Comparison of New MRI Methods for Quantitative Assessment of Myocardial Perfusion With Quantitative PET Perfusion Imaging
Phase: NA
Conditions: MRI Scans
Sponsor: University of Utah

 
Protocol Summary (ERICA) 
 
IRB_00058133 
Page 1 of 7 
 
IRB Approval 6/11/2019 
 
 
Quantitative Cardiac MRI Perfusion for longitudinal 
Studies 
 
Protocol Summary 
 
 
 
IRB Approval 
Date of 
Current 
Version: 
6/11/2019 
University of 
Utah IRB #: 
IRB_00058133 
Sponsor: NIH NATIONAL HEART LUNG & BLOOD INST 
  
Principal 
Investigator: 
Edward Di Bella 
Internal Staff 
and  Sub-
Investigators: 
Site Name  
Staff Names  
University of Utah 
Edward Di Bella 
 
Nousheen Alasti 
 
Majd (Mark) Ibrahim 
 
Brent Wilson 
 
Leif Jensen 
 
Jennifer Springer 
 
Nassir Marrouche 
 
Erik Bieging 
 
John Hoffman 
 
Collin Arsenault 
 
Ganesh Adluru 
 
 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 
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IRB Approval 6/11/2019 
 
Background and Introduction 
 
Heart disease is the leading cause of death in the U.S. Detection and characterization of 
coronary artery disease (CAD) can contribute significantly towards reducing mortality and 
improving quality of life for large numbers of people. Currently, SPECT and echo imaging are 
the clinical standards for non-invasive assessment of regional blood flows (perfusion) in the 
myocardium, but do not provide quantitative estimates of regional myocardial blood 
flow.  While quantitative MRI perfusion, in its current state, is a useful clinical and research 
tool, improved methods are needed along with better benchmarks of how well the methods 
quantify perfusion in humans. The techniques proposed here will be advantageous for 
quantifying myocardial perfusion and are ideally suited for studying patients with atrial 
fibrillation. 
Our initial cardiac MRI work under IRB 8157 and IRB 10342 has shown promising results and 
this project builds on these past experiences.  
This protocol is to support the development and validation of new pulse sequences and 
automated mathematical modeling approaches to provide practical and accurate methods for 
assessment of myocardial perfusion and viability.  
  
 
 
 
Purpose and Objectives 
 
This work seeks to develop, evaluate and use new MRI methods for non-invasive quantitative 
assessment of myocardial perfusion reserve (MPR). The methods will be designed to work 
robustly for patients with arrhythmias or poor ECG signals. The methods will be applied along 
with left ventricular (LV) and left atrial (LA) function and LA fibrosis measurements to study 
changes due to treatment for atrial fibrillation (AF). 
Specific aims are (1) To design and test highly-undersampled ungated perfusion acquisitions 
and reconstructions. (2) To provide robust quantitative perfusion estimates by improved 
processing and by identifying an accurate arterial input function using methods that are widely 
applicable across a range of doses and acquisition types. (3) To determine the validity and 
repeatability of the proposed quantitative methods and the differences in perfusion and MPR 
measured at systole and diastole, including determining if systole or diastole is most repeatable 
when quantifying perfusion.  (4) To determine the changes over time in perfusion reserve and 
cardiac function and left atrial fibrosis, after ablative treatment for AF. This will allow for 
determining the extent of perfusion improvement acutely due to conversion to sinus rhythm 
and the degree of recovery of perfusion reserve that recovers more slowly over months. 
 
 
 
Study Population 
 
Age of Participants: 18-60 + 
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Sample Size: 
At Utah: 
140  
All Centers: 
NA 
 
Inclusion Criteria: 
All participants will be over the age of 18 and able to provide consent 
Control Group A (healthy or non-AF volunteers): Volunteers will be in normal sinus rhythm and available for at 
least one study visit. 
Control Group B (risk based volunteers): Volunteers will consist of both normal sinus rhythm and suspected or 
confirmed paroxysmal or persistent AF. 
Atrial Fibrillation MRI and PET cohort will have suspected or confirmed paroxysmal 
or persistent AF.  
Atrial Fibrillation Blood Flow MRI  cohort will be patients with paroxysmal or persistent 
AF that are scheduled for RF catheter ablation treatment. These subjects will 
require clinical MRI scans to assess pulmonary vein stenosis and LA fibrosis before 
ablation, 1-3 days after, and 6 months after ablation. The study visits will be 
schedule according to the three clinical MRIs. Research scans will not be added in 
the acute (1-3 days after) MRI studies, but at pre-ablation and at later time points.  
  
  
  
 
 
Exclusion Criteria: 
Exclusion criteria for all cohorts: 
Critically ill patients, patients on ventilators, patients with unstable angina or with hypotension, asthmatics, and 
other patients whose medical care or safety may be at risk from undergoing an MRI examination will be 
excluded. Patients with claustrophobia will also be excluded from the study if this cannot be controlled with 
standard methods (valium or benadryl). Patients with contraindication to MRI (pacemaker, metal implants, or 
certain types of heart valves), pregnant patients, minors, mentally disabled patients and prisoners will be 
excluded from this study. (All criteria apply to patients and normal volunteers). Gadolinium nephrotoxicity will be 
addressed by having patients with abnormal kidney function (GFR<30) excluded from the study due to the (very 
small) risk associated with gadolinium contrast agents. This threshold may be modified, depending on practices 
determined by the Radiology Department and the IRB. Patients with a known allergy or contraindication to 
Adenosine and/or Regadenoson will be excluded from stress MRI cohorts. 
All participants that will receive a stress agent will refrain from consuming caffeine for at least 12 hours prior to 
each MRI 
Atrial Fibrillation cohorts: 
AF participants will be selected to have very low pre-test likelihood of coronary artery disease based on being 
asymptomatic and having none of the following risk factors: diabetes, family history of premature coronary artery 
disease, hyperlipidemia, hypertension, and smoking. 
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Volunteers: 
No contra-indications in addition to those listed above for all cohorts. Volunteers with 
a  known allergy or contraindication to Adenosine and/or Regadenoson will only be enrolled 
in scans where no stress agent will be administered. 
  
 
 
 
Design  
 
Prospective Clinical Research 
 
 
 
 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
  
Subjects will be recruited from those being treated by colleagues in the Cardiology 
clinic, that fit the inclusion criteria given above.    
We are planning on using clinical schedule review and an opt in recruitment letter for 
increasing enrollment. We plan on being able to identify potential subject from the 
information gained from EPIC to meet subjects in the clinic. We will plan on discussing their 
possibility of being part of the research study with the physician prior to meeting the patient. 
Healthy volunteers will be recruited by study coordinators and use of a volunteer information 
sheet (attached). A participant pool will be used to recruit healthy volunteers. This pool 
consists of previous study participants that have agreed to be contacted for future research 
studies.  
Volunteers will also be recruited from the University of Utah using flyers (attached) posted on 
campus. 
Participants who are University Staff, Students, and Faculty will be recruited only when there is not the chance of 
coercion or undue influence to participate in the study. Specifically, anyone who works for the PI or receives a grade from the 
PI will not be allowed to volunteer.  
The volunteer information sheet will be given to people that contact the study staff and show interest in research participation. 
The study will be listed online at http://healthcare.utah.edu/clinicaltrials with staff contact 
information listed for volunteers that would like to participate. We will also list the study in 
the ResearchMatch database (also known as the National Recruitment Registry Project). 
 
 
Informed Consent: 
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Description of location(s) where consent will be obtained:  
At the hospital or at INC or at HCH, depending on which imaging study is being performed. 
 
Description of the consent process(es), including the timing of consent:  
When possible, consents are emailed to the participants a week ahead. Otherwise, consents are 
done prior to the imaging procedure when the subjects arrive at the imaging center. Subjects 
may take as much time as they like to read and ask questions, and to think about whether they 
want to participate. 
 
Procedures: 
STUDY PROCEDURE 
As described in the participant characteristics, all subjects will be imaged with MRI, and some also with PET. All 
subjects enrolled in the AF cohorts will have three study visits or will consist of extra scans added to a clinically 
scheduled MRI. All subjects enrolled in the healthy volunteer and risk based cohorts will have at least one study 
MRI and up to three study MRIs depending on the study aim. It will not be a deviation if not all three visits are 
completed for these cohorts 
For the below, LV=left ventricle, LA=left atrium, LGE=late gadolinium enhancement 
(to see atrial fibrosis), MRA=magnetic resonance angiography 
MRI Protocol Each study will first hook up ECG and IV. Then the imaging protocol will include: 1) 0.05 mmol/kg 
adenosine or regadenoson stress perfusion, with initial 1/10 concentration volume matched dual bolus. For all 
perfusion sequences, gadolinium is given i.v. with a power injector at 5cc/s, 25 ml saline flush at 5cc/s. 2) LV cine 
with tags in the same 5 slices imaged with perfusion. 3) LV wall motion cine (without tags), short axis of whole 
heart. 4) 0.05 mmol/kg rest perfusion, with dual bolus. 5) MRA of the LA (used for guiding the ablation procedure) 
with 0.1mmol/kg. 6) Finish LV cines and do LA cines - 4 chamber view stack for LA function. 7) High resolution 3D 
LGE scan of the LA. 
We estimate the time in the scanner (after IVs and ECG leads are in place) as 5 min. scouts, 10 min. perfusions, 5 
min. MRA, 20 min. tags and cines, 10 min. LGE = ~60 minutes. 
For the subjects undergoing repeated MRIs, a second MRI study will also be scheduled up to 10 weeks later to 
see how repeatable the MRI measurements are. The second MRI study will be identical to the first. A third MRI 
visit will be optional and offered to the subject at the end of the second MRI. 
For the PET or PET/CT scans: a study at rest and at adenosine or regadenoson stress will be performed. For each 
PET study, you will receive through the IV a small amount of a radioactive tracer. Each scan will last approximately 
30 minutes. A transmission scan or a low-dose X-ray CT scan to provide information about your anatomy in order 
to enhance the PET data will also be performed. (The PET data shows blood flow rather than body structure). This 
will take approximately 1-15 minutes. 
For the subjects undergoing both an MRI and a PET scan, the order of the tests will depend on scheduling issues 
and may be on the same or different days. For both imaging sessions, you will be asked to not have any caffeine 
for at least 12 hours before the scan. An IV (Intra-Venous) line will be inserted into a vein in each of your arms, 
and ECG (electrocardiogram) leads will be placed on your chest or back.  
 A blood draw has been added to each cohort and for each study visit. A hematocrit will be 
ordered for the day of the study visit and will be drawn at the time the IV is placed in an 
attempt to limit patient discomfort. In the event that the lab can not be obtained while the IV is 
placed the patient will be escorted to the outpatient lab in the hospital after the scan has been 
completed. 
  
Study Visit 1 
Study Visit 2 
Study Visit 3 
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Day 1 
  
  
Control Group 
A Non-AF 
MRI with contrast Blood Draw *Optional Scan* MRI with 
contrast Blood Draw 
*Optional Scan* MRI with 
contrast Blood Draw 
  
Day 1 
within 10 weeks of 1st MRI 
within 10 weeks of 2nd MRI 
Control Group 
B with and 
without AF 
MRI with contrast, stress 
agent and Blood Draw 
MRI with contrast, stress 
agent and Blood Draw 
*Optional Scan* MRI with 
contrast, stress agent and 
Blood Draw 
  
Day 1 PET or PET/CT can be done at study visit 1 or 2 
within 10 weeks of first MRI 
MRI and PET 
Group AF 
MRI with contrast and stress 
agent Blood Draw 
PET or PET/CT with 
radioactive tracer, stress 
agent and Blood Draw 
MRI with contrast and stress 
agent Blood Draw 
  
Day 1 pre-ablation 
post ablation 
final 
Blood Flow 
MRI AF Clinical 
Scans 
Clinical MRI with research 
scans, contrast, stress agent, 
blood draw 
Clinical MRI with research 
scans, contrast, stress agent, 
blood draw 
Clinical MRI with research 
scans, contrast, stress agent, 
blood draw 
  
 
 
Procedures performed for research purposes only:  
All of the procedures described in #6, above, will be done for research purposes only, exce
for the subjects that are undergoing clinical MRIs before and after AF ablation treatment 
(blood flow MRI AF clinical scans). In those subjects, some of the above scans will be 
performed and billed clinically. That is, the LV wall motion cines, the MRA, and the LGE
the LA form a portion of the standard clinical scan.  
 
 
 
Statistical Methods, Data Analysis and Interpretation 
 
Statistical Analysis The primary hypothesis is that MPR will significantly increase due to ablation therapy. The 
significance (computed with a t-test) of any changes in perfusion and MPR will take into account the inter-study 
variability from D.3 by using the procedure by Bland-Altman. Considering 3 independent territories per study, and 
estimating mean MPR changes of 0.3, the power of a paired t-test to detect significant change is 85% with 20 
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patients. 30 subjects are planned and it is expected that ~33% of the patients will recur, leaving 20 subjects. 
Additional analysis of changes in MPR in the patients that recur will also be done, although with reduced power. 
Results from the gender and age-matched control group of 10 subjects without AF will be used to determine how 
MPRs before and after ablation compare to normal values. 
Further comparisons of perfusion, MPR, function including strain, and LA fibrosis size will be done with t-tests and 
Bland-Altman methods. ANOVAs will be performed to analyze relations between MPR, function, and fibrosis size. 
MPR for coronary artery territories as well as smaller regions and division of each region into an endocardium 
portion and an epicardium portion will be studied with separate analyses. We do not expect MPR to be the best 
predictor of recurrence, since LA size and function and fibrosis are known to be powerful predictors. We will test if 
MPR is an independent predictor of recurrence. And a combined best linear predictor for recurrence will be 
constructed from the LA and LV function and size, along with LA fibrosis and perfusion values. This analysis will 
add to our understanding and serve as a basis for designing larger trials if there are particularly promising 
integrated metrics that predict response to therapy. 
The longitudinal dataset that will be collected here will be extremely valuable. While the most unique piece with the 
most unanswered questions is the perfusion data, the inclusion of LA fibrosis which is still relatively new, along 
with LA and LV function and sizes forms a valuable resource that will be freely shared with the scientific 
community to allow additional analyses and comparisons. For example the results may shed light on whether MPR 
changes instigate the remodeling process, or result from the anatomical changes (smaller LA and improved 
function). If LA first shrinks and then MPR returns to baseline, this implies the latter. 
The addition of obtaining labs from each subject at each visit will be to collect a hematocrit level for the day of the 
scan. The hematocrit can be used along with the T1 maps to calculate extracellular volume (ECV).  We want to 
measure ECV along with perfusion and other parameters within this project. 
  
 
 
The Trial Version