Magnetic Resonance Elastography of Cardiac Transplant Rejection
Phase: NA
Conditions: Acute Graft Rejection
Sponsor: Ohio State University

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
Page 1 of 9 
 
 
 
Title: 
Magnetic Resonance Elastography of Cardiac 
Transplant Rejection 
 
 
Principal Investigator: 
Name  
Richard D. White, MD  
 
 
 
 
Address 
395 12th Ave, Room 450 
 
 
 
 
Address 
Columbus, OH  43210 
 
 
 
 
Phone  
614-293-4456 
 
 
 
 
Email  
Richard.white@osumc.edu 
 
Co-Investigators 
 
Name  
 Arunark Kolipaka, PhD 
 
 
 
 
Address 
 395 W. 12th Ave, 4th Floor 
 
 
 
 
Address 
 Columbus, OH 43210 
 
 
 
 
Phone  
 614-366-0268 
 
 
 
 
Email  
 Arunark.kolipaka@osumc.edu 
 
Name  
Robert S. Higgins, MD 
 
 
 
 
Address 
395 W. 12th Ave, Room 192 
 
 
 
 
Address 
Columbus, OH 43219 
 
 
 
 
Phone  
614-293-8701 
 
 
 
 
Email  
Robert.higgins@osumc.edu 
 
 
 
 
 
Name  
Ayesha Hasan, MD 
 
 
 
 
Address 
473 W. 12th Ave, Ste 200 
 
 
 
 
Address 
Columbus, OH 43210 
 
 
 
 
Phone  
614-293-4967 
 
 
 
 
Email  
Ayesha.hasan@osumc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name  
Tibor Nadasdy, MD 
 
 
 
 
Address 
320 W. 10th Ave, M018 Starling-Loving Hall 
 
 
 
 
Address 
Columbus, OH 43210 
 
 
 
 
Phone  
614-293-9258 
 
 
 
 
Email  
tibor.nadasdy@osumc.edu 
 
Name  
Ahmet Kilic, MD 
 
 
 
 
Address 
401 W. 10th Ave, N-831 Doan Hall 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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Address 
Columbus, OH 43210 
 
 
 
 
Phone  
614-293-8878 
 
 
 
 
Email  
Ahmet.kilic@osumc.edu 
 
Study Contact 
 
Name  
Barbara McCracken, CCRC 
 
 
 
 
Address 
395 W. 12th Ave, 4th Floor 
 
 
 
 
Address 
Columbus, OH 43210 
 
 
 
 
Phone  
614-688-8934 
 
 
 
 
Email  
Barbara.mccracken-bussa@osumc.edu 
 
 
 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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Contents 
 
1. 
Objectives ................................................................................................................................................. 4 
2. 
Background .............................................................................................................................................. 4 
3. 
Patient Selection ...................................................................................................................................... 4 
3.1  Inclusion Criteria .............................................................................................................................. 4 
3.2  Exclusion Criteria ............................................................................................................................. 5 
4. 
MRE Procedure ....................................................................................................................................... 5 
5. 
MRE Examination Schedule .................................................................................................................. 6 
6. 
Adverse Events ........................................................................................................................................ 7 
6.1  Definition: .......................................................................................................................................... 7 
6.2  Reporting ........................................................................................................................................... 8 
7. 
Duration of Study ..................................................................................................................................... 8 
8. 
Statistical Considerations ....................................................................................................................... 8 
9. 
References ............................................................................................................................................... 8 
 
 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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1. Objectives 
To establish the relationship between the “gold standard” invasive histologic assessment of 
cardiac transplant rejection (CRT) by direct endomyocardial biopsy (EMB) and noninvasive 
viscoelastic (i.e. stiffness) assessments for CRT by magnetic resonance elastography (MRE).  
This will be accomplished by collecting as many MRE data sets as possible that correspond 
temporally to standard-of-care EMB procedures for statistical comparisons.  
2. Background 
 
Cardiac transplant rejection is a significant cause of mortality (11% of deaths) during the year 
post-transplantation1.  Histology of myocardial tissue is the “gold standard” for CTR 
surveillance, subjecting patients to repetitive EMB2.  CTR is typically graded for acute cellular 
rejection3.  However, due to: 1. sampling error related to patchiness of CTR; 2. variability in 
histological interpretations; and 3. non-routine screening for antibody-mediated rejection, 
biopsy-negative CTR is common (< 20%)4. Consequently, significant myocardial injury can 
occur before immunosuppression is intensified. Furthermore, EMB is: 1. invasive (0.5–1.5% 
complications); 2. expensive; and 3. disliked by patients. These factors hinder needed 
monitoring, thereby limiting titration of immunosuppressants2,5.  Thus, non-invasive approaches 
to evaluating CTR are desired. 
 
The pleuipotentiality of cardiac magnetic resonance (CMR) makes it an excellent candidate. 
T2-relaxation is most often investigated for detecting CTR because it is directly proportional to 
myocardial water content/edema6.  Unfortunately, evidence supporting T2-weighted imaging for 
CTR is to date inconsistent7-9.  In addition, late-enhancement CMR has demonstrated 
insufficient sensitivity to detect the microscopic and diffuse myocyte necrosis associated with 
CTR9,10. 
 
MRE is a validated MRI technique for quantitating soft-tissue mechanical properties based on 
propagation of shear waves during MRI; it is FDA-approved for evaluating liver stiffness related 
to fibrosis. Use of MRE to quantitatively assess viscoelastic properties of the heart in animals 
has been reported11. 
 
3. Patient Selection 
 
Entry to this study is open to men and women aged 18 years and older, and to all racial and 
ethnic subgroups.  Up to 15 cardiac transplant patients will be enrolled.  
 
3.1  Inclusion Criteria 
 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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Figure 1. Non-Invasive MRE Driver Introduces Waves.   
Waves are generated from an active driver placed outside the 
scan room.  The waves propagate through the air within a hollow 
plastic tube.  A passive driver (a drum with thin diaphragm) is 
placed on the chest wall.  Sound waves are non-invasively 
transmitted through the chest wall into the heart.   
3.1.1 Patients must have undergone cardiac transplantation at the Ohio State 
University Ross Heart Hospital. 
3.1.2 Patients must be able to lie flat on their back in the scanner for up to 60 
minutes 
3.1.3 Patient must be able to hold their breath for up to 15 seconds at a time. 
 
 
 
3.2  Exclusion Criteria 
 
 
 
 
 
 
 
3.3.1 Patients who are claustrophobic  
3.3.2 Patients who are pregnant, due to potential risks to the fetus. 
3.3.3 Patients with any unapproved, non-MRI safe metal/devices in their bodies. 
 
4. MRE Procedure 
 
MRE is an MRI-based technique.  The procedure for performing MRE is much the same as that 
used for CMR.  The main difference is the use of a small, silicone device (passive driver) that is 
placed on the outside of the chest.  The passive driver represents a small drum which transmits 
sound waves non-invasively through the chest wall into the heart.  The passive driver is driven 
by an active driver that is placed outside the scan room.  Sound waves are transmitted from the 
active driver to the vibrating/humming passive driver via a hollow plastic tube. (See illustration) 
 
 
 
 
 
 
 
 
 
 
 
The patient will be asked to lie down on the scanner bed.  The small passive driver will be 
placed on the patient’s chest and secured with Velcro straps to enhance contact. One end of 
the plastic tube will be connected to the passive driver; the other end will be connected to the 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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active driver outside the scan room.  Vibrations of frequencies in the range of 20Hz – 2kHz will 
be produced by the active driver and transferred to the passive driver on the patient’s chest,  
producing mild vibrations/humming.  These vibrations produce wave images and are captured 
by the MRI scanner.    
 
Patients will be able to speak with the imaging technologist while they are in the scanner.  They 
will also be given a small ball they can squeeze should they need urgent assistance at any time 
during the examination.  
 
MRE is a noninvasive and safe non-radiation-based imaging procedure that does not require 
the use of oral or IV contrast.  Some people may experience claustrophobia (a feeling of being 
closed in) while in the MRI scanner.  The passive component of the driver, which is secured 
with a Velcro straps, may be uncomfortable to some patients. This study population will have 
undergone multiple, comprehensive medical examinations prior to transplantation; thus, the risk 
of scanning a patient with a known contraindication to MRI would be exceedingly unlikely.   
  
5. MRE Examination Schedule 
 
Myocardial biopsy is a procedure used to detect CTR and is an important part of routine care 
after cardiac transplantation.  Presently, this is the only method available to detect CTR.  The 
frequency of biopsies is the greatest in the first three months post-transplant.  The typical 
biopsy schedule for cardiac transplant patients is as follows: 
 
 
Every week over month 1 
 
Every other week over months 2-3 
 
Monthly over months 4-12 
 
Every 3 months over year 2 
 
Every 6 months over years 3-5 
 
Yearly starting in year 6 
 
We will begin imaging (MRE and basic CMR) patients in month 2 (so as to avoid post-surgical 
affects on the myocardium or pericardium), as soon as they are able to lie on the scanner bed 
for up to 60 minutes and hold their breath for up to 15 seconds.  Imaging will ideally occur 
within one day before or after the patient’s scheduled biopsy, but imaging within 3 days of the 
EMB is acceptable as long as alteration of CRT treatment (i.e. immunosuppression) has not 
occurred in the interval. If CRT treatment is modified between the MRE examination and the 
planned subsequent EMB, the data will not be used in the comparison; if post-EMB treatment 
changes occur before planned corresponding MRE, the MRE examination will not be 
performed.   
 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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De-identified digital image data on study patients will be stored on a secure password-
protected research portion on the OSUWMC Vender Neutral Archival system with 
administrative rights given only to the Principal Investigator; images will be stored for up to 10 
years, consisted with current Department of Radiology practices.  
  
 
Incentives 
 
OSUWMC Ross Heart Hospital has the only adult heart transplant program in Central Ohio.  
Many patients travel over 100 miles one way to receive medical care at the Ross.  Subjects will 
receive $20.00 in pre-paid gas cards at each MRE appointment to help defray the cost of 
participating in this trial.  
 
Adverse Events 
 
All solid organ transplant recipients suffer from transplant related co-morbidities.  For the 
purpose of this study, we will report only those serious adverse events (SAEs) that are 
possibly, probably, or definitely related to the MRE procedure. 
 
6.1  Definition: 
 
An AE is any unfavorable and unintended (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely possible, probable or definite). AEs include toxicities which are related to the 
disease, to study-related procedures, or to other unknown causes. (International Conference 
on Harmonisation [ICH] E2A, E6). 
 
AEs (expected or unexpected) include worsening of a pre-existing conditions (increased 
severity, frequency or duration of the condition and/or associated with significantly worse 
outcomes) which occur during the specified collection period, whether observed by the 
investigators or by the patient, and whether or not thought to be related to study procedures. 
A SAE is any adverse experience that occurs while participating in a clinical trial that results in 
any of the following outcomes:  
 
 
Death 
 
 
A life-threatening adverse drug experience 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
 
A persistent or significant disability/incapacity 
 
 
Congenital anomaly/birth defect 

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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An unexpected AE is one that is not listed as a known toxicity of the investigational procedure 
in the protocol, the consent form, the package insert, or the investigator's brochure. 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered an SAE when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. [CTEP, NCI Guidelines: Expedited Adverse Event Reporting 
Requirements. December 2004] 
6.2 Reporting 
SAEs or unexpected AEs related to the MRE procedure will be reported to the IRB within 10 
working days.  Potential risks and adverse events that may reasonably expected while 
participating in this trial will be described in the informed consent and do not require prompt 
reporting.  These will be reported in summary form at the time of continuing review.  
6. Duration of Study 
 
Patients will remain in the study for six months after cardiac transplantation or until they decide 
to withdraw, or until illness or general or specific changes in their health render them 
unacceptable for MRI.  
 
7. Statistical Considerations 
 
The expected small size of the data will set limits on possibilities for statistical analyses.  
Comparisons of 2 continuous variables (e.g. myocardial stiffness values vs. CRT grades) will 
likely rely on regression analyses.   Comparisons of a continuous variable (e.g. means of 
myocardial stiffness values) with a categorical variable (e.g. CRT results warranting 
immunosuppression vs. CRT results not warranting immunosuppression) will likely rely on t-
testing.   
 
8. References 
 
1. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The registry of the international society for 
heart and lung transplantation: Twenty-seventh official adult heart transplant report-2010. J 
Heart Lung Transplant 2009;29:1089-1103.  PMID:  20870165. 
2. Yilmaz A, Kindermann I, Kindermann M, et al. Comparative evaluation of left and right 
ventricular endomyocardial biopsy: Differences in complication rate and diagnostic 
performance.  Circulation 2010;122:900-909.  PMDI: 20713901  

Protocol No: 2013H0318 
IRB Approval Date: 2/18/2015 
Version: 8/29/2014 
 
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3. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the 
standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 
2005;24:1710-1720.  PMID: 16297770 
4. Subherwal S, Kobashigawa JA, Cogert G, et al. Incidence of acute cellular rejection and 
non-celluar rejection in cardiac transplantation. Transplant Proc 2004;36:3171-3172.  PMID: 
15686721. 
5. Baraldi-Junkins C, Levin HR, Kasper EK, et al.  Complications of endomyocardial biopsy in 
heart transplant patients. J Heart Lung Transplant 1993;12:63-67. PMID: 8443204. 
6. Higgins, CB, Herfkens R, Lipton MJ, et al.   Nuclear magnetic resonance imaging of acute 
myocardial infarction in dogs: Alterations in magnetic relaxation times. Am J Cardiol 
1983;52:184-188.  
7. Marie PY, Angioi M, Carteaux JP, et al. Detection and prediction of acute heart transplant 
rejection with the myocardial T2 determination provided by a black-blood magnetic 
resonance imaging sequence. J Am Coll Cardiol 2001;37:825-831.  PMID: 11693758. 
8. Wisenberg G, Pflugfelder PW, Kostuk WJ, et al.  Diagnositc applicability of magnetic 
resonance imaging in assessing human cardiac allograft rejection. Am J Cardiol 
1987;60:130-136.  PMID: 3300244. 
9. Taylor AJ, Vaddadi G, Pfluger H, et al. Diagnostic performance of multisequential cardiac 
magnetic resonance imaging in acute cardiac allograft rejection. Eur J Heart Fail 
2010;12:45-51. PMID: 20023044. 
10. Steen H, Merten C, Refle S, et al. Prevalence of different gadolinium enhancement patterns 
in patients after heart transplantation. J Am Coll Cardiol 2008;52:1160-1167.  PMID: 
18804744. 
11. Kolipaka A, McGee KP, Manduca A, et al. In vivo assessment of MR elastography-derived 
effective end-diastolic myocardial stiffness under different loading conditions. J Magn 
Reson Imaging 2011;33:1224-1228. PMID:  21509882.