We included two study populations, one comprising 25 healthy volunteers and the other 53 patients with intermediate to high pre-test likelihood of cardiovascular disease with no known coronary artery disease (CAD) (n = 30) or known CAD (n = 23) referred for both 82Rb-PET and subsequent coronary angiography and FFR assessments. Both study populations gave both informed and written consent to participate in the study. The studies were filed under protocol numbers [H-15009293 and H-42014046, respectively], following approval from the Scientific Ethics Committee and the Capital Region of Denmark, and the Danish Data Protection Agency.

The volunteer cohort comprised 25 healthy young persons who underwent repeat 82Rb rest/adenosine stress MPI within 2 weeks (Table 1).8,9 Inclusion criteria were age > 18 years, no regular consumption of medicine, no known medical condition, no use of tobacco and euphoric substances (except alcohol) within 3 months before study participation, and no caffeine intake (plasma caffeine concentrations < 1,000 µg/L). Exclusion criteria were pregnancy, allergy or intolerance to theophylline or adenosine, any prior medical history of asthma, and inability to adhere to the study protocol.

The patient cohort included 53 patients (Table 1).

Inclusion criteria were age > 50 years, while exclusion criteria were claustrophobia, severe asthma, or renal failure (plasma creatinine > 140 µM). Coronary stenoses > 50% identified by invasive angiography were, in all cases, assessed for hemodynamic significance by measuring FFR during continuous adenosine infusion (140 μg/kg/min) for 2 minutes. A FFR< 80% was considered significant and led to subsequent percutaneous coronary intervention (PCI) where technically possible.

All study participants underwent rest/adenosine stress MPI in a 128 slice Siemens Biograph mCT PET system using targeted injection doses of 1,100 MBq (30 mCi) 82Rb. Pharmacological stressing was obtained using adenosine infused intravenously at a rate of 140 mg/kg/min for 6 minutes, with PET emission acquisition starting 2.5 minutes into the infusion. Each imaging session started with a low-dose CT for attenuation correction purposes acquired using a free-breathing protocol,10 followed by the PET emission scans. All participants were instructed to abstain from caffeine at least 16 hours before each of the imaging sessions.

Two PET reconstruction protocols were evaluated. Both reconstruction protocols employed data obtained between 150 and 360 seconds into the 82Rb-PET acquisitions,11 using the following reconstruction parameters: 2 iterations, 21 subsets, corrections for Time-of-Flight and point spread, and a 5 mm Gaussian filtration. The first reconstruction protocol provided a conventional static reconstruction (StandardRecon), as used in routine assessments. The second reconstruction protocol provided a triple-motion-corrected image series (3xMC), including corrections for myocardial creep and cardiorespiratory motion correction (described in detail below).

The myocardial creep events were detected retrospectively in the acquired PET raw data (listmode) using a center-of-mass-based analysis,6,7,12 employing a temporal resolution of 200 ms to facilitate the detection of myocardial creep events with a high temporal resolution. This proposed motion detection technique differed from previous attempts at detecting patient repositioning events6,7 as 82Rb MPI scans are affected by tracer-kinetics during the acquisitions. To this end, we hypothesize that the myocardial creep events may be detected by comparing radiotracer kinetic uptake in tissues with and without specific uptake. For the myocardium, 82Rb is being trapped via Na-K-ATPase, while healthy lung tissue, on the other hand, tends to have a non-specific uptake pattern. Given both tissues follow the same respiratory repositioning events, any significant change in the center-of-mass for the two tissues indicates a myocardial creep event. In this study, we tested this assumption by convolving the center-of-mass signals obtained in the myocardium and surrounding tissues (Figure 1). From the convoluted center-of-mass signals, it is possible to extract information on myocardial creep using a piece-wise fit [myocardial creep was defined as changes of ≥ 20% within 5 seconds (repositioning event) or 8% over 30 seconds (change in the respiratory baseline)], while the respiratory signal was obtained by filtering all the inspiratory peaks in the frequency-band (0.1-0.65 Hz).

Data-driven motion detection and correction. All datasets obtained ECG-triggering events from a 3-lead external marker, while myocardial creep and respiratory motion were detected using data-driven techniques employing only the acquired 82Rb-PET raw data. The myocardial position was calculated with a temporal resolution of 200 ms (CoM evaluation). The creep detection was obtained comparing the count rates observed in the myocardium to the count rates obtained in the surrounding tissues, using a convolution function. Changes in the signal of more than 20% within 5 seconds (sudden creep event) or 8% over 30 seconds (drifting creep event) were considered myocardial creep events. The respiratory signal was extracted by filtering the CoM signal with a frequency between 0.1 and 0.65 Hz). Using the triggering signals, the data was reconstructed into a triple gating event which was co-registered to obtain the 3xMC. CoM, center-of-mass

3xMC was obtained by introducing a cardiorespiratory (dual-gated) reconstruction protocol for each myocardial creep event, as based on a previous proposal.6 All gated reconstructions were co-registered using a local-registration matrix surrounding the segmented heart ± 15 slices (slice thickness = 2.07 mm) in all directions). The co-registration was obtained using a non-rigid registration protocol (demons) in MatLab.

We report the average translation observed in the myocardium during the scans, the total perfusion deficits for all reconstructed datasets [rest and stress total perfusion deficits (rTPD and sTPD, respectively)], and the ischemic total perfusion deficit (iTPD) calculated as the respective sTPD minus rTPD for the individual MPI sessions.11,13 Of note, rTPD, sTPD, and iTPD are given in % of the left ventricular wall volume. In this study, an iTPD ≥ 10% was considered abnormal.14

We also report the test-retest repeatability using the standard error of measurement (SEM) of the motion-induced perfusion deficits observed for the healthy volunteers. For the patient cohort, we report the crosstab assessments, including the prevalence of disease, the sensitivities, and specificities, in addition to the positive and negative predictive values obtained for the StandardRecon and 3xMC assessments.

In addition, two experienced readers (combined experience of > 30 years) were asked to visually evaluate the images concerning the potential of motion-induced artifacts in the images while being blinded to the used reconstruction protocol. All assessments were performed in the clinical software toolbox (QPET, Cedars-Sinai). The images were scored on a scale from 1 to 5, with 1 being scored when the readers were certain of motion-induced artifacts in the automatic assessments; conversely, 5 was given when the images did not show any signs of motion artifacts. Finally, we report the TPD values and the area under the receiver operating curve (AUC) for the patient cohort as the primary end-point for this study.11,13

The data were tested for normality using Shapiro-Wilk test. Continuous data were presented as mean ± SD or median and interquartile ranges, and categorical data as percentages. Employing the FFR findings for the patient population, the impact of the myocardial creep motion correction was evaluated using receiver operating characteristic curves. All receiver operating characteristic curves were compared using the DeLong and DeLong method,15 using the area under the curve (AUC) as the primary end-point for this study. Test-retest repeatability was calculated as the standard error of measurement (SEM) and the 95% confidence intervals of the SEM. Differences in bias were evaluated using the Pitman-Morgan test, with P-values < .05 being considered statistically significant. Finally, the number of creep events and patient motion across the different cohorts were evaluated using a two-way ANOVA.