Dotarem

The sequence was simulated by Bloch equations to calculate the transverse magnetization as a function of all the protocol and tissue parameters in order to construct the LUT corrections for both the AIF and myocardial imaging protocols. Input to the LUT was the normalized signal SR/PD, where PD used the FLASH protocol and SR used either a b-SSFP or FLASH protocol. LUT were validated by phantom measurement by comparing the estimates of [Gd] after LUT correction with the known [Gd] using least squares fitting. A set of gadolinium doped saline phantoms were constructed at concentrations up to 10 mmol/L using both Gadoterate meglumine (Dotarem, Guerbet LLC) and Gadobutrol (Gadavist, Bayer Healthcare). LUT estimates of [Gd] vs known [Gd] were calculated with and without T2* correction. The phantom T1 values were measured using an inversion recovery GRE sequence at multiple inversion times (TI) with TR = 10s such that the longitudinal magnetization was fully relaxed after each RF excitation, and T1 was estimated by 3-parameter fitting to the mono-exponential inversion recovery S = A-Bexp(-TI/T1). The phantom T2 values were measured using a spin echo sequence (TR = 10s) with varying echo times (TE) and using T2 estimates from a 2-parameter fit to the mono-exponential decay curve, S = Aexp(-TE/T2). The coefficients for relaxivity rates (r1 and r2) were calculated from the T1 and T2 measurements vs known [Gd] using linear fitting, i.e., R1 = R1₀ + r1[Gd] with R1 = 1/T1.

The research received approval from the local research ethics committee and all participants provided written informed consent. EQ-CMR was performed as described previously [9 (link)]. CMR was performed on a 1.5T magnet (Avanto, Siemens Medical Solutions). Within a standard clinical scan (pilots, transverse white and black blood images, volumes, and LGE imaging) T1 measurement pre-contrast was performed using (a) FLASH-IR at increasing inversion times from 140 to 800 ms (or 900 ms if patient heart rate permitted), “multibreath-hold technique”, Figure 1a and (b) ShMOLLI T1 mapping “single breath-hold technique”, Figure 1b. After a bolus of Gadoterate meglumine, (0.1 mmol/kg, gadolinium-DOTA, marketed as Dotarem © Guerbet S.A. France) and standard LGE imaging, at 15-minute post bolus, an infusion at a rate of 0.0011 mmol/kg/min contrast (equivalent to 0.1 mmol/kg over 90 minutes) was given. The patient was typically removed from the scanner at this time. At between 45 minutes and 80 minutes post bolus, the patient was returned to the scanner, still with the infusion, and the T1 measurement repeated using both multi and single breath-hold techniques. Separate regions of interest (ROIs) were placed in all available images and recovery curve was reconstructed by fitting the relaxation formula to ROI averages. Heart rate correction was used for the multibreath-hold technique [9 (link)]. In the ShMOLLI sequence, T1 maps were generated using previously published algorithm [12 (link)]. A single ROI was drawn directly in each T1 map at the same location as the multibreath-hold technique and T1 averaged between all pixels (Figure 1b). A haematocrit was taken in all subjects. The ECV was calculated with each method as Myocardial ECV = (1-haematocrit) × (ΔR1_myocardium/ΔR1_blood) [1 (link)]. T1 was measured in the basal to mid septum avoiding areas of late gadolinium enhancement, except in myocardial infarction (where the infarct zone was assessed) and amyloid (where the regions was drawn irrespective of the ill-defined presence/absence of LGE). The blood T1 was assessed in the descending aorta. All the analysis were performed blinded.

VW-MRI was performed with a 3.0-T MR system (Magnetom Skyra; Siemens, Erlangen, Germany) with a 64-channel head and neck coils. The magnitude and phase images of multi-echo (seven echoes) GRE were obtained for QSM reconstruction, followed by isotropic three-dimensional (3D) MR images. Seven-echo GRE was obtained using a 3D gradient echo sequence (flip angle = 15°; repetition time (TR) = 24 ms; echo times (TE) = 4.92 ms, 7.38 ms, 9.84 ms, 12.30 ms, 14.76 ms, 17.22 ms, and 19.68 ms; matrix size = 320 × 240; field of view = 230 mm × 172 mm; slice thickness = 2 mm; scan coverage   =  140 mm).
3D VW-MRI was performed using sampling perfection with application-optimized contrasts by using different flip-angle evolutions (SPACE), which is a 3D turbo spin-echo sequence^{50 (link)}. T2-weighted, proton density-weighted, precontrast T1-weighted, and postcontrast T1-weighted images were obtained using SPACE. Postcontrast T1-weighted images were obtained after intravenous administration of gadoterate meglumine (Dotarem; Guerbet, Paris, France) at a dose of 0.1 mmol per kilogram of body weight. The imaging volume ranged from the mandibular angles (approximately proximal internal carotid artery) to the vertex, which allowed for the inclusion of the intracranial vertebral arteries. The acquisition time for each sequence was approximately 8 min. The 3D images were reconstructed into coronal, axial, and sagittal images and displayed with an isovoxel of 0.5 × 0.5 × 0.5 mm³. Detailed parameters for VW-MRI were described in Supplemental Materials.

The CMR examinations were performed with a 1.5 Tesla Siemens Avanto scanner (Siemens AG, Erlangen, Germany). For dynamic stress, all patients received an adenosine infusion of 140 μg/kg body weight/minute. After 3 minutes of infusion, a contrast injection with 0.05 mmol/kg dimeglumine gadopentetate (Dotarem – Guerbet, Paris, France) at a flow rate of 5 mL/s was started. Simultaneously, the stress pCMR image acquisition was initiated. The patient was asked to stop breathing when contrast arrived in right ventricle. The image acquisition lasted for 120 heartbeats with three short-axis slices sampled on each heartbeat. Adenosine infusion was stopped after approx. 50 heartbeats. We applied the following imaging parameters: Saturation recovery segmented gradient echo pulse sequence with TR/TE/TI of 167/1.11/120 ms, 108 × 144 matrix, 340–430 mm field of view, 1 NEX, 8 mm slice thickness.
After 10 minutes, rest of the pCMR imaging was performed without adenosine infusion, but with otherwise identical contrast parameters and pulse sequence parameters.
After another 10 minutes, LGE imaging was performed with 3 long-axis slices and short-axis slices that covered the entire left ventricle. Imaging parameters are phase sensitive gradient echo pulse sequence triggered on every second heart beat in diastolic phase with typical TR/TE/TI of 800/3.33/300 ms, 156 × 256 matrix, 330 mm field of view, 1 NEX, 8 mm slice thickness.
For CMR, a 16 segment score sheet, where the apical part had been excluded from a 17 segment sheet,^{6 (link)} was filled in for all patients. Each segment was assessed for perfusion and late gadolinium enhancement (LGE) pathology. The diagnosis of perfusion defect was based on a visual analysis with comparison between regions to identify relative hypo-perfusion according to current guidelines from the Society of Cardiovascular Magnetic Resonance.^{7 (link)} A comparison between stress and rest images was performed to identify inducible perfusion defects and artifacts. Perfusion defects in regions with LGE were only interpreted as reversible if the extent of the perfusion defect was clearly beyond the extent of LGE.
For evaluation of ischemia and infarct, a score was assigned to each segment indicating a normal (0), borderline (1), or pathologic (2) finding. The final overall score for LGE was deemed pathologic if at least one of the segments was classified as pathologic with a high degree of confidence. Similarly, the final score for pCMR was deemed pathologic if there was at least one segment with a high confidence of transmural pathology or two adjacent segments with high confidence of subendocardial pathology.^{8 (link)}