Stress Cardiac MRI for Evaluation of Nonspecific Allograft Dysfunction

Study Overview
=================
Brief Summary
-----------------
The investigators will use cardiac MRI to measure the myocardial perfusion reserve and amount of myocardial edema and fibrosis in heart-transplant patients with nonspecific allograft dysfunction in contrast to those with normal graft function. The investigators hypothesize that patients with nonspecific allograft dysfunction will demonstrate decreased myocardial perfusion reserve, related to microvascular allograft vasculopathy, compared to those with normal graft function.

Detailed Description
-----------------
Adult heart-transplant patients, excluding those with a GFR less than 30 mL/min/1.73m2, contraindications to MRI and allergies to either regadenoson or gadolinium contrast, will be enrolled over 10 months. Patients will be recruited from UC San Diego and San Diego Veterans Affairs. The investigators will specifically enroll patients with nonspecific allograft dysfunction and patients with normal graft function. Brief protocol: Cardiac MRI is performed. Cine images in standard views are obtained. T2 mapping sequences are performed on short axis images. For stress imaging, intravenous regadenoson is given as a 0.4 mg bolus followed by a 5 mL saline flush. After 30 seconds, short-axis images are acquired for 30 consecutive heartbeats with administration of gadolinium. Rest imaging is performed 30 minutes after stress imaging. Lastly, late gadolinium enhancement images are obtained in standard views. Images are analyzed offline by a blinded independent reader. Patients will be followed for one month after enrollment for MACE.

Official Title
-----------------
Stress Cardiac MRI Using Regadenoson for Evaluation of Nonspecific Allograft Dysfunction

Conditions
-----------------
Heart Transplant, Acute Graft Rejection, Chronic Graft Rejection

Intervention / Treatment
-----------------
* Drug: Regadenoson
* Drug: Gadolinium
* Procedure: Cardiac MRI


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age greater than or equal to 18 years old. At least three months status post heart transplantation. Heart-transplant patients with normal graft function (left ventricular ejection fraction equal to or greater than 55%) and no prior history of clinically significant acute rejection episodes that required modification of the immunosuppressive regimen or cardiac allograft vasculopathy. Heart-transplant patients with nonspecific allograft dysfunction (left ventricular ejection fraction equal to or less than 50% AND decrease from post-transplant baseline ejection fraction by an absolute difference of 10% or greater, no formal diagnosis of allograft vasculopathy by coronary angiogram or coronary vascular ultrasonography, and no history of prior acute rejection episodes known to have decreased left ventricular ejection fraction to or less than 50%). Exclusion Criteria: Biopsy proven acute rejection episode in the past 3 months. Patients with symptoms or signs of acute myocardial ischemia or recent acute coronary syndrome in the past 3 months. Uncontrolled obstructive ventilatory disease including asthma and COPD. Second or third degree AV nodal block. Sinus node dysfunction. Contraindications to MRI including pacemakers or implantable cardioverter-defibrillators. Renal dysfunction with an estimated GFR less than 30 mL/min/1.73m2. Prior adverse reaction to either regadenoson or gadolinium contrast. Prior adverse reaction to adenosine will be assessed on a case-by-case basis. Any invasive procedure, including endomyocardial biopsy and left coronary angiogram, performed within one week. Systolic blood pressure greater than 180 or less than 85 mmHg. Diastolic blood pressure greater than 120 or less than 40 mmHg. Resting heart rate greater than 120 or less than 45 beats per minute. Severe claustrophobia.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nonspecific allograft dysfunction<br>Patients with nonspecific allograft dysfunction will undergo stress cardiac MRI with regadenoson in addition to performing late gadolinium enhancement and obtaining mean segmental T1 values of the heart. | Drug: Regadenoson<br>* For use in stress myocardial perfusion imaging.<br>* Other names: Lexiscan;Drug: Gadolinium<br>* For use in both perfusion imaging and late gadolinium enhancement.<br>* Other names: Magnevist;Procedure: Cardiac MRI<br>* Cardiac MRI will be the imaging modality for perfusion imaging, late gadolinium enhancement and obtaining mean T1 segmental values of the heart.<br>|
| Experimental: Normal graft function<br>Patients with normal graft function will undergo stress cardiac MRI with regadenoson in addition to performing late gadolinium enhancement and obtaining mean segmental T1 values of the heart. | Drug: Regadenoson<br>* For use in stress myocardial perfusion imaging.<br>* Other names: Lexiscan;Drug: Gadolinium<br>* For use in both perfusion imaging and late gadolinium enhancement.<br>* Other names: Magnevist;Procedure: Cardiac MRI<br>* Cardiac MRI will be the imaging modality for perfusion imaging, late gadolinium enhancement and obtaining mean T1 segmental values of the heart.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Perfusion Reserve | Myocardial perfusion reserve calculates the increase in myocardial perfusion after stress in comparison to rest. Outcome measure time frame specifies when the myocardial perfusion reserve was obtained in relation to date of heart-transplant for each patient. This was a one time measurement made after heart-transplantation. | Range of 1 to 12 years after heart transplantation for subjects and an average of 4 years after heart-transplantation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Ischemia/Infarction | Myocardial ischemia or infarct occurring from time of enrollment (when cardiac MRI performed) over subsequent 10 month period. | 10 months after enrollment (when cardiac MRI was performed) | 
| Hospitalization for Cardiac Related Causes | Hospitalization for cardiac related causes after enrollment. Time frame after enrollment (date of cardiac MRI) was 10 months | 10 months after enrollment (from date of cardiac MRI) | 
| Re-transplantation | Re-transplantation of the heart after enrollment (date of cardiac MRI). Measured 10 months after enrollment. | 10 months after enrollment (from date of cardiac MRI) | 
| Late Gadolinium Enhancement | Late gadolinium enhancement demonstrates myocardial scar by cardiac MRI. This is measured the day of the cardiac MRI scan and is a one time measurement. Time frame is measurement of late gadolinium enhancement from date of heart-transplantation. | Range of 1 to 12 years after heart transplantation for subjects and an average of 4 years after heart-transplantation. | 
| Mean Segmental T1 Values of the Left Ventricle | T1 values are obtained at the time of the cardiac MRI and indicate the amount of myocardial edema. This was a one time measurement. Outcome measure time frame indicates when T1 values of the left ventricle were obtained in relation to heart-transplantation. | Range of 1 to 12 years after heart transplantation for subjects and an average of 4 years after heart-transplantation. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
heart transplantation, cardiac MRI, graft rejection, nonspecific allograft dysfunction, allograft vasculopathy