Patients With Post Orthotopic Heart Transplantation Status
Conditions
Keywords
Heart transplant patients
Brief summary
The primary purpose of this study is to measure the level of an enzyme in a patient's heart called inducible nitric oxide synthase(iNOS) using Positron Emission Tomography (PET) imaging with a radioactive tracer called 18F-NOS. These PET results will be compared to tissue results obtained during routine endomyocardial heart biopsy. The enzyme iNOS produces nitric oxide in inflammatory diseases such as acute heart transplant rejection, diabetes, Alzheimer's and cancer. Thus, PET with the radioactive tracer 18F-NOS may be a useful tool for detecting the early stages of these diseases. The safety of 18F-NOS during the study will also be assessed. All PET imaging will be performed with a CTI/Siemens Biograph 40 PET/CT scanner. Protocol was revised to add new imaging modality, Biograph mMR PET-MR scanner in order to investigate new hardware and software in order to optimize scanning procedures in order to refine image quality so that we can apply the findings to future standard clinical scans and research imaging studies. Ten additional status-post OHT patients who are scheduled for standard of care endomyocardial biopsy for allograft rejection surveillance will undergo PET/MR imaging with \[18F\](+/-)NOS.
Detailed description
Nitric oxide (NO) is an important and unique mediator of a variety of physiological and pathological processes. NO is generated from the oxidation of L-arginine to L-citrulline in a two-step process by nitric oxide synthase (NOS) enzymes. In the NOS family, there are two constitutive isozymes of NOS, neuronal NOS (nNOS) and endothelial NOS (eNOS), and one inducible isozyme (iNOS). The three isozymes of NOS are expressed in different tissues to generate NO for specific physiological roles. nNOS generates NO as a neurotransmitter and neuromodulator, mainly in brain and peripheral nerve cells; eNOS regulates blood pressure, and blood flow primarily in vascular endothelial cells. The induction of iNOS occurs by various inflammatory stimuli (e.g., endotoxin) in activated macrophages and other types of cells and plays a crucial role in the host defense and the inflammatory processes. Normally, the basal level of NO in all parts of the body is very low, mainly due to the constitutive nNOS and eNOS. In contrast, once expressed, iNOS can continue to generate NO in large amounts (up to μM concentrations) for a prolonged period of time. Studies have shown that production of NO by iNOS is implicated in a variety of acute and chronic inflammatory diseases (e.g., sepsis, septic shock, organ transplant rejection, vascular dysfunction in diabetes, asthma, arthritis, multiple sclerosis, and inflammatory diseases of the gut). iNOS activity has also been found in many tumors. Because of the central role of iNOS in NO-related diseases, numerous efforts have been made to develop iNOS inhibitors as pharmaceuticals ranging from the nonselective L-arginine analogues to the selective inhibitors reported recently. Some inhibitors of iNOS have shown promising results in animal models of sepsis, lung inflammation, arthritis, and autoimmune diabetes. Therefore, the development of a radiolabeled iNOS inhibitor for probing iNOS expression in vivo using noninvasive positron emission tomography (PET) imaging will be of tremendous value to the study and treatment of NO-related diseases. Acute allograft rejection is the major contributor to mortality in patients receiving orthotopic heart transplantation (OHT). Specifically, iNOS has been thought to be the main NOS involved in producing NO that is active in acute cardiac allograft rejection. Up-regulation of iNOS occurs in macrophage cellular infiltrates and later within the graft parenchymal cells. In human cardiac transplantation a positive correlation has shown between iNOS expression and left ventricular contractile dysfunction measured by echocardiography and Doppler techniques. We have recently developed a novel PET radiotracer, \[18F\](+/-)NOS, designed to measure cellular iNOS activity. This study evaluates the feasibility of the method in OHT patients undergoing surveillance endomyocardial biopsy as part of their normal post-transplant evaluation for potential allograft rejection. More specifically, it will compare the myocardial kinetics of this radiotracer measured by PET with tissue measurements of iNOS measured by immunohistochemistry.
Interventions
DRUG[18F](+/-)NOS
Injection of radiotracer \[18F\](+/-)NOS for PET imaging and kinetic data analysis
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. The OHT patients will be undergoing surveillance endomyocardial biopsy and will Patients 21 years of age or older of either sex, who are status-post OHT and normal healthy volunteers (2 women and 2 men) will be enrolled.be on standard immunosuppressive therapy and anti-hyperlipidemic, anti-hypertensive and anti-diabetic therapies as needed. Healthy volunteer is someone who has volunteered to be imaged and who, based on physical exam and baseline electrocardiogram, has no evidence of cardiovascular disease, is not on medication, such as steroids, that will interfere with the accuracy of measuring \[18F\](+/-)NOS activity and is not under the care of a physician for any active medical conditions. 2. Able to give informed consent. 3. Not currently pregnant or nursing: Female subjects must be either: surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), post menopausal (cessation of menses for more than 1 year), or of childbearing potential for whom a urine pregnancy test (with the test performed within the 24 hour period immediately prior to administration of \[18F\](+/-)NOS) is negative.
Exclusion criteria
1. Patients with an unstable cardiovascular (e.g., severe rejection) or other clinical condition (e.g., active severe infection) that in the opinion of the Principal Investigator or designee or Dr. Ewald precludes participation in the study. 2. Unable to tolerate 60-90 mins of PET imaging or is claustrophobic. 3. Normal volunteers with evidence of cardiovascular disease or other diseases based on clinical evaluation and/or blood laboratory tests, which are judged by the Principal Investigator or designee to interfere with accurate determination of the of \[18F\](+/-)NOS on such measures.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To Measure Free Fatty Acid by Imaging Patients With Increased Levels of iNOS Using [18F](+/-)NOS. | 24-72 hours post [18F](+/-)NOS injection |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine Human Dosimetry in Both Normal Adult Healthy Volunteers and Heart Transplant Patients. | 24-72 hours post [18F](+/-)NOS injection | All subjects will receive a single intravenous administration of 7 mCi of \[18F\](+/-)NOS followed by dynamic PET/CT imaging |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dosimetry Group-measuring Radioisotope in Blood To determine its potential for use in humans, we measured the level of 18F-NOS radiopharmaceutical in patients after orthotopic heart transplantation (OHT) (3 women and 9 men) and normal healthy volunteers (2 women and 2 men), and correlated it with pathologic allograft rejection, tissue iNOS levels, and calculated human radiation dosimetry.
The level of 18-F-NOS was measured at different time points in minutes after injection of the radioisotope: The measurement time points were 0/120 minutes, 30/150 minutes, 60/180 minutes, and 90/210 minutes. The imaging began from mid thigh, to the base of the brain. | 16 |
| Kinetic Analysis Group-measuring Levels of Nitric Oxide Measurement of myocardial levels of enzyme nitric oxide synthase(iNOS) using PET and 18F-NOS in post heart transplant patients (5 women and 5 men) undergoing endomyocardial biopsy as part of their normal post-transplant evaluation. Kinetic data of the tracer will be compared with the heart tissue measurements of iNOS measured by immunohistochemistry. | 10 |
| Total | 26 |
Baseline characteristics
| Characteristic | Total | Kinetic Analysis Group-measuring Levels of Nitric Oxide | Dosimetry Group-measuring Radioisotope in Blood |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 10 Participants | 16 Participants |
| Dosimetry and Kinetics | 0 Participants | — | — |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Region of Enrollment United States | 26 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Female | 16 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 10 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 10 |
| other Total, other adverse events | 0 / 16 | 0 / 10 |
| serious Total, serious adverse events | 0 / 16 | 0 / 10 |
Outcome results
Primary
To Measure Free Fatty Acid by Imaging Patients With Increased Levels of iNOS Using [18F](+/-)NOS.
Time frame: 24-72 hours post [18F](+/-)NOS injection
Population: The PI has left the institution and all efforts to locate data have been exhausted. There is no access to study data and it therefore cannot be reported.
Secondary
To Determine Human Dosimetry in Both Normal Adult Healthy Volunteers and Heart Transplant Patients.
All subjects will receive a single intravenous administration of 7 mCi of \[18F\](+/-)NOS followed by dynamic PET/CT imaging
Time frame: 24-72 hours post [18F](+/-)NOS injection
Population: The PI has left the institution and all efforts to locate data have been exhausted. There is no access to study data and it therefore cannot be reported.