Ethical statement and study design
The local Ethics Committee approved this study (Ethics Committee of IRCCS Ospedale San Raffaele; protocol code “Cardioretro Ricerca Spontanea”; approved on September 14, 2017, and amended on July 18, 2019). This study was supported by local research funds of IRCCS Policlinico San Donato, a clinical research hospital partially funded by the Italian Ministry of Health. This research received no specific grant from funding agencies in the public, commercial, or non-profit sector. Due to the retrospective nature of this study, specific informed consent was waived.
Study population
All patients who had undergone a contrast-enhanced CMR examination with administration of gadobutrol (Gadovist, Bayer Healthcare, Leverkusen, Germany), at our institution between March 2014 (the introduction of our newer magnetic resonance unit) and May 2018, and who were diagnosed with chronic myocardial infraction from clinical findings and CMR, were included in our study. Exclusion criteria were the presence of oedema, indicating acute phase of infarction, presence of relevant artefacts which rendered differentiation of the myocardial scar difficult, and non-transmural, thin infarcts which were either only subendocardial (≤ 50% of wall thickness) or too small (scar ≤ 10% of the myocardium), as such conditions do not allow the calculation of SNR and CNR of the scarred region [15]. Moreover, in patients with subendocardial infarction, image contrast may vary according to acquisition timing, and thus this may provide data that are not compatible with those of transmural scars [16].
Patients were then divided into three subgroups, depending on the contrast dose administered during their CMR: the first group (A) received 0.10 mmol/kg, the second (B) 0.15 mmol/kg, and the third (C) 0.20 mmol/kg. These different doses were mainly due to choices of the physicians in charge of the examination during the study period, not related to a specific patient’s condition.
Image acquisition
All subjects were imaged using one 1.5-T whole-body magnetic resonance unit (Magnetom Aera, Siemens Healthineers, Erlangen, Germany) with 45 mT/m gradient power and an 18-channel surface phased-array coil. The examined patient was lying supine and the coil was placed over the thorax. All images were acquired with breath-holding and ECG gating.
The imaging protocol of all patients included cine and LGE sequences.
Cine images were acquired in multiple short- and long-axis planes using an ECG-triggered bright-blood steady-state free-precession pulse sequence.
LGE images were acquired after intravenous administration of 0.10, 0.15, or 0.20 mmol/kg of gadobutrol (Gadovist, Bayer Healthcare, Leverkusen, Germany) and were performed using a 2D segmented inversion-recovery fast gradient-echo sequence covering the entire left ventricle. Earlier exams utilised higher-contrast doses, which were then lowered over time. Nevertheless, the sequence for LGE imaging remained the same. The time of echo was 3.33 ms, while the time of repetition was adapted to patients’ heart rates, and inversion time was progressively modified from 260 to 330 ms, to blacken cardiac muscle; flip angle was 25°, slice thickness 8 mm, and pixel size 3.6 mm2. LGE images were reconstructed using magnitude reconstruction. From the R wave of the electrocardiogram, a delay period was used to ensure that image acquisition occurred in mid-diastole, when the heart is relatively motionless, therefore reducing motion artefacts. Data were acquired every other heartbeat, although in tachycardic patients data were acquired every third heartbeat, while in bradycardic patients and in patients with difficulties in breath holding acquisition was performed every heartbeat. Timing between contrast administration and acquisition of delayed enhancement scans was tailored to the contrast dose that was utilised in each case, according to literature recommendations [14].
Image analysis
Image analysis was performed using QMass 7.6 (Medis Medical Imaging Systems, Leiden, The Netherlands). The epicardial contour of the left ventricle was manually traced for all short-axis slices at end-diastolic and end-systolic phases in cine sequences. Afterwards, a blood-thresholding technique (Mass-K mode) was applied to automatically segment myocardium and blood pool. The software then calculated end-diastolic and end-systolic volumes, both indexed and non-indexed to body surface area, myocardial mass, stroke volume, and ejection fraction.
For LGE quantification, manual segmentation of endocardium and epicardium of the left ventricle was performed in inversion recovery sequences after contrast agent injection. Then the software automatically detected the myocardial scar as being 6 standard deviations above average myocardial intensity [17]. Manual corrections were made when the software erroneously detected additional scarred areas, or when it failed to properly detect the scar. LGE was quantified as percentage over the whole myocardium. Two regions of interest were automatically placed in the scarred and healthy myocardium. An example of LGE segmentation is shown in Fig. 1.
SNR and CNR were calculated using data provided by automatic LGE quantification, namely intensities from the two ROIs automatically placed in the scarred and healthy myocardium, and two additional ROIs traced in the left ventricular blood pool and in the background air. SNR was calculated as \( \mathrm{SNR}=0.655\bullet \frac{\mathrm{signal}\ \mathrm{intensity}}{{\mathrm{SD}}_{\mathrm{background}}} \) according to a study by Kaufman et al. [18], while CNR was calculated as \( {\mathrm{CNR}}_{1/2}=\frac{\mid {\mathrm{signal}\ \mathrm{intensity}}_1-{\mathrm{signal}\ \mathrm{intensity}}_2\mid }{{\mathrm{SD}}_{\mathrm{background}}} \). SNR was calculated on the scar tissue (SNRscar), while CNR was calculated between scar tissue and remote myocardium (CNRscar-rem), and between scar tissue and blood (CNRscar-blood). Timings between contrast injection and acquisition of LGE sequences were also reported.
Subjective image quality was also analysed, using a 4-point Likert scale, defining score as follows: 0: non-diagnostic; 1: diagnostic exam, sufficient quality; 2: diagnostic exam, good quality; 3: diagnostic exam, excellent quality. The quality definition was based on the visual contrast differences between blood pool signal and LGE.
Statistical analysis
Data were reported as median and interquartile range (IQR). Differences between groups were appraised with Kruskal-Wallis test for numerical variables, and post hoc tests when a significant difference was appraised by Kruskal-Wallis test, or Fisher χ2 tests for non-numerical variables.
Statistical analysis was performed with MATLAB R2018b (Mathworks, Natick, MA, USA), and p values ≤ 0.05 were considered statistically significant.