Safety and prognostic value of regadenoson stress cardiovascular magnetic resonance imaging in heart transplant recipients

We identified consecutive heart transplant recipients undergoing regadenoson stress CMR performed on at the University of Minnesota Medical Center, Minneapolis, Minnesota, USA between April 2012 and December 2017. For the safety analysis, these regadenoson stress CMRs were matched by patient age and gender in a 2:1 ratio to comparison regadenoson stress CMRs performed in non-heart transplant patients during the same time period. All stress CMRs were identified from the University of Minnesota Cardiovascular Magnetic Resonance Registry, an ongoing observational registry including all patients that undergo CMR at the University of Minnesota [14]. This study was approved by University of Minnesota’s Institutional Review Board with a waiver of informed consent.

Regadenoson stress CMRs were performed using a 1.5 T scanner (Siemens Aera, Siemens Healthineers, Erlangen, Germany) with phased-array coil systems. All patients underwent a CMR protocol consisting of: 1) cine CMR at rest for assessment of left ventricular (LV) function; 2) gadolinium first pass perfusion imaging 1–2 min after regadenoson injection for assessment of stress perfusion; 3) gadolinium first-pass perfusion imaging without regadenoson for assessment of rest perfusion; and 4) late gadolinium enhancement (LGE) CMR 10–15 min later. Typically, the procedure was completed in 45 min. Patients were asked to refrain from caffeine for 24 h before the regadenoson stress CMR. Patients with pre-existing second- or third-degree atrioventricular block or sinus node dysfunction were excluded. After cine CMR, the patient table was partially pulled outside the scanner bore to allow access to the patient for regadenoson administration. Regadenoson 0.4 mg (Astellas, Northbrook, Illinois, USA) was injected over approximately 10 s into a peripheral vein followed by a 5 mL saline flush. The patient was centered back into the scanner and the perfusion sequence was started within 1–2 min of regadenoson injection. Gadolinium-based contrast (0.075 mmol/kg gadobenate dimeglumine, Bracco Imaging or 0.1 mmol/kg gadobutrol, Bayer HealthCare LLC, Milan, Italy) was infused at 4–5 ml/s followed by a saline flush (50 ml) via an antecubital vein for both stress and rest perfusion. All patients were monitored by CMR-compatible, three-lead wireless continuous electrocardiogram (ECG) system and pulse oximetry during the study. Blood pressure was monitored before and after regadenoson administration, and a 12-lead ECG was performed before and after the study. Prior to April 2014, aminophylline was used for significant patient symptoms. All studies performed after April 2014 routinely received aminophylline 100 mg intravenously for reversal of hyperemia after stress images were acquired [15]. Patients were routinely asked about their symptoms before and after regadenoson and aminophylline administration. Stress-related adverse events including death, myocardial infarction, ventricular tachycardia, ventricular fibrillation, hospitalization, bronchospasm, and non-life-threatening arrhythmias were noted in the electronic medical record by trained nurses. For this study, data on arrhythmias were extracted from the ECGs and the nurse notes.

All stress CMR exams were interpreted blinded to patient outcomes by a consensus of two CMR physicians with > 10 (C. S.) and 2 (F. K.) years of experience respectively. Perfusion and LGE images were assessed in a qualitative fashion. A perfusion defect was identified as a regional dark area that: 1) persisted for > 2 beats while other regions enhanced during the first-pass of contrast through the LV myocardium; and 2) involved the subendocardium. LV systolic dysfunction was defined as an abnormality in global or regional systolic function on cine imaging. Ischemia was defined as a segmental stress perfusion defect without matching hyperenhancement (same location and size) on LGE imaging. A match between a perfusion defect and hyperenhancement on LGE was considered as fibrosis without ischemia. As in routine clinical practice, systolic dysfunction, ischemia and LGE images were interpreted in a binary fashion as normal or abnormal. A normal regadenoson stress CMR was defined as normal global and regional LV systolic function, no ischemia and no fibrosis.

Follow up data were collected through review of patient medical records from all locations within our institution’s health system. Mortality status and death dates were also cross-referenced with data from the Minnesota Department of Health’s Office of Vital Records. Collected outcomes included: myocardial infarction, percutaneous intervention, cardiac hospitalization, retransplantation and death. These events together formed the composite endpoint of major adverse cardiovascular events.

Continuous variables were expressed as means and standard deviations, or medians and inter-quartile ranges (IQR) for data that were not normally distributed. Regadenoson stress CMR in the heart transplant recipient and comparison groups were compared using generalized estimating equations in the form of linear regression or logistic regression, as appropriate. Prognostic endpoints were compared using Kaplan-Meier survival analyses and log rank testing. All tests were two-tailed. A p of < 0.05 was used to denote statistical significance. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina, USA).

In the study group, 78 regadenoson stress CMRs were performed in 57 unique heart transplant recipients at a median of 2.74 (interquartile range 1.02–7.25) years after transplantation. Thirty-four (44%) CMRs were performed in the first two years after heart transplantation.

Forty-one patients had one, 12 patients had two, three patients had three, and one patient had four regadenoson stress CMRs each. In the comparison group, only one instance of regadenoson stress CMR was included per patient. Patient characteristics are summarized in Table 1. Compared to the heart transplant recipient group, the comparison group had higher rates hyperlipidemia, tobacco use, prior myocardial infarction, and chronic obstructive lung disease.

Baseline electrocardiographic (ECG) characteristics are listed in Table 2. In the heart transplant recipient group, there were no instances of patients with pre-existing sinus node dysfunction or atrioventricular block of any degree. In 24 (31%) instances, patients had a right bundle branch block, which was significantly higher than in the comparison group. In 47 (60%) instances, they had ST-T abnormalities.

In the heart transplant recipient group, the mean heart rate increased from 92 ± 11 bpm to 107 ± 12 bpm, while it increased from 73 ± 15 bpm to 100 ± 13 bpm in the comparison group. There were no significant changes in pre- and post-stress blood pressures in both the heart transplant recipient and comparison groups (Table 3).

All regadenoson stress CMRs were completed in both heart transplant recipient and comparison groups. Adverse effects are listed in Table 4. One stress CMR in a heart transplant recipient had to be temporarily interrupted due to regadenoson-related abdominal cramps; the patient received a second dose of regadenoson after 20 min without any further symptoms. Side-effects requiring an intervention occurred in two patients (3%) in the heart transplant recipient group – one had chest pain requiring nitroglycerin and one had symptomatic hypotension requiring intravenous fluids – and in one patient (0.6%) in the comparison group that had symptomatic hypotension requiring intravenous fluids (p = 0.26). In all three cases, the symptoms resolved with treatment and the patients were discharged home after the regadenoson stress CMR. Minor side-effects not requiring any interventions such as dyspnea, nausea and headache occurred at similar rates in both groups. There were no occurrences of death, asystole, sinus pause, sinus arrest, high-degree atrioventricular block, ventricular arrhythmias, stress-induced atrial fibrillation, or myocardial infarction. No patients required hospitalization or emergency room evaluation.

Among 57 heart transplant recipients, 20 had an abnormal regadenoson stress CMRs while 37 had normal testing. Example images of heart transplant recipients from the study are provided in Fig. 1. At a median follow up of 1.3 years (interquartile range 0.5–2.1 years), there were no instances of myocardial infarction, four percutaneous coronary interventions, four cardiac hospitalizations, three retransplantations, and four deaths, accounting for 10 composite outcomes. On Kaplan-Meier analyses, the cumulative incidence estimates were significantly different between patients with abnormal regadenoson stress CMRs and those with normal regadenoson stress CMRs (3-year cumulative incidence estimates of 32.1% vs. 12.7%, p = 0.034; Fig. 2). Due to the small number of events, multivariable analysis was not performed.