Background
Developed as a positron emission tomography (PET) imaging agent to target the cardiac sympathetic nervous system, carbon-11-labeled meta-hydroxyephedrine ([
11C]HED) is a norepinephrine analog that is taken up by nerve terminal varicosities in the myocardium, and used to assess sympathetic nerve function [
1]. Since its genesis, it has been the cornerstone PET tracer for cardiac sympathetic innervation, employed in determination of neuronal-based defects leading to improved diagnosis and prognosis for pathologies such as heart failure, arrhythmia, and cardiomyopathy, in which cardiac neuronal function is often compromised, leading to decreased catecholamine sensitivity and lowered beta adrenergic receptor density [
1]. Using PET [
11C]HED imaging of cardiac tissues, the volume of distribution (V
T) of the injected radiotracer is an invaluable metric that quantifies the uptake and retention of tracer, providing an index of sympathetic nerve density and reuptake-1 transporter activity. For cardiac PET applications especially, V
T and other kinetic modeling parameters measured in the myocardium may be used to aid in the diagnosis of various innervation and perfusion-based pathologies.
In PET imaging studies, V
T is defined as the equilibrium ratio of tracer concentration in tissue to that of unmetabolized parent tracer in plasma, but this direct measurement is typically not feasible due to the long time needed to reach equilibrium. Alternatively, kinetic modeling is commonly used to determine V
T from a significantly shorter temporal sample following tracer injection [
2]. While the physiological kinetics of [
11C]HED may be modeled using a two-tissue-compartment model, the one-tissue-compartment (1TC) model has been shown to provide a robust representation with optimal clinical reproducibility in myocardial uptake studies, without sacrificing the accuracy of V
T quantification [
3]. Two graphical methods reported in the literature for kinetic modeling of reversible-binding tracers are the Logan [
4] and Multilinear Analysis-1 (MA1) models [
5], which are both computationally simpler than non-graphical (compartmental) methods [
6], while being able to provide visual representations of kinetic parameters. The Logan method has been established as the standard graphical model to estimate V
T in a wide range of PET applications in the brain and heart, while MA1 was proposed as an alternative numerical formulation to estimate V
T with lower noise bias compared to Logan estimates [
5]. Although [
11C]HED is a widely used tracer, a comprehensive evaluation of the performance of the graphical and non-graphical methods to quantify its kinetics has not been performed. Furthermore, the effects of partial-volume losses on quantification of V
T have not been well defined in the context of graphical kinetic modeling in the heart, where the effects of blood-pool spillover and motion are more apparent compared to the brain. The goal of this study was to determine a method of partial-volume correction applicable to graphical kinetic modeling and to compare the Logan and MA1 models to the standard 1TC kinetic model for accurate quantification of myocardial sympathetic innervation using dynamic [
11C]HED PET-CT studies.
Discussion
In an effort to improve and expand the use of kinetic modeling in cardiac PET studies of sympathetic innervation, we sought to evaluate multiple kinetic models for the analysis of [11C]HED studies. This was achieved by comparing the inter-method differences in VT quantified by the Logan and MA1 graphical models compared to the reference 1TC model in a sample of heart failure patients and assessing the test-retest repeatability between baseline and follow-up scans. HED PET is often used to evaluate therapy or disease progression in heart failure patients; therefore, evaluation of the test-retest repeatability is most relevant in this same population, as opposed to healthy normal subjects who generally have lower sympathetic tone. The patients’ heart failure symptoms and medications were stable over the test-retest interval; therefore, any impact on the repeatability data should be minimal.
The MA1 model exhibited excellent agreement with 1TC, the Logan model exhibited good-to-excellent agreement with 1TC, and all models had good-to-excellent test-retest repeatability. Logan V
T values were significantly lower than MA1 and 1TC V
T values, while MA1 V
T values were not significantly different from those obtained using the 1TC model (Table
3). While 1TC is the reference standard kinetic model in this instance, graphical models such as the Logan and MA1 are computationally simpler alternatives that allow for linearized visualization and analysis of tracer kinetic data. Our findings support the reliable use of both graphical analysis methods in addition to the standard 1TC model for tracer kinetic analysis of V
T. These findings agree with previous studies using other PET tracers that compared various graphical models, including the Logan method, finding the results to be in agreement with standard compartment models, but computationally simpler, and potentially more robust [
24‐
27].
In the present cardiac PET study, partial volume and spillover corrections were critical to implement into the graphical modeling calculations to avoid misinterpretation. The commonly used Logan and MA1 methods (Eqs. 12 and 13) only estimate the volume of distribution in the PET image region (V
ROI) as opposed to the myocardial tissue of interest (V
T). Compared to PET measurements in other organ systems such as the brain, in cardiac studies, the measured ROI region contains much more spillover of blood signal within and adjacent to the myocardial tissues. Our implementation of a partial-volume correction method based on estimated recovery coefficients and whole-blood spillover fractions allowed accurate measurement of myocardial V
T values using Logan and MA1 graphical models on a scan-specific basis. In this validation study, F
WB was estimated first using the 1TC with spillover model, and then used to calculate the corresponding RC values for consistent partial-volume and spillover correction of the graphical model V
ROI estimates. It is clear that independent estimates of RC and F
WB are required to determine V
T from V
ROI as shown in Eq.
11; therefore, any error in the estimation of these correction factors in practice will be propagated directly into the corresponding values of V
T. In the present study, the average F
WB value was 0.37 ± 0.07, which could be used to estimate RC and hence V
T in similar patient population studies with minimal added variability.
We investigated the effect of varying
t* on the graphical model results (Table
2), which quantified V
T using the plotted values at
t ≥
t*. It has been reported that
t* may be deduced directly from kinetic modeling data for some tracers [
5], but the method we presented used a simpler and systematic approach to determine the
t* which produced the same V
T values on average compared to the MA1 plots. This approach is beneficial for tracers for which it is more difficult to estimate
t* directly from the study data, such as those with relatively slower kinetics [
28]. It also removes the need to estimate
t* for each individual scan, which may be subject to variable noise effects. We propose
t* = 5 min as an effective start-time for cardiac studies employing [
11C]HED as it also gave the highest quality of linear fit (
r2 > 0.95) using the Logan model, in addition to MA1 estimates of V
T that were equal to the 1TC reference value on average. This start time was shown with our comparison of the three models to be robust, producing results for V
T with excellent goodness-of-fit to the graphical models and inter-method agreement. It is worth noting that a slightly later start time of 10–15 min may have provided Logan V
T values that correspond better with 1TC and MA1 (Fig.
1), but at the cost of a lower quality fit of the linear model and wider variability due to fewer fitted points.
Interestingly, the V
T values determined by Logan were significantly lower than those determined by both MA1 and 1TC, while V
T values determined by MA1 did not show a significant difference to those obtained from 1TC. More precisely, Logan exhibited a greater negative bias where V
T was underestimated relative to 1TC, whereas a bias was not present between MA1 and 1TC (Table
4). In a similar kinetic model comparison using [
18F]FCWAY and [
11C]MDL neurological tracers, Ichise et al. [
6] demonstrated that the MA1 model generated higher V
T estimates than Logan, and that MA1 exhibited less bias compared to Logan at multiple imaging noise levels. Our results are consistent with these findings, affirming the original report of MA1 as a method to reduce the magnitude of bias induced by noise when using the Logan model [
6]. Although Logan seemed to underestimate V
T in our study population, it should be realized that the median bias of − 14.5% relative to the 1TC gold standard did not greatly affect the inter-model reproducibility of the models, which exhibited good to excellent agreement despite the bias that was present.
The use of [
11C]HED to examine sympathetic function in cardiac PET is becoming increasingly widespread. Recently, it has been shown to be a powerful diagnostic and prognostic tool for patients with heart failure, arrhythmias, flow-innervation mismatches, and microvascular dysfunction in both infarcted and non-infarcted tissues [
1,
29‐
33]. This field continues to be improved and shows promise for a wider variety of applications [
34]. As cardiac innervation tracers increase in prevalence, the optimization and validation of kinetic modeling techniques becomes more important; extensions of the current study may be anticipated, such as those investigating the use of a two-tissue-compartment model to quantify cardiac NET re-uptake function more specifically. Moreover, comparisons of multiple kinetic modeling options, in particular those of a graphical nature as presented here, are possible with other cardiac innervation-based tracers such as the [
18F]-labeled sympathetic innervation tracers MFBG, MHPG, LMI1195, etc., for more detailed evaluation of their kinetics [
35,
36].
A few limitations were present in this study. The current study is a retrospective, single-center study that examined stable heart failure patients only from the PET-OSA trial. The results may be limited by the relatively small sample size (N = 18). Larger prospective studies would be beneficial to further validate the performance of the kinetic models as proposed.