Introduction

Rb-82 positron emission tomography (PET) myocardial perfusion imaging (MPI) is a robust tool for the evaluation for coronary artery disease (CAD), and has very good sensitivity and specificity.1,2 However, gastric uptake and spillover in Rb-82 PET studies can be extensive and may affect the image quality and diagnostic accuracy. Gastric spillover can be seen in 10% of studies, which most commonly affects the inferior wall and precludes the accurate identification of myocardial ischemia.3,4

Rb-82 gastric uptake is variable and anecdotally has been more frequently observed. Concomitantly, the use of proton pump inhibitors (PPI) has also been on the rise.5,6,7,8 We sought to understand the relationship between Rb-82 gastric uptake and PPI use.

Methods

600 consecutive patients who presented for a clinically indicated Rb-82 PET MPI study were prospectively enrolled. No patients were excluded from analysis. In addition to the clinical history, PPI use was ascertained (medication, dose, frequency and duration of use, and time of last dose). Patients were categorized as active PPI users and non-PPI users. Active PPI users were further categorized based on the time interval between last PPI use and the PET MPI scan.

Each patient underwent dipyridamole Rb-82 PET MPI as per our local protocol and image acquisition was performed adhering to ASNC guidelines.9 After a rest CT for attenuation correction, rest and stress images were acquired using either the GE Discovery PET/CT 690 or GE Discovery PET/CT 600 (GE Healthcare, Waukesha, WI) using 3D acquisition mode.10,11,12,13

Myocardial perfusion images were reviewed and qualitatively scored using the 17 segment model and 5 point scoring system (normal (0), mildly abnormal (1), moderately abnormal (2), severe abnormal (3), and absence (4) of radiotracer uptake).

The fused CT/perfusion images were used to identify cardiac and extracardiac structures. The maximal resting Rb-82 uptake (Bq/cc) was measured in the myocardium, stomach wall, and liver (Figure 1). Using axial images, measurements were performed by placing a large ROI over the organ of interest, ensuring the area with greatest Rb-82 uptake was within the ROI. Maximal SUV values within each ROI were recorded. Absolute uptake ratios (gastric(max):myocardium(max) and gastric(max):hepatic(max)) were calculated and compared between the 2 groups.

Figure 1
figure 1

Regions of interest used to measure activity (Bq/cc) in the myocardium (A), gastric wall (B), and liver (C) using fused CT/PET images

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Statistical Analysis

Continuous variables are presented as means and standard deviation, while categorical variables are presented as frequencies. Statistical analyses were performed using SPSS version 24 (IBM, Armonk, NY, USA). The comparison between groups was performed with the student t-test and chi-square test. A P value of < 0.05 was considered statistically significant.

Results

Of 600 enrolled patients, 181 (30.2%) patients were actively using PPI (Table 1). The most commonly used PPI was pantoprazole and PPI users were more likely to have hypertension, dyslipidemia, and history of percutaneous coronary intervention.

Table 1 Baseline characteristics
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The gastric Rb-82 uptake in PPI users was 23% higher than non-PPI users (146 ± 52 kBq/cc and 119 ± 40 kBq/cc, respectively (P < 0.001)) (Table 2, Figure 2). Of 419 non-PPI users, patients were further stratified as those using H2 blocking agents (12 patients). Since there was no difference in gastric uptake between those using H2 blocking agent and all other non-PPI users, they were combined (Table 2).

Table 2 Rest Rb-82 uptake (kBq/cc)
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Figure 2
figure 2

Box-Whisker plots of absolute gastric, myocardial, and hepatic uptake (A) and gastric/myocardial and gastric/hepatic ratios (B) in patients using PPI (red) and not using PPI (blue)

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There was similar hepatic Rb-82 uptake in PPI and non-PPI users (56 ± 11 kBq/cc and 56 ± 12 kBq/cc, respectively (P = 0.78)) (Table 2). The gastric:hepatic Rb-82 uptake ratio was 23% higher in PPI users (2.7 ± 1.0) than non-PPI users (2.2 ± 0.8; P < 0.001).

Myocardial Rb-82 uptake was 5% higher in the PPI users than the non-PPI users (122 ± 20 kBq/cc and 116 ± 21 kBq/cc, respectively (P = 0.002)). The gastric:myocardial Rb-82 uptake ratio was 16% higher in PPI users compared to non-PPI users (1.22 ± 0.43 and 1.05 ± 0.37, respectively (P < 0.001)).

Time Interval Between PPI Use and PET Imaging

PPI users were further categorized based on the time interval between PPI ingestion and the Rb-82 PET scan (< 36 and ≥ 36 hours) with each group comprising of 170 and 11 patients, respectively. The gastric:hepatic ratio was higher in the < 36 hour group than the ≥ 36 hour group (2.71 ± 0.96 and 1.98 ± 1.12, respectively (P = 0.016)). The gastric:myocardial ratio was also higher in the early group (1.2 ± 0.4 and 0.9 ± 0.4, (P = 0.006)).

Of patients for whom PPI dose was available, we also categorized PPI users as low, standard, and double PPI dose usage.14 The number of patients using low dose, standard dose, and double dose were 4, 140, and 37 patients, respectively. The gastric:hepatic ratio for standard and high PPI doses were similar (2.72 ± 1.03 and 2.60 ± 0.69, respectively (P = 0.508)) as were the mean gastric:myocardial ratios (1.23 ± 0.43 and 1.22 ± 0.36, respectively (P = 0.960)).

We categorized patients into those with and without hiatus hernia. Both gastric uptake and gastric:hepatic ratios did not differ in patients with and without hiatus hernia. The differences in gastric uptake and gastric:hepatic ratios between PPI and non-PPI patients were still significantly different in those without hiatus hernia. There was a trend observed in those with hiatus hernia, but was underpowered to demonstrate a statistically significant difference (Table 3).

Table 3 Gastric and gastric:hepatic ratio stratified according to PPI use and presence of hiatus hernia
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Discussion

Rubidium, like thallium, is a potassium analogue and thus the myocardial uptake is dependent on Na+/K+ ATPase active transporters.15 Gastric uptake of Rb has been well studied and relates to the presence of H+/K+ ATPase transporter located in the apical membrane of the gastric parietal cells.16,17. The impact of PPI on H+/K+ ATPase transporter activity, upregulation, and density is less well understood. This hypothesis generating study attempts to understand the impact of PPI on Rb-82 gastric uptake and its time-related effects. The results of our study confirm that PPI use is associated with greater Rb-82 gastric uptake and may identify a population that may be more susceptible to gastric spillover artifact (Figure 3).

Figure 3
figure 3

Rb-82 PET MPI and gastric uptake in a patient treated with PPI (A) and a patient without PPI (b)

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Subdiaphragmatic spillover artifact remains a limitation in MPI studies and can conceal perfusion defects or cause photopenic defects (negative ramp or ringing artifact). Minimizing sources of spillover would potentially improve diagnostic accuracy. Goel et al. studied 138 Tc-99m sestamibi SPECT patients and found that prolonged use of PPI was associated with increased gastric wall activity.18 Our study confirms that a similar issue exists with Rb-82 PET.

Identifying methods for minimizing gastric uptake would be clinically useful. Patient preparation such as timing for withholding medications prior to Rb-82 PET MPI could optimize image quality. In our subgroup analysis, gastric uptake was lower in patients who had stopped their PPIs for ≥ 36 hours and perhaps instructions for PPI abstinence should be considered. Withholding PPI > 36 hours prior to Rb-82 PET MPI may reduce the potential spillover from gastric uptake. Given the small sample size, we could not evaluate the relationship between PPI doses. Further studies are needed to better understand the relationship between timing and dose of PPI use and gastric Rb-82 uptake for further optimization of patient preparation.

The mechanism by which PPI patients have increased Rb-82 gastric uptake has not been well elucidated. The inhibition of H+/K+-ATPase active transporter reduces hydrogen secretion by parietal cells. Theoretically, this inhibition would reduce the uptake of K+ and thus the Rb-82 uptake by parietal cells; however, PPIs may have other effects on the gastric mucosa that impact on potassium utilization. A meta-analysis of 16 studies (1920 patients) found that long-term use of PPI causes hyperplasia of enterochromaffin-like cells and moderate hypergastrinemia.19 A randomized, placebo-controlled, double-blinded, multicenter study showed that long-term PPI therapy increased parietal cell protrusion, swelling and bulging, and the gradual development of fundic gland cysts.20 The impact on these findings on gastric potassium utilization is unknown and further understanding is needed.

New Knowledge Gained: Proton pump inhibitor use is associated with an increased gastric uptake of Rb-82. Spillover from gastric uptake could impact on the interpretation of adjacent myocardium on Rb-82 PET MPI studies. Withholding PPI > 36 hours prior to Rb-82 PET MPI may reduce the potential spillover from gastric uptake.

Study Limitations

Our prospective study examines the impact of PPI on gastric uptake and suggests a relationship between PPI use and increased gastric uptake. Although we found slightly lower Rb-82 uptake in patients who had held PPI ≥ 36 hours, our relatively small sample size precluded in-depth analysis of timing and varying doses. Further prospective studies are needed to study the effect of PPI cessation. Similarly, the potential benefit of acute PPI administration at the time of Rb-82 PET could also be explored.

Indications for the use of PPI and the presence of concomitant conditions such as gastroesophageal reflux disease were not available. Although such conditions may be confounders, gastric measures were performed below the diaphragm and therefore should limit confounding effect of structural abnormalities.

The clinical ramifications of PPI-induced gastric uptake are unknown. Since patients did not undergo routine angiography, FFR, or invasive CFR measurements, the true false positive and false negative rates are unknown. The clinical impact of increased gastric uptake on Rb-82 PET MPI is uncertain and warrants further investigation. The impact of gastric uptake on measurements of myocardial blood flow was not specifically collected or analyzed. Future studies examining its clinical impact would be important to understand if extracardiac uptake potentially affects the accuracy of quantitative myocardial blood flow.

Conclusions

The gastric uptake of Rb-82 appears to be greater in patients actively using PPI and may identify a group who might be at greater risk of a non-diagnostic Rb-82 PET MPI study.