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Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF).

Methods

Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC).

Results

Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93–0.99). Observer reproducibility (NPC = 3–13%) was lower than test-retest repeatability (NPC = 12–61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2–12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30–61%) compared with the RI.

Conclusions

Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

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The data will not be shared because it will be used in other upcoming studies.

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Funding

KYW was a MD candidate supported by the University of Ottawa. JZ is an MD/PhD candidate supported in part by a Vanier Canada Graduate Scholarship. RSB is a Career Investigator supported by the Heart and Stroke Foundation of Ontario (HSFO), Tier 1 Chair in Cardiac Imaging Research, and Vered Chair in Cardiology at the University of Ottawa Heart Institute. LM is a Mid-Career Clinician Scientist supported by HSFO and Tier 2 Chair in Heart Failure Research. This study was funded by HSFO (T-6426, NA-7158) and Canadian Institutes of Health Research (CIF-99470) Grants.

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Author notes

  1. Kai Yi Wu and Jason G.E. Zelt contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Alberta Faculty of Medicine & Dentistry, Edmonton, Alberta, Canada

    Kai Yi Wu

  2. National Cardiac PET Centre, Department of Medicine (Cardiology), University of Ottawa Heart Institute, Ottawa, Ontario, Canada

    Kai Yi Wu, Jason G.E. Zelt, Robert Miner, Catherine Lapierre, Nicole Kaps, Aaryn Lavallee, Jennifer M. Renaud, Lisa M. Mielniczuk, Shin-Yee Chen, Ian G. Burwash, Rob S.B. Beanlands & Robert A. deKemp

  3. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada

    Jason G.E. Zelt & Rob S.B. Beanlands

  4. Department of Physiology, University of Toronto, Toronto, Canada

    Tong Wang

  5. Department of Radiology, University of Calgary, Calgary, Alberta, Canada

    Vincent Dinculescu

  6. Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany

    James Thackeray

  7. Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada

    Jean N. DaSilva

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  1. Kai Yi Wu
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  2. Jason G.E. Zelt
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Corresponding author

Correspondence to Robert A. deKemp.

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Conflict of interest

JMR is consultant for Jubilant DraxImage Inc. and receives revenues from the sales of FlowQuant software. RdK is consultant for and received grant funding from Jubilant DraxImage Inc. RSB is consultant for and received grant funding from GE Healthcare, Lantheus Medical Imaging, and Jubilant DraxImage Inc. RdK receives revenues from Rubidium-82 generator technology licensed to Jubilant DraxImage Inc., and from sales of FlowQuant software.

Ethics approval

All research subjects provided written informed consent, as approved by the Human Research Ethics Board at the University of Ottawa Heart Institute. The study has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Wu, K.Y., Zelt, J.G., Wang, T. et al. Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET. Eur J Nucl Med Mol Imaging 47, 1722–1735 (2020). https://doi.org/10.1007/s00259-019-04629-5

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