibbs, Dr Joseph Boyle 
 
Study Management: Department of Cardiothoracic Surgery, Hammersmith Hospital 
 
 
Study Coordination Centre 
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study Coordinator: Dr Jonathan Afoke 
E-mail:  jonathan.afoke@nhs.net 
Address: BN2/25 B Block, Hammersmith Hospital  
 
Tel: 02033132025  
 
 
 
 
 
 
Fax:  02033132334 
 
 
 
 
 
 
 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Jonathan Afoke who will direct the query to the 
appropriate person 
 
 
Sponsor 
 
Imperial College, London is the main research Sponsor for this study.  For further 
information regarding the sponsorship conditions, please contact the Head of Regulatory 
Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London & Imperial College Healthcare NHS Trust 
2nd Floor Medical School Building 
St Mary’s Hospital 
Praed Street 
London 
W2 1NY 
Tel: 0207 594 1872 
 
 
Funder 
 
Funding applications to Heart Research UK, Rosetrees Trust and British Heart Foundation 
are currently pending 
 
 
 
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This protocol describes the RIPCOM1 study and provides information about procedures for entering 
participants.  Every care was taken in its drafting, but corrections or amendments may be necessary. 
These will be circulated to investigators in the study.  Problems relating to this study should be 
referred, in the first instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the NHS Research Governance Framework for 
Health and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data 
Protection Act and other regulatory requirements as appropriate.  
 
Table of Contents 
1. 
INTRODUCTION 
6 
1.1 BACKGROUND 
6 
2.  STUDY OBJECTIVES 
8 
3.  STUDY DESIGN 
8 
3.1 STUDY OUTCOME MEASURES 
11 
4. 
PARTICIPANT ENTRY 
11 
4.1 PRE-REGISTRATION EVALUATIONS 
11 
4.2 INCLUSION CRITERIA 
11 
4.3 EXCLUSION CRITERIA 
12 
4.4 WITHDRAWAL CRITERIA 
12 
5. 
ADVERSE EVENTS 
12 
5.1 DEFINITIONS 
12 
5.3 REPORTING PROCEDURES 
12 
6. 
ASSESSMENT AND FOLLOW-UP 
13 
7. 
STATISTICS AND DATA ANALYSIS 
13 
8. 
REGULATORY ISSUES 
13 
8.1 ETHICS APPROVAL 
13 
8.2 CONSENT 
14 
8.3 CONFIDENTIALITY 
14 
8.4 INDEMNITY 
14 
8.5 SPONSOR 
14 
8.6 FUNDING 
14 
8.7 AUDITS AND INSPECTIONS 
14 
9. 
STUDY MANAGEMENT 
14 
11. 
PUBLICATION POLICY 
14 
12. 
REFERENCES 
14 
APPENDIX 1. 
SUMMARY OF INVESTIGATIONS, TREATMENT AND ASSESSMENTS 
16 
 
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GLOSSARY OF ABBREVIATIONS 
CPET 
Cardiopulmonary exercise testing 
cMRI 
Cardiac magnetic resonance imaging 
MR 
Mitral regurgitation 
MS 
Mitral stenosis 
NYHA 
New York Heart Association 
PFT 
Pulmonary function tests 
RHC 
Right heart catheterization 
QoL 
Quality of life  
TTE 
Transthoracic echocardiogram 
 
KEYWORDS 
Mitral regurgitation, mitral stenosis, mitral valve disease, pulmonary hypertension, 
cardiopulmonary exercise testing, quality of life 
 
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STUDY SUMMARY 
 
TITLE The right ventricular pulmonary circulation continuum in mitral valve 
disease study 1 
DESIGN Observational clinical study 
AIMS 
1. To correlate pre-operative exercise capacity on cardiopulmonary 
exercise testing with measurements of quality of life, cardiac 
function on transthoracic echocardiogram and cardiac magnetic 
resonance imaging and respiratory function on lung function tests. 
2. To define the histological changes in the left and right ventricular 
in severe mitral valve disease with or without pulmonary 
hypertension. 
3. To obtain pilot data in changes in exercise capacity early after 
surgery. 
4. To measure the accuracy of measurements of pulmonary artery 
pressures on transthoracic echocardiogram against the gold 
standard measurement of right heart catheterization in a 
prospective mitral valve disease cohort. 
OUTCOME 
MEASURES 
1. The accuracy of transthoracic echocardiogram compared to right 
heart catheterization in measuring pulmonary artery pressures in 
a prospective severe mitral valve disease cohort.  
2. Correlation between objective measurements of exercise capacity 
on cardiopulmonary exercise testing with quality of life and 
measurement 
of 
cardiac 
function 
on 
transthoracic 
echocardiogram and cardiac MRI in severe mitral valve disease. 
3. Histological changes in the left and right ventricle in severe mitral 
valve disease. 
4. Pilot data on changes in exercise capacity and quality of life and 
relationship to transthoracic echocardiogram, cardiac MRI and 
pulmonary function tests early after mitral valve surgery. 
POPULATION 50 patients 
ELIGIBILITY Patients undergoing cardiac surgery for severe mitral valve disease with 
or without concomitant coronary artery bypass grafting or tricuspid valve 
surgery or atrial fibrillation surgery.  
 
This will be an observational study since all patients will already be 
accepted for surgery under the current guidelines.  
DURATION 2 years (January 2017-March 2019) 
 
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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
Mitral regurgitation (MR) is one of the most prevalent valvular heart conditions in population 
based studies (1) and the hospital and outpatient patient population (2). The incidence of 
mitral valve surgery has been shown to be increasing in a European series (3) and the 
United States (4). One of the major driving forces has been an appreciation of the benefits of 
successful mitral valve repair over mitral valve replacement in terms of operative mortality, 
potential avoidance of lifelong anticoagulation and long term survival. This has resulted in an 
increase in mitral valve repair rates in Europe and the United States. 
 
The current indications for surgery for MR include symptomatic status; asymptomatic status 
with echocardiographic features such as impaired left ventricular function or increased left 
ventricular dimensions; new onset atrial fibrillation or pulmonary hypertension; asymptomatic 
status with a high likelihood of durable repair and low co-morbidity (5). The limitation in 
strength of the current evidence base is reflected by the class of evidence being expert 
opinion (level C) for all of the above indications with the sole exception of symptomatic 
patients, which is level B.  
 
The fulcrum point between asymptomatic status and symptomatic status at which patients 
would derive prognostic benefit and thus should be referred for surgery on prognostic 
grounds still remains unclear and controversial. Although elective mitral valve repair carries 
a low risk of mortality (4), it has been demonstrated that asymptomatic patients with severe 
degenerative MR can be safely followed up before becoming symptomatic or reaching cutoff 
values for left ventricular dimensions, size or pulmonary hypertension; with no significant 
difference with expected survival. As a result, prophylactic surgery for all patients with 
asymptomatic severe degenerative MR can not be recommended on prognostic grounds (6). 
 
At the other end of the clinical spectrum, the increased operative mortality and worse long 
term prognosis of symptomatic patients is well proven. Patients with New York Heart 
Association Class III or IV status have excessive operative mortality and significantly 
increased mortality at 10 years (7). Both this study and another (8) have demonstrated that 
preoperative ejection fraction is an independent predictor of long term survival. Although this 
evidence base does not support prophylactic surgery on asymptomatic patients, it does 
highlight the importance of avoiding the long term sequelae of MR in causing symptomatic 
status or left ventricular impairment. Hence attention has turned to objective markers or 
investigations independent of symptomatic status that may be subjectively assessed in the 
early phases; to help identify patients who would prognostically benefit from earlier surgical 
intervention. 
 
As a result of rheumatic fever being the most common etiology, mitral stenosis (MS) is the 
least common valvular lesion in the hospital population (2) and has a low prevalence rate in 
epidemiological studies (1) in industrialized countries. However, it still causes significant 
morbidity and mortality worldwide. The preferred treatment for severe mitral stenosis in 
those patients with favourable valvular anatomy is percutaneous mitral commissurotomy. In 
one single centre follow up, there was a low immediate risk of the procedure with 89% of 
patients obtaining good immediate results defined as a final mitral valve area greater than 
1.5cm2 without significant mitral regurgitation and a 20 year rate of good functional results of 
30.2% (9). 
 
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However, in those patients with unfavourable valvular anatomy; there are no randomised 
trials to guide the best timing of surgery. Survival benefit increases with more advanced 
symptoms, but surgical risk increases with pulmonary hypertension so it has been suggested 
to intervene when symptoms are more than mild, but before the development of pulmonary 
hypertension (10). An area of uncertainty exists in asymptomatic patients with severe MS or 
those with symptoms out of proportion with the severity of MS. Current guidelines suggest 
the use of stress echocardiography and intervention if the mean transmitral pressure 
gradient is greater than 15mmHg during exercise or peak pulmonary artery systolic pressure 
exceeds 60mmHg (11). However, this guidelines is based on level C evidence and there is 
no data comparing these parameters with objective measurements of exercise capacity and 
its relationship with operative risk or long term prognosis. 
 
In summary, severe mitral valve disease is a common valvular pathology that causes a 
significant burden of disease in the United Kingdom and worldwide. Current guidelines for 
timing of operative intervention are mostly based on expert opinion rather than randomised 
trials or studies. There is currently no proven prognostic benefit from surgery on 
asymptomatic patients. Patients with significant symptoms benefit from surgery, but have 
worse long term prognosis than the general population. It is difficult to assess early or mild 
symptoms and there is no significant evidence base objectively measuring exercise capacity 
and its correlation with quality of life and markers of cardiac or respiratory function before 
and after surgery. 
 
Pathophysiology of severe mitral valve disease 
In the initial compensated phase of MR, there is eccentric hypertrophy of the left ventricle 
and enlargement of the left atrium to accommodate volume overload. As a result of the 
increased capacitance there is a normal pulmonary vascular resistance and transpulmonary 
pressure gradient. In the final decompensated phase, there is heart failure characterized by 
increase in left ventricular dimensions, elevation of left sided filling pressures, increase in 
transpulmonary pressure gradient and decline in biventricular contractile function (12). This 
is associated with progressive histological changes to the pulmonary vasculature which 
range from medial hypertrophy and intimal proliferation in small muscular pulmonary arteries 
to progressive fibrous vascular occlusion and arterial dilatation and the end stage of 
haemosiderin deposition and necrotizing arteritis (13). This in turn affects the alveolar-
capillary unit and can increase impedance to gas transfer. From a clinical end point, this 
results in pulmonary hypertension and potentially reduced gas transfer factor.  
 
Right heart catheterisation (RHC) is regarded as the gold standard for establishing a 
diagnosis of pulmonary hypertension and allows invasive haemodynamic assessment. 
Transthoracic echocardiogram allows a non-invasive assessment of pulmonary pressures by 
calculating transtricuspid pressure gradient using the modified Bernoulli equation and adding 
right atrial pressure. However, this method is restricted by the limitations of acquiring a 
continuous wave signal and severe tricuspid regurgitation (14). One metaanalysis comparing 
the accuracy of echocardiography and RHC in 29 studies reported modest correlation 
between the two methods and that RHC remains the gold standard. Of the 29 studies, only 8 
evaluated cardiac disease, none evaluated a mitral disease cohort and the studies were 
subject to significant biases (15).  
 
Although pulmonary hypertension is an important risk factor and indication for surgery, there 
is currently no prospective comparison of measurements on transthoracic echocardiogram 
and RHC. In addition, the changes in the histology of the left and right ventricle and changes 
in pulmonary function have not been related to changes in pulmonary haemodynamics. 
 
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1.2 
RATIONALE FOR CURRENT STUDY 
To identify objective markers of exercise capacity, cardiac or respiratory function that will 
demonstrate the earliest point at which patients with severe mitral valve disease derive 
prognostic benefit from surgery. 
 
Patients with severe mitral valve disease and symptoms although gaining benefit from 
surgery have a worse long term prognosis and quality of life than the general population. 
There is currently no proven prognostic benefit for surgery on asymptomatic patients. 
Therefore there will be an objective point between the two ends of the disease spectrum at 
which patients will derive early prognostic benefit and enable a return to a normal life 
expectancy and quality of life. 
 
 
2.  STUDY OBJECTIVES 
 
Primary objective 
Correlation between objective measurements of exercise capacity on cardiopulmonary 
exercise testing with quality of life and measurement of cardiac function on transthoracic 
echocardiogram and cardiac MRI in severe mitral valve disease. 
 
Secondary objective 
1. The accuracy of transthoracic echocardiogram compared to right heart catheterization in 
measuring pulmonary artery pressures in a prospective severe mitral valve disease cohort.  
 
2. Histological changes in the left and right ventricle in severe mitral valve disease. 
 
 
3.  STUDY DESIGN 
 
Observational clinical study with tissue collection lasting two years (October 2016-October 
2018). According to the validated returns to the national audit for the Society For 
Cardiothoracic Surgery, Mr Punjabi operates on 40-50 patients a year who meet the 
inclusion criteria.  
 
This will be an observational study since all patients will already be accepted for surgery 
under the current guidelines. For the purposes of comparison, the cohort will be stratified 
into three groups: asymptomatic patients with preserved left ventricular function (defined as 
ejection fraction greater than 60%), symptomatic patients with preserved left ventricular 
function and patients with impaired left ventricular function (defined as ejection fraction less 
than 60%). 
 
 
Recruitment and consent process 
Patients will be identified at their initial surgical consultation or from the surgical waiting list 
(mitral valve surgery with or without coronary artery bypass grafting or tricuspid valve 
surgery or atrial fibrillation surgery) by the direct care team.  
 
For patients identified at initial surgical consultation, the Patient Information Sheet and 
Patient Invitation Letter will be given to the patient and the patient given an opportunity to 
ask questions and give consent before the investigations are arranged.  
 
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For patients identified from the surgical waiting list, the patient will be contacted by phone 
and Patient Information Sheet and Patient Invitation Letter sent to the patient. After 
confirming initial interest, the investigations will be arranged. The patient will be given the 
opportunity to ask further questions and give consent at the initial study visit.  
 
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Pre-operative investigations 
The additional pre-operative investigations will be co-ordinated with the preassessment team 
to minimize changes to the normal patient pathway. If patients have already had pre-
operative investigations required as part of the study protocol prior to enrolment, the data 
from these investigations may be used for the purposes of research.  
 
Clinical history and examination- Patients will be reviewed at initial surgical consultation, 6-8 
weeks after surgery and one year after surgery.  
 
Right heart catheterisation- It is the usual gold standard practice at our institution for patients 
to have a right heart catheterisation before being referred for surgery. The few patients who 
have not had one before surgery will be referred to the Department of Pulmonary 
Hypertension at Hammersmith Hospital for this test to be performed.  
 
Cardiac MRI- patients will have a T1 weighted non-contrast cardiac MRI. One strength of 
cardiac MRI over transthoracic echocardiogram is the ability to provide objective 
measurements of right heart function. Parameters measured will be left and right ventricular 
ejection fraction, cardiac chamber dimensions, patterns of myocardial fibrosis. 
 
Cardiopulmonary exercise testing (CPET)- CPET is a quantitative and validated method of 
assessing cardiorespiratory function and exercise capacity with commonly measured 
variables including maximal oxygen consumption (VO2 max) and the clearance of carbon 
dioxide during exercise (Ve/VCO2). The patient’s gaseous exchange is monitored during a 3 
minute rest period, a three minute “rolling basal” period when they perform exercise on a 
bicycle with no load; and subsequently during the exercise phase when the work load 
increases at a rate of 30 Watts per minute. The exercise continues until the patient has to 
stop or predicted maximum heart rate is achieved. 
 
Pulmonary function tests- Patients will have routine spirometry tests and also assessment of 
transfer factor (DLCO and KCO). It is normal practice for patients to have spirometry at 
preassessment clinic and those with abnormal spirometry or a significant history of 
respiratory disease to have transfer factor measured. 
 
Transthoracic echocardiogram- It is normal practice for patients to have a transthoracic 
echocardiogram at preassessment clinic to assess biventricular function, dimensions and 
cardiac structural disease. 
 
Quality of life questionnaire- At the preassessment clinic, patients will be asked to fill out a 
validated quality of life questionnaire (SF-36 health survey). 
 
Intra-operative specimens 
Heart muscle biopsies will be obtained at the time of clinically indicated heart surgery. Two 
small heart samples approximately 0.8 grams each or the size of a cooked rice grain will be 
taken from the left and right ventricle. The specimens will be preserved in formalin and 
processed and analysed at the Department of Pathology by a pathologist with a specialist 
interest in cardiac pathology. The samples will be fixed and analysed with haematoxylin and 
eosin for structure, Elastin van Gieson stain for elastin, Martius, Scarlet and Blue stain for 
fibrin, Picrosirius red stain for collagen, Perls’ Prussian blue stain for iron, Periodic acid-
Schiff stain for polysaccharides, Desmin stain for smooth muscle, CD68 for monocytes, 
CD45 for leucocytes, smooth muscle actin for smooth muscle and CD31 for vascular 
endothelium. 
 
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By correlating the results of the histological analysis with clinical markers such as left and 
right ventricle function and pulmonary hypertension, and the cardiac imaging on 
transthoracic echocardiogram and cardiac MRI this will enable us to grade microscopic 
changes in the myocardium throughout the spectrum of mitral valve disease from 
asymptomatic to symptomatic.  
 
In addition, the results of the histological analysis will be the basis of further collaborative 
work with the Myocardial Function group at the Imperial Centre for Translational and 
Experimental Medicine. 
 
Post-operative follow up 
6-8 weeks- it is normal practice for patients to be reviewed at 6-8 weeks after surgery in 
clinic with clinical history and examination. Patients will be asked to fill in a quality of life 
questionnaire at this time. 
 
6-9 months- Patients will have a repeat transthoracic echocardiogram, cardiac MRI, CPET, 
pulmonary function tests. A quality of life questionnaire will be mailed to patients with a self-
addressed envelope. 
 
12 months- it is normal practice for patients to be followed up at 12 months after surgery with 
clinical history and examination. 
 
Review of investigations 
All pre and post-operative investigations will be reviewed on an individual basis with the 
Chief Investigators and if there are any abnormalities, these and any additional 
investigations will be discussed with the patient. The patient’s GP and referring cardiologist 
will be informed of any progress with the permission of the patient.  
 
3.1 
STUDY OUTCOME MEASURES 
1. The 
accuracy 
of 
transthoracic 
echocardiogram 
compared 
to 
right 
heart 
catheterization in measuring pulmonary artery pressures in a prospective severe 
mitral valve disease cohort.  
2. Correlation 
between 
objective 
measurements 
of 
exercise 
capacity 
on 
cardiopulmonary exercise testing with quality of life and measurement of cardiac 
function on transthoracic echocardiogram and cardiac MRI in severe mitral valve 
disease. 
3. Histological changes in the left and right ventricle in severe mitral valve disease. 
4. Pilot data on changes in exercise capacity and quality of life and relationship to 
transthoracic echocardiogram, cardiac MRI and pulmonary function tests early after 
mitral valve surgery. 
 
 
 
4. 
PARTICIPANT ENTRY  
 
4.1 
PRE-REGISTRATION EVALUATIONS  
Transthoracic echocardiogram showing severe mitral valve disease meeting the current 
indications for open heart surgery.   
 
4.2 
INCLUSION CRITERIA 
Patients undergoing cardiac surgery for severe mitral valve disease with or without 
concomitant coronary artery bypass grafting or tricuspid valve surgery or atrial fibrillation 
surgery.  
 
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4.3 
EXCLUSION CRITERIA 
Age <18 years or >85 years, pregnancy, critical preoperative status with multi-organ 
dysfunction, emergency cardiac surgical intervention, unable to give informed consent or 
unwilling to participate in research, patients with definite contraindication for MRI would be 
excluded from the cardiac MRI element of the study, patients unable to take adequate 
biopsies due to technical difficulties would be excluded from the myocardial biopsy element 
of the study, other significant valve lesions requiring concomitant surgery. 
 
 
4.4 
WITHDRAWAL CRITERIA 
Patients who develop a life expectancy limiting medical condition subsequent to enrolment 
will be withdrawn from the study. Patients will have the right to withdraw from the study at 
any time. Patients who lose capacity will be withdrawn from the study but data and tissue 
already collected with consent will be retained and used in the study with no further data or 
tissue collected.  
 
5. 
ADVERSE EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
 
• 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one 
of the other outcomes listed in the definition above, should also be considered serious. 
 
5.3 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1 Non serious AEs 
All such events, whether expected or not, should be recorded.   
 
5.3.2 Serious AEs 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  
However, relapse and death due to mitral valve disease, and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the <name of REC> where in the opinion of the Chief 
Investigator, the event was: 
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• 
‘related’, ie resulted from the administration of any of the research procedures; 
and 
• 
‘unexpected’, ie an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
Fax: 02033132334, attention Dr Jonathan Afoke 
Please send SAE forms to: Bn2/25 B Block, Hammersmith Hospital 
Tel: 02033132025 (Mon to Fri 09.00 – 17.00) 
 
6. 
ASSESSMENT AND FOLLOW-UP  
 
Patients will be followed up at 6-8 weeks after surgery in clinic as normal practice and will be 
asked to fill in a quality of life questionnaire at this time. 
 
It is normal practice for patients to be followed up at one year after surgery with a repeat 
transthoracic echocardiogram prior to this appointment. Before this appointment, they will 
have an additional repeat cardiac MRI, CPET, pulmonary function tests and quality of life 
questionnaire at 6-9 months after surgery. 
 
 
7. 
STATISTICS AND DATA ANALYSIS 
 
The myocardial specimens will be preserved in formalin and transferred to the pathology 
laboratory at Hammersmith Hospital for processing and histological analysis. Spare sections 
will be fixed in Polysine slides and stored in the pathology laboratory at Hammersmith 
Hospital. 
 
All data will be expressed as mean with standard error. Statistical comparison will be 
performed by one-way ANOVA followed by unpaired t-test as appropriate. Results will be 
considered statistically significant if P<0.05. 
 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study at Imperial College.   
 
 
8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
The Chief Investigator has obtained approval from the xxx Research Ethics Committee and 
the HRA.  The study will be conducted in accordance with the recommendations for 
physicians involved in research on human subjects adopted by the 18th World Medical 
Assembly, Helsinki 1964 and later revisions. 
 
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8.2 
CONSENT  
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration.  Signed 
participant consent should be obtained.  The right of the participant to refuse to participate 
without giving reasons must be respected.  After the participant has entered the study the 
clinician remains free to give alternative treatment to that specified in the protocol at any 
stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should 
be recorded.  In these cases the participants remain within the study for the purposes of 
follow-up and data analysis.  All participants are free to withdraw at any time from the 
protocol treatment without giving reasons and without prejudicing further treatment. 
 
8.3 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. All patients will be anonymised by assigning 
a study number. The code to this and study data will be kept on Imperial College NHS Trust 
computers. Only anonymised data will be analysed by the statisticians at Imperial College, 
London. 
 
8.4 
INDEMNITY 
Imperial College, London holds negligent harm and non-negligent harm insurance policies 
which apply to this study. 
 
8.5 
SPONSOR 
Imperial College, London will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
This study is pending funding applications to Heart Research UK, Rosetrees Trust and 
British Heart Foundation. 
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College London under their 
remit as sponsor and other regulatory bodies to ensure adherence to GCP and the NHS 
Research Governance Framework for Health and Social Care (2nd edition).  
 
 
9. 
STUDY MANAGEMENT 
 
The day-to-day management of the study will be co-ordinated through Dr Jonathan Afoke 
and Mr Prakash Punjabi, Department of Cardiothoracic Surgery, Hammersmith Hospital.   
 
 
10. PUBLICATION POLICY 
 
Study data will be disseminated through academic presentations and publications. 
 
 
10. REFERENCES 
1. 
Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. 
Burden of valvular heart diseases: a population-based study. Lancet. 2006;368(9540):1005-
11. 
2. 
Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Barwolf C, Levang OW, et al. A 
prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey 
on Valvular Heart Disease. European heart journal. 2003;24(13):1231-43. 
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3. 
Siregar S, de Heer F, Groenwold RH, Versteegh MI, Bekkers JA, Brinkman ES, et al. 
Trends and outcomes of valve surgery: 16-year results of Netherlands Cardiac Surgery 
National Database. European journal of cardio-thoracic surgery : official journal of the 
European Association for Cardio-thoracic Surgery. 2014;46(3):386-97; discussion 97. 
4. 
Gammie JS, Sheng S, Griffith BP, Peterson ED, Rankin JS, O'Brien SM, et al. 
Trends in mitral valve surgery in the United States: results from the Society of Thoracic 
Surgeons 
Adult 
Cardiac 
Surgery 
Database. 
The 
Annals 
of 
thoracic 
surgery. 
2009;87(5):1431-7; discussion 7-9. 
5. 
Joint Task Force on the Management of Valvular Heart Disease of the European 
Society of C, European Association for Cardio-Thoracic S, Vahanian A, Alfieri O, Andreotti F, 
Antunes MJ, et al. Guidelines on the management of valvular heart disease (version 2012). 
European heart journal. 2012;33(19):2451-96. 
6. 
Rosenhek R, Rader F, Klaar U, Gabriel H, Krejc M, Kalbeck D, et al. Outcome of 
watchful waiting in asymptomatic severe mitral regurgitation. Circulation. 2006;113(18):2238-
44. 
7. 
Tribouilloy C, Grigioni F, Avierinos JF, Barbieri A, Rusinaru D, Szymanski C, et al. 
Survival implication of left ventricular end-systolic diameter in mitral regurgitation due to flail 
leaflets a long-term follow-up multicenter study. Journal of the American College of 
Cardiology. 2009;54(21):1961-8. 
8. 
Enriquez-Sarano M, Tajik AJ, Schaff HV, Orszulak TA, Bailey KR, Frye RL. 
Echocardiographic prediction of survival after surgical correction of organic mitral 
regurgitation. Circulation. 1994;90(2):830-7. 
9. 
Bouleti C, Iung B, Laouenan C, Himbert D, Brochet E, Messika-Zeitoun D, et al. Late 
results of percutaneous mitral commissurotomy up to 20 years: development and validation 
of a risk score predicting late functional results from a series of 912 patients. Circulation. 
2012;125(17):2119-27. 
10. 
Carabello BA. Modern management of mitral stenosis. Circulation. 2005;112(3):432-
7. 
11. 
Picano E, Pibarot P, Lancellotti P, Monin JL, Bonow RO. The emerging role of 
exercise testing and stress echocardiography in valvular heart disease. Journal of the 
American College of Cardiology. 2009;54(24):2251-60. 
12. 
Patel H, Desai M, Tuzcu EM, Griffin B, Kapadia S. Pulmonary hypertension in mitral 
regurgitation. Journal of the American Heart Association. 2014;3(4). 
13. 
Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a 
description of six grades of structural changes in the pulmonary arteries with special 
reference to congenital cardiac septal defects. Circulation. 1958;18(4 Part 1):533-47. 
14. 
Greiner S, Jud A, Aurich M, Hess A, Hilbel T, Hardt S, et al. Reliability of noninvasive 
assessment of systolic pulmonary artery pressure by Doppler echocardiography compared 
to right heart catheterization: analysis in a large patient population. Journal of the American 
Heart Association. 2014;3(4). 
15. 
Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocardiography for 
pulmonary hypertension: a systematic review and meta-analysis. Heart. 2011;97(8):612-22. 
 
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Appendix 1. Summary of investigations, treatment and assessments 
 
Exam 
 
Months after operation 
Pre-operative 
Operation 
2 
6-9 
12 
Clinical history/examination 
X 
 
X 
 
X 
Transthoracic echocardiogram 
X 
 
 
X 
 
Informed consent 
X 
 
 
 
 
Cardiac MRI 
X 
 
 
X 
 
Right heart catheterization 
X 
 
 
 
 
Cardiopulmonary exercise 
test/lung function tests 
X 
 
 
X 
 
Quality of life questionnaire 
X 
 
X 
X 
 
Intra-op myocardial biopsies 
 
X 
 
 
 
 
 
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