Adaptive CRT Effect on Electrical Dyssynchrony
Phase: NA
Conditions: Cardiomyopathy, Heart Failure, Left Bundle Branch Block
Sponsor: Larisa Tereshchenko

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Title: Adaptive CRT effect on ELectrical dysSYNChrony (aCRT ELSYNC) 
 
Clinical Investigation Plan 
 
1st year 
 
Version 6 
November 20th, 2015 
 
 
 
 
 
PI Larisa Tereshchenko MD, PhD,  
Oregon Health & Science University, 
3181 SW Sam Jackson Park Rd. UHN62 
Portland, OR, 97239 
. 

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Table of Contents 
 
 
Abbreviations .................................................................................................................. 3 
Introduction ..................................................................................................................... 3 
Study Purpose ............................................................................................................................. 3 
Hypothesis................................................................................................................................... 4 
Study Scope ................................................................................................................................ 4 
Background and Justification ...................................................................................................... 5 
Study Objectives ............................................................................................................. 7 
Primary Objective(s) ................................................................................................................... 7 
Secondary Objective(s) ............................................................................................................... 7 
Device and intended use: ............................................................................................................ 7 
Methodology .................................................................................................................... 8 
Study Design ............................................................................................................................... 8 
Subject Selection ......................................................................................................................... 9 
System Description ................................................................................................................... 10 
Study Procedures .......................................................................................................... 11 
Informed Consent Process ........................................................................................................ 11 
Randomization .......................................................................................................................... 11 
Blinding, or Masking ................................................................................................................ 13 
Data Collection ......................................................................................................................... 13 
Follow-up .................................................................................................................................. 19 
Study Exit/Withdrawal.............................................................................................................. 20 
Statistical Methods and Data Analysis .......................................................................... 21 
Justification for Sample Size .................................................................................................... 21 
Risk Analysis ................................................................................................................. 22 
Potential Risks .......................................................................................................................... 22 
Risk Minimization .................................................................................................................... 24 
Potential Benefits ...................................................................................................................... 26 
BUDGET ......................................................................... Error! Bookmark not defined. 
Appendix: Bibliography .................................................................................................. 27 

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Abbreviations  
aCRT – adaptive cardiac resynchronization therapy 
 
CRT-D – CRT with defibrillation therapy 
 
CRT-P – CRT with pacemaker only therapy 
 
cCT – Computed Tomography 
 
ECG – electrocardiogram 
 
ECGi – electrocardiographic imaging 
 
EDI – electrical dyssynchrony index 
 
EGM – electrogram 
 
ICD – implantable cardioverter defibrillator 
 
LV/RV – left ventricle/right ventricle 
 
LBBB – left bundle branch block 
 
NYHA Classification – New York Heart Association heart failure classification 
 
SAI QRST – sum absolute QRST integral 
 
Introduction 
 
Study Purpose 
This is an investigator-initiated prospective, single-center, randomized, double-
blind paralleled controlled clinical trial comparing adaptive cardiac resynchronization 
therapy (aCRT)1 to a standard CRT in patients with currently approved (class I-II) 
indications for CRT2. The purpose of this study is two-fold: First, to determine if aCRT is 
superior as compared to standard CRT, as evidenced by a superior degree of reduction 
of electrical dyssynchrony index 6-month post-CRT. An Intra-LV electrical dyssynchrony 
index will be computed from the electrocardiographic imaging (ECGi) LV epicardial 
activation maps; Second, to determine if a surface ECG metric sum absolute QRST 
integral (SAI QRST) is a superior estimate of an intra-LV dyssynchrony, as compared to 
an averaged across 12-lead QRS duration.  
 

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 All study participants will receive the commercially available Viva™ XT CRT-D 
Model DTBA1D4, DTBA1D1, Viva™ Quad XT CRT-D Model DTBA1Q1, DTBA1QQ, 
Viva™ Quad S CRT-D Model DTBB1Q1, DTBB1QQ, Viva™ S CRT-D Model 
DTBB1D1, DTBB1D4 or Viva™ XT CRT-P Model C6TR01. All the above models with 
the exception of the Viva™ Quad S and Viva™ S CRT devices have aCRT available27-
31. All CRT-D devices (Models DTBA1D4, DTBA1D1, DTBA1Q1, DTBA1QQ, DTBB1D1, 
and DTBB1D4, DTBB1Q1, DTBB1QQ) detect ventricular tachyarrhythmias and can 
provide treatment in order to resynchronize the pacing of the left and right ventricles and 
can provide full defibrillation in the case of ventricular fibrillation. These models have the 
same indications and contraindications. The CRT-P device (Model C6TR01) similarly 
detects ventricular tachyarrhythmias, but only responds with resynchronization pacing 
therapy, not defibrillation. CRT-D and CRT-P models are both indicated in patients with 
heart failure according to the inclusion and exclusion criteria set forth by this protocol. 
Choice of model is made on a case-by-case basis depending on patient symptoms that 
would increase likelihood of need for defibrillation. The model and lead type used will be 
at the discretion of the physician implanting the device. All patients will be randomized 
to one of two pacing therapy arms, aCRT ON or aCRT OFF.  
The outcome of this study is expected to support use of SAI QRST as an 
estimate of an intra-LV electrical dyssynchrony, and to improve our understanding of the 
mechanisms behind aCRT effect. 
Hypothesis 
We hypothesize that (1) aCRT is superior as compared to standard CRT, as 
evidenced by a superior degree of reduction of electrical dyssynchrony index 6-month 
post-CRT; and (2) a surface ECG metric SAI QRST3-5 is a superior estimate of an intra-
LV dyssynchrony, as compared to an averaged across 12-lead QRS duration. 
Study Scope 
Study will be conducted at the Oregon Health & Science University. It is a prospective, 
single-center, randomized, double-blind paralleled controlled clinical trial. As estimated, 
32 participants will be enrolled. All study participants will get commercially available 
Viva™ XT CRT-D device. Participants will be randomized 1:1 to one of two pacing 
therapy arms, aCRT ON or aCRT OFF (traditional BiV CRT). Patients who are receiving 
CRT device without available adaptive CRT feature (i.e. it is impossible to program 
adaptive software feature ON or OFF) per their clinical team (post-screening) will be 
placed into a third, non-randomized, non-blinded CRT registry arm. Study participants 
will undergo cardiac MRI and ECGi before device implantation. A second ECGi will be 
performed within two weeks  hours after CRT implantation. Duration of assigned 
intervention is 6 months. At least 6-month post CRT (within 30-day interval) participants 
will undergo a 3rd ECGi and echocardiogram. There are 2 primary outcomes in this 
study: (1) regression slope of Electrical Dyssynchrony Index values measured by ECGi 
6 months post-CRT, regressed against Electrical Dyssynchrony Index values measured 
by ECGi prior CRT; (2) difference in regression slopes of SAI QRST against Electrical 
Dyssynchrony Index values measured by ECGi vs. QRS duration against Electrical 
Dyssynchrony Index (EDI) values measured by ECGi. 

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Background and Justification 
Cardiac resynchronization therapy prolongs life and decreases risk of heart failure 
exacerbation in patients with low ejection fraction (EF) and wide QRS.6-9  Aging 
population with high prevalence of obesity, diabetes and hypertension, along with 
advancements in the treatment of acute cardiovascular diseases resulted in an increase 
in the incidence and prevalence of the heart failure (HF) over the past decades. Studies 
estimate that about 2-3% of the population suffer from HF. Despite advances in therapy 
and management, HF carries substantial morbidity and mortality, and high rates of 
hospitalizations and hospital readmissions represent large burden to the health-care 
system. CRT is an effective treatment for patients with HF, wide QRS, and reduced EF. 
However, about 30% of CRT recipients do not demonstrate mechanical response on 
CRT.  
QRS duration and LBBB serve as criteria for favorable response to CRT. QRS 
duration served as a main ECG criterion for assessment of electrical dyssynchrony. 
However, QRS duration has limitations and better measure of electrical dyssynchrony is 
needed. Approach to patients with QRS 120-150 ms is unclear. We recently showed in 
blinded analysis of SMART AV study (Tereshchenko et al, abstract presented at HRS 
2014) that a novel measure of electrical dyssynchrony, sum absolute QRST integral 
(SAI), better predicts CRT response than QRS duration alone. Patients with the high 
mean SAI (3rd tertile) have 2.5 times greater odds of response than those with low mean 
SAI (1st tertile), and 2.0 times greater than the lower two tertiles combined. Trend 
towards the interaction between SAI and left BBB was observed (P=0.08). The effect 
size was stronger in the non-LBBB patients. Thus, high SAI QRST was strongly 
independently (beyond QRS duration) associated with CRT response in the SMART-AV 
study. However, association of SAI QRST with a gold standard of LV electrical 
dydssynchrony (ECGi EDI) has not been tested in a prospective study, and SAI QRST 
was not compared with QRS duration.  
Adaptive CRT is a device-based algorithm that regularly measures the intrinsic 
conduction intervals that result in continuous optimization of AV and VV delays, and 
promote synchronized LV pacing1, 10. Synchronized LV pacing is a CRT pacing 
configuration that times the LV pacing with intrinsic RV conduction11, 12. It is known that 
the RV pacing, alone or during BiV pacing, in patients with LV systolic dysfunction 
worsens LV and RV performance13. As was previously reported in GREATER-EARTH 
study, there was 17% improvement of CRT response by switching from BiV pacing non-
responders to LV pacing14. Randomized aCRT clinical trial showed that aCRT improves 
the LV performance and clinical CRT response, and demonstrated superiority of aCRT 
as compared to echo-optimized BiV pacing1. Subsequent analysis of aCRT trial showed 
that a higher percentage of synchronized LV pacing in the aCRT trial was associated 
with a decreased risk of mortality and HF hospitalizations12, with Kaplan-Meier curves 
starting separation after first 6 months of CRT.  
However, mechanistic differences in aCRT effect are incompletely understood, and 
the population of patients, who would benefit from aCRT the most, is not very well 
defined. The following knowledge gaps remain and will be addressed in the proposed 
study. 

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1. Post-hoc analysis of aCRT trial12 showed superiority of aCRT in a subgroup of 
patients with normal intrinsic AV interval at randomization, defined by the device as 
the interval from the right atrial (RA) activation to the right ventricular (RV) intrinsic 
activation ≤ 200ms if in sinus rhythm or ≤ 250 ms if in atrial pacing. However, this 
finding was not replicated in a prospective study, and mechanisms are not 
completely understood. Currently the best correlate to RA-RV activation time on 
surface ECG is unknown. It is unknown if PR interval on the surface ECG (or 
another surface ECG parameter) could predict the response to aCRT, as compared 
to response on traditional BiV CRT. At the same time, presence of an interaction 
between PR interval and CRT was shown by several other studies. Recent post-hoc 
analysis of MADIT-CRT15 showed that patients with a long PR interval (and non-
LBBB) obtained the largest benefit from BiV CRT, whereas patients with normal PR 
interval (and non-LBBB) did not respond on BiV CRT. This data confirms presence 
of an interaction of CRT with PR interval. Mechanisms behind such an interaction 
are not entirely clear, and will be addressed by the proposed study.  
2. Few conducted observational ECGi studies16, 17 showed presence of significant 
variations in electrical dyssynchrony substrate. Proposed study is the first 
randomized clinical trial with ECGi-measured electrical dyssynchrony index as an 
outcome. Proposed study will help to explain results of previously conducted CRT 
trials and will demonstrate effect of aCRT on electrical dyssynchrony substrate, 
characterized by ECGi. 
3. aCRT trial was conducted in patients who underwent echo-optimization of AV delay. 
However, echo-optimization of AV delay is not routinely used in clinical practice18. 
SMART-AV study19 did not show difference in outcomes of echo-optimized and fixed 
AV delay (120 ms). Proposed study will compare nominal programming without AV 
optimization to aCRT.  

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Study Objectives 
 
Primary Objective(s) 
1. To determine if aCRT is superior to standard CRT, as evidenced by a superior 
degree of reduction of electrical dyssynchrony index 6-month post-CRT. An Intra-
LV electrical dyssynchrony index will be computed from the electrocardiographic 
imaging (ECGi) LV epicardial activation maps as the difference & standard 
deviation of activation times at 352/700 sites on the LV epicardium, including the 
epicardial aspect of the septum.  Outcome measured: Change in EDI from 
baseline to 6-mo post CRT. 
2. To determine if a surface ECG metric sum absolute QRST integral (SAI QRST) is 
a superior estimate of an intra-LV dyssynchrony, as compared to QRS duration. 
Outcome measured: Regression slope of SAI QRST against EDI value and 
regression slope of QRS duration against EDI value 
 
Secondary Objective(s) 
1. To determine if the interval between the end of P-wave and the onset of QRS 
complex in lead V1 (PeRV1) is associated with intracardiac RA-RV activation 
time. Outcome measured: AVinterval from EGM and PR interval in ECG 
2. To determine if aCRT is associated with the development of reverse electrical 
remodeling (defined as shrinking of non-paced QRS duration above or equal 10 
ms at least 6-months post-CRT), and development of mechanical response, 
defined as a decrease in left ventricular end-systolic volume ≥ 15mls after 6 
months of CRT. Outcome measured: non-paced QRS duration from ECG and 
left ventricular end-systolic volume from echo. 
3. To determine if aCRT is associated with improvement of the quality of life and 
adverse events, and other clinically important outcomes. Outcome measured: 
questionnaire scores, hospitalizations, death, device removal/complications, 
NYHA classification, and 6 minute walk scores. 
4. To determine if spatial QRS-T angle and QRS & T loops derived from 
intracardiac EGMs, correlate with spatial QRS-T angle and QRS & T loops 
derived from orthogonal ECG (transformed from recorded 12-lead ECG). 
Outcome measured: QRS-T angle and loop values from ECG and EGM. 
Device and intended use: 
All study participants will receive the commercially available Medtronic Viva™ XT CRT-
D Model DTBA1D4, DTBA1D1, Viva™ Quad XT CRT-D Model DTBA1Q1, DTBA1QQ, 
Viva™ Quad S CRT-D Model DTBB1Q1, DTBB1QQ, Viva™ S CRT-D Model 
DTBB1D1, DTBB1D4 or Viva™ XT CRT-P Model C6TR01 and three leads (one right 
atrial, one right ventricular, and one left ventricular lead), implanted as clinically 
indicated, as part of routine medical care. 
 
 

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Methodology 
 
Study Design 
We will conduct an investigator-initiated prospective, single-center, randomized, 
double-blind paralleled controlled clinical trial comparing adaptive cardiac 
resynchronization therapy (aCRT)1 to standard CRT in patients with currently approved 
(class I-II) indications for CRT2. Following verification that inclusion/exclusion criteria are 
met, all patients will undergo baseline evaluation/testing. All study participants will 
receive the commercially available Medtronic Viva™ XT CRT-D Model DTBA1D4, 
DTBA1D1, Viva™ Quad XT CRT-D Model DTBA1Q1, DTBA1QQ, Viva™ Quad S CRT-
D Model DTBB1Q1, DTBB1QQ, Viva™ S CRT-D Model DTBB1D1, DTBB1D4 or Viva™ 
XT CRT-P Model C6TR01. These devices are already used in standard-of-care for 
patients receiving CRT implantations.  No co-investigators will be paid by Medtronic 
funding for use of these devices. Following successful implantation, ECG/EGM 
recording and device programming will be performed according to the protocol and 
participants will be randomized to either the aCRT ON or the aCRT OFF pacing arm. 
Should implantation or randomization not be successful, patients will be followed as 
defined in further sections. Protocol-required 6-month follow-up visit will occur at least 6 
months post randomization (within 30-days window). Patients will remain randomized in 
the assigned therapy arm until 6-month follow-up visit. After that, no study visits is 
planned. Follow-up will continue during next 5 years remotely (via phone, remote follow-
up, RedCap surveys).  
 
 
 
 
 
 
 

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Study Schema 
Subject Selection 

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Number of patients: The study will require up to 16 patients randomized to one of two 
pacing therapy arms (up to 32 patients enrolled). 
 
Patients of both genders with mild to moderate heart failure who meet all 
inclusion/exclusion criteria are eligible for this study. Listed below are the specific 
inclusion and exclusion criteria: 
 
Inclusion criteria:  
• Patient has a standard class I or class II indications for CRT-P or CRT-D 
implantation in accordance with ACC/AHA/HRS guidelines (2012 
ACCF/AHA/HRS Focused Update Incorporated Into the ACCF/AHA/HRS 2008 
Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities)2.At least 
18 years of age at the time of consent 
• Is willing and able to comply with the protocol 
 
Exclusion criteria:  
• Chronic atrial arrhythmias defined as: “Atrial fibrillation is permanent when it has 
resisted all attempts to restore sinus rhythm or when the physician and patient 
decide that no such attempt should be made.” 
• Patient has ever had a previous or has an existing CRT system, ICD, or 
pacemaker that has PACED the patient the majority of the time. 
• GFR <30ml/min 
• Patient has had unstable angina, acute myocardial infarction, coronary artery 
bypass graft surgery, or percutaneous transluminal coronary angioplasty within 
30 days prior to study enrollment 
• Patient has primary valvular disease and is indicated for valve repair or 
replacement 
• Patient is enrolled in ≥1 concurrent studies that would confound the study results 
(any other interventional trial) 
• Patient is pregnant or of childbearing potential and not on a reliable form of birth 
control. All women of child-bearing potential must undergo a pregnancy test. 
• Patient status post heart transplant 
• Patient has been classified as NYHA functional class IV within 3 months prior to 
study enrollment 
• Concomitant conditions other than cardiac diseases that were associated with a 
higher likelihood of death during 1 year after enrollment 
• Patient, legal guardian or authorized representative is unable or unwilling to 
cooperate or give written informed consent 
 
System Description 
All study participants will receive the commercially available, clinically indicated (no 
study expense) Medtronic Viva™ XT CRT-D Model DTBA1D4, DTBA1D1, Viva™ Quad 
XT CRT-D Model DTBA1Q1, DTBA1QQ, Viva™ Quad S CRT-D Model DTBB1Q1, 

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DTBB1QQ, Viva™ S CRT-D Model DTBB1D1, DTBB1D4 or Viva™ XT CRT-P Model 
C6TR01. 
 
Study Procedures 
 
Informed Consent Process 
Study protocol will be reviewed and approved by the OHSU IRB before the beginning of 
the enrollment in the study. All study participants will sign consent form before entering 
the study. We will request IRB to give us permission (via a Prep to Research form) to 
review medical records of study candidates for inclusion/exclusion criteria. This 
information will not be recorded.  The research study coordinator will screen the OHSU 
Arrhythmia and Heart Rhythm Clinic schedule through Epic for patients who may be 
candidates for CRT and will contact the care provider to discuss if patient is a 
candidate. Patients, who have approved class I-II indications for CRT-D or CRT-P 
according to current guidelines, who are scheduled for Medtronic CRT-D or CRT-P 
device implantation will be approached in the clinic at the time of scheduling for CRT 
implantation.  At this point the study and informed consent form will be explained to the 
patients. These patients who are willing and able to sign the consent form will be invited 
to participate in the study and a baseline enrollment visit will be scheduled. Final 
determination of eligibility will be made during the initial visit and scheduled baseline 
study visit. After signing consent form eligible study candidate will become study 
participant.  
 
Randomization 
Assignment of patients into aCRT on or off will occur through the randomization module 
in REDCap.  Only the study coordinator and primary investigator will have access to 
view patient treatment assignments on the REDCap database.  The following 
information outlines the randomization module implemented via REDCap.   
 
The unit of randomization: a person (study participant). 
The type of randomization: random stratified block 
 
Assignment ratio: 1:1 
 
Assignment strata: (1) gender (male vs female); (2) cardiomyopathy type 
(ischemic vs. non-ischemic). 
 
Block size: random (2, 4, or 6) with allocation proportional to the elements of 
Pascal’s triangle. 
Random seed used and the randomization list were created using the –ralloc- program 
in Stata version 13.1 
 
Randomization will be enacted via an envelope-based system, via sealed envelopes 
containing randomization assignments. Random treatment assignments will be placed 
in advance in a set of sealed envelopes. Each envelope will be numbered (#1-32), 

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opaque, and otherwise tamperproof. When a participant is randomized, his/her name 
and the number of the next unopened envelope are first recorded in the presence 
of a second staff member and both sign the envelope. Then the envelope is 
opened, and the treatment group contained therein assigned to the participant and 
recorded on a log.  
 
Study participants who, because of clinical reasons per clinical team decision, will 
receive a CRT device without the adaptive software feature enabled will NOT be 
randomized, but instead, will be included in the study registry arm.

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Blinding, or Masking 
In order to minimize the introduction of bias, this study will be double-blinded (double-
mask). Patients will not have access to their randomization assignment. To obtain non-
biased information and perform non-biased assessments, physicians and their staff who 
will evaluate NYHA classification and heart failure stage, and administer the Minnesota 
Living with Heart Failure Questionnaire, and Patient Global Assessment tools will be 
masked to the patient’s assignment and device programming. Un-masked physicians 
and staff will be responsible for randomization, programming the system, monitoring the 
system performance, and collecting system data for this study. Study personnel will be 
trained to take special care to ensure that patients do not inadvertently learn of their 
assignment as a result of communication with their care provider. A log will be 
maintained to identify staff that will remain blinded to the randomization assignment and 
programming.  
 
Data Collection 
For patients that meet all inclusion/exclusion criteria, are enrolled in the study, clinical 
data will be collected for patient history, implant, pre- and post-implant baseline 
evaluation/testing, randomization, protocol-required scheduled follow-up visit, remote 
follow-up visits, system modification and study exit (including death) until study closure 
(5 years). Hospitalizations and adverse events (including adverse event-related 
emergency department and urgent care visits) will be reported until the patient exits the 
study or study closure. 
 
All data will be entered in the digital secure web-based database (REDCap Consortium 
partner http://www.project-redcap.org/). 
 
Data collection requirements are summarized in Table 1. 
 
Subject Follow-Up Schedule 
 
During the first year of the study, first follow-up visit will be made at least 6 months after 
CRT-D implantation (within 30-day range). After the six-month follow-up visit, follow-up 
via phone call, REDCap surveys, or data collection from routine clinic visits will be 
scheduled at 12 months, 24-, 36-, 48-, 60-months post-CRT implantation.  Follow-up 
after six months will be optional based on patient availability. 
 
 

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Table 1. Overview of Data Collection for the aCRT ELSYNC Study 
Study procedure 
Before 
device 
implantation  
During first 
two weeks  
after device 
implantation  
Study F/U 
Visit #1 – 
6-month 
post-CRT 
Remote F/U via 
phone call/ 
ReDCap 
survey/ remote 
device F/U/ 
medical chart 
review once a 
year up to 5 
years post-
implant 
Enrollment 
X 
 
 
 
Randomization 
X 
 
 
 
Medical History 
X 
 
 
 
Cardiovascular 
medications recorded 
X 
x 
X 
X 
Lead position imaging 
 
X 
 
 
NYHA functional 
classification recorded 
X 
 
X 
X 
MLHFQ and SF-36 
X 
 
X 
X 
Venipuncture 
X 
 
X 
 
Cardiac MRI or cCT 
X 
 
 
 
Body surface mapping 
(ECGi) 
X 
X 
X 
 
Kinect-sensors ECG leads 
position 
registration/placement 
X 
X 
X 
 
Digital intracardiac EGMs 
and ECG recording ON 
RVP, LVP, BiVP 
 
X 
X 
 
Digital intracardiac EGMs 
and ECG recording in 
sinus rhythm (OFF 
pacing) 
X 
X 
X 
 
Echocardiogram 
 
 
X 
 
Digital resting 12-lead 
ECG (10-sec) 
X 
X 
X 
 
Holter ECG during 6-min 
walk 
X 
 
X 
 
Central venous pressure 
(CVP) non-invasively by 
Mespere Venis 1000 
X 
X 
X 
 
Hospitalizations, death, 
adverse events or 
updates 
 
X 
X 
X 

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Cardiovascular medications will be collected at patient history and required scheduled 
follow-up visits. Current cardiovascular medications and dosages must be reported at 
each required scheduled follow-up visit. The dose reported should reflect the dosage 
that the patient is on at the end of the visit. If a medication is not given daily, the 
average daily dose over a seven-day period should be calculated and recorded. 
 
Lead position imaging. After CRT implantation, biplane fluoroscopy in orthogonal views 
(left anterior oblique [LAO] 60° and right anterior oblique [RAO] 30°) will be performed, 
as well as traditional AP and lateral views. 
 
The Minnesota Living with Heart Failure Questionnaire and SF-36 Questionnaire will be 
completed. Every effort should be made to have the patient complete the questionnaire 
himself or herself. However, blinded study personnel may administer the questionnaire 
if necessary. The name(s) of blinded personnel administering/overseeing completion of 
this form must be documented in the patient’s medical record. 
 
cCT data acquisition and analysis 
Patients with a contraindication to MRI due to personal preference (i.e. severe claustrophobia), 
body size too large for the MRI bore or medical reasons such as presence of a medical device 
(pacemaker or ICD not pacing the patient the majority of the time) will undergo a prospective 
cardiac computed tomography (cCT) scan rather than MRI. cCT will be performed at OHSU. 
 
 
CMR data acquisition and analysis by tissue tracking 
Cardiac research MRI will be performed at OHSU.  
Enrolled participants will undergo CMR using 1.5T whole body MRI scanners 
(Avanto; Siemens Medical Systems, Erlangen, Germany) on the same day as the ECG 
and ECGi recordings.  
 
Clinical echocardiography laboratory at OHSU will analyze the echo images 
obtained. A handbook detailing instructions for imaging and data acquisition will be 
provided to the echocardiographers performing the examinations. Traditional 
assessment of LV structure and function will be performed. 
Echocardiogram performed for clinical indications before CRT-D implantation will serve 
as baseline echocardiogram. 
 
Cardiovascular medications currently being taken by each subject will be recorded at 
the baseline visit.  Changes in medications will be recorded over the course of the 
study. 
 
NYHA Classification will be evaluated as part of standard of care by the care provider.  
This will be recorded at baseline, 6-month follow-up, and subsequent follow-up dates. 
 
The study participant will have Holter ECG monitoring that will record for 30 
minutes. 6 Minute Walk Test: The 6MWT will be performed in the hospital where 

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emergency equipment and personnel are readily available. An indoor walking course of 
150 feet in length has been identified A starting line, designating the beginning and end 
will be marked. The test will be stopped for severe dyspnea, staggering, ashen 
appearance, or significant chest discomfort. The patient will be instructed on the 
performance of the test according to the ATS statement: Guidelines for the Six-Minute 
Walk Test. At the beginning of the test, vital signs will be recorded. The 10-point Borg 
rating of perceived exertion will also be recorded to measure the individual’s baseline 
dyspnea, and overall fatigue will also be recorded [0=nothing at all; 10=Very, very 
severe (maximal)]. A timer for 6 minutes will be set. The subject will walk as far as 
possible for six minutes, back and forth along the 150- foot hallway. The subject will be 
told every minute how much time remains. Following 6 minutes, vital signs and the post-
walk Borg dyspnea and fatigue levels will be assessed. The distance covered in 
meters/feet will be recorded. Blood pressure and heart rate will be measured after lying 
supine for 10 minutes, then after 2 minutes after standing up. 
 
 
Pregnancy test 
If a woman is of childbearing age, urine HCG will be sent to obtain pregnancy status 
before MRI is performed. MRI with contrast will not be performed on a pregnant woman. 
 
ECG: Standard 12 Lead ECG, Signal Average ECG, and Vectocardiogram. Body 
surface mapping. High resolution (1000 Hz) 12-lead ECG will be recorded during 
10 min at rest (via Mortara Holter recorder) in the supine position and in standing 
the position, and during 6-min walk test.  
 
 
Kinect-sensors ECG leads position registration/placement will be used in order to 
ensure placement of body surface ECG electrodes at the same location at 6 month 
post-CRT visit, as it was at the baseline. We will collaborate with Peter van Dam (Peacs 
(Arnhem, the Netherlands) and will use his Kinect software. He developed 3D Kinect 
Camera software integrated into CIPS that localizes the ECG electrodes. He recently 
demonstrated the reproducibility of the registration of the 3D image with the MRI derived 
torso models, by using his custom software. The CIPS software that integrates and 
registers the 3D camera image of the electrodes to the MRI derived torso model is 
reproducible. The 3D camera is critical for quantitative localization of electrode positions 
for CIPS to accurately localize the position of the electrodes to the cardiac anatomy as 
imaged with a 3D camera. We will use subcontract with Dr. van Dam for the use of his 
software and training. We will use this approach for recording of ECGi data within two 
weeks after CRT implantation (to test accuracy of leads placement at the time when 
heart has not been remodeled yet post-CRT). We will repeat the same procedure at 6-
month post-CRT. 
 
Simultaneous Recording of intracardiac EGMs and 12-lead surface ECG will be 
performed within two weeks after device implantation, before discharge, and at 6-month 
follow-up visit.  

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Intracardiac digital EGMs will be recorded via programmer and NI digitizer (NI USB-
9215A portable data acquisition [DAQ] system). 
EGMs will be recorded according to the following protocol: 
Intrinsic rhythm (pacing OFF) 
RV pacing 
LV pacing 
BiV pacing 
All available configurations of electrograms will be recorded. 
 
During the follow-up, CRT-D device will be interrogated, and all events with stored 
EGMs will be saved to disk, and then translated with translational utility and further 
analyzed.  
 
Electrocardiographic imaging (ECGi) is a novel non-invasive advanced technique, 
characterizing activation and recovery of electrical activity on the epicardial surface of 
the heart. A patient-specific heart-torso model derived from cardiac CT or MRI with 291 
heart-surface nodes will be used to perform ECGI inverse solution. Figure below 
illustrates ECGI procedure. Recoding of ECGI essentially does not differ from recording 
of routine surface electrocardiogram. Surface ECG is recorded in multiple points (133) 
on the torso. ECG body surface mapping will be performed immediately before cardiac 
MRI so that attached electrodes will stay in place during MRI data acquisition.. 
 
Tereshchenko laboratory recently purchased new Active Two Biosemi ECGI system. 
System and electrodes application is illustrated by the figures below. 

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Postdoctoral fellow of PI (Dr. Muammar Kabir, BME PhD) recently completed 2-week 
Image-based modeling course at the University of Utah. http://ibbm.sci.utah.edu/ 
The electrical dyssynchrony index (EDI) is computed as the standard deviation of 
activation times at 350/700 sites on the LV epicardium. 
 
 
 
 
ECGI will be performed 3 times: first before CRT implantation. Second time – within two 
weeks post-CRT implantation. Third time – 6 months post-CRT. ECGi will be will be 
recorded according the following protocol: 
• Pacing OFF, in intrinsic rhythm 
• During BiV pacing 
• During RV pacing 
• During LV pacing 
 
At the end of the study de-identified digital data (intracardiac EGMs, ECGI and 
imaging data) will be provided to Medtronic. 
 
 
 
Questionnaires (SF-36 and MLHFQ). Patients will be asked to fill 2 questionnaires: 
SF-36 and Minnesota Living with Heart Failure Questionnaire (MLHFQ) for assessment 
of quality of life. 
Follow-up 
Follow-up in office visit at 6 months of CRT – for assessment of reverse mechanical and 
electrical remodeling. Follow-up visit will be scheduled as special study visit, additional 
and separate from routine clinical follow-up visit. Study follow-up visit will be scheduled 
at 6 months of CRT. Intracardiac digital EGMs will be recorded via programmer and NI 
digitizer (NI USB-9215A portable data acquisition [DAQ] system) at rest simultaneously 

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with 12-leads and orthogonal ECG during bi-ventricular pacing ON (5 min) and OFF 
(during 10 min). CRT-D device will be interrogated, and all events with stored EGMs will 
be then translated with translational utility and further analyzed. Echocardiogram will be 
performed and fully analyzed to assess mechanical response to CRT after 6 months of 
CRT.  
 
After that, at 12-month post CRT, and then during 5 years once a year – phone call F/U 
(collection of the history of hospitalizations, ICD shocks, death), RedCap surveys, 
remote device follow-up 
 
Study Exit/Withdrawal 
Terms under which subjects can/will be exited  
• Subject death 
• Subject lost to follow-up 
• Subject no longer able to perform study follow-up procedures, or unwilling to 
continue follow-up and withdraw study consent. 
• Subject becomes pregnant before cardiac MRI procedure. 
 

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Statistical Methods and Data Analysis 
Primary Outcome: There are 2 primary outcomes in this study: (1) regression slope of 
Electrical Dyssynchrony Index values measured by ECGi 6 months post-CRT, 
regressed against Electrical Dyssynchrony Index values measured by ECGi prior CRT; 
Only randomized patients (treatment arm adaptive CRT, and control arm regular CRT) 
will be included in this analysis. (2) difference in regression slopes of SAI QRST against 
Electrical Dyssynchrony Index values measured by ECGi vs. QRS duration against 
Electrical Dyssynchrony Index (EDI) values measured by ECGi. All study participants 
(randomized two arms, and non-randomized registry arm) will be included in this 
analysis. 
 
Main analysis: linear regression 
 
Predictors:  
Electrical Dyssynchrony Index The electrical dyssynchrony index (EDI) is computed as 
the standard deviation of activation times at 350/700 sites on the LV epicardium. 
SAI QRST 
QRS duration 
 
The proposed predictors as variables of interest will be measured as continuous 
variables and could be dichotomized or divided by quartiles. The distribution of variables 
of interest will be defined, and Log transformation (or other transformation, if required, 
depending on the particular case) will be performed for any variable that displays non-
normal distribution, with subsequent verification of an achieved normal distribution. 
Simple and multiple linear regression models will be explored to determine factors that 
may play the role of predictors of our tested marker of interest, presented as a normally 
distributed continuous variable. For such linear regression models, the tested marker 
will be an outcome variable.  
Results will be presented as mean ± standard deviation (SD) for normally 
distributed variables, and as median and inter-quartile range for non-normally 
distributed variables. Continuous variables will be compared using the independent 
samples t test if normally distributed and the Wilcoxon rank sum test if skewed. The 
Pearson chi-square test will be used to compare categorical variables. A p-value of 
<0.05 will be considered significant.  
 
 
Justification for Sample Size 
 
We are planning a study with 15 experimental subjects and 15 controls in which we will 
regress values of Electrical Dyssynchrony Index values measured by ECGI 6 months 
post-CRT against Electrical Dyssynchrony Index values measured by ECGI prior CRT 
within each treatment group. Prior data17 (Ghosh et al, 2911) indicate that the standard 
deviation of Electrical Dyssynchrony Index is 3.9 and 2.3 in the responders and non-
responders, respectively. We conservatively assumed that the standard deviation of the 

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regression errors will be 0.08. If the true difference in the slopes of these 2 regression 
lines is 0.05, we will be able to reject the null hypothesis that these slopes are equal 
with probability (power) 0.954. The Type I error probability associated with this test of 
this null hypothesis is 0.05. Figure 1 below illustrates the difference in statistical power 
as a function of sample size and the difference in regression slopes (λ2 –λ1) that we 
wish to detect. Therefore, estimated sample size is 30 study participants (15 in 
experimental aCRT arm, and 15 in control arm). After adjustment of the sample size for 
a loss of follow-up (+ 6%) estimated sample size is 32 participants (16 in in 
experimental aCRT arm, and 15 in control arm).  
 
Figure 1. Statistical power estimation as a function of sample size of aCRT arm for a range 
of the differences in the slopes of the regression lines for the experimental and control 
groups that we wish to detect (shown by different colors). 
 
Risk Analysis 
 
Potential Risks 
This is a randomized clinical trial of 2 FDA-approved CRT strategies. Patients will 
receive commercially available FDA-approved device. There is no incremental risk of 
health for study participants. 
 
Very low risk of confidentiality loss always exists in any clinical research. All efforts will 
be made to keep confidentiality. Patient will be notified immediately if any unforeseen 
breach in confidentiality occurs (e.g. stolen computer). Safeguards will be in place to 
protect the identity of the patients and their private health information. Study ID will be 
assigned by the study coordinator, and all following collected data will be connected 
with this study ID, but not with the name of the patient. Private health information 
connected with patient’s name will be locked in a secure location in the office, and 
limited number of people will have access to it (PI and study coordinator). 
 

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MRI with IV Contrast: The effects of magnetic fields in an MRI scanner have been 
extensively studied, and there are no known significant risks with an MRI exam. 
Patients will not be allowed to participate if they have a pacemaker, an implanted 
defibrillator or certain other implanted electronic or metallic devices. Gadolinium 
contrast will be administered, which is FDA-approved and used routinely for MRI 
exams. The injection of contrast may cause discomfort, tingling or warmth in the lips, 
metallic taste in the mouth, tingling in the arm, nausea, or headache. These symptoms 
occur in less than 1% (less than 1 in 100) of people and go away quickly. There is a 
small risk of an allergic reaction to gadolinium; however, severe allergic reaction occurs 
in less than one in 300,000 people. Pregnant women have higher risk of complications 
with MRI and will be excluded from this study. 
Insertion of the needle to give gadolinium may cause minor pain, bruising and/or 
infection at the injection site. People with severe kidney failure who receive gadolinium 
are at risk of developing Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing 
Dermopathy (NSF/NFD). Patients with severe kidney failure that receive gadolinium 
have a risk of developing NSF/NFD of 1-5 %. Patients with severe kidney disease, 
measured by GFR <30ml/min will not be allowed to participate. 
Patients with a prior history of being a machinist, welder, metal worker, or similar activity 
that poses the potential risk of metal exposure to the eyes, will be asked to undergo 
screening orbit x-rays to rule out the presence of metal fragments. The amount of 
radiation exposure from the required series of skull x-rays is approximately 0.01 rems. 
Six Minute Walk Test: Six-minute walk tests pose no more risk than a subject would 
experience walking down the street. Should there be any cardiac symptoms while 
walking, the test will be stopped, and the participant allowed to rest. 
ECG/ECGi: There is a low risk that mild skin irritation may occur from the electrode 
patches used to obtain an electrocardiogram (ECG body surface mapping). 
 
CT Scan: Although the amount of radiation the patients will be exposed to is higher than 
from a typical x-ray, the risk of harmful effects from a single exam is very small.  
Intravenous Radiocontrast Agent Omnipaque 350 and Oral Beta Blocker:  Most 
people do not experience side effects or complications; however, out of more than 
73,000 patient studied25, Mild to moderate reactions - defined as reactions that either 
require no therapy or if therapy is given and patient is sent home from the radiology 
department - occur in 0.2% of cases. Severe reactions that necessitate intravascular 
epinephrine use in the emergency room or urgent therapy and follow up in the ER or 
hospital admission occur in 0.016% of cases. The risk of death is 1/100,000 patients25.  
Potential side effects of non-ionic Iodinated contrast that can cause adverse reactions 
include: Death (1/100,000 persons), sneezing and nasal congestion, hives, itching, 
rash, and swelling; laryngeal (oral) edema; bronchospasm; and anaphylaxis, rigors 
(shaking, chills, fever); seizure; numbness; malaise and achiness; pulmonary edema; 
chest pain; and hypertension25. 
The radiocontrast agent given along with saline intravenously during cardiac CT will be 
Omnipaque 350 iodinated contrast unless the decision is made by radiology staff to 
substitute a different FDA-approved iodinated contrast agent.  
 

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A Beta blocker, Metoprolol, is often given before undergoing CT scans. The patient’s 
clinical staff providing care and/or the radiologist at the diagnostic imaging department 
at the time of the scan will determine whether administration of a beta blocker is 
necessary before CT scan and will not be administered to a patient if a contraindication 
exists.  
Needle Insertion 
Insertion of the needle to administer contrast may cause minor pain, bruising and/or 
infection at the injection site. 
 
Risk Minimization 
All efforts will be made to keep confidentiality. Safeguards will be in place to protect the 
identity of the patients and their private health information. Study ID will be assigned by 
the study coordinator, and all following collected data will be connected with this study 
ID, but not with the name of the patient. Private health information connected with 
patient’s name will be locked in a secure location in the office, and limited number of 
people will have access to it (PI and study coordinator). 
 
IVs and or blood draws will be performed by trained research coordinators using good 
clinical practice and standard aseptic technique. 
Gadolinium administration: 
Patients with renal insufficiency with GFR <30ml/min and pregnant women will be 
excluded to minimize any risks associated with gadolinium administration for the 
contrast-enhanced MRI. A physician will be available during the procedure to administer 
any necessary care if side effects do occur, and to determine when or if the injection of 
the gadolinium should be stopped. 
MRI examination: 
No one will be allowed to enter the magnet room when a patient is in the magnet room 
unless they are involved in the study. No one will be allowed to bring magnetic metal 
objects near the magnet when other persons are in or near the magnet. The magnet 
room will be kept closed during the study, and will be opened only by the technologist at 
the end of the study. Individuals with metal implants and fillings are excluded from the 
study as described in the exclusion criteria. Patients will be asked to leave magnetic 
metal objects outside the magnet room, and patients will be required to fill out a 
questionnaire regarding MR safety and the presence of metal objects in their bodies. 
Care will be taken to limit the RF power deposition and gradient rise times to well within 
FDA guidelines. The MRI scanner’s software contains safeguards to prevent both 
excessive RF power and above-threshold gradient changes. The operating technologist 
will be in voice contact with the patient, and the patient will be told that he/she can 
contact the operator at any time with a request to be taken out of the magnet. All 
subjects will be carefully screened for the presence of any contraindications prior to 
them signing the consent form. 
Six Minute Walk Test: 

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CPR certified personnel will accompany the participant and access to emergency 
equipment will be available. The participants’ vital signs will be monitored before and 
after the six minute test. 
Psychological risk: 
The psychological risk of participating in the study may be a transient increase in worry 
about potential disease. Subjects will be given the opportunity to ask questions of study 
personnel on this topic. The study coordinators and investigators have extensive 
experience working with patients with these diseases. 
Pregnant women: 
Most women included in this study will not be of child-bearing potential (post-
menopausal).  Women of child-bearing potential who are not on reliable birth control (as 
assessed by physician) will have a urine HCG test done to obtain pregnancy status 
before MRI is performed. MRI with contrast will not be performed on a pregnant woman.  
If participants become pregnant over the course of the study, they will be asked to notify 
their physician immediately.  If patients who become pregnant have already completed 
the cardiac MRI, they will be maintained as study participants, otherwise they will be 
excluded.  There is no additional risk of CRT to pregnant women. 
cCT examination: 
Cardiac CT will be acquired using a prospective scan. Total effective dose is 3-4mSv, 
the equivalent of 7.5-10 mammograms.26 Patients will complete both the “Cardiac CT 
Screening Form” and “Patient Contrast Questionnaire and Procedure Record” prior to 
undergoing scanning. These two forms are standard procedure in the OHSU diagnostic 
radiology department prior to CT scanning with contrast. The OHSU diagnostic 
radiology department will review both forms before scanning.  
 
IVs and or Blood Draws  
All IVs and/or Blood Draws will be performed by trained research coordinators or clinical 
staff using standard OHSU clinical practice and standard aseptic technique. 
 
CT Contrast administration - GFR: 
Patients with renal insufficiency with GFR <30ml/min and pregnant women will be 
excluded to minimize any risks associated with contrast administration for the contrast-
enhanced CT. A physician will be available during the procedure to administer any 
necessary care if side effects do occur, and to determine when or if the injection of the 
contrast should be stopped. 
 
A GFR test will be ordered and paid for by the study team in the event of any of the 
qualifying criteria below exist in an enrolled subject. The patient will complete the test 
according to the following timeline per criteria based off Policy # 300.02 in the OHSU 
Diagnostic Radiology manual. 
 
1)Creatinine/eGFR required within 30 days of CT scan:  
Patients >60 years of age 
Patients with a history of hypertension requiring medication 
Patients with diabetes mellitus 

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Patients with kidney disease: kidney transplant, single kidney, kidney cancer, kidney 
surgery 
 
2) Creatinine/eGFR required within 24 hours of CT scan: 
Patients whose most recent eGFR<60 and >30 
Any patient whose most recent eGFR <30 will be excluded from the study 
 
 
Plan for reporting unanticipated problems or study deviations. 
Data Safety Monitoring Board is monitoring safety of participants and study 
conduct. 
Serious adverse advents will be reported to the IRB 
 
Potential Benefits 
 
There is potential for benefit to the patient since this is the patients’ last opportunity to 
get quality imaging of their heart before CRT implantation. All patients are about to 
receive a CRT device. CRT devices create immense amounts of artifact on both MRI 
and CT. Images will be made available to the patients’ treating physicians. 
This study will advance our understanding of the mechanisms of reverse electrical and 
mechanical remodeling with aCRT, and will help in identifying appropriate candidates 
for aCRT.  

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