SCar Location and Acute Haemodynamic Response to MultiPoint Pacing in Patients With Ischemic Cardiomyopathy (SCAR MPP Study)
Phase: NA
Conditions: Heart Failure, Ischemic Cardiomyopathy
Sponsor: Oxford University Hospitals NHS Trust

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
Version/Date: 1.1 /6th April 2019 
IRAS Ref:  211326 
Ethics Ref: 16/SC/0662 
 
 
 
 
Page 1 of 27 
 
 
Study Title: SCar location and Acute haemodynamic Response to MultiPoint Pacing in patients with 
cardiomyopathy  
 
Internal Reference Number / Short title: SCAR MPP study 
Ethics Ref: 16/SC/0662 
 
Date and Version No: 06th April 2019, version 1.1 
 
Chief Investigator: 
Dr Tim R Betts, Consultant Cardiologist and Electrophysiologist 
Oxford University Hospitals NHS Foundation Trust 
Investigators:  
Dr Milena Leo, Clinical Research Fellow 
Oxford University Hospitals NHS Foundation Trust 
Dr Erica Dall’Armellina, BHF Intermediate Clinical Research Fellow and 
University Research Lecturer, AVIC Clinical CMR Lead, Honorary 
Consultant Cardiologist 
University of Oxford 
Sponsor:  
Oxford University Hospitals NHS Foundation Trust  
Funder: 
BRC Research Capacity Funding 
Chief Investigator Signature:   
 
Potential conflicts of interest to declare: none. 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 
 

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
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TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................................................... 4 
2. 
ABBREVIATIONS .......................................................................................................................................... 5 
3. 
KEY CONTACTS SECTION ............................................................................................................................. 6 
4. 
BACKGROUND AND RATIONALE ................................................................................................................. 7 
3.1 Research question and hypothesis ............................................................................................................... 9 
5. 
STUDY DESIGN ............................................................................................................................................ 9 
6. 
OBJECTIVES AND OUTCOME MEASURES .................................................................................................. 11 
7. 
STUDY RISKS AND BENEFITS ..................................................................................................................... 11 
7.1. 
Study risks ......................................................................................................................................... 11 
7.1.1 Cardiac MRI ............................................................................................................................................. 11 
7.1.2. CRT-D implant ......................................................................................................................................... 11 
7.1.3 Invasive acute haemodynamic measurements ....................................................................................... 13 
7.1.4 Electroanatomical mapping of the CS venous system ............................................................................ 13 
7.2. Study benefits ............................................................................................................................................ 13 
8. 
PARTICIPANT IDENTIFICATION ................................................................................................................. 14 
8.1. 
Study Participants ............................................................................................................................. 14 
8.2. 
Inclusion Criteria ............................................................................................................................... 14 
8.3. 
Exclusion Criteria .............................................................................................................................. 14 
9. 
STUDY PROCEDURES ................................................................................................................................ 14 
9.1. 
Recruitment ...................................................................................................................................... 15 
9.2. 
Baseline visit ..................................................................................................................................... 15 
9.2.1. 
Informed Consent ......................................................................................................................... 15 
9.2.2. 
Screening and Eligibility Assessment ............................................................................................ 15 
9.2.3. 
Cardiac MRI .................................................................................................................................. 16 
9.2.4. 
CRT-D implant procedure (including three dimensional mapping of the CS venous anatomy and 
invasive acute haemodynamic measurements) ........................................................................................... 17 
9.3. 
Pre-discharge review ........................................................................................................................ 18 
9.4. 
Discontinuation/Withdrawal of Participants from Study ................................................................. 18 
9.5. 
Definition of End of Study ................................................................................................................ 19 
10. 
INTERVENTIONS .................................................................................................................................... 19 
11. 
SAFETY REPORTING .............................................................................................................................. 19 

 
 
Subject: Research protocol 
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11.1. 
Definition of Serious Adverse Events ........................................................................................... 19 
11.2. 
Reporting Procedures for Serious Adverse Events ....................................................................... 19 
12. 
STATISTICS AND ANALYSIS .................................................................................................................... 20 
12.1. 
The Number of Participants ......................................................................................................... 20 
12.2. 
Description of Statistical Methods ............................................................................................... 20 
12.3. 
Analysis of Outcome Measures .................................................................................................... 20 
13. 
DATA MANAGEMENT ........................................................................................................................... 21 
13.1. 
Access to Data .............................................................................................................................. 21 
13.2. 
Data Recording and Record Keeping ............................................................................................ 21 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................................... 22 
14.1. 
Declaration of Helsinki.................................................................................................................. 22 
14.2. 
Guidelines for Good Clinical Practice ........................................................................................... 22 
14.3. 
Approvals ...................................................................................................................................... 22 
14.4. 
Reporting ...................................................................................................................................... 22 
14.5. 
Participant Confidentiality ............................................................................................................ 22 
14.6. 
Expenses and Benefits .................................................................................................................. 22 
14.7. 
Other ethical considerations ........................................................................................................ 23 
15. 
FINANCE AND INSURANCE ................................................................................................................... 23 
15.1. 
Funding ......................................................................................................................................... 23 
15.2. 
Insurance ...................................................................................................................................... 23 
16. 
PUBLICATION POLICY ............................................................................................................................ 23 
17. 
REFERENCES ......................................................................................................................................... 24 
18. 
APPENDIX A:  STUDY FLOW CHART ...................................................................................................... 25 
19. 
APPENDIX B:  SCHEDULE OF TIMING OF STUDY APPOINTMENTS AND STUDY PROCEDURES ............. 26 
20. 
APPENDIX C:  AMENDMENT HISTORY .................................................................................................. 27 
 
 
 

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
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1. SYNOPSIS 
 
Study Title 
SCar location and Acute haemodynamic Response to MultiPoint Pacing in 
patients with cardiomyopathy 
Internal ref. no. / short title 
Scar MPP study 
Study Design 
Pilot study 
Study Participants 
Patients with left ventricular myocardial scar and clinical indication to 
implant of a Cardiac Resynchronization Therapy- Defibrillator (CRT-D) 
device 
Planned Sample Size 
15 patients 
Planned Follow-up duration 
1 day 
Recruitment end date 
31st June 2020 
 
Objectives 
Outcome Measures 
Primary 
To assess whether the added benefit 
of multipoint pacing (MPP) over 
conventional single-site LV pacing is 
consistent in the peri-scar region 
compared to the remote 
myocardium 
- Acute haemodynamic response 
to MPP (percentage increase of 
LV-dP/dTmax produced by MPP 
over spontaneous ventricular 
activation) in the peri-scar region 
and in the remote myocardium   
- Percentage increase of LV dP/dT 
max produced by MPP over 
conventional single-site LV pacing 
in the peri-scar region and in the 
remote myocardium  
 
 
 
 
 
 

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
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2. ABBREVIATIONS 
 
AHR 
Acute Haemodynamic Response 
BiV 
Biventricular 
CRM 
Cardiac Rhythm Management 
CRT 
Cardiac Resynchronization Therapy 
CS  
Coronary sinus 
GP 
General practitioner 
LV 
Left ventricle/ ventricular 
MPP 
MultiPoint Pacing 
LV-dP/dT max 
Maximal (max) rate of rise of left ventricular pressure (LV-dP) over time (dT) 
MRI 
Magnetic Resonance Imaging 
NHS 
National Health System 
OUH 
Oxford University Hospitals  
QoL 
Quality of Life 
RV  
Right ventricle/ventricular 
SOP 
Standard Operating Procedure 
 
 
 
 

 
 
Subject: Research protocol 
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3. KEY CONTACTS SECTION 
 
Chief Investigator 
Dr Tim R Betts, Consultant Cardiologist and Electrophysiologist 
Department of Cardiology, Level 2, Blue Outpatient Area   
John Radcliffe Hospital  
Oxford University Hospitals NHS Foundation Trust  
Headley Way, Oxford OX3 9DU                                  
 
Tel: 01865 220256 Fax: 01865 221194 
 
E-mail: tim.betts@ouh.nhs.uk 
 
Leading fellow 
 
Dr Milena Leo, Clinical Research Fellow 
 
Clinical Research Fellows Office, Level 2, Blue Outpatient Area   
John Radcliffe Hospital 
Oxford University Hospitals NHS Foundation Trust,  
Headley Way Oxford OX3 9DU        
 
Tel 01865 220255 
 
e-mail: milena.leo@ouh.nhs.uk 
 
Sponsor 
Ms Heather House 
 
Research and Development Department, Joint Research Office 
Block 60, Churchill Hospital 
Oxford OX3 7LE 
 
Tel 01865 (5) 72970 
 
E-mail: ouh.sponsorship@nhs.net 
 
 
 
 

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
Version/Date: 1.1 /6th April 2019 
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Page 7 of 27 
 
 
4. BACKGROUND AND RATIONALE 
Many patients with cardiomyopathy and heart failure have an abnormality of the heart’s electrical system 
resulting in an uncoordinated (asynchronous) contraction pattern of the bottom chambers of the heart 
(electrical dissynchrony). This further reduces the pumping ability of a weakened heart muscle.  
Cardiac resynchronization therapy (CRT) is a widely accepted treatment option in these patients.  It works 
by sending tiny electrical impulses to the bottom chambers (ventricles) of the heart to make them beat 
together again in a more synchronised pattern. The heart’s ability to pump blood and oxygen to the body is 
so improved.  
A CRT device consists of a unique type of cardiac pacemaker which has two or three electrodes (or leads), 
one in the right ventricle, one in one of the branches of a vein on the outer surface of the left ventricle 
(called coronary sinus or CS), and often one in the right atrium (right top chamber, in order to ensure also 
synchronism between top and bottom chambers) (fig 1).  
 
The simultaneous activation of the left and right ventricle can restore a coordinated, or synchronous, 
pumping action (1). In most patients CRT improves symptoms of heart failure and quality of life, reduces the 
chance of being admitted to hospital with worsening heart failure, it makes people live longer (2,3).  
The implant procedure usually takes a few hours and it is performed under X-ray guidance. Local 
anaesthetic is injected into the upper chest wall, most commonly on the left side. An incision is made and a 
pocket is created under the skin. A venous blood vessel is punctured under the clavicle and pacing leads are 
guided through it into the heart chambers. A contrast injection (venogram) is usually performed in the 
coronary sinus in order to identify its branches and guide the placement of the LV lead. The leads are 
attached to the generator box, or battery, and all device components are placed into the pocket. The site is 
then sutured either with dissolvable or not dissolvable sutures which if the later, need to be removed 7-10 
days post procedure. A chest x-ray and a pacing check are carried out post procedure to ensure that the 
pacing leads are in the correct position, and that the pacemaker is functioning correctly.  
Once implanted, the device needs to be worn permanently and stimulate the heart continuously in order to 
keep its positive effects on heart function. The battery needs to be replaced every few years (depending on 
Fig 1. CRT device components. 

 
 
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Page 8 of 27 
 
 
amount of pacing and battery characteristics); the leads do not need replacement unless in case of 
malfunction.  
Although most patients have a significant improvement from CRT therapy, up to one third of patients do 
not benefit from it and to date there are no useful criteria to predict the response to CRT (4).  
In an effort to improve CRT response, alternative methods of CRT delivery have been developed. One 
potential strategy to improve response is multisite left ventricular (LV) stimulation, i.e. simultaneous 
stimulation of more than one area of the left ventricle in addition to right ventricular (RV) pacing.   
In this scenario, a new pacing feature has been recently become available that allows simultaneous LV 
stimulation from two different sites by means of a single lead with four electrodes (quadripolar lead). It is 
called MultiPoint Pacing (MPP; St. Jude Medical, Sylmar, CA) and it is available for some CRT devices in 
combination with a quadripolar LV lead. Both the devices with MPP and the quadripolar leads are already 
widely used as part of standard care and they are CE-marked.  Of note, they are already used as standard 
care at Oxford University Hospitals (OUH) NHS Foundation Trust. 
Simultaneous excitation of a larger mass or volume of cardiac tissue through MPP should theoretically 
result in faster depolarization velocity and early depolarization of sites of late intrinsic activation, with 
shorter LV trans-ventricular conduction times, better synchronization and increased cardiac output (5-7).  
Although the MPP technology has a proven safety and efficacy profile comparable to the other CRT 
techonology, evidence regarding the long term additional benefits of this pacing modality over conventional 
single site LV pacing is lacking.  To this aim, a randomized multicentre study (MORE CRT MPP study) is 
currently underway to show the superiority of MPP over conventional single site LV pacing.  
Some data are available about acute effects of MPP, i.e. the acute change in cardiac haemodynamics as 
MPP is activated. LV-dP/dTmax, consisting in the maximal rate of rise of LV pressure during cardiac 
contraction, is often measured to this aim. Basically a pressure manometer wire is temporarily placed into 
the LV during the CRT procedure and it continuously measures the left ventricular pressure.  Studies 
investigating the Acute Haemodynamic Response (AHR) of MPP over conventional single site LV pacing with 
this or other techniques have documented small, variable and often not clinically significant improvements 
from MPP compared to single site LV pacing.  
Study sub-analyses seem to suggest that MPP pacing could be particularly beneficial in specific subgroups of 
patients (12) and when stimulating particular areas of the LV, with up to 35-40% improvement in LV 
dP/dtmax if compared to conventional single-site LV pacing in the same site (13). Studies using biophysical 
modelling suggest that MPP from a quadripolar lead may exert its benefit mainly in patients with ischaemic 
heart disease resulting in LV scar (14).  
In order to optimize the response rate to CRT, it is extremely important to understand how MPP works, 
which subgroup of patients may benefit more from it and if a specific LV location should be chosen in order 
to have an added benefit from it. Of note, this pacing feature requires specific devices and higher energy, 
with increased battery drainage leading to more frequent battery changes and increased risk of infections 
so it is really important to understand when it is worth using it.  

 
 
Subject: Research protocol 
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Chief Investigator: Tim Betts  
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3.1 Research question and hypothesis 
We plan to investigate if the added benefit of MultiPoint Pacing over conventional single-site LV pacing is 
related to the presence of scar in the left ventricle and the position of the pacing lead relative to it.  
Our hypothesis is that MMP produces a better AHR compared to conventional single site LV pacing if there 
is scar in the left ventricle and when the lead is placed closed to the scar because this allows the 
recruitment of large areas of peri-scar viable tissue, characterized by slow conduction, with quicker 
electrical activation and more vigorous contraction (fig.2). 
 
Fig.2. When positioned at sites of healthy myocardium, MPP gives no incremental benefit over conventional 
single site LV pacing because there are no areas of slow conduction and block (left panel). On the other 
hand, when the LV lead is positioned next to myocardial scar, where there are areas of slow ventricular 
conduction and block, MPP can improve the electrical activation by recruiting more tissue at the same time 
(right panel). 
 
5. STUDY DESIGN 
A prospective single-centre pilot study will be conducted to investigate this topic. Fifteen patients with both 
ischemic and non-ischemic cardiomyopathy resulting in left ventricular myocardial scar and elected to CRT 
implant at the OUH, will be enrolled in this study.  
Compared to standard practice, additional research investigations will be a baseline visit for eligibility 
assessment, informed consent and pre-CRT implant cardiac MRI, a three-dimensional electroanatomical 
map reconstruction of the CS venous system during the standard CRT implant and the evaluation of the 
acute haemodynamic response (AHR, percentage increase of LV-dP/dT max) of MPP over conventional 
single-site LV pacing during the CRT implant.    
1. The cardiac Magnetic Resonance Imaging (MRI) will be performed in each patient 1-2 weeks before the 
CRT implant during the baseline visit. It will provide information regarding left ventricular (LV) function and 
volumes, characterization of LV tissue, presence and location of myocardial scar, anatomy of the CS venous 
system. Moreover, the peri-scar region (viable tissue immediately close to the scar) and the remote 

 
 
Subject: Research protocol 
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Version/Date: 1.1 /6th April 2019 
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Page 10 of 27 
 
 
myocardium (viable tissue farther from it) will be identified according to a 17-segments LV segmentation 
model (see intervention section for more details). 
2. A de-novo CRT implant will be performed under fluoroscopic guidance as per standard care. All subjects 
will be implanted with a regulatory approved St. Jude Medical CRT device compatible with MPP feature 
(models n° CD3271-40(Q), CD3371-40(Q), CD3371-40C(QC) or newer) and St. Jude Medical quadripolar left 
ventricular lead (Quartet 1458Q or newer). The choice of the right ventricular and right atrial leads will be 
left to the operator. After implant of the right ventricular and right atrial leads, a CS venogram will be then 
performed as per standard practice (see intervention section for more details).  
3. A three-dimensional electroanatomical map of the CS venous system will be constructed with Precision 
mapping system and a Biotronik Vision wire (Biotronik Se & Co. KG, Berlin, Germany) by using the CS 
venogram as a guide. The map will be merged with the correspondent cardiac MRI images in order to locate 
the myocardial scar in respect to the CS branches. This will allow the identification of two target CS 
branches for the study measurements, one located in the peri-scar region and one located in the remote 
myocardium.  
4. A Certus PressureWire will be then introduced into the LV. A PhysioMon software (Radi Medical Systems, 
Uppsala, Sweden) will be used for electronic calculation of the LV-dP/dTmax from every heartbeat for a 
period of at least thirty seconds to ensure steady-state conditions. The baseline LV-dP/dTmax will be 
measured during ventricular spontaneous rhythm. 
A St. Jude Medical quadripolar left ventricular lead will be sequentially placed in the “peri-scar” CS branch 
and in the “remote myocardium” CS branch. In each site the percentage increase in LV-dP/dTmax (Acute 
Haemodynamic Response, AHR) produced by both conventional single-site and MPP LV pacing to will be 
measured. All 4 poles of the quadripolar lead will be used in turn for conventional single-site LV pacing, 3 
different configurations will be used in turn for MPP. The LV-dP/dTmax will be recorded for each pacing 
configuration in order to identify the MPP and the single-site LV pacing configurations producing the best 
AHR (best percentage increase of LV-dP/dTmax).  
The AHR produced by the best MPP configuration in peri-scar region will be compared with the AHR 
produced by the best MPP configuration in the remote myocardium. Moreover, the percentage increase of 
LV-dP/dTmax produced by the best MPP configuration over the best conventional single-site LV pacing in 
the peri-scar region will be compared with the same measurement obtained in the remote myocardium.    
The decision about the final position of the LV lead and the activation of MPP feature after the CRT implant 
will be left to operator preference. This is usually decided on the basis of minimum pacing output required 
to achieve capture, lead stability and ECG changes suggestive of good resynchronization. 
As standard practice, the patient will be discharged the day after the procedure. A pre-discharge review will 
be performed by the patient’s standard care team. Any recorded peri-procedural complications will be 
communicated to the research team who will report them in the correspondent study CRF. 
 

 
 
Subject: Research protocol 
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6. OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measures  
Timepoint(s) of 
evaluation of outcome 
measure  
Primary 
 
 
To assess whether the added 
benefit of multipoint pacing 
(MPP) over conventional single-
site LV pacing is consistent in the 
peri-scar region compared to the 
remote myocardium 
- Acute haemodynamic response to 
MPP (percentage increase of LV-
dP/dTmax produced by MPP over 
spontaneous ventricular activation) in 
the peri-scar region and in the remote 
myocardium   
- Percentage increase of LV dP/dT max 
produced by MPP over conventional 
single-site LV pacing in the peri-scar 
region and in the remote myocardium  
 
CRT-D implant 
procedure 
 
7. STUDY RISKS AND BENEFITS 
7.1. Study risks 
7.1.1 Cardiac MRI 
Cardiac MRI is a safe and non-invasive technique with no known risks when appropriately supervised. It 
does not involve ionising radiation. Potential participants with ferromagnetic objects in their bodies or with 
implanted devices will be excluded (see Exclusion Criteria) because the cardiac MRI magnet could cause 
heating issues, dislocation of leads , malfunction of the device. All participants entering the scanner room 
are currently screened for such objects.  
Gadolinium contrast is widely used for clinical indications in cardiac MRI and it is safe. Occasionally it 
may cause a mild headache, nausea, itching and very rarely (< 1 in 1000) a more severe allergic reaction. It 
is cleared within hours by the body. Gadolinium has recently been associated with nephrogenic systemic 
fibrosis in patients with severe renal dysfunction; hence, according to Food and Drug Administration 
guidelines, all patients with glomerular filtration rate (GFR) < 30 ml/min (stage 3-5 renal disease) should not 
be given gadolinium. For this study, all potential participants with a GFR < 30 ml/min will be excluded (see 
Exclusion Criteria).  
7.1.2. CRT-D implant 

 
 
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Standard risks associated to a CRT-D implant are:  
- incision site complications: pain, bruising, bleeding or haematoma. In general pain from the incision is 
easily controlled with simple analgesia and resolves after a few days (significant bruising occurs in about 10-
20% of patients).  
- vascular access complications: venous bleeding, arterial damage (5% of patients).  
- arrhythmia (approximately 5%). There is a risk of causing ventricular or atrial arrhythmias from the 
procedure. These can be treated at the time of occurrence as required.  
- risk of lead displacement (approximately 3%).  
- pneumothorax (approximately 1% of patients).  
- additional lifetime risk of cancer due to radiation exposure for leads placement and CS venogram. The 
estimated radiation dose for a CRT implant is 13.5 mSv, equivalent to 5 years exposure to UK background 
radiation. It may theoretically be associated with an increased lifetime risk of developing a cancer of 0.03-
0.06%. If compared with the lifetime risk of developing a cancer in the general population of around 30% to 
40%, this overall represents a very small addition to the underlying cancer risk from all causes.  
- infection of wound, device or leads (approximately 1%). It is known that infection of pacemaker devices or 
leads can lead to the need for extraction of the leads and device. In most cases this can be performed 
percutaneously, but very rarely open cardiac surgery can be required to remove the leads.  
-Once implanted, the device needs to be worn permanently and stimulate the heart continuously in order 
to keep its positive effects on heart function. The battery needs to be replaced every few years (depending 
on amount of pacing and battery characteristics); the leads do not need replacement unless in case of 
malfunction. Every battery change or leads revision carries a 2-5% risk of device infection.  
If compared with the standard procedure:  
- the research CRT implant will take longer than a standard procedure (we estimate 20-30 additional 
minutes on average) due to movement of the left ventricular lead from one vein to another and due to AHR 
measurements;  
- there will be a slightly increased risk of damage to the CS venous system from extra manipulation of leads 
within it.  
Specific S Jude Medical devices and quadripolar leads allowing MPP algorithm will be chosen. They are 
already used as part of standard care at the OUH and they are CE-marked. The MPP feature will be used 
only for a few minutes during the implant procedure, therefore it will have a negligible effect on battery 
duration. The decision to use MPP after the implant will be left to the operator. 
The potential risks and benefits of both procedures and implants will be explained to participants as part of 
their standard care.  
 

 
 
Subject: Research protocol 
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Chief Investigator: Tim Betts  
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Page 13 of 27 
 
 
7.1.3 Invasive acute haemodynamic measurements  
- An arterial access will be required for the pressure wire. This will be performed via the femoral artery or 
radial artery on the contra-lateral side of the patient to the CRT procedure (so in most cases the right side.) 
The arterial access carries a small risk of vascular damage (approximately 1%) and rarely of coronary artery 
damage, arrhythmia or stroke (less than 0.1%). We will minimise the risk of vascular damage by performing 
the procedure from the radial artery where possible, which has been shown to reduce the vascular 
complications of these procedures. 
 
- There is a small risk of thrombus (clot) forming on the pressure wire during the procedure, which could 
result in a stroke (less than 1%). This will be minimized by giving the patient a dose of intravenous heparin 
before the catheter is inserted. The use of heparin carries a small risk of increased bleeding during the CRT 
procedure, however trials have shown that performing CRT procedures on higher levels of anticoagulation 
is safe, and so we do not expect this to be problematic. 
 
- There is a small risk of left ventricular perforation requiring a drain (less than 1%). This risk will be 
minimized by careful catheter manipulation.  
 
- A small amount of extra radiographic screening will be needed to place the pressure wire in the LV. The 
additional dose required for insertion of RADI pressure wire under fluoroscopic guidance has been 
estimated as 3 mSv for a recent research study using RADI pressure wire measurements during CRT implant 
(RADI CRT study, randomized multicentre study currently ongoing also in our hospital). This dose is 
equivalent to 13 months exposure to UK background dose, 16 months exposure for domestic pilots, 150 
hours of airline flights. It may theoretically be associated with an increased lifetime risk of developing a 
cancer of 0.005-0.001%. If compared with the lifetime risk of developing a cancer in the general population 
of around 30% to 40%, this overall this represents a very small addition to the underlying cancer risk from 
all causes.  
 
7.1.4 Electroanatomical mapping of the CS venous system   
- No additional venous access will be required for the electroanatomical mapping of the CS venous system 
because it will be performed via the same subclavian access used for the CRT-D implant procedure.   
- The manipulation of the pacing lead or a wire into the CS venous system might be associated to a small 
risk of vascular damage. A careful technique will be used to prevent it.  
7.2. Study benefits 
No direct benefit is anticipated for the study patients. However, a better understanding of the rationale 
behind MPP could translate into an increased response rate to CRT, with massive benefits for the future 
patients in terms of both quality (improved symptoms, reduced risk of hospital admissions) and quantity of 
life (reduced risk of death) and reduced costs for the health system. Moreover, the focused use of MPP 
would mean battery saving in the patients who would not benefit from it, with reduced number of battery 

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
Version/Date: 1.1 /6th April 2019 
IRAS Ref:  211326 
Ethics Ref: 16/SC/0662 
 
 
 
 
Page 14 of 27 
 
 
replacements and reduced risk of device infections. All these improvements would also translate into 
reduced health costs.  
 
8.  
PARTICIPANT IDENTIFICATION 
8.1. Study Participants 
Patients with history of ischemic or non-ischemic cardiomyopathy and elected to a CRT-D implant 
procedure.  
8.2. Inclusion Criteria 
 
• 
Age of 18 years or over 
• 
Left ventricular myocardial scar; 
 
• 
Standard indication to CRT-D (NYHA functional class III-IV despite optimal medical therapy, LV 
ejection fraction (LVEF) ≤35 %, QRS duration ≥120 msec, LBBB); 
• 
Will and ability to give informed consent for participation in the study. 
 
8.3. Exclusion Criteria 
 
• 
Pregnancy, trying for a baby or breast feeding; 
• 
Any other significant disease or disorder which, in the opinion of the investigator, may either put 
the participants at risk because of participation in the study, or may influence the result of the 
study, or the participant’s ability to participate in the study; 
• 
Inability to tolerate MRI scanning (e.g. claustrophobia, unable to lie flat) 
• 
Contraindications to MRI scanning (e.g. implantable devices, cranial aneurysm clips, metallic ocular 
foreign bodies, hypersensitivity to gadolinium); 
• 
Significantly impaired renal function (eGFR < 30ml/min); 
• 
History of allergy to cardiac MRI contrast media;  
• 
Severe claustrophobia. 
 
9. STUDY PROCEDURES 

 
 
Subject: Research protocol 
Short Title: SCAR MPP study 
Chief Investigator: Tim Betts  
Version/Date: 1.1 /6th April 2019 
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9.1. Recruitment 
Potential participants will first be approached some weeks before the CRT-D procedure. They will be 
identified from CRT Device implantation clinic lists. Their outpatient clinic letters will be screened by a 
member of the research team to assess suitability for inclusion in the study.  A letter of invitation, a patient 
information leaflet and a consent form will be given to potential participants by the researchers who are 
also members of the participant’s care team at their routine clinic visits or sent by post at the time their 
procedure date is determined (usually 6 weeks in advance). The participant will be allowed time to consider 
the information, and the opportunity to ask questions to the Investigator, their GP or other independent 
parties to decide whether they will participate in the study. He/she will be invited to contact the 
investigator if wishes to discuss the study further. In case of will to take part, the participant will be 
approached at his/her pre-admission visit before the procedure (1-2 weeks before the implant) by a 
member of his/her care team, followed by a member of the research team for a baseline visit including 
informed consent, screening, eligibility assessment and cardiac MRI. 
9.2. Baseline visit 
9.2.1. Informed Consent 
Informed consent will be obtained by a qualified and experienced investigator who is familiar with the study 
protocol and procedures. This may be the chief investigator, a principal investigator, the research fellow or 
a research nurse. The list of eligible individuals will be specified in the delegation log.  
Written versions of the Participant Information and Informed Consent will be presented to the participants 
detailing no less than: the exact nature of the study; what it will involve for the participant; the implications 
and constraints of the study and the benefits and risks involved in taking part. It will be clearly stated that 
the participant is free to withdraw from the study at any time without giving a reason or any prejudice to 
future care and rights.  
Written Informed Consent will then be obtained by means of participant dated signature and dated 
signature of the person who presented and obtained the Informed Consent.  One original signed informed 
consent form will be retained by the participant, the other original will be kept in the participant’s 
casenotes and a copy will be kept in the trial master file. A copy of the signed consent form will be given to 
the participants. The original signed form will be retained at the study site. The participant must personally 
sign and date the latest approved version of the informed consent form before any study specific 
procedures are performed. 
 
9.2.2. Screening and Eligibility Assessment 
It will include:  
a. demographics; 
b. exclusion of pregnancy or breast feeding in case of child-bearing age female; 
c. detailed collection of any relevant medical history;  
d. list of current medications. 

 
 
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This information will be obtained from both participant and medical records. It will be recorded in a 
not identifiable paper CRF by a study investigator or a member of the research team.  
9.2.3. Cardiac MRI 
Cardiac MRI will be performed as additional research procedure during the baseline visit. It will 
comprehensively characterize myocardial tissue and assess myocardial function and metabolism.  
In this research study, patients may undergo the following CMR imaging techniques:  
a. Functional imaging/cine CMR to image the heart pumping the blood in circulation of the body and 
to assess ventricular and atrial volumes and function and define the anatomy of the CS venous 
system; 
b. First pass perfusion and contrast based techniques (gadolinium enhancement techniques or tissue 
characterization techniques) which include the use of ‘dye’ to directly detect impaired blood supply 
patency of microvessels, capillary leak and myocardial fibrosis/irreversible damage;  
These techniques will allow a clear location of myocardial scar, the peri-scar region and the remote 
myocardium and the definition of the anatomy of the CS venous system as detailed below.  
As per standard practice, the LV walls will be artificially divided into 17 segments (fig. 3) and the positions of 
the scar, the viable tissue immediately around it (peri-scar region, 1 segment from scar) and of the viable 
tissue farther from it (remote myocardium, 2 or more segments from scar) will be identified according to 
this 17-segments model (fig.3). 
 
Fig.3. 17-segment model segmentation for LV.  
The location of the myocardial scar, the peri-scar region and the remote myocardium in relation to the CS 
anatomy will allow the identification of a “peri-scar” CS branch and a “remote myocardium” CS branch 
(fig.4).  
17 

 
 
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      Fig.4. Schematic representation of LV Bull’s eye view (LV seen from 
the apex), with myocardial scar (black area), peri-infact region (yellow-lined area) and correspondent CS 
branch (yellow arrow), remote myocardium (red-lined area) and correspondent CS branch (red arrow).   
 
During the acquisition of the images, participants will be in constant communication with the staff running 
the scan and  they will be able to decide to stop the scan at any time. 
No scan report will be generated. In case of incidental findings the CMR consultant will oversee 
arrangements to contact the participant and to ensure that the participant’s GP is notified as per internal 
SOP. Data will be recorded on a not identifiable paper CRF. No additional research analyses will be 
performed.  
 
9.2.4. CRT-D implant procedure (including three dimensional mapping of the CS venous 
anatomy and invasive acute haemodynamic measurements)  
The patient will be admitted, as routine for the procedure, generally 1-2 weeks after the baseline visit. 
At first, arterial access will be obtained. A small 5 French sheath will be used to pass a 5F catheter into the 
left ventricle. A 2500 units bolus of heparin will be given intravenously to minimise the risk of thrombosis. 
Venous subclavian access will be then obtained. A right ventricular lead and a right atrial lead will be placed 
as normal at the start of the procedure. The choice of the right ventricular and right atrial leads will be left 
to the operator.  
ACS venogram will be then performed as per standard practice. Briefly, contrast dye will be injected in the 
CS under fluoroscopic guidance by using a dedicated occlusive catheter in order to delineate its anatomy 
and identify its branches. 
A three-dimensional electroanatomical map of the CS venous system will also be constructed with Precision 
mapping system and a Biotronik Vision wire (Biotronik Se & Co. KG, Berlin, Germany) by using the CS 
venogram as a guide. The map will be merged with the correspondent cardiac MRI images in order to locate 
 
 

 
 
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the myocardial scar and the target CS branches for the study measurements, one located in the peri-scar 
region and one located in the remote myocardium.  
A 0.014-inch diameter high fidelity Certus PressureWire will be then introduced into the LV from femoral or 
radial arterial access site. A PhysioMon software (Radi Medical Systems, Uppsala, Sweden) will be used to 
calculate electronically LV-dP/dTmax from every heartbeat for a period of at least thirty seconds to ensure 
steady-state conditions.  
The LV-dP/dTmax will be measured during spontaneous ventricular rhythm. A St. Jude Medical quadripolar 
left ventricular lead (Quartet 1458Q or newer) will be then sequentially placed in the “peri-scar” CS branch 
and in the “remote myocardium” CS branch and the LV-dP/dTmax will be measured during conventional 
single-site and MPP LV pacing in each site. In each site the AHR to both conventional single-site and MPP LV 
pacing will be performed by measuring the percentage change in LV-dP/dTmax compared to spontaneous 
ventricular rhythm. Different single-site (all 4 poles in turn) and MPP (3 configurations) LV pacing settings 
will be tested to this aim in order to identify the best MPP and single-site LV pacing configurations.  
The AHR produced by the best MPP configuration in peri-scar region will be compared with the AHR 
produced by the best MPP configuration in the remote myocardium. Moreover, the percentage increase of 
LV-dP/dTmax produced by the best MPP configuration over the best conventional single-site LV pacing in the 
peri-scar region will be compared will the same measurement obtained in the remote myocardium.    
All measurements will be repeated at least twice in order to make sure they are reliable and reproducible. 
The pressure wire and the sheath will be removed after all measurements are complete. 
Data will be electronically captured from the pressure wire and automatically extracted on an excel 
database. 
The LV-dP/dTmax measurements will not influence the operator’s decision about the final position of the LV 
lead. This will be dictated, as standard practice, by minimum pacing output required to achieve capture, 
lead stability and ECG changes suggestive of good resynchronization. 
All subjects will be implanted with a regulatory approved St. Jude Medical CRT device compatible with MPP 
feature (models n° CD3271-40(Q), CD3371-40(Q), CD3371-40C(QC) or newer).   
9.3.  Pre-discharge review 
As part of standard care, each patient will be reviewed the day after the procedure, before discharge. The 
occurrence of any procedural complications will be investigated and recorded by a study investigator or a 
member of the research team in a not identifiable paper CRF.  
9.4. Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time.  In addition, the Investigator may 
discontinue a participant from the study at any time if the Investigator considers it necessary for any reason 
including: 

 
 
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• 
Pregnancy 
• 
Ineligibility (either arising during the study or retrospectively having been overlooked at screening) 
• 
Significant protocol deviation 
• 
Significant non-compliance with study requirements 
• 
Withdrawal of Consent 
• 
Loss to follow up 
No specific procedures or observations will be required in case of discontinuation/withdrawal of 
participants from study rather than standard medical care.  
The reason for withdrawal will be recorded in the CRF. 
In case of withdrawal from the study in an early stage (before the study interventions), the patient data will 
be excluded from the analysis and a new participant will be enrolled.  
9.5. Definition of End of Study 
The end of study will be the date of CRT-D implant procedure of the last patient.  
 
10. INTERVENTIONS 
These are described in the Study Procedures section above. 
11. SAFETY REPORTING 
11.1. 
Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
congenital anomaly/birth defect 
• 
results in persistent or significant disability/incapacity 
 
Other ‘important medical events’ may also be considered serious if they jeopardise the participant or 
require an intervention to prevent one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the participant 
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. 
11.2. 
Reporting Procedures for Serious Adverse Events 

 
 
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12. ‘A serious adverse event (SAE) occurring to a participant should be reported to the REC 
that gave a favourable opinion of the study where in the opinion of the Chief 
Investigator the event was ‘related’ (resulted from administration of any of the 
research procedures) and ‘unexpected’ in relation to those procedures. Reports of 
related and unexpected SAEs should be submitted within 15 working days of the Chief 
Investigator becoming aware of the event, using the HRA report of serious adverse 
event form (see HRA website)’STATISTICS AND ANALYSIS 
12.1. 
The Number of Participants 
This is a pilot study that aims at investigating a possible relation between scar location and AHR to MPP 
more than proving a statistical significant different between AHR to MPP in the peri-scar region compared 
to the remote myocardium. Therefore, a small sample size of 15 patients has been chosen just in order to 
confirm the validity of the study hypothesis to be further investigated in a bigger study.  
Of note, a recent study (13) has documented a variable AHR to MPP over single-site LV pacing with a 
percentage increase in LV-dP/dT between 0% and 40% according to LV site. If our hypothesis is confirmed 
and the best and worst MPP sites correspond to peri-scar and remote-myocardium respectively, 15 patients 
could be also enough in order to show a statistically significant difference between the two sites with a 95% 
confidence level and a 80% power.  
12.2. 
Description of Statistical Methods 
Comparison of response to the two different pacing sites will be made using appropriate statistical testing. 
We would expect the data to be normally distributed, in which case T-tests will be used. 
12.3. 
Analysis of Outcome Measures 
The following measurements will be collected and analysed: 
- LV-dP/dTmax during spontaneous ventricular rhythm;  
- LV-dP/dTmax during single site LV pacing in 4 different pacing configurations (4 different poles used in turn), 
with the LV lead either in the peri-scar CS branch or in the remote myocardium CS branch. The pacing 
configuration producing the biggest  LV-dP/dTmax over spontaneous ventricular rhythm will be considered 
the best pacing configuration in each CS branch and used for further comparisons and analyses;  
- LV-dP/dTmax during single MPP LV pacing in 3 different configurations, with the LV lead either in the peri-
scar CS branch or in the remote myocardium CS branch. The pacing configuration producing the biggest LV-
dP/dTmax will be considered the best pacing configuration in each CS branch and used for further 
comparisons and analyses. 

 
 
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The percentage change in LV-dP/dTmax produced by the best single site LV pacing configuration over 
spontaneous ventricular rhythm will represent the best Acute Haemodynamic Response (AHR) of single site 
LV pacing in each CS branch.  The percentage change in LV-dP/dTmax produced by the best MPP LV pacing 
configuration over spontaneous ventricular rhythm will represent the best Acute Haemodynamic Response 
(AHR) of MPP LV pacing in each CS branch.   
The following comparisons will be made as outcome measures:  
- AHR produced by the best MPP configuration in the peri-scar region versus AHR produced by best MPP 
configuration in the remote myocardium;  
- percentage increase of LV-dp/dTmax produced by the best MPP configuration over single site LV pacing in 
the peri-scar region versus percentage increase of LV-dp/dTmax produced by the best MPP configuration 
over the best conventional single-site LV pacing in the remote myocardium.   
Our hypotheses are that:  
- the AHR produced by the best MPP configuration will be consistently and statistically significantly higher in 
the peri-scar region compared to the remote myocardium;  
- the percentage increase of LV-dp/dTmax produced by the best MPP configuration over single-site LV pacing 
will be consistently and statistically significantly higher in the peri-scar region compared to the remote 
myocardium.  
13.  DATA MANAGEMENT 
13.1. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor or host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. 
13.2. 
Data Recording and Record Keeping 
• 
The study staff will ensure that the participants’ anonymity is maintained.  
• 
NHS code of confidentiality will be followed. 
• 
Personal data will be anonymised with the use of a study participant number. The study number 
will be correlated with personal data about the patient in one electronic file, which will be 
individually password protected and secured as above. 
• 
All electronic records (excel databases) will be stored on a NHS server within password-protected 
user accounts and they will be anonymized. 
• 
The MRI scans will be stored in the usual manner on the OCMR server. 
• 
The file linking personal data to the study ID will be stored separately to the study data. 
• 
Paper records will be stored in a locked filing cabinet to which only the research team have access. 
The study will comply with the Data Protection Act which requires data to be anonymised as soon 
as it is practical to do so. 

 
 
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• 
EP data analysis will be performed by Dr Leo and Dr Betts in the JR hospital. No further data transfer 
will be performed. 
• 
As per Trust Policy, after the end of the trial period, all study data will be kept for a further period of 
5 years before being deleted, to allow for full analysis and results publication. Personal data will be 
only kept for a few months after the study has finished, before being destroyed. 
14. ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the Declaration 
of Helsinki.  
14.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
14.3. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising material 
will be submitted to an appropriate Research Ethics Committee (REC), and host institution(s) for written 
approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
14.4. 
Reporting 
The CI shall submit once a year throughout the study or, on request, an Annual Progress report to the REC 
Committee, host organisation and Sponsor.  In addition, an End of Study notification and final report will be 
submitted to the same parties. 
14.5. 
Participant Confidentiality 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by initials and a participants ID number on the CRF and any electronic database.  All 
documents will be stored securely and only accessible by study staff and authorised personnel. The study 
will comply with the Data Protection Act, which requires data to be anonymised as soon as it is practical to 
do so. 
Participants anonymity will be maintained and no patient identifiable information will be published. 
14.6. 
Expenses and Benefits 

 
 
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Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
We intend that the majority of study visits will be performed at the time of routine clinical visits to hospital 
so would not expect that patients will have to make many extra visits to hospital. 
Light refreshments will also be available. 
14.7. 
Other ethical considerations 
No other ethical considerations are involved in this study. 
15. FINANCE AND INSURANCE 
15.1. 
Funding 
This research study was selected for the NIHR Oxford Biomedical Research Centre (BRC) Young investigator 
Award in 2015 and will be supported by the corresponding research grant awarded. Any shortfalls will be 
covered by the CRM Hub.  
15.2. 
Insurance 
NHS bodies are legally liable for the negligent acts and omissions of their employees. If you are harmed 
whilst taking part in a clinical research study as a result of negligence on the part of a member of the study 
team this liability cover would apply. 
Non-negligent harm is not covered by the NHS indemnity scheme. The Oxford University NHS Trust, 
therefore, cannot agree in advance to pay compensation in these circumstances. 
In exceptional circumstances an ex-gratia payment may be offered. 
 
16. PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any 
other publications arising from the study.  Authorship will be determined in accordance with the ICMJE 
guidelines and other contributors will be acknowledged. For participants who have stated they wish to 
receive a copy of the research results, a copy of these results will be sent by post. 
 
 

 
 
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17. REFERENCES 
1. Rao et al. Circulation 2007; 115:2136-44. 
2. Abraham et al. N Engl J Med 2002;346:1845-1853. 
3. Cleland et al. N Engl J Med 2005; 352: 1539-1549.  
4. Tracy et al. Heart Rhythm 2012;9:1737–1753.  
5. Rinaldi et al. Europace 2015;17:7–17.  
6. Lloyd et al. J Cardiovasc Electrophysiol. 2007; 18:1167-71. 
7. Theis et al. J Cardiovasc Electrophysiol. 2009;20(6):645-9.  
8. Rinaldi et al. J Interv Card Electrophysiol 2014 40:75–80.  
9. Pappone et al. Heart Rhythm 2014;11:394–401. 
10. Thibault et al. Europace 2013;15:984–991.  
11. Ploux et al. Heart Rhythm 2014;11:119–125.  
12. Sohal et al. Heart Rhythm.2015 Jul 9.  
13. Zanon et al. Heart Rhythm. 2015;12(5):975-81.  
14. Niederer et al. Pacing Clin Electrophysiol. 2012 Feb;35(2):204-14. 
 
 
 

 
 
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18. APPENDIX A:  STUDY FLOW CHART 
 
 
 
 
 
 
 
 

 
 
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19. APPENDIX B:  SCHEDULE OF TIMING OF STUDY APPOINTMENTS AND STUDY 
PROCEDURES 
 
 
Recruitment 
Baseline 
visit 
Study 
intervention 
Pre-discharge 
review 
Time since CRT-D implant 
procedure 
≥ 6 wks 
- 1-2 wks 
0 
+ 1 d 
Study procedures 
 
Eligibility assessment 
X 
X 
 
 
Patient’s information 
X 
 
 
 
Informed consent 
 
X 
 
 
Demographics 
 
X 
 
 
Medical history 
 
X 
 
X 
Cardiac MRI 
 
X 
 
 
CRT-D implant 
 
 
X 
 
3D map of CS venous system 
 
 
X 
 
Acute haemodynamic 
response measurements 
 
 
X 
 
 
d = day; f-up = follow-up; wks = weeks. 
 
 
 

 
 
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20. APPENDIX C:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of changes 
Details of Changes made 
1 
1.1 
 
M Leo, T Betts 
- All Patients with 
myocardial scar 
(regardless of ischemic 
and non-ischemic 
aetiology) included in the 
study 
 
- Study end date 
extended of 12 months.