Original ArticlePrognostic value of myocardial flow reserve obtained by 82-rubidium positron emission tomography in long-term follow-up after heart transplantation
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
References (41)
- et al.
The registry of the international society for heart and lung transplantation: Thirty-fourth adult heart transplantation report-2017; focus theme—allograft ischemic time
J Heart Lung Transpl.
(2017) - et al.
International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010
J Heart Lung Transpl
(2010) - et al.
The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients
J Heart Lung Transpl
(2010) - et al.
Imaging in heart transplant patients
JACC
(2018) - et al.
Allograft vasculopathy: The Achilles’ heel of heart transplantation
J Am Coll Cardiol
(2016) - et al.
Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making
J Am Coll Cardiol
(2013) - et al.
Serial assessment of coronary flow reserve by rubidium-82 positron emission tomography predicts mortality in heart transplant recipients
JACC Cardiovasc Imaging
(2020) - et al.
Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection
J Heart Lung Transpl
(2005) - et al.
American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American College of Cardiology task force on clinical expert consensus documents
J Am Coll Cardiol
(2001) - et al.
Impact of point spread function modeling and time-of-flight on myocardial blood flow and myocardial flow reserve measurements for rubidium-82 cardiac PET
J Nucl Cardiol
(2014)
Cardiac PET imaging for the detection and monitoring of coronary artery disease and microvascular health
JACC Cardiovasc Imaging
ASNC imaging guidelines/SNMMI procedure standard for positron emission tomography (PET) nuclear cardiology procedures
J Nucl Cardiol
The international thoracic organ transplant registry of the International Society for Heart and Lung Transplantation: thirty-fifth adult heart transplantation report-2018; focus theme: Multiorgan transplantation
J Heart Lung Transpl
Impaired myocardial flow reserve on rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia
J Am Coll Cardiol
Relationship between coronary function by positron emission tomography and temporal changes in morphology by intravascular ultrasound (IVUS) in transplant recipients
J Heart Lung Transpl
PET assessment of epicardial intimal disease and microvascular dysfunction in cardiac allograft vasculopathy
J Am Coll Cardiol
Serial PET measurements of myocardial blood flow for prognosis assessment in heart transplant patients: The forest and the trees
JACC Cardiovasc Imaging
Graft coronary disease: The lesions and the patients
Transpl Proc
Interacting mechanisms in the pathogenesis of cardiac allograft vasculopathy
Arterioscler Thromb Vasc Biol
Cardiac allograft vasculopathy: recent developments
Circulation
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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.