Effects of CRT Optimization on LV Mechanical Synchrony, Structure, and Function in CRT Patients as Assessed by Cardiac MR
Phase: NA
Conditions: Heart Failure, Systolic
Sponsor: Minneapolis Heart Institute Foundation

 
 
 
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General Study Information 
 
Protocol Title:  
Effects of CRT Optimization on LV Mechanical Synchrony, 
Structure, and Function in CRT Patients as Assessed by Cardiac 
MR  
 
Short Title:   
 
CRT and MRI 
 
Principal Investigators: 
Alan J. Bank, MD; João L. Cavalcante, MD; Jay D. Sengupta, MD 
 
 
Version Date and number:  V1, 01-MARCH-2021 
 
 
Sponsor/Funder:  
 
There is no direct study-specific funding to support this research 
 
Site: 
 
 
 
Minneapolis Heart Institute Foundation  
 
 
 
 
920 East 28th Street, Suite 100 
 
 
 
 
Minneapolis, MN 55407 
 
 
 
 
(612) 863-3900 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Overview 
 
Background 
Cardiac resynchronization therapy (CRT) has been shown in large multi-center randomized 
studies to improve symptoms, quality of life, left ventricle (LV) size and function, hospitalization 
rate, and mortality in selected heart failure (HF) patients with low ejection fraction (EF) and 
wide QRS.  However, ~30% of patients are considered non-responders, and a large but less well-
defined number of patients are incomplete-responders.  One major reason for non-response is 
suboptimal CRT programming.  There is no well-accepted and proven clinical approach to 
optimizing CRT programming despite the vast number of publications on this topic.  For this 
reason, the vast majority of CRT patients do not undergo any type of optimization procedure and 
are left at their standard device settings.  We have developed and patented a novel methodology 
using a multi-lead ECG system for measuring electrical dyssynchrony and generating electrical 
dyssynchrony maps (EDM) over a wide range of atrio-ventricular (AV) and ventriculo-
ventricular (VV) delays.  A pilot non-randomized study has shown that CRT optimization using 
this technology is practical, reproducible, and results in improvements in cardiac function.   
The main purpose of the present study is to extend these findings by assessing the acute and 
chronic effects of CRT optimization on mechanical synchrony, LV regional wall motion and LV 
structure/function in CRT non-responders or incomplete-responders using cardiac magnetic 
resonance imaging (CMR).  It has previously been challenging to perform CMR in patients with 
CRT devices due to difficulty with image quality and concern about the effects of CMR on 
device settings or function.  This is no longer the case at Minneapolis Heart Institute (MHI) as a 
specific protocol has been developed and is in use for assessing cardiac structure, function and 
dyssynchrony in patients with an implantable CRT device in a safe manner. 
CRT non-responders or incomplete-responders will have electrical dyssynchrony maps acquired. 
They will subsequently have CMR images obtained at 3 different settings to assess the acute 
effects of CRT: native (CRT off), current baseline CRT setting, and best CRT setting (optimal 
electrical synchrony).  Subjects will be randomized 1:1 to either their baseline setting or the 
optimized setting.  After ~ 6 months subjects will have repeat CMR studies to assess the chronic 
effects of CRT optimization, and patients randomized to the control arm will crossover and have 
their device reprogrammed to the optimal. All subjects will follow up ~6 months later with an 
echocardiogram to further assess chronic effects of CRT optimization.  We believe the 
information gained from this study will help us demonstrate that improvement in LV electrical 
synchrony using our new methodology translates into improvement in LV mechanical synchrony 
and LV function both acutely and chronically.  This will support the clinical strategy of routine 
CRT optimization using EDMs for management of this complex and high-risk group of patients. 
 
 

 
 
 
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Primary Objectives 
1. Quantify acute differences in LV mechanical synchrony, regional wall motion, and LV 
function at native (off CRT), baseline, and optimal CRT settings. 
2. Determine whether programming at optimal CRT setting results in chronic improvement 
in LV mechanical synchrony, regional wall motion, and LV structure/function.  
3. Correlate changes in electrical synchrony as measured by cardiac resynchronization index 
(CRI) with changes in LV mechanical synchrony, regional wall motion, and LV function 
both acutely and chronically. 
 
Secondary Objectives 
1. Assess differences in 6 minute hall walk (6MHW) in patients randomized to baseline 
CRT setting vs optimal CRT setting 
2. Assess differences in quality of life (QOL) in patients randomized to baseline CRT    
setting vs optimal CRT setting 
 
Study Design 
This is a prospective, proof-of-concept single-blind pilot study of patients with HF and CRT.  
Subjects will be recruited for this study from clinics at MHI at United and MHI at Abbott 
Northwestern. We anticipate enrolling 40 subjects in the present study. Subjects will be blinded 
to randomization assignment and randomized in 1:1 fashion to experimental and control arms 
and subsequent control arm cross-over as described below. There will be an interim analysis 
performed after the first 6 subjects to assess efficacy.  
Study Population 
Inclusion criteria:  
• Currently on standard medical therapy 
• 
CRT device in place for > 4 months 
• 
Non-responder (EF improvement with CRT < 5%) or incomplete responder (EF < 
40%) 
• 
Suboptimal electrical wavefront fusion at current CRT programming as observed 
on 12-lead ECG 
• 
LBBB, IVCD, or RV paced underlying QRS complex 
• 
Age > 18 years 
 
Exclusion criteria:  
• Decompensated heart failure 
• RBBB  
• Pregnancy or lactation 
• History of severe allergic reactions to ECG gels, electrode adhesives, and/or CMR 
contrast 

 
 
 
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• Implantation of pacing lead in the his bundle or left bundle branch 
• Frequent ventricular ectopy as defined as >10% PVC burden by either device 
interrogation or Holter monitor, or sustained ventricular tachycardia/ventricular 
fibrillation  
• Uncontrolled atrial fibrillation (HR > 100 bpm)  
• Severe kidney disease as defined as glomerular filtration rate (GFR) <30 mL/min 
• Patient is enrolled in concurrent research study that would potentially confound 
the results of this study (noting co-enrollment acceptable if patient is enrolled in 
registry study) 
 
Study Activities  
This study consists of four research visits after subjects provide consent.  
Visit 1 – All subjects will undergo baseline assessments, device check, and multi-lead ECG 
assessment/ generation of EDM(s) 
• 
Medical chart abstraction via CRF includes: 
o Demographics 
o Cardiovascular history 
o CRT device data 
o Imaging (includes values and images from past chest x-rays, cardiac MRI, 
echocardiograms, fluoroscopic images from CRT implant, CT imaging) 
o Medications 
o Lab values  
o Vital signs 
• 
6MHW  
• 
QOL will be assessed (KCCQ) and research questionnaire (see Appendix C) 
• 
NYHA classification  
• 
Device Check 
• 
Multi-lead ECG assessment, data collection, and generation of EDM(s) 
EDMs will be reviewed by study staff to determine optimal CRT device programming. 
Randomization of study arm will be determined prior to Visit 2. 
Visit 2 – Subjects will return to study site for CMR study and randomization to study arm/ 
reprogramming of CRT programming. A device nurse will be present to assist in the 
programming of the device during the CMR study and during the randomization. Subjects will 
be blinded to device programming throughout duration of the 6 month follow up period. All 
patients will receive gadolinium contrast during CMR study at Visit 2. Creatinine levels will be 
drawn prior to admistration of gadolinium contrast to determine renal function and if use of 
contrast is safe. 
• 
CMR study at the following: 
o Native rhythm (CRT off) 
o Current baseline CRT programming 
o Optimal CRT programming (optimal electrical synchrony) 

 
 
 
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• 
Subjects will be randomized 1:1 to either the control arm or experimental arm after 
completion of CMR study 
o Control arm: Subject randomized to the control arm will remain at their current 
baseline settings for the next 6 months 
o Experimental arm: Subjects will be programmed to the optimal settings based on 
the EDM(s) for the next 6 months  
Visit 3 – Subjects will return to study site for follow-up CMR study and assessments 6 months 
after Visit 2. No patients will receive gadolinium contrast during CMR study at Visit 3. 
• 
CMR study at current, randomized programming 
• 
Medical chart abstraction 
o Review chart for interim cardiovascular events and medication changes 
o CRT device data (remote or in-clinic device checks) 
o Imaging (abstraction of interim values and images of chest x-rays, cardiac MRIs, 
echocardiograms) 
• 
6MHW 
• QOL will be assessed (KCCQ) and research questionnaire (see Appendix C) 
• NYHA classification assessment 
• Device check and reprogramming: At Visit 3, patients randomized to the control arm will 
have their device reprogrammed to the optimal programming as determined by the multi-
lead ECG assessment at Visit 1. Patients randomized to the experiment arm will remain 
at the optimal programming implemented at Visit 2.  
Both groups will have the optimal programming as determined by the multi-lead ECG 
assessment at the end of visit 3.  
Visit 4 – Subjects will return to study site for an echocardiogram 6 months after Visit 3 
• 
Medical chart abstraction 
o Review chart for interim cardiovascular events and medication changes 
o CRT device data (remote or in-clinic device checks) 
o Imaging (abstraction of interim values and images of chest x-rays, cardiac MRIs, 
echocardiograms) 
• 
6MHW 
• QOL will be assessed (KCCQ) and research questionnaire (see Appendix C) 
• NYHA classification assessment 
• Standard of care echocardiogram will be obtained from both study arm subjects to 
continue to evaluate and monitor chronic response to CRT optimization. 
• Standard of care device check (remote or in-clinic) 
 
Subject participation in the study will end after follow-up echocardiogram. CRT 
programming and management of heart failure will continue under discretion of clinical 
providers upon completion of the study. Standard 12-lead ECGs will be ordered and 
collected whenever CRT device programming is altered during the study to ensure most up-
to-date ECG is available in the medical record. 
Visit Windows:  

 
 
 
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Visit 2 must be completed within 3 months after Visit 1. 
Visit 3 must be completed within 6 months (- 4 weeks/ +12 weeks) after Visit 2.  
Visit 4 must be completed within 12 months (- 4 weeks/ +12 weeks) after Visit 3.  
Study Duration: The duration of this study for an individual subject can be up to 24 months.  
Identification of Potential Participants: Potential participants for this research study will be 
identified by screening the electronic medical record system (EPIC) from both MHI at United 
and MHI at Abbott Northwestern to determine eligibility prior to requesting consent and HIPAA 
authorization from patients. In addition, there are no other practical ways to obtain contact 
information or appointment schedules in order to reach out to potential subjects or determine 
when they will be at a study site to approach and gauge interest in this study. Subjects’ release of 
information MRA boxes will be reviewed prior to conducting screening procedures. Subjects 
who have opted out of this release of information for research or missing MRA will not be 
screened, and their medical charts will be immediately closed. For this reason, we will be 
requesting a partial waiver of HIPAA authorization, which will only apply during the screening 
process. Name, date of birth, MRN, and eligibility criteria will be recorded in a password-
protected excel spreadsheet (screening log) housed in the password-protected Allina Health share 
drive with access granted only to study staff. Patients who are not eligible to participate will 
remain in the screening list until completion of study, so repeated screening does not occur. 
Subjects who decline participation will remain in the screening log, and declined participation 
notes will be added to the screening log and medical record, so these subjects are not contacted 
or approached again regarding participation in the study. The screening log will be destroyed 
upon study completion and closure.  
Study Recruitment Process: Eligible subjects will be identified by physician referral or 
screening through the electronic medical record. Qualified study physician will determine 
whether or not potential subjects satisfy eligibility criteria. Subjects will be contacted either by 
phone or approached in clinic by study staff to gauge interest in participation. If recruited in one 
of the enrolling sites' clinics, subjects' privacy will be ensured by having encounters held in a 
private setting away from non-site staff. If contacted via a telephone encounter (phone 
interview), the conversation will take place in a room away from non-site staff. A phone script is 
to be used if patients are contacted by phone. Subjects will be allotted time to ask questions and 
be given sufficient time to make a decision (up to 30 days) about whether or not they want to 
participate. Subjects who choose to voluntarily participate in the study will be asked to sign 
HIPAA authorization and consent prior to the start of any study-related activities. The consent 
process and subsequent research activities and visits will be documented in the subject's medical 
chart. 
Compensation to Subjects: Subjects will not be paid for their participation.  
Electrical Dyssynchrony Mapping  
Appendix A provides details of EDM generation and the measurements made from EDMs.  
Briefly, EDMs are generated using 2 standards, clinical ECG machines with 9 electrodes from 

 
 
 
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one machine placed anteriorly over the chest and 9 electrodes from another machine placed 
posteriorly over the upper back. Multiple atrio-ventricular delays (AVD) and ventriculo-
ventricular delays (VVD) are tested over the practical range of programmable settings with 20 
ms steps between settings.  A butterfly plot of the 18 electrograms for a single beat is generated, 
and the area under the curves (AUC) of multiple pairs of anterior and posterior electrograms is 
quantified using a proprietary algorithm.  Cardiac resynchronization index (CRI) is calculated as 
the absolute value of the percent change in AUC at any given setting as compared to native.  CRI 
values at each setting are plotted on a color-coded map using Matlab software. An optimal 
synchrony line (OSL) is generated on the EDM and optimal synchrony is defined as a setting on 
the OSL.  
 
EDMs will be acquired at current (baseline) device vector.  In some subjects, an EDM at a 
different vector (e.g. pacing from a different quadripolar LV lead) will be obtained, particularly 
if electrical synchrony using the baseline pacing vector appears suboptimal.   
 
Variables measured from EDM 
1. Optimal CRI (overall, during BiV pacing, during LV-only pacing) 
2. Timing of native, RV-paced (RVp) pacing and LV-paced (LVp) electrical wavefronts 
 
Cardiac MR 
CMR will be performed after measurement of EDMs at Visit 2 and 6 months later at Visit 3.  
The acute CMR study data will be acquired at three different settings at Visit 2: native (CRT 
off), current baseline CRT setting, and optimal CRT setting.  The three settings will be 
programmed randomly, and the reader will be blinded to the device settings.  At Visit 3, the 6 
month CMR study will be acquired at the randomized programmed setting only, and the reader 
will be blinded to this setting. In the instance of incidental findings, study doctor(s) will relay 
findings to patient’s care team or cardiologist for clinical follow-up if appropriate.   
A list of CMR values collected are listed in Appendix B. 
NYHA assessment, QOL questionnaires, 6MHW 
This data will be acquired at baseline and at 6 months (Visits 1 and 3, respectively).  NYHA 
class will be assessed by study staff blinded to patient randomization.  QOL will be measured 
using Kansas City Cardiomyopathy Questionnaire (KCCQ), and a study-specific questionnaire 
found in Appendix C. Delegated study staff will perform 6MHWs.  
Randomization 
All subjects will be randomized 1:1 to experimental and control arms of the study using a 
computer program to randomly generate assignments. The prepopulated randomization 
assignment for each enrolled subject will be placed in sealed envelopes and labeled with the 
corresponding study ID number. These randomization assignment envelopes will be kept in the 
keypad secured research drug closet at MHI at United and are only accessible by research staff. 
Randomization envelopes will be opened after generation and review of EDM(s), and 

 
 
 
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determination of optimal CRT programming after Visit 1 and prior to Visit 2. An excel 
spreadsheet of all randomization assignments will be kept on the secured Allina Health share 
drive to confirm correct assignment. This spreadsheet will be password protected and only 
accessible by the research staff delegated to oversee randomization assignments.   
Alternatives to Participation 
Alternative to participation, include (but not limited) to the following: 
• 
12-lead ECG CRT optimization: Patient can alternatively undergo non-research 
electrocardiography guided CRT optimization at either MHI at United or MHI at Abbott 
Northwestern. The 12-lead ECG CRT optimization uses fewer electrodes to collect a 
more limited amount of information about which CRT device settings are more optimal.  
 
This alternative listed above would both involving the changing of CRT device settings during 
ECG acquisition similar to that of the multi-lead ECG assessment and EDM generation. 
However, the alternative options do not implement the use of CMR and contrast, mitigating the 
risks as described below in the protocol under “Risks Associated with Cardiac Magnetic 
Resonance Imaging” and “Risks and Side Effects from the Required Intravenous Agents: 
Gadolinium”. 
Interim Analysis: 
After the first six subjects complete the study, an interim analysis will be completed to assess the 
efficacy of multi-lead ECG assessment and EDM generation in optimizing patients with CRT 
and deemed non-responders/ incomplete responders to the therapy. Acute and chronic changes to 
LV mechanical synchrony, regional wall motion, and function will be assessed by CMR imaging 
and echocardiography in order to measure response to CRT optimization. 
Data Safety Monitoring Plan: 
Subjects’ medical and cardiovascular history will be abstracted at follow up Visit 3 and Visit 4, 
and abstractions will be reviewed by study doctors alongside the medical imaging collected 
during the interim and at these study visits. Study doctors will determine if there has been a 
decline in cardiovascular health related to the interventional component of altering CRT 
programming during the study and whether it is safe for subjects to continue participation.   
If it has been determined by a study doctor that it is no longer safe for a subject to continue 
participation, a study doctor will contact patient and inform them that it is unsafe for the subject 
to remain in the interventional portion of the study. A study doctor will consult with 
electrophysiology provider(s) overseeing the device management of the subject prior to 
withdrawal. The subject may be asked by a study doctor to return to the study site for a clinical 
follow-up with the device clinic and/ or office visit with an electrophysiologist provider to assess 
CRT programming prior to being withdrawn from the study. All requested follow-up prior to 
withdrawal is voluntary, but a subject’s decision not to follow up prior to withdrawal from the 
interventional portion of the study due to safety concerns may pose additional risks that are 
unknown at this time and may include worsening symptoms of heart failure. A study doctor 

 
 
 
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may ask if the subject wishes to participate in continued follow-up as described in the consent 
form and may ask if the research team can continue to review and record information from the 
subject’s medical chart as listed in Appendix D for the remaining duration of the study. Verbal 
permission from the subject for continuing review and recording of information from the 
subject’s medical chart will be documented in their medical chart prior to withdrawal from the 
interventional component of the study. Patients who are withdrawn from the interventional 
component of the study and who also decline further review and recording of information from 
their medical chart will be withdrawn from the study. 
Subjects who are withdrawn from the interventional component of altering CRT programming 
during study will have CRT programming either set back to baseline CRT programming (same 
programming prior to enrollment) or further changes to CRT device programming will be under 
the discretion of the subject’s device, cardiology, and electrophysiologist providers.  
 
Records and Data Collection Procedures 
 
Data Management  
 
Data Collection: See Appendix D variable lists  
 
Data Storage:  Upon completion of data abstraction, data recorded will be split into two 
files. The first file will be a linking key which will contain identifiable PHI (Name, 
MRN, DOB, etc.), and the second file will be a limited data set. The linking key will be 
stored in a folder separate from the limited data set. The data will not be transferred 
outside of Allina Health. 
 
Data Sharing and Use Agreements: Not required for this study.  
 
Data and Security and Confidentiality: The confidentiality of records identifying the 
subject will be maintained to the extent permitted by applicable laws and/or regulations. 
Paper documents will be secured physically in a secure office suite with badge access. 
Electronic study records will be protected with electronic safeguards, which include 
computer passwords, access privileges, and firewalls. Confidentiality statements are 
required of research staff upon hire. Access to study records will be limited to research 
staff. The site will not use collected information for purposes other than the research 
purposes for which a waiver of consent and HIPAA Authorization was obtained. 
 
An auditor, IRB, and/or other regulatory authorities as required by law will have access 
to study-related records. Study-related records identifying the subject will be kept 
confidential and, to the extent permitted by applicable laws and/or regulations, will not be 
made publically available. If any results of the study are published, the subject’s identity 
will remain confidential 
 
Data Retention & Destruction:  

 
 
 
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Storage and access: After verifying that the study results have been published, the 
dataset will be reviewed to ensure de-identification and retained indefinitely. De-
identified datasets will be housed in the password-protected Allina Health share 
drive. The linking key will also be retained electronically on the Allina share 
drive, will be password protected, stored in a separate location from the de-
identified dataset, and will be restricted to key personnel responsible for 
managing archived study data. The linking key will be retained in order to 
validate any inquiries regarding study results after publication and closure of the 
study, as well as if a subject’s medical providers has questions regarding 
participation and continuing cardiovascular care. The screening log will be 
destroyed upon closure of the study. The destruction of documents containing 
identifiers after publication and study closure will be conducted as follows: 
 
Paper files will be shredded in a secure bin. Electronic files, which are stored on 
the Allina server network, will be deleted using Allina's electronic data practices. 
14 days after these files and data are deleted, they cannot be recovered and will 
therefore be destroyed. 
 
De-identified data collected for this study may be used by MHIF for future 
research purposes and may be shared in de-identified form with outside 
researchers for their use in other research studies. 
 
 
Sharing of Results with Subjects:  
Study staff or study doctor(s) will discuss these results with participants in clinic 
or over the phone after the 12 month/ Visit 4 follow-up visit and completion of all 
study activities. Patients will be un-blinded to randomization assignments after 12 
month/ Visit 4 follow-up visit and complete all study activities. Study doctors will 
be made available if needed. A research or telephone encounter will be created to 
document the review of the results of the study. Patients will be informed of the 
detailed information regarding their heart’s function when seen in follow-up. 
 
 

 
 
 
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Consent/HIPAA Waiver Criteria 
 
Consent and HIPAA Authorization Details for all Aspects of Study  
 
Written Informed consent 
Informed consent and HIPAA authorization will be obtained for the prospective 
collection of data for patients consenting to participation in the trial.  
HIPAA Authorization – Partial Waiver Request and Justification 
To identify potential participants for this research study, pre-screening procedures using 
EPIC need to be performed prior to requesting patients to sign the consent form. It is not 
practical for the research team to request HIPAA Authorization from every patient who is 
seen at MHI for CRT, who might be eligible to participate in the study. By approaching 
all patients, who may be ineligible, eligible patients may be missed and would not have 
the opportunity to participate in the research study. In addition, requiring HIPAA 
Authorization for pre-screening procedures would not only be burdensome and 
challenging for the research team and make the research not practical to carry out, but 
also patients' total time in hospital would lengthen because more patients presenting for 
coronary angiography would be approached to provide such authorization, who may be 
found to not be eligible to participate and such knowledge could have been gained from 
the information in EPIC, thus lengthening overall standard of care visits for patients who 
do not otherwise qualify.   
Without access to and use of PHI, eligible participants could not be identified for this 
research study. Therefore, as PHI is required for the identification of eligible participants 
and manual extraction of data from the EMR and EDW, the research could not 
practicably be conducted without access to and use of PHI. 
 
Study Risks and Benefits 
 
The benefits associated with participation in the study include, but not limited to, the following: 
Subjects may benefit from having CRT device programming optimized which could result in 
improvements to cardiovascular function and/or improvements in heart failure symptoms. 
Subjects may also benefit from early discovery of new or worsening cardiovascular issues if 
present during time of the multi-lead ECG assessment or CMR. In the case that study staff 
identifies new cardiovascular issues, such issues will be acknowledged and relayed to an 
appropriate physician for clinical follow-up. 
This study may not provide benefit to some subjects but may offer further insights on patients 
deemed non-responders to cardiac resynchronization therapy as well as future treatment in 
patients implanted with CRT devices  
The risks associated with participation in the study include, but are not limited to, the following: 

 
 
 
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Risks Associated with Multi-lead ECG Assessment  
The multi-lead ECG assessment does not, by design or intention, introduce energy into the 
subject. The multi-lead ECG assessment captures data similar to a standard 12-lead ECG but has 
more electrodes. There are risks of irritation or allergic reaction to electrode adhesives and gels; 
however, severe reactions are rare, and most subjects have had some form of ECG prior with no 
adverse reactions to the use of electrode adhesives and gels. The research team has utilized the 
multi-lead ECG in more than 100 subjects in other studies and has reported no injuries or allergic 
reactions. 
The risks of changing CRT device settings during the multi-lead ECG assessment are similar to 
those associated with changing device settings using standard 12-lead ECGs. A device nurse will 
be present during the device check and multi-lead ECG assessment. Having a device nurse 
present will minimize risks by: 
• 
Monitoring heart rhythm 
• 
Reviewing any irregular heart rhythms recorded by a patient’s device (arrhythmias) 
• 
Ensuring device settings tested during the data collection are appropriate for the patient 
based on their underlying conduction 
• 
Setting up and reviewing device monitoring parameters per site’s clinical protocols  
• 
Address and forwarding any cardiovascular health concerns to other providers as a 
component of a patient’s clinical care if needed 
 
Risk Associated with Changing Cardiac Device Settings: 
Risk of changing device settings from the information obtained from the multi-lead ECG 
assessment are similar to those associated with changing device settings using information from 
standard electrocardiography. These risks could include worsening symptoms of heart failure, 
although instances of worsening heart failure due to changes in cardiac device settings as part of 
device optimization have been rarely observed in hundreds of previous patients. Some examples 
of worsening symptoms of heart failure include, but are not limited to, the following: 
• 
Shortness of breath when performing activities 
• 
Buildup of fluid in the legs (edema) 
• 
Tiredness or fatigue 
• 
Impaired thinking or confusion 
• 
Lack of hunger or feeling sick (nausea) 
• 
Persistent coughing or wheezing 
 
Risks Associated with Cardiac Magnetic Resonance Imaging 
Magnetic fields and radio waves are not associated with any known risks unless patients have an 
implanted medical device that is magnetic. The main risks/discomforts associated with CMR are 
related to lying flat in the scanner and not moving for approximately one hour. These are listed 
below: 

 
 
 
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• Claustrophobia (fear of confined spaces) during CMR scan 
• Mild diaphoresis (sweating) during and up to 1 hour after CMR scan  
• Sensation of bodily warmth during and up to 1 hour after CMR scan 
• Hearing Impairment (less than 24 hours) 
• Body stiffness related to immobility (less than 48 hours) 
 
Risks and Side Effects from the Required Intravenous Agents: Gadolinium 
GADOLINIUM.  Patients undergoing a CMR will require an intravenous (IV) dye (contrast) 
known as gadolinium. Gadolinium is a liquid chemical that has useful magnetic properties 
allowing a high resolution image of the heart muscle and any scar tissue which may be present. 
Gadolinium is FDA approved and considered quite safe.  Potential risks and side effects are 
listed below:   
• Extravasation.  A rare side effect from any IV contrast injection is extravasation. 
Extravasation means that the contrast material went outside the blood vessel and has gone 
into the surrounding tissue. Extravasation may result in moderate local irritation, redness, 
or swelling at the injection site.  
 
• Nephrogenic Systemic Fibrosis (NSF).  Nephrogenic systemic fibrosis (NSF) is a 
fibrosing (scar tissue) disorder seen only in patients with advanced kidney disease.  The 
condition often first appears as swelling or itching of the skin. It can lead to thickening or 
hardening of the skin and deposits in other parts of the body, such as the lung and muscle. 
Nephrogenic systemic fibrosis has been linked to patients receiving gadolinium contrast 
agents in the presence of underlying severe kidney disease.  
Over the past several years, no new cases of nephrogenic systemic sclerosis have been 
reported. This is likely the consequence of the use of less toxic gadolinium agents and 
limiting the use of gadolinium in patients with severe kidney disease. Newer gadolinium 
agents are considered much less toxic. The agent patients in this study will receive - 
Gadavist (gadobutrol) is in this class, and toxicity cases reported.   
• Allergic Reactions.   Patients who have had an allergic reaction to the contrast used in 
CT, IVP, and angiographic examinations are at increased risk of allergic reactions to 
other contrast agents, including gadolinium.  There is no way to predict who will have an 
allergic reaction before the contrast (gadolinium) is given. Allergic reactions generally 
develop within 10 minutes. Minor contrast reactions are the most common but happen in 
less than 0.05% of cases. Symptoms may include headache, sneezing, nausea, vomiting, 
hives, and swelling and usually, resolve rapidly. Occasionally medications may be 
required to help treat these symptoms if they persist. Rarely, a severe reaction can 
happen. This may include a rapid or slow heart rate, low blood pressure, an asthma attack 
(bronchospasm), or complete circulatory arrest/shock. Such reactions require urgent 
medical treatment, which our offices are prepared to handle.  
 
• Gadolinium retention.  Gadolinium may persist for months in some body areas, such as 
the brain, or in bone. The importance of this is unclear, and no disease process has been 

 
 
 
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associated. The lowest retention has been shown with the type of agents (macrocyclic) 
used at all of our clinics. 
 
Statistical Considerations and Data Analysis 
 
AUC and CRI values derived from the multi-lead ECG assessment are exported to de-identified 
digital spreadsheets. CMR values will be stored on de-identified paper CRFs in the subject 
binders and then entered into a digital spreadsheet that can be imported into statistical analysis 
software. Student t-tests will be utilized to compare continuous variables. Paired t-tests will 
compare CMR values collected between study visits, while two-sample tests will compare values 
between experimental and control arms. Fischer’s Exact Test will compare categorical variables 
(i.e. proportional differences) between the groups. An alpha level of 0.05 will be considered 
significant.   
APPENDICES 
 
APPENDIX A: Electrical Dyssynchrony Map 
 
APPENDIX B:  CMR variables 
 
APPENDIX C: Research Questionnaire (study-specific) 
 
APPENDIX D: Data Collection 
 
 
 
 
 

 
 
 
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APPENDIX A: Electrical Dyssynchrony Map (EDM) 
 
An EDM from an HF patient with LBBB, QRSd 178 ms, and PR interval 200 ms is shown. 
Atrial to RV-pace (A-RVp) and atrial to LV-pace (A-LVp) intervals are shown in milliseconds 
on the “y” and “x” axes, respectively. The AUC from each setting collected during the multi-lead 
ECG assessment is calculated using the propriety algorithm, and the corresponding CRI value is 
used to fill each A-RVp and A-LVp location in a grid-like fashion in the EDM.  The mesh-grid 
of CRI values is then interpolated using MatLab software to generate an EDM where high 
electrical dyssynchrony (low CRI value) is depicted in cool colors, and low electrical 
dyssynchrony (high CRI value) is depicted in warm colors. 
 
 
 
The bold horizontal line traversing from the lower-left corner to the upper right corner of the 
EDM shows CRI during simultaneous BiV pacing at a range of different AVDs. The dashed box 
across the top of the EDM depicts electrical synchrony at LV-only pacing since the A-RVp is 
very long and not contributing to LV depolarization. The optimal synchrony line (OSL) is 
depicted as a dashed line through the middle of the red area on the graph and allows for 
calculation of the native, RVp, and LVp electrical wavefronts as well as the optimal CRI overall. 
The optimal setting during simultaneous BiV pacing is the highest CRI along the bold horizontal 
line; likewise, the optimal setting during LV-only pacing is the highest CRI in the dashed box.  
 

 
 
 
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APPENDIX B:  Magnetic Resonance Imaging variables (at each one of the CRT settings). 
 
● Left and Right Ventricular volumes (end-diastolic, end-systolic, stroke volume, forward 
stroke volume) (ml) 
● Left and Right Ventricular mass (g) 
● Left and Right Ventricular ejection fraction (%) 
● Left and Right Ventricular Global Longitudinal Strain (%), Global Circumferential Strain 
(%) and Global Radial Strain (%) 
● Time difference between the anteroseptal and posterior wall segmental peak strain (msec) 
● Left and Right Atrial volume (ml) 
● Forward LV and RV stroke volume (ml) 
● Mitral regurgitation (reg. volume and reg. fraction) 
 
The following variables will not be modified by the CRT pacer settings and measured only once:  
● Native T1 mapping (pre-contrast) (msec) 
● Post Contrast T1 mapping (msec) 
● Scar Burden (%) - ratio between scar mass/LV mass 
● Extracellular volume fraction (%) 
 
 

 
 
 
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APPENDIX C: Research questionnaire (study-specific) 
 
Each subject will be asked at baseline and follow-up visits (Visit 1 and Visit 3, respectively) the 
following questions regarding CRT implantation and cardiovascular health. 
 
Visit 1: Research Questionnaire 
 
In regards to your cardiovascular health and heart failure symptoms, how have you felt since 
implantation of your cardiac resynchronization therapy device? 
 
o Worse 
o Same 
o Mildly Better 
o Moderately Better 
o Markedly Better 
 
Visit 3: Research Questionnaire 
 
In regards to your cardiovascular health and heart failure symptoms, how have you felt since the 
beginning of this study? 
 
o Worse 
o Same 
o Mildly Better 
o Moderately Better 
o Markedly Better 
 
Visit 4: Research Questionnaire 
 
In regards to your cardiovascular health and heart failure symptoms, how have you felt since the 
beginning of this study? 
 
o Worse 
o Same 
o Mildly Better 
o Moderately Better 
o Markedly Better 
 
 
 
 
 

 
 
 
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APPENDIX D: Data collected from medical chart  
 
Data to be collected on enrolled subjects: 
 
1. Demographics (abstracted from medical chart) 
a. Medical record number (MRN) 
b. Date of birth (DOB)/ age 
c. Gender 
d. Body mass index (height/ weight) 
e. Race/ethnicity 
2. Medical and cardiovascular history (abstracted from medical chart) 
a. Cardiovascular history 
b. Respiratory and pulmonary history 
c. Cardiac electrical conduction history  
d. Current cardiac medications 
e. Labs and vitals 
3. Imaging (includes imaging prior to CRT implantation) 
a. Echocardiographic values and images 
b. CMR values and images  
c. Chest x-rays images 
d. Fluoroscopic images from CRT implantation 
e. CT images 
4. CRT device and device interrogations 
a. Date of implant 
b. Manufacturer of device 
c. Lead positions 
d. Types of leads present 
e. Programming of device 
f. Arrhythmia episodes 
g. Device measurements and values 
5. ECGs 
a. Pre-CRT ECGs 
b. Post-CRT ECGs 
c. Interim ECGs 
d. Multi-lead ECG data (collected during study)