Late-gadolinium enhancement is common in older pediatric heart transplant recipients and is associated with lower ejection fraction

This study is a cross-sectional, retrospective cohort study of PHTR who underwent comprehensive structure-function CMR with LGE at a single center from 2015 to 2021. The Institutional Review Board (IRB) approved this Health Insurance Portability and Accountability Act (HIPAA)-compliant study. PHTR were included with clinician ordered CMR and excluded if LGE sequences were incomplete or the quality was inadequate for analysis. Although all patients were followed at a pediatric center, age was not an exclusion criterion. We used all observations available for this study, which included multiple CMR studies for some patients.

CMR images were obtained according to a comprehensive, standardized protocol including structure and function analysis and delayed gadolinium-enhanced images [17]. All studies were performed on 1.5T scanners (Aera, Siemens Healthineers, Erlangen, Germany), with gadobutrol (Gadavist, Bayer HealthCare, Berlin, Germany) as the gadolinium-based contrast agent. A total gadobutrol dose of 0.15 mmol/kg was administered in up to three separate aliquots (if regadenoson stress perfusion imaging was performed), with LGE sequences performed 20–30 min from the time of initial contrast injection and at least 5 min after the last dose. For LGE sequences, the inversion time was selected using an inversion time scout scan to optimally null the normal myocardium. Segmented inversion-recovery sequences were obtained in three orientations: 4-chamber, 2-chamber, and short axis, from base to apex (TR = 2.8 ms, TE = 1.2 ms, slice thickness = 8 mm, flip angle 50°, in plane resolution = 1.4 × 1.4 mm²). In addition, 2D cine balanced steady-state free-precession (bSSFP) images were obtained in the 2-chamber, 3-chamber and 4-chamber, and short axis orientations (TR = 3.0 ms TE = 1.26–1.3 ms; flip angle = 90°, slice thickness = 6 mm, in plane resolution = 1.0 × 1.0 mm².

CMR-derived structure and function analysis (including LV/RV end-diastolic and end-systolic volume indices (LV/RV EDVI and ESVI), LV mass index (LVMI), and LV/RV ejection fraction (EF) was performed at the time of completion of the CMR report using 2D bSSFP short-axis stack using dedicated commercially available software (Q Mass, Medis Suite 4.0.38.2, Medis Medical Imaging Systems, Leiden, The Netherlands). Ventricular volumes and LV mass were indexed to body surface area.

Two reviewers (LG and NH), determined the presence of LV LGE by visual identification of areas of relatively increased signal intensity on delayed-contrast enhanced images by consensus review. Orthogonal planes were used to confirm the presence of LGE. The reviewers assessed the distribution of LV LGE by the American Heart Association (AHA) 17-segment model and further classified the pattern as infarct-typical, with subendocardial involvement, or infarct-atypical, as described by Braggion-Santos et al. [18]. In addition, based on segmental distribution, three non-mutually exclusive descriptive patterns of LV LGE were observed: inferoseptal (posterior RV insertion point), lateral LV wall (involving AHA segments 5, 6, 11, 12, or 16), and diffuse (present in ≥ 4 LV AHA segments). Reviewers were blind to patient history.

For studies with LV LGE by qualitative assessment, two reviewers (AAL and NH) quantified the LGE burden by consensus review. Commercially available post-processing software (Q Mass, Medis Suite 4.0.38.2, Medis Medical Imaging Systems, Leiden, The Netherlands) was used. The reviewers selected 4–7 slices from base to apex in the short axis plane in which the myocardium was well visualized. Then, they manually traced LV epicardial and endocardial borders. The reviewers placed regions of interest in an area of healthy myocardium and an area of hyperenhanced tissue. Next, the LGE burden was quantified using the full-width half-maximum method. The LV borders were inspected again and adjusted, if necessary, to completely exclude the blood pool. LGE burden was recorded as a percentage of LV myocardium by mass (\(\frac{LGE \, mass \left(g\right)}{Total \, LV \, mass\left(g\right)}\times 100\%\)). Quantification was not performed if fewer than four short axis slices were analyzable. A single reviewer (NH), blinded to the prior results, performed a second round of LGE quantification in a subset of 5 LGE + patients to evaluate reproducibility.

Demographic, clinical, and cardiac catheterization data were obtained by chart review. Clinical concern (e.g., active rejection, history of significant rejection, cardiac allograft vasculopathy, changes on echocardiogram, or changes in catheterization-derived hemodynamic parameters) was noted from clinical notes or CMR indication at the time the study was ordered. Patients were classified as having history of moderate to severe rejection if there was acute cellular rejection (ACR) ≥ 2R or antibody mediated rejection (AMR) ≥ 2 per International Society of Heart and Lung Transplantation criteria at any point since the most recent transplantation [19, 20]. The closest human leukocyte antigen—panel reactive antibody (HLA-PRA) prior to transplant was obtained, when available, and classified as > 10% or < 10%. The 10% threshold is a frequently used cut-point given the association between HLA-PRA > 10% and both AMR and decreased 1-year graft survival [21]. If hemodynamic catheterization and EMB were performed within 6 months of the CMR, the right atrial pressure, pulmonary capillary wedge pressure (PCWP), and EMB results were reported from the catheterization closest to the time of CMR. Patients were classified as having a history of CAV if there was any prior diagnosis of CAV from the time of transplantation through the annual catheterization with coronary angiography performed nearest to the time of CMR (before or up to 12 months after the CMR study). The interventional cardiologist performing the procedure graded angiograms for CAV according to International Society of Heart and Lung Transplantation criteria [22].

We performed separate univariate analyses on the entire dataset of CMR studies as well as the set of initial CMR studies per PHTR, excluding follow-up studies. To test for significance, we used a t-test for continuous variables and Chi-squared test for categorical variables (Stata 17, College Station, TX, USA). We performed ordinary least squares regression analysis for presence of LGE with robust standard errors. We performed a Bland-Altman analysis to evaluate the agreement between LGE mass percentage values obtained by two blinded observers on 19% (5/27) of the LGE + cohort.

During the study period, 81 CMR studies were performed on 59 unique PHTR. Reviewing the data for all CMR studies (n = 81), mean age at CMR was 14.8 ± 6.2 years with an average time since transplantation of 7.3 ± 5.0. Congenital heart disease was the most common indication for transplantation in this cohort 53% (43/81), followed by cardiomyopathy 35% (28/81), and re-transplantation 12% (10/81). A documented history of moderate/severe AMR or ACR prior to CMR was present in 29% (23/80) of all CMR studies, while a history of CAV was present in 11% (9/81). Specifically, there were 4 CMR studies of patients with CAV 1, two with CAV 2, and three with CAV 3. The indication for CMR was routine surveillance (without clinical concerns) in 63% of the studies (51/81). In the remaining 37% (30/81), a clinical concern was present. Clinical concerns, which were not mutually exclusive, included history of recent, significant rejection (n = 9) or CAV (n = 10), changes in catheterization-derived hemodynamic parameters (n = 4), changes in echocardiographic parameters (n = 3), LGE on prior CMR (n = 3), or unexplained cardiac symptoms (n = 2). The mean CMR-derived volumetric and functional parameters for all studies (n = 81) and initial studies (n = 59) are given in Table 1. Regadenoson-based stress perfusion was performed in 79/81 studies.

LV LGE was present in 36% of all CMR (29/81) and 32% (19/59) of initial CMR per PHTR. Among LGE + scans, the mean number of AHA segments involved was 2.5 ± 2.7 (the segmental distribution is given in Fig. 1). The observed pattern was nearly exclusively infarct-atypical, in 97% (28/29) of LV LGE + studies. A single CMR showed an infarct-typical, subendocardial LGE pattern. That patient had CAV 3 with stenosis of the left main coronary artery with LGE in a basal-lateral and inferolateral distribution. Inferoseptal enhancement was most frequent, noted in 76% of LGE + studies (22/29), followed by lateral wall in 41% (12/29), and diffuse in 21% (6/29) (Fig. 2). RV LGE was found in 4% of all studies (3/81) and 2% of initial studies (1/59); each of these studies also had diffuse LV LGE.

Of the 29 CMR studies with qualitative LGE, two studies were disqualified from LGE quantification due to significant motion artifact precluding quantitative analysis. A median of 5.0 slices (range 4–7) were used for analysis. The mean LV LGE mass percentage was 18.0 ± 9.0% (range 4.1–37.0%) in the LGE + studies. A subset of 5 LGE + patients had repeat LGE quantification performed by a single reviewer to evaluate reproducibility of quantification results. A Bland-Altman analysis revealed no significant mean bias between the two observers for LV LGE mass percentage (− 0.01 ± 7.2% LGE); however, the 95% limits of agreement were wide (− 14.6 to 14.6% LGE).