Impact of regadenoson-induced myocardial creep on dynamic Rubidium-82 PET myocardial blood flow quantification

The use of myocardial blood flow (MBF) quantification using Rubidium-82 (Rb-82) in myocardial perfusion imaging (MPI) with positron emission tomography (PET) is increasing rapidly.1-3 MPI using Rb-82 PET is of added value in the diagnosis of coronary artery disease, and the MBF quantification provides valuable additional prognostic information about the extent and functional importance of possible stenosis.4-6

A dynamic PET acquisition including the capture of the first-pass bolus of the activity is required for MBF quantification. Pharmacological vasodilators are generally used to induce stress, while the patient is lying inside the PET scanner.1,7 The three commonly used vasodilators are adenosine, dipyridamole, and regadenoson. Due to the stimulation of A₁, A_2B, and A₃ receptors, adenosine and dipyridamole are associated with undesirable short-term side-effects as general discomfort, chest pain, and hypotension, and more severe side-effects such as atrioventricular block or bronchospasm.8,9 An alternative is regadenoson which is a more selective vasodilator that only stimulates A_2A receptors and is fast and better tolerated by patients.10-15 Regadenoson has shown to result in accurate calculation of quantitative MBF values in MPI using Rb-82 PET with similar accuracy compared to adenosine or dipyridamole.10,12,16-18 An additional advantage of regadenoson is the significantly lower degree of patient motion compared to adenosine, which can significantly affect the MBF quantification.19-23

Despite the reduced patient motion when using regadenoson, in clinical practice, we frequently observe repositioning of the heart after administration of regadenoson. This so-called myocardial creep is presumably caused by an increasing respiration and lung volume and thereby the repositioning of the diaphragm and heart after induction of pharmacological stress.24 This motion may result in biased MBF measurements and may hamper diagnostic accuracy. Our aim was to determine the percentage of patients with this myocardial creep and to determine its effect on MBF values before and after correction in patients undergoing Rb-82 PET.

Of the 119 patients, 11 (9%) were excluded due to the presence of both patient motion and myocardial creep in the stress data. An additional four patients (3%) were excluded due to unreliable TACs. An example of an unreliable TAC is shown in Figure 1. Of the remaining 104 patients, four (3%) showed only general patient motion in stress.

The baseline characteristics of the remaining 104 patients are summarized in Table 1. 54 (52%) Patients showed a myocardial creep during the stress scan, as illustrated in Figure 2. Patients with and without myocardial creep did not differ regarding gender, weight, body mass index (BMI), cardiac risk factors and scan outcomes (P ≥ 0.10). Yet patients with myocardial creep were younger (64 years old) than patients without myocardial creep (70 years old, P = 0.004). Of the 54 patients with myocardial creep during stress, two patients also showed myocardial creep during the rest scan.

The uncorrected and corrected MBF and MFR measurements, in both rest and stress, for each of the three territorial segments and for the myocardium as a whole (global result) are shown in Table 2 and Figure 3. When comparing the uncorrected and corrected data, the largest differences were found for the RCA territory where the mean MBF decreased from 4.0 to 2.7 mL/min/g (P < 0.001) and the mean MFR from 3.5 to 2.4 (P < 0.001). Moreover, the MBF of the RCA decreased in 91% (49/54) of the patients, and the MFR of the RCA decreased in 89% (48/54) of the patients, as shown in Figure 3D. Furthermore, differences in MBF and MFR were found for the LAD territory and for the whole myocardium. The mean MBF increased for the LAD from 2.5 to 2.6 mL/min/g (P = 0.03) and for the MFR from 2.2 to 2.3 (P = 0.006), and for the whole myocardium, the mean MBF and MFR values decreased from 2.7 to 2.6 mL/min/g (P = 0.01) and from 2.4 to 2.3 (P = 0.03), respectively. No significant differences were found for the LCX territory in stress (P = 0.3) nor in the rest scans (P ≥ 0.11). In the 54 patients with myocardial creep, 45 (83%) had a change > 10% in MBF and 45 (83%) had a change > 10% in MFR in one of the territories or the whole myocardium.

In this study, we have demonstrated that a myocardial creep occurs in more than half of the patients during regadenoson-induced stress MPI using Rb-82 PET. Moreover, correction of this myocardial creep resulted in significantly lower MBF and MFR values for the RCA territory and may improve diagnostic accuracy. Besides the large impact on MBF and MFR values in the RCA territory, myocardial creep also resulted in significant differences in stress MBF and MFR values for the LAD and the whole myocardium. These differences can be explained by the anatomic position and direction of myocardial creep, as illustrated in Figure 4. During the first-pass phase when the Rb-82 activity is in the LV, there is a strong overlap between the activity and the part of the myocardium contour that is perfused by the RCA and to a lesser extent by the LAD when myocardial creep is present. After correction, the overlap diminishes, which directly affects the MBF and MFR measurements.

Multiple studies have reported the occurrence of myocardial creep, also known as non-returning motion of the heart, primarily occurring in the post-stress period during MPI using different pharmacological vasodilators.19,23,24,27,28 A recent study by Memmot et al. reported a non-returning motion or myocardial creep in 36% (11/30) of their patients during MPI using Rb-82 PET and regadenoson as vasodilator independent of age.19 This percentage is in fair agreement with the 52% found in this study, although we used a different methodology to assess the presence of myocardial creep and a slightly different time-framing combination. Furthermore, they showed that 69% (11/16) of the patients stressed with regadenoson with visible motion were categorized as myocardial creep which is in fair agreement to the 78% (54/69) found in our study. Moreover, they reported that only 10% (3/30) of their patients showed significant motion, which was defined as motion greater than half the width of the myocardial wall. Although we did not assess severity or amount of myocardial creep, we did observe that correcting for myocardial creep majorly affected the MBF quantification in most patients and presumably also in patients with only a limited amount of myocardial creep. Lee et al. recently reported that greater motion was observed during stress, especially in the inferior direction which reflects myocardial creep which is in high agreement with our study.28 They also reported that motion resulted in the largest changes in the MBF and MFR in the RCA territory, consistent with our results.

Multiple mechanisms are hypothesized in the literature to explain the occurrence of myocardial creep. Karacalioglu et al. hypothesised that myocardial creep is caused by gravity on the organs when patients switch from a standing to a lying position in the scanner. They reported that a five-minute bed rest on the scanner table significantly decreased the vertical motion of the heart.29 A CT-scan followed by the rest scan was performed before the stress scan in our protocol. Therefore, the mechanism described above does not explain the myocardial creep we found during stress imaging. Although this gravity theory might explain myocardial creep during rest acquisitions, we observed myocardial creep in only 2% of the rest scans and therefore think this is most likely caused by anxiety at the start of a MPI scan.30

Another mechanism previously described by Friedman et al. which is more likely to cause myocardial creep is that after administration of a pharmacological vasodilator, in our case regadenoson, lung volume increases which causes a repositioning of the diaphragm and heart.24 Hence, we are unable to prevent this repositioning of the heart and thus the occurrence of myocardial creep.

Several limitations of this study should be recognized. First, we were unable to determine the effect of myocardial creep correction on the diagnostic accuracy due to the lack of a reference standard. However, in some patients myocardial creep resulted in unrealistic high MBF values (>5 mL/min/g) which decreased after correction to realistic values. Hence, we assume that correcting for myocardial creep increases diagnostic reliability.

Second, manual actions are required in the quantification process and for the myocardial creep correction which could have introduced additional operator variability. Although this operator variability might have introduced additional variance, the changes in stress MBF quantification were higher than the previously reported ± 10% test-re-test reproducibility errors when calculating the MBF using Rb-82 PET in MPI.31 Thus, the operator variability is expected to be of limited influence.

Third, a high fraction of the patients had a normal MBF, possibly limiting generalization. However, in case of the poorly perfused tissue with myocardial creep, the influence of spillover from the LV is expected to be larger than that for the normal perfused tissue resulting in a relatively larger overestimation of the modeling parameter k1 and, hence, MBF.28 This could result in larger differences between MBF values in the RCA territory before and after myocardial creep correction than those reported in this study.

Finally, we only corrected the myocardial creep in the attenuation-corrected PET images. However, only the PET data acquired between 2:30 and 7:00 minutes were co-registered to the CT to create an attenuation map. As myocardial creep only occurs in the earlier time frames, misregistration and, hence, attenuation-correction artifacts may occur. This misregistration could result in altered MBF measurements.32-35 Adding a second low-dose CT-scan immediately before the stress PET acquisition is unlikely to improve PET/CT registration as the myocardial creep misregistration occurs after induction of stress and is only temporary. However, we believe that frame-based co-registration of the stress-PET and CT data can improve PET/CT registration and thereby the reliability of Rb-82 PET quantification in patients with myocardial creep.28

If myocardial creep is present but remains uncorrected in clinical practice, the stress MBF and MFR of the RCA territory will be overestimated, as shown in Figure 3D, which can lead to incorrect diagnosis. The MFR of the RCA may fall within the normal range of the MFR values (> 1.7), while after correcting for myocardial creep, the MFR drops below this threshold, affecting the diagnosis.3 Moreover, Memmot et al. showed that myocardial creep occurs more frequently when adenosine is used as pharmacological vasodilator (96%) in comparison with regadenoson (69%).19 Therefore, we strongly recommend to check the presence of myocardial creep in all patients regardless of the used pharmacological vasodilator and correct for it to achieve reliable MBF and MFR measurements.

There are two practical ways to recognize myocardial creep in clinical practice. The first sign is an elevated time activity concentration of the RCA during the first-pass phase in the TAC in comparison with the LCX and LAD. As no activity is yet present in the myocardium, the whole activity measured in this phase is due to spillover and should therefore be constant across the three vascular territories, as shown in Figure 1. The second sign is the misalignment between the automatically drawn myocardium contour and the observed activity during the first-pass phase. As in 83% of our patients with myocardial creep an MBF change >10% occurred after correction, this implies that even a small myocardial creep should be corrected in clinical practice.

Myocardial creep was seen in 52% of the patients who underwent regadenoson-induced stress Rb-82 PET. Correcting for myocardial creep significantly changed MBF measurements during stress and MFR quantification, especially in the RCA territory. As this may hamper diagnostic accuracy, detection and correction of myocardial creep seem necessary for reliable quantification when using regadenoson.