Original Paper
Splenic switch-off as a novel marker for adenosine response in nitrogen-13 ammonia PET myocardial perfusion imaging: Cross-validation against CMR using a hybrid PET/MR device

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Abstract

Background

No methodology is available to distinguish truly reduced myocardial flow reserve (MFR) in positron emission tomography myocardial perfusion imaging (PET MPI) from seemingly impaired MFR due to inadequate adenosine response. The adenosine-induced splenic switch-off (SSO) sign has been proposed as a potential marker for adequate adenosine response in cardiac magnetic resonance (CMR). We assessed the feasibility of detecting SSO in nitrogen-13 ammonia PET MPI using SSO in CMR as the standard of reference.

Methods and Results

Fifty patients underwent simultaneous CMR and PET MPI on a hybrid PET/MR device with co-injection of a gadolinium-based contrast agent and nitrogen-13 ammonia during rest and adenosine-induced stress. In CMR, SSO was assessed visually (positive vs negative SSO) and quantitatively by calculating the ratio of the peak signal intensity of the spleen during stress over rest (SIR). In PET MPI, the splenic signal activity ratio (SAR) was calculated as the maximal standard uptake value of the spleen during stress over rest. The median SIR was significantly lower in patients with positive versus negative SSO in CMR (0.57 [IQR 0.49 to 0.62] vs 0.89 [IQR 0.76 to 0.98]; P < .001). Similarly, median SAR in PET MPI was significantly lower in patients with positive versus negative SSO (0.40 [IQR 0.32 to 0.45] vs 0.80 [IQR 0.47 to 0.98]; P < .001).

Conclusion

Similarly to CMR, SSO can be detected in nitrogen-13 ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel coronary artery disease.

Introduction

Positron emission tomography myocardial perfusion imaging (PET MPI) is a robust and excellent tool for quantitative and semi-quantitative assessment of myocardial blood flow.1 Besides physical exercise or dobutamine stress, pharmacological vasodilators such as adenosine, regadenoson or dipyridamole are commonly used to induce coronary hyperaemia. However, adequate patient response to the latter is crucial to detect ischemia or reduced myocardial flow reserve (MFR), and conversely, an inadequate response might result in a false-negative result, decreased extent of ischemia or seemingly reduced MFR. Rates of up to 5% to 10% of false-negative MPI examinations have been reported,2,3 and up to one-third of these may be attributed to inadequate stress.4 Haemodynamic parameters such as an increase in heart rate or a drop in systolic blood pressure are commonly used to assess the response to vasodilators, however, whether this reflects true coronary response remains doubtful.5,6 Recently, for patients undergoing stress cardiac magnetic resonance (CMR), the splenic switch-off (SSO) sign, which is the visually assessed decrease in splenic enhancement during adenosine stress, has been proposed to be a marker for haemodynamic response. Its validity as a marker for adenosine response is based on the assumption that while adenosine receptor stimulation results in splanchnic vasodilation, the splenic circulation is not affected by this mechanism, potentially even showing an opposite reaction in the form of vasoconstriction.7,8 The utility of SSO for identifying inadequate adenosine response in CMR was first described in the CE-MARC study cohort, where significantly more false-negative than true negative exams failed to show the sign.9 A subsequent study in a real-world population also showed an increased prevalence of SSO in true positive as compared to false-negative CMR exams, although not reaching statistical significance.10

In the present study, we test the hypothesis that similarly to CMR, SSO can be assessed in nitrogen-13 ammonia PET MPI. To this aim, we assessed patients undergoing simultaneous CMR and PET MPI with adenosine-induced stress on a hybrid PET/MR device with co-injection of a gadolinium-based contrast agent (GBCA) and nitrogen-13 ammonia using SSO in CMR as the standard of reference.

Section snippets

Study design and population

Data of this prospective single-centre study were derived from ongoing PET/MR projects. We assessed patients who underwent cardiac PET/MR for evaluation of coronary artery disease (CAD) or myocarditis and obtained written informed consent from all patients. The study protocol was approved by the local ethics committee (KEK-ZH-Nr. 2014-0187 and BASEC-Nr. 2018-00170). Patients younger than 18 years, and patients with contraindications against CMR (e.g. non-CMR-compatible implanted cardiac

Results

All 50 patients successfully underwent adenosine stress PET/CMR. Detailed patient baseline characteristics are given in Table 1.

Positive SSO in CMR was found in 37 patients (74%). SIR, as derived from CMR, was significantly lower in patients with positive versus negative SSO (0.57 [IQR 0.49 to 0.62] vs 0.89 [IQR 0.76 to 0.98]; P < .001; Figure 3a). Similarly, SAR, as derived from PET, was significantly lower in patients with positive versus negative SSO (0.4 IQR [0.32 to 0.45] vs 0.8 IQR [0.47

Discussion

To the best of our knowledge, this is the first study demonstrating the feasibility of detecting and quantifying SSO in adenosine stress nitrogen-13 ammonia PET MPI. We established a novel indicator for the presence of SSO in nitrogen-13 ammonia PET: the SAR, which was calculated by dividing the peak splenic activity during stress over the peak splenic activity at rest similar to the SIR in CMR. A SAR of 0.46 was found to be a highly accurate threshold to differentiate positive from negative

New Knowledge Gained

SSO in PET MPI, as derived from SAR, corresponds with SSO in CMR and can be used as a marker for adequate adenosine response.

Limitations

The low patient number may be perceived as a limitation of our study. However, as a pilot study used for the initial validation of SAR in selected patients undergoing hybrid PET/MR MPI, we believe that it allows drawing the above conclusions. Furthermore, we did not assess the predictive value of SAR to identify non-responders as only two patients had an impaired MFR. The patient population, consisting of both patients with coronary artery disease, as well as myocarditis may not be

Conclusion

Similarly to CMR, SSO can be detected in nitrogen-13 ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel CAD.

Disclosure

The authors—Adam Bakula MD, Dimitri Patriki MD, Elia von Felten MD, Georgios Benetos MD, PhD, Aleksandra Sustar MD, PhD, Dominik C Benz MD, Muriel Wiedemann-Buser MD, Valerie Treyer PhD, Aju P Pazhenkottil MD, Christoph Gräni MD, PhD, Catherine Gebhard MD, PhD, Philipp A Kaufmann MD, Ronny R Buechel MD and Tobias A Fuchs MD have no conflict of interest to disclose.

Funding

Open access funding provided by University of Zurich.

Funding

This work was, Swiss National Science Foundation (SNSF supported by a grant from the Project No. 175640).

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Ronny R. Buechel and Tobias A. Fuchs have contributed equally to this work.

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