Determining the Association of Microvascular Disease as Assessed by PET and Graft Injury by Donor Derived Cell Free DNA

The DEPICT Prospective Study: Determining the Association of Microvascular Disease as Assessed by PET and Graft Injury as Assessed by Donor Derived Cell Free DNA Post Transplantation

The goal of this research study is to understand if a blood test in people who have had heart transplants can detect and predict the following:

• Blockages in the small blood vessels of the heart.
• Whether small blockages can turn into more severe blockages in the future.

Participants will undergo blood draws once every 3 months in the first year of the study (4 blood draws total, taking 15 minutes each) and their medical records will be reviewed for 3 years after the date they are enrolled in the study.

A prospective, single center, assessment of donor derived cell free DNA in subjects who are post-heart transplant to assess correlation with microvascular flow as assessed by myocardial flow reserve (MFR) on positron emission tomography (PET).

Study design: This prospective, single center registry will enroll up to 88 subjects at Yale New Haven Health System (YNHHS). Patients who get PET scans for routine post-transplant surveillance will be included in the study. Up to an anticipated 44 subjects with low MFR and up to an anticipated 44 subjects with normal MFR will have dd-cf DNA drawn every 3 months for a year.

Patient population: A total of 88 adults referred to have an annual PET stress test as part of routine post-transplant surveillance for cardiac allograft vasculopathy and who are at least 3 years from heart transplantation and meet all eligibility criteria will be enrolled.

Diagnostic assessment: All subjects will have quarterly blood draws during the first year of enrollment to assess the levels of dd- cf DNA. All subjects will also undergo standard of care annual PET scans.

Subject follow up: All subjects will have routine follow-up as clinically necessary based on standard of care. Screening and follow-up data collection will occur through the electronic medical record.

Follow up duration: 3 years after enrollment.

Primary endpoint: Elevated dd-cf DNA levels in subjects with low MFR compared to normal MFR at up to one year follow-up post-enrollment.

Secondary Endpoints: The following secondary endpoints will be reported at 3 years post-enrollment based on the routine post-transplant standard of care:

• Combined clinical events of rejection, reduction in ejection fraction, need for revascularization, myocardial infarction, heart failure admissions and death or need for retransplantation.
• All-cause, cardiovascular, and non-cardiovascular mortality
• Myocardial infarction (Fourth Universal Definition)
• Revascularization (PCI or CABG)
• Hospitalization for heart failure
• Rejection
• Decrease in ejection fraction from baseline echo to 3 years follow up.
• Retransplantation

Procedure summary: Patients will undergo routine post-transplant surveillance and management per the discretion of the treating physician and per YNHHS post-heart transplant protocols. Quarterly study blood draws will be conducted in the first year of the study and will include dd-cf DNA measurements. These results will not be available to study team or the patients. All study participants will be blinded to these results.

Potential subjects must meet all of the following criteria to be eligible for inclusion in the study:

General Inclusion Criteria:

• The patient is over 18 years of age.
• The patient underwent orthotopic heart transplantation and is undergoing routine cardiac allograft vasculopathy (CAV) surveillance with PET.
• The patient has no evidence of cardiogenic shock.
• The patient has no evidence of acute rejection.
• The patient, or legally authorized representative, has been informed of the nature of the study, agrees to its provisions, and has provided written informed consent, approved by the appropriate Institutional Review Board (IRB) or Ethics Committee (EC).

Potential subjects will be excluded if any of the following conditions apply:

Exclusion Criteria:

• Evidence of moderate to large area of ischemia on the PET.
• Multiorgan transplantation.
• Life expectancy <1 year due to non-cardiac conditions.
• Less than 3 years from transplantation.
• Patient appears unlikely or unable to participate in the required study procedures, as assessed by the study PI, study coordinator, or designee (ex: clinically-significant psychiatric, addictive, or neurological disease).