Original Article
Prognostic value of myocardial flow reserve obtained by 82-rubidium positron emission tomography in long-term follow-up after heart transplantation

https://doi.org/10.1007/s12350-021-02742-3Get rights and content

Abstract

Background

Cardiac allograft vasculopathy (CAV) is a leading cause of death following heart transplantation (HTx) and non-invasive prognostic methods in long-term CAV surveillance are needed. We evaluated the prognostic value of myocardial flow reserve (MFR) obtained by 82-rubidium (82Rb) positron emission tomography (PET).

Methods

Recipients undergoing dynamic rest-stress 82Rb PET between April 2013 and June 2017 were retrospectively evaluated in a single-center study. Evaluation by PET included quantitative myocardial blood flow and semiquantitative myocardial perfusion imaging. Patients were grouped by MFR (MFR ≤ 2.0 vs MFR > 2.0) and the primary outcome was all-cause mortality.

Results

A total of 50 patients (68% men, median age 57 [IQR: 43 to 68]) were included. Median time from HTx to PET was 10.0 (6.7 to 16.0) years. In 58% of patients CAV was documented prior to PET. During a median follow-up of 3.6 (2.3 to 4.3) years 12 events occurred. Survival probability by Kaplan–Meier method was significantly higher in the high-MFR group (log-rank P = .02). Revascularization (n = 1), new CAV diagnosis (n = 1), and graft failure (n = 4) were more frequent in low-MFR patients. No retransplantation occurred.

Conclusions

Myocardial flow reserve appears to offer prognostic value in selected long-term HTx recipients and holds promise as a non-invasive method for CAV surveillance possibly guiding management strategy.

Introduction

Cardiac allograft vasculopathy (CAV) remains a major determinant of late mortality after heart transplantation (HTx).1 The pathoanatomical hallmark of CAV is concentric intimal thickening causing luminal narrowing and loss of vasodilatory capacity.2,3 It is diffusely distributed and affects both the epicardial vessels and microvasculature of the allograft.4,5 While allograft denervation often disguises typical clinical symptoms, progressive myocardial ischemia caused by CAV ultimately leads to graft failure and death.

As treatment interventions are available, recipients typically undergo yearly surveillance for CAV. Invasive coronary angiography (ICA) remains standard surveillance due to wide availability and prognostic value.6,7 Intravascular ultrasound (IVUS) offers superior diagnostic accuracy; however, the invasive methods incur small but significant risks and are further limited by the lack of assessment of distal vessels and microvasculature.8 Established non-invasive methods for CAV surveillance are limited by reliance on regional abnormalities, which are typically absent in diffuse epicardial and microvascular disease.9

Cardiac positron emission tomography (PET) myocardial perfusion imaging potentially overcomes these challenges as a non-invasive modality allowing for assessment of perfusion distribution as well as quantification of myocardial blood flow (MBF).10 Myocardial flow reserve (MFR; stress MBF/rest MBF) serves as an integrated measure of focal, diffuse and microvascular disease, and might thus represent a more reliable measure of the true ischemic burden posed by CAV.11 The diagnostic and prognostic value of MFR in HTx recipients have been suggested in previous literature.12, 13, 14, 15

Whether the prognostic utility of MFR obtained by 82-rubidium (82Rb) PET extends to long-term follow-up of HTx recipients remains largely unknown. As both CAV and conditions precluding invasive surveillance become more prevalent with time after HTx, this seems highly clinically relevant and was addressed in this study.

Section snippets

Study Design and Population

Consecutive adult HTx recipients undergoing successful rest-stress 82Rb PET between April 2013 and June 2017 were retrospectively evaluated in a single-center study (Figure 1). Fifty patients were included based on available MFR measures. According to institutional protocol, 82Rb PET was performed as part of annual routine CAV surveillance in HTx recipients not eligible for invasive evaluation mainly due to poor renal function, previous procedural complications to ICA, access site concerns, or

Study Population

A total of 59 HTx recipients underwent 82Rb PET at our institution between April 2013 and June 2017 as part of standard yearly CAV surveillance. We excluded patients with multiorgan transplant (n = 5) and patients with missing MBF quantification data precluding calculation of MFR (n = 4). Fifty patients thus comprised the study population (Figure 1) and were grouped by MFR into a (i) low-MFR group with MFR ≤ 2.0 (n = 25, 50%) and a (ii) high-MFR group with MFR > 2.0 (n = 25, 50%). Median

Discussion

The current study adds to the existing literature and confirms the prognostic value of MFR by 82Rb PET in terms of all-cause mortality at an extended follow-up after HTx, and addresses the interplay with invasively documented CAV. As a prognostic tool in long-term HTx surveillance, MFR has the potential to guide monitoring- and management strategies in terms of CAV in recipients unsuited for invasive CAV surveillance.

Despite significant advances in survival after HTx, CAV remains a major

Limitations

This study reports the retrospective experience of a single-center and is further limited by the small study population and number of events precluding meaningful multivariable analysis and possibly limiting statistical power. Patients were highly selected and time since HTx was varying. Inclusion was conditional on survival to PET, which adds to the selection bias and follow-up after PET was relatively short. The presence of CAV was defined retrospectively without re-evaluation of invasive

New Knowledge Gained

This study ascertains the prognostic utility of MFR obtained by 82Rb PET in highly selected long-term HTx recipients at a median of 10 years after HTx. Our findings suggest MFR to be prognostically useful even in the absence of previously documented epicardial CAV.

Conclusion

Myocardial flow reserve obtained by 82Rb PET appears to offer prognostic value in selected long-term HTx recipients and might thus serve as a useful alternative to invasive CAV surveillance.

Acknowledgements

The authors are very grateful to the clinical staff at the Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, for the conduct and reporting on the 82Rb PET scans evaluated in this study, and to the Heart Transplant Program at Rigshospitalet for patient management.

Author Contributions

All authors have contributed substantially to the submitted work through participation in study design or the acquisition, analysis, interpretation, or reporting of data. LMN, TEC, KR, PH, and FG have

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  • The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarises the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.com.

    All editorial decisions for this article, including selection of reviewers and the final decision, were made by guest editor Saurabh Malhotra, MD, MPH.

    Funding: L.M.N. was supported by research grants from The Danish Heart Foundation (14-R97-A5275-22861). The Research Foundation of Rigshospitalet, and The Heart Center Research Foundation of Rigshospitalet.

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