Comparison of volumetric and functional parameters in simultaneous cardiac PET/MR: feasibility of volumetric assessment with residual activity from prior PET/CT

Objective To compare cardiac left ventricular (LV) parameters in simultaneously acquired hybrid fluorine-18-fluorodeoxyglucose ([18F] FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with residual tracer activity of upstream PET/CT. Methods Twenty-nine patients (23 men, age 58±17 years) underwent cardiac PET/MRI either directly after a non-cardiac PET/CT with homogenous cardiac [18F] FDG uptake (n=20) or for viability assessment (n=9). Gated cardiac [18F] FDG PET and cine MR sequences were acquired simultaneously and evaluated blinded to the cross-imaging results. Image quality (IQ), end-diastolic (LVEDV), end-systolic volume (LVESV), ejection fraction (LVEF) and myocardial mass (LVMM) were measured. Pearson correlation and intraclass correlation coefficient (ICC), regression and a Bland–Altman analysis were assessed. Results Except LVMM, volumetric and functional LV parameters demonstrated high correlations (LVESV: r=0.97, LVEDV: r=0.95, LVEF: r=0.91, LVMM: r=0.87, each p<0.05), but wide limits of agreement (LOA) for LVEDV (−25.3–82.5ml); LVESV (−33.1–72.7ml); LVEF (−18.9–14.8%) and LVMM (−78.2–43.2g). Intra- and interobserver reliability were very high (ICC≥0.95) for all parameters, except for MR-LVEF (ICC=0.87). PET-IQ (0–3) was high (mean: 2.2±0.9) with significant influence on LVMM calculations only. Conclusion In simultaneously acquired cardiac PET/MRI data, LVEDV, LVESV and LVEF show good agreement. However, the agreement seems to be limited if cardiac PET/MRI follows PET/CT and only the residual activity is used. Key Points • [ 18 F] FDG PET-MRI is feasible with residual [ 18 F] FDG activity in patients with homogenous cardiac uptake. • Cardiac volumes and function assessed by PET/MRI show good agreement. • LVEDV and LVESV are underestimated; PET overestimates LVMM and LVEF. • Cardiac PET and MRI data correlate better when acquired simultaneously than sequentially. • PET and MRI should not assess LV parameters interchangeably.


Introduction
Cardiac magnetic resonance imaging (MRI) provides incremental impact on clinical decision-making by delivering data about myocardial anatomy, function, tissue characterization, perfusion, diffusion and also metabolism when using MR spectroscopy [1]. MRI is the clinical standard of reference for the volumetric and functional assessment of the heart [2][3][4][5]. Cardiac positron emission tomography (PET) can provide precise information on cardiac perfusion, viability, myocardial metabolism and other molecular processes [6]. [ 18 F] FDG cardiac PET visualizes the glucose metabolism in the viable myocyte and is the gold standard for the direct visualization of viability [7]. The unique combination of PET and MRI offers a comprehensive approach for cardiac diseases [6,8], i.e. in inflammatory diseases like myocarditis, sarcoidosis or rejection after heart transplantation [9,10]. Both modalities can assess cardiac function.
Recently, hybrid PET/MR systems have been introduced [11], and allow the evaluation of simultaneously acquired volumetric cardiac data of both modalities. Thus, the question arises whether volumetric parameters could be used interchangeably. Validation studies on co-registering of sequentially acquired [ 18 F] FDG-PET and MRI data sets showed a good agreement of LV parameters with a systematic bias [12][13][14]. However, inter-and/or intraday variability of LV parameters can occur, if not acquired simultaneously [14]. Even the inherent differences in acquisition times between PET and MRI can cause misalignment, mostly due to patient motion or respiration [8].
LV function and especially the normalized LVESV (LVESVI) is a relevant prognostic factor in patients with coronary artery disease (CAD) and a LVESVI > 100 ml/m 2 predicts worse outcome [15]. In comparative studies, [ 18 F] FDG-PET showed a non-significant tendency to overestimate LVESV and to underestimate LVEDV, resulting in an underestimation of LVEF values [2]. The lower temporal and spatial resolution of cardiac [ 18 F] FDG-PET [2] as compared to MRI [8] might be a reason.
But, the temporal resolution of gated [ 18 F] FDG-PET has been improved lately and spatial resolution of MRI is lower in the through-plane direction. Also, cardiac function by [ 18 F] FDG-PET has been mainly evaluated in patients with CAD, whom often show a heterogeneous myocardial uptake, while patients who undergo [ 18 F] FDG-PET for non-cardiac reasons sometimes show a homogenous uptake [16].
The aims of this study were: 1. To test whether an observed homogeneous uptake is sufficient to perform a simultaneous cardiac PET/MR with the residual activity after a PET/CT for non-cardiac indication. 2. To analyse whether the acquired data is sufficient for a LV volumetric and functional analysis. 3. To assess whether bias and limits of agreement are small enough in a way that cardiac PET or MRI volumetric and functional data could be used interchangeably.

Patients
The present study was performed under the guidelines of the 1964 Helsinki Declaration and approved by the local ethics committee. All patients gave written informed consent and agreed to the anonymous evaluation of their data. The nine patients with CAD gave written consent for viability assessment by PET/MRI the day before. Patients who were scheduled for a non-cardiac PET/CT were asked about their willingness to participate in the PET/MR study prior to the PET/CT acquisition. Twenty of all screened patients between November 2011 and September 2015 with a sufficient, homogeneous myocardial FDG uptake in PET/ CT received an additional PET/MRI. Image quality (IQ) was visually graded by the homogeneity of myocardial tracer uptake on a four-point analogue scale (3 = very homogenous, 0 = very low or heterogeneous). Indications for PET/CT are given in Table 1. Inclusion criteria for this group were: cardiac [ 18 F] FDG uptake evaluated as >1 as seen in PET/CT, and age > 18. An incomplete PET or MRI scan, contraindications for MRI, claustrophobia and state of pregnancy were exclusion criteria. Patients prior to PET/CT received the appropriate fasting protocol [17] and no additional [ 18 F] FDG activity for the PET/MR examination; patients for viability assessment received a glucose load protocol [18]-modified in diabetes mellitus [19].

PET/MR protocol
Patients were examined in supine position using a simultaneous hybrid PET/MR system (mMR Biograph; Siemens, Erlangen, Germany) with dedicated phased-array surface coils (mMRBody, mMRSpine) for combined PET/MR measurements [3]. For attenuation correction (AC) of the PET data, a two-point Dixon volumetric interpolated breath-hold examination (Dixon-VIBE) sequence was acquired in endexpiration [20,21]. The cardiac MRI and PET emission data were acquired simultaneously. The PET data was acquired in list mode. The MRI protocol consisted of a single-slice, steady-state free precession (SSFP) sequence acquired in a two-chamber and a four-chamber view and a stack of contiguous short axis slices. Short-axis SSFP sequences covered the whole heart during several end-expiration breath holds. The repetition time (TR) was automatically adjusted according to the volunteer /patient´s heart rate. The following parameters were applied: slice thickness/in-

Data analysis
Three observers evaluated the datasets. Observer (O1) evaluated the MRI and PET datasets. Observer 2 (O2) evaluated only PET and observer 3 (O3) evaluated only MRI data, all blinded to the results of the other method. To assess intraobserver reliability, each evaluation was repeated after a 3month waiting period, to exclude memory bias. The first measurement is named M1, the second M2 and for the first observer with the modality as index (e.g. M1 PET or M1 MRI ).

MRI data analysis
The MRI data was evaluated with CMR42 [Version 4.0.2 (151), Circle Cardiovascular Imaging Inc., Calgary, Canada]. The observer was blinded to the results of the gated [ 18 F] FDG-PET analysis. LVEDV, LVESV and LVMM were assessed using Simpson´s method. Epicardial and papillary contours were drawn only in end-diastole and endocardial contours semi-automatically in all cardiac phases (Fig. 1). Total LVMM was calculated as the sum of the mass of the papillary muscles and the compacted myocardial mass, and LVEF was calculated with the usual formula [22]: (LVEDV-LVESV)/LVEDV.

PET data analysis
The co-registration of the averaged PET and Dixon-VIBE data-used for AC-was visually inspected to rule out misclassifications prior to the analysis with Corridor 4DM (Ann Arbor, MI, USA, Version 6.1.5) [22]. The mitral valve and apex were visually identified, tagged manually and an initial estimate of the ventricles were created by the software on the basis of a twodimensional gradient image [2]. LVEDV, LVESV, LVEF and LVMM were calculated automatically from the computed epi-and endocardial contours [23] (Fig. 2).

Statistical analysis
Statistical analyses were performed using MedCalc for Windows, Vers.12.5 (MedCalc Software, Ostend, Belgium). Mean differences between both modalities were tested using the Student's t test for paired samples. A p value < 0.05 was considered to be statistically significant. Correlation between methods was calculated using Pearson coefficients. Intra-and interobserver reliability were assessed as intraclass correlation coefficient (ICC) and analysed as follows: Intra-observer reliability: M1 and M2 of O2 and O3, respectively. Inter-observer reliability: M1 PET of O1 and M1 of O2; M1 MRI of O1 and M1 of O3 Inter-modality reliability: M1 of O2 and M1 of O3.
Furthermore, linear regression analysis was performed and Bland-Altman plots [24] generated.

Patient characteristics
Twenty-nine patients (23 male, 6 female) were includeddetailed characteristics are shown in Table 1. Twenty patients underwent a non-cardiac PET/CT, and the other nine patients with CAD received viability assessment. Mean study population age was 58 ±17 years, while the CAD patients were significantly older. Patients who underwent PET/MR after PET/CT had no history of cardiac diseases (non-CAD).

Image quality
All patients showed a diagnostic IQ; non-CAD and CAD patients had a mean IQ of 2.5 ±0.7 and 1.6 ±1.1, respectively (p < 0.0001). The IQ was ≤1 in six out of nine CAD patients and >1 in all non-CAD patients. Two CAD patients had diabetes mellitus without influencing the IQ of the FDG-PET. Nevertheless, the IQ influenced negatively the correlation of LVMM (Table 2).
Acquisition time, heart rate (HR) and radiation exposure Acquisition time was 900 ±0 s, i.e. 15 min for gated PET and 229 ±57 s (i.e. 3.82 min) for MRI. The mean HR during the MR acquisition was 64 bpm (SD: ±13; range: 41-94 bpm), and the resulting mean RR interval was 970 ms (SD: ±196; range: 640-1475 ms). As expected, the mean HR and other HR-dependent parameters of the PET acquisition were comparable to the data of the simultaneously acquired MR acquisition with a mean PET HR of 65 bpm (SD: ±13; range: 48-93 bpm), and a resulting mean RR interval of 950 ms (SD: ±173; range: 647-1237 ms).
Initially administered activity for the PET/CT was 330 ±61 MBq resulting in an effective dose of 6.3 ±1.2 mSv. Due to PET/CT being prior to PET/MR in the majority of

LV volumetric and functional parameters
A summary of the results is shown in Table 3.  Fig. 6).

Reproducibility
Intraobserver reliability was very high and comparable in both modalities for all LV parameters (ICC ≥ 0.95). Interobserver reliability was very high for all LV parameters in PET (ICC ≥ 0.96). In MRI, the interobserver reliability was high for LVEF (ICC = 0.87), and very high for all other LV parameters (

Discussion
Assessment of left ventricular volumes, function and mass data is feasible with a homogenous residual activity of a previous PET/CT examination. If acquired with simultaneous cardiac PET/MR, parameters correlated well between PET and MRI readouts with only small bias, (Table 3). However, the limits of agreement (LOAs) are rather wide, such that PET and MRI functional and volumetric data could be used interchangeably. Intra-and interobserver reliability was slightly lower in PET as compared to MRI, although MRI is a frequently used standard of reference. These results are not surprising, because the cardiac PET algorithm for the volumetric and functional evaluation does not allow much user-software interaction. Observers can only change the LV axis, the position of the apex and the mitral valve. Epicardial and endocardial contours are detected automatically and cannot be changed manually. Papillary muscles are merged into the contours or neglected due to low uptake. With more possible user interaction, the inter-and intraobserver variability increases [25]. The contours, defined in the MRI datasets, can be modified substantially and partial volume effects of the papillary muscles and the manual correction can lead to discrepancies in the different measurements. Therefore, we conclude that the higher intraand interobserver variability deduces itself from higher usersoftware interaction and can be decreased by reader consensus training [26].
We acquired the SSFP sequences in expiration, because our own unpublished experience in consensus to other studies has revealed [20,21] that this method leads to the most accurate thoracic image fusion, due to free breathing being mainly an end-expiration phase [27]. Additional respiratory gating of the PET acquisition, usually triggered by MR navigator pulses,  may improve image fusion, however, at the cost of higher acquisition time [21,27].
The correlation between MRI and PET with corresponding coefficients for LVEDV, LVESV and LVEF is comparable to other studies [2,12,13], except LVMM, which was lower in one study [13]. All three studies quoted in Table 3 examined patients exclusively with coronary CAD and reduced LVEF. In our study, only 31% of patients had CAD.
Different temporal resolutions can significantly alter the correct assessment of LVEF, if the end-diastolic and endsystolic phases are not detected properly [28,29]. In patients with severely impaired LVEF, the differences between LV volumes in each phase are smaller. Therefore, a lower temporal resolution has less influence on LVEF compared to patients with normal or slightly decreased LVEF [4].
The TR of our used SSFP sequence was automatically adjusted to HR and ranged between 46-52 ms. The mean TR of our examined cohort was 50 ms (SD: ±1.3; range: 46-52), the mean HR was 64 bpm (SD: ±13; range: 41-94 bpm), the resulting mean RR interval was 970 ms (SD: ±196; range: 640-1475 ms). Therefore, in our cohort, the mean HR was rather low, and the corresponding RR interval was high, which are rather optimal conditions to achieve a high temporal resolution. Taking this information into account, we had a mean maximum phase duration of 970/20 = 48.5 ms to catch the systolic phase appropriately within 5% of the RR interval. However, a Btemporal partial volume effect^may occur with a loss of precision in the determination of systolic volumes in some patients, and thus a potential underestimation of the ejection fraction.
Due to the fact that a fixed number of 16 gates were reconstructed with the PET acquisition, the mean gate length of the PET reconstruction was 60 ms (SD: ±11; range: 40-77 ms) in our cohort. Therefore, the mean temporal resolution of the PET acquisition was obviously lower than the temporal resolution of the MR acquisition with a mean percentage of the PET gate length with the MR TR of 118% (SD: ±23; range: 79-159%).
However, the reconstructed temporal resolution of MRI in our study was nearly 40% higher with a fixed number of 25 reconstructed phases per cardiac cycle in MRI as compared to a fixed number of 16 gates in cardiac PET, compared to all other cited studies ( Table 2) While the spatial Bin-plane^resolution-the voxel size was 1.4 × 1.4× 8.0 mm 3 for MRI and 1.4 × 1.4 × 2.03 mm 3 for PET-was the same for MRI and PET, the spatial Bthrough-plane^resolution was higher in PET. However, since the orientation in cardiac MRI is along the cardiac axis, while in PET it is along the z-axis of the patient, the spatial resolution is not directly comparable, especially if the variable position of the heart is considered. However, the higher spatial Bthrough-plane^resolution of PET is, in our opinion, not the main factor for the difference between the results.
Comparable to other trials, the volumetric assessment of simultaneously acquired PET and MRI data showed significantly lower mean left ventricular volumes with PET as compared to MRI, also in the subgroups with and without CAD (Table 3). Furthermore, there were tendencies towards higher calculated LVEF and LVMM values with PET.
Non-CAD patients demonstrated similar results to Schaefer et al. [2], but narrower LOA and a smaller bias for LVESV as well as LVEDV compared to other studies [12,13] and comparable results to another. LVEF showed similar bias and wider LOA [12,13]. However, the interobserver reliability in PET is lower than in the study of Khorsand et al. (values in brackets): −0.3 ±9 mL (5 ±16 mL) for LVEDV, 2% ±5% (1 ±5%) for LVEF and −3.3 ±12 g (24 ±17 g) for LVMM, although all values did not significantly differ from 0 [12,13]. In contrast to Khorsand et al., in our study, gated PET overestimated the mean LVMM by 18 g as compared to MRI. Also, different definitions of the LV cavity may contribute to this: In MRI, segmentation is driven by the visible anatomical structures, while in PET, algorithms of the maximal [ 18 F] FDG uptake in t h e m y o c a r d i a l w a l l a r e u s e d t o d e f i n e a n intramyocardial centreline from which the endo-and epicardial contours are estimated [12]. Unfortunately, the algorithms behind these volumetric calculations are not fully public yet. Morphological data from simultaneously acquired MRI could be used to further improve segmentation algorithms for gated PET.
There is a lack of consensus concerning preparation of patients undergoing cardiac [ 18 F] FDG-PET [16]. The nine patients for viability assessment received a glucose load [11]. In contrast, the 20 patients that underwent PET/ MR as a subsequent examination after PET/CT followed a fasting protocol that suppresses body muscle [ 18 F] FDG uptake but does not prevent an incidental homogenous cardiac uptake [30]. In our case, only patients with this incidental homogenous myocardial uptake after PET/CT and who agreed to undergo another PET/MRI examination and had no contraindications to MRI were included in the study. This incidental homogenous uptake occurred in approx. 20% of the patients examined, which is in line with a prior study [31]. Better image quality of the cardiac PET in patients that underwent PET/CT for non-cardiac reasons compared to that of patients with ischaemic scar tissue is probably due to the fact that the first group had presumably no history of cardiac pathologies (Table 3, Fig. 2). However, differences in PET IQ influenced negatively the evaluation of LV parameters for LVMM calculations only (

Limitations
If our mean reported TR of 50 ms is considered as the Brealt emporal resolution of our CINE-SSFP sequence, as some authors recommend [32], rather than the reconstructed frames/phases per heartbeat, which were fixed at 25 phases, then the underestimation of PET functional parameters is not only caused by the use of residual activity, but also intrinsically due to the MR technology used itself. Furthermore, the interpretation of our results is limited due to the small number of patients, though comparable to other studies in terms of patient number and results. We examined patients with and without CAD, different to Slart [12]. However, it has been demonstrated, that the use of half of the usual activity in PET/MR seems prudent [33] and high-definition hybrid cardiac FDG PET/MR has been shown to be diagnostic using a mean activity of only 150 ±70 MBq [34], which is approximately half of the mean dose used in our study. It is comparable to the mean activity still available after 2.8 h on average in our non-CAD patients, which corresponds to 1.5 half-lifes of [ 18 F] FDG or 165 min.

Conclusion
Despite a decent correlation between volumetric analysis of simultaneously acquired LVEF and LVMM PET data, obtained with model-based automated analysis software, comparable to sequentially acquired data in the literature, biases are observed with an expected underestimation of LVEF and LVSV. However, since the LVEF especially shows wide LOAs, the methods should not be used interchangeably. Cardiac volumetric analysis is feasible from PET data in patients who incidentally present with a homogenous cardiac uptake after previous whole-body PET/CT under fasting conditions, so that the fast, automated LV segmentation algorithms from cardiac PET analysis software can still be used reliably to allow for a fast and standardized evaluation. If residual myocardial [ 18 F] FDG activity is used in PET/MR examinations, one should rely on MRI SSFP cine imaging as the gold standard. However, our results support the proposal to reduce the usual applied [ 18 F] FDG activity in cardiac PET/MR for viability assessment from other groups [11,35], which is of interest in terms of patient radiation protection.

Compliance with ethical standards
Guarantor The scientific guarantor of this publication is Matthias Gutberlet.

Conflict of interest
The authors of this manuscript declare relationships with the following companies: Siemens: Matthias Gutberlet, Henryk Barthel, Osama Sabri: Financial activities not related to the present article: authors received lecturing fees from Siemens. Henryk Barthel, Osama Sabri, Matthias Gutberlet: Financial activities not related to the present article: authors received travel and accommodation expenses from Siemens.
All other authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.
Funding This study has received funding by the German Research Council. The PET/MRT system was co-funded by the Max Planck Society and the Heart Center Leipzig (grant no. SA 669/9-1).

Statistics and biometry
No complex statistical methods were necessary for this paper.
Informed consent Written informed consent was obtained from all subjects (patients) in this study.
Written informed consent was waived by the Institutional Review Board.
Ethical approval Institutional Review Board approval was obtained.

Methodology
• prospective • diagnostic or prognostic study • performed at one institution Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.