Intravenous insulin administration preparation for myocardial 18F-uorodeoxyglucose viability imaging has the potential to reduce radiation exposure dose

Purpose This study aimed to identify and validate the optimal 18 F-FDG activity and acquisition time for cardiac viability imaging with intravenous insulin administration based on a xed 18 F-FDG activity. Methods Cardiac positron emission tomography (PET) images from 30 patients with coronary artery disease (CAD) were retrospectively reconstructed into 900, 360, 180, 90, and 45 s durations. An optimal product of the maximum standardized uptake value (SUV) of the myocardium and segmental uptake (SU) and acquisition time (MSAT) was determined through a receiver operating characteristic curve. The optimal acquisition time (OAT) was equal to MSAT divided by mean SUV of the myocardium (MyoSUV) and validated in another 26 patients with CAD.


Introduction
High signal-to-noise ratio is a critical factor for a precise positron emission tomography (PET) quantitative analysis. The signal-to-noise ratio of PET image improvement depends on the new crystals [1,2], new reconstruction methods [3][4][5], time-of-ight application [6,7], axial eld of view expansion [8], and use of magnetic resonance [9] and ultrasound [10] equipment. In clinical practice, optimizing acquisition time [11], increasing tracer dosage [12], and enhancing the tracer uptake ability of the organ of interest improve PET image quality. Insulin enhances myocardial glucose uptake by stimulating glucose transporter 4 onto the cardiomyocyte membrane [13] and surpasses the standardized glucose loading preparation protocol for myocardial viability 18 F-uorodeoxyglucose ( 18 F-FDG) imaging [14].
Therefore, insulin has the potential to obtain high-quality cardiac 18 F-FDG images with decreasing 18 F-FDG activity to reduce radiation dose.
Counts in the myocardium are lower with greater variability of segmental 18 F-FDG uptake in low-dose 18 F-FDG imaging compared to normal-dose imaging. However, coronary artery revascularization in severe left ventricular dysfunction is based on precise myocardial 18 F-FDG uptake analysis [15,16]. 18 F-FDG activity is positively associated with the radiation dose and the PET image count, whereas the count variation is negatively associated with the PET image count. Measurement error is greater with smaller counts; therefore, precise analysis is needed to avoid high doses of radiation caused by high 18 F-FDG activity.
The optimal 18 F-FDG activity for cardiac viability imaging remains unknown. Since the product of 18 F-FDG activity and scan duration per bed position (MBq/kg × min/bed) is a critical factor for optimizing PET data acquisition, the 18 F-FDG activity is inversely proportional to the scan duration [17]. Therefore, this study aimed to validate, following the determination of the optimal 18 F-FDG activity, the optimal acquisition time (OAT) for cardiac viability 18 F-FDG imaging based on a xed 18 F-FDG activity.

Participants
In this retrospective study, a total of 30 patients with coronary artery disease were included from our registered trial (ChiCTR1800019741) to develop an OAT for cardiac viability 18 F-FDG imaging. Another group of patients with coronary artery disease for cardiac viability 18 F-FDG imaging was randomly selected from our database and approved by the ethics committee of our hospital (registration number 106). All patients signed an informed consent form before imaging with insulin loading preparation. The patients fasted ≥ 6 h before blood glucose measurement. In the development group, routine intravenous insulin (dosage (IU) = blood glucose (mmol/L) − 2) was administered approximately 24 min before 18 F-FDG injection with a 10% incremental dose for diabetic patients [14]. In the validation group, intravenous Qualitative and quantitative image analyses Standardized uptake value (SUV) measurements were performed with TrueD (Siemens, Malvern, PA, USA). A volume of interest with approximately 1.6 cm diameter was placed in the right atrium to measure the mean SUV of the blood (BloSUV). Moreover, 41% maximal myocardial SUV (MyoSUVmax) was set as the cutoff value to measure the mean SUV of the myocardium (MyoSUV) [17]. Segmental uptake (SU) percent was automatically analyzed using the quantitative perfusion single-photon emission computed tomography 2012 version (Cedars-Sinai Medical Center, Los Angeles, CA, USA) and displayed on a 17segment polar map. SUVs and SU from 900 and 600 s image durations were set as true values in the development and validation groups, respectively. Bias of SUV and SU describes the relative percentage difference of their estimated values from true values. Bias within ±0.10 was acceptable [19]. The OAT was de ned to obtain more than 16/17 segments with biases within 0.10 of the minimum acquisition time.

Statistical analyses
Continuous variables are expressed as mean ± standard deviation. Categorical variables are expressed as percentages. Between-group comparisons were performed using equivalence paired t-tests and chisquared tests as appropriate. The equivalent limitation values of the SUV of the blood pool and myocardium were set as ± 0.1 and ± 0.5, respectively. The power and signi cance were set at 90% and 5%, respectively. Because biases of SU were affected by counts in the volume of interest, the product of MyoSUVmax and SU and acquisition time (MSAT) was set as the independent variable. A receiver operating characteristic curve analysis was performed, and the cutoff value of MSAT was determined, with a speci city ≥ 16/17. The area under the receiver operating characteristic curve was 0.833 ± 0.018 (95% con dence interval [CI], 0.798-0.869; P < 0.001). When MSAT was > 848.2, the ratio of bias of SU beyond ± 0.10 was ≤ 5.3%; in other words, the ratio of SU within ± 0.10 was ≥ 16/17 segments (FIG 1). A total of 26 patients were required in the validation group to obtain signi cant results. The baseline characteristics of patients in the validation group were similar to those of the development group (TABLE   2). In the validation group, the MyoSUV was 7.94 ± 3.02 on the PET 30 s image duration. The OAT was 129 ± 76 s (95% CI, 99-160). The MyoSUV was equivalent for the difference (0.15 ± 0.21, P < 0.001) between the PET OAT image duration and 600 s image duration (7.71 ± 3.01 vs. 7.56 ± 2.94). The SU was

Discussion
The concept of cardiac 18 F-FDG viability imaging with insulin loading preparation, acquired with optimal time was established and con rmed for the rst time in this study. Our results are robust. The optimization acquisition time was determined through objective analysis instead of subjectivity adjustment [8,20] and it was con rmed in another similar validation group. The MyoSUV and SU were signi cantly equivalent between cardiac OAT image duration and 600-s image duration (P < 0.001). The OAT was only approximately one-third of the usual acquisition time (360 s) with a xed 18 F-FDG dose (3.7 MBq/kg). This suggests that only one-third of the radiation dose exposure to 18 F-FDG may be achieved when the 18 F-FDG dose is reduced to 1.2 MBq/kg with usual acquisition time (360 s). Because the effective dose of 18 F-FDG for adults is 0.019 mSv/MBq [21], the average effective radiation dose is only 1.6 mSv for a 70-kg patient.
SU in 17 segments is a semiquantitative assessment of myocardial 18 F-FDG viability [22]. It is more precise than MyoSUV. Because SUs obtained from quantitative perfusion single-photon emission computed tomography are equivalent between cardiac OAT and 600-s image durations, it implies that the e ciency of cardiac viability assessment based on 18 F-FDG image acquisition duration OAT is similar to that of 600 s acquisition duration.
Because the variation of MyoSUV is large (> 30%), an empirical OAT is di cult to determine. However, a pragmatic self-adapting acquisition mode can solve that problem. The OAT can be calculated according to the MyoSUV obtained from a prior acquiring cardiac data (30-s duration). Moreover, the data acquisition will continue to trigger the OAT. This type of simulating acquisition mode has been con rmed in the validation group. We believe that this type of pragmatic self-adapting acquisition mode would be produced in the future.

Limitations
There are two limitations in this study. First, the MSAT was determined from cardiac data acquisition with a three-dimensional mode using PET/computed tomography and only adapted this condition. Because detection sensitivity and noise equivalent count rates vary among commercial PET scanners [23,24], even acquisition modes (two-dimensional/three-dimensional) in the same gantry [25], as well as MSAT values, may differ and must be determined under each condition. Second, cardiac motions were noncorrected for myocardial PET images in this study. Because the signal-to-noise ratio increases with cardiac motion correction for myocardial PET images [26], the MSAT could decrease with motion correction, which may cause a shorter OAT and a lower radiation exposure dose.

Conclusion
Intravenous insulin administration preparation has the potential to reduce radiation exposure and acquisition time of cardiac 18 F-FDG viability imaging without losing the accurate measurement of MyoSUV or SU percent when reaching an OAT.

Declarations
Ethics approval and consent to participate This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The ethics committee of Quanzhou 1 st hospital approved this study. All patients signed an informed consent form before imaging with insulin loading preparation.

Consent for publication
Not applicable.

Availability of data and material
The datasets generated and analysed during the current study are not publicly available due to participant privacy but are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
The trial was supported by the Natural Science Foundation of Fujian Province (Grant numbers 2015J01516, 2018J01202, 2020J011280), and the Quanzhou Science and Technology Commission (Grant number 2019C023R).

Authors' contributions
Yangchun Chen and Ruozhu Dai received various funding and supervised this study. Yangchun Chen designed this study, and Huoqiang Wang modi ed that designation. Qingqing Wang, Peihao Huang, Yuehui Wang, Yuxuan Chen, Huilin Zhuo, and Yangchun Chen conducted this study. Yangchun Chen wrote the draft manuscript. We have read, revised that draft and approved the nal version of this manuscript.   Figure 1 The association between the product of maximal myocardial standardized uptake value and segmental uptake and acquisition time (MSAT) and the ratio of bias of segmental uptake within ±10%.

Figure 2
A series of representative myocardial 18F-uorodeoxyglucose viability images reconstructed in 30, 121, and 600 s durations is shown as short axial, vertical long axial, and polar map images. The mean standardized uptake value of the myocardium (MyoSUV) on the prior positron emission tomography (PET) 30 s acquisition duration is 7.0. The MyoSUV and segmental uptake in each segment are equivalent (bias < ±0.05) on PET images reconstructed between 121 and 600 s duration.