Abstract Abstract
Glucose metabolism measurement using 2-deoxy-2-[18F]-fluoro-d-glucose (18FDG) positron emission tomography (PET) could provide in vivo information about pulmonary vascular remodeling. The purpose of this study was to assess whether pulmonary 18FDG uptake in idiopathic pulmonary arterial hypertension (IPAH) patients changes and, if so, to determine whether the change is related to disease severity and survival. Sixteen IPAH patients who were treated with IPAH-specific therapy and 7 patients who had a myocardial infarction (MI) without pulmonary hypertension were included. IPAH disease severity was determined using the 6-minute walk test and right heart catheterization 2 days before 18FDG PET. Regions of interest were defined for left and right lungs, and standardized uptake values (SUVs), normalized to body weight, injected dose, and plasma glucose level, were derived. Mean SUVs for IPAH left and right lungs were 
and 
(
), respectively. In MI patients, SUVs were 
and 
(
) in left and right lungs, respectively. Total lung SUVs were similar in IPAH and MI patients (
vs. 
; 
). There was no correlation between SUV and IPAH disease severity parameters. In addition, lung SUV did not predict survival in IPAH patients (hazard ratio, 1.155; 95% confidence interval, 0.16–8.26; 
). In conclusion, pulmonary 18FDG uptake in treated IPAH patients is low and is not associated with disease severity and survival, thereby limiting its clinical use in patient care.
Keywords: positron emission tomography, glycolysis, pulmonary hypertension, glucose analogue, nuclear medicine.
Introduction
To date, treatment of pulmonary arterial hypertension (PAH) has been directed toward reduction of pulmonary vascular remodeling, i.e., vasoconstriction and proliferation of pulmonary artery smooth muscle cells (PASMCs).1 Treatment effects can be monitored using the 6-minute walk test, right heart catheterization, cardiopulmonary exercise testing, and serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels.2 Many of these parameters, however, are measures of right ventricular function and are rather indirect indicators of changes in lung vasculature. In pulmonary vascular remodeling, cellular (glucose) metabolism and mitochondrial function are abnormal,3,4 but methods to noninvasively measure abnormal remodeling and metabolism of the pulmonary vasculature are not available in the clinic yet.
Glucose metabolism can be measured using 2-deoxy-2-[18F]-fluoro-d-glucose (18FDG) positron emission tomography (PET). 18FDG is an analogue of glucose that cannot be catabolized after phosphorylation to 18FDG-6-PO4, and therefore it is essentially trapped in cells. This accumulating signal can be visualized and measured using PET.4,5 Recently, Marsboom et al.3 reported increased in vivo pulmonary 18FDG uptake in two rat models of PAH, which subsequently decreased after PAH treatment. These data suggest that 18FDG PET may be a useful tool for evaluating response to treatment in patients. In addition, two pilot studies have reported increased 18FDG uptake in the lungs of patients with idiopathic PAH (IPAH), but no relationship between 18FDG uptake and disease severity has been shown.6,7 Therefore, the purpose of the present study is twofold: (1) to measure 18FDG uptake in the lungs of IPAH patients and (2) to relate these measurements to PAH disease severity and survival.
Subjects and methods
Patients
Patients with IPAH who had undergone 18FDG PET for cardiac research purposes, as described elsewhere by Wong et al.,8 were retrospectively included in the current analysis. Briefly, 16 patients with IPAH who had been receiving IPAH treatment and were clinically stable for at least 3 months were included. To assess clinical and hemodynamic characteristics, they underwent a 6-minute walk test and right heart catheterization 2 days prior to the PET study.8 In addition, 18FDG scans from 7 patients who had a myocardial infarction (MI) were included as a comparison group. Pulmonary hypertension secondary to pulmonary venous congestion after MI was excluded by echocardiography in these patients. The study was approved by the Medical Ethics Review Committee of the VU University Medical Center, and each patient provided written informed consent prior to inclusion.
Data acquisition
The scanning protocol has been described in detail elsewhere.8 Briefly, patients had to fast overnight, and 2 and 1 hours prior to 18FDG injection they received a single oral dose of 250 mg of acipimox (Nycomed, Hoofddorp, Netherlands) and a carbohydrate- and protein-enriched meal for glucose loading.9 All scans were performed using an ECAT EXACT HR+ scanner (Siemens/CTI, Knoxville, TN) in 3D acquisition mode. Before intravenous injection of 18FDG, a 10-minute transmission scan was performed to correct the subsequent emission scan for tissue attenuation. Starting at the time of 18FDG injection, a dynamic emission scan was acquired for 60 minutes (39 frames with increasing frame duration). Venous blood samples were drawn to measure serum glucose and free fatty acid levels at 30, 40, and 50 minutes after the beginning of the scan in IPAH patients. MI patients were prepared in the exact same way and underwent static imaging 45–60 minutes after 18FDG injection, with serum glucose level measurement at the beginning of the scan.
Data analysis
Sinograms were reconstructed and processed as described elsewhere.10,11 In addition, for pulmonary 18FDG measurements, two regions of interest (comprising entire left and right lungs) were drawn on transaxial planes (Fig. 1). The number of planes used for analysis ranged from 8 to 13 per patient (mean, 
planes), with a mean total volume of interest for left and right lungs, respectively, of 
and 
mL in IPAH patients and 
and 
mL in MI patients. In addition, in IPAH patients, four separate regions of interest were drawn in the anterior or posterior parts of the left and right lungs (mean volume of interest, 11 mL).
Figure 1.
Typical example of a transaxial 2-deoxy-2-[18F]-fluoro-d-glucose (18FDG) positron emission tomography image from an idiopathic pulmonary arterial hypertension (IPAH) patient, acquired 55–60 minutes after 18FDG administration. The color scale represents 18FDG uptake, ranging from dark blue (lowest uptake) to dark red (highest uptake). LV: left ventricle; RV: right ventricle. Red lines indicate total lung regions of interest.
Standardized uptake values (SUVs) were calculated by normalizing obtained tissue radioactivity concentrations to body weight and injected dose and by correcting for plasma glucose levels, the latter normalized to a (normal) glucose level of 5 mmol L−1.12 SUV was determined 50–60 minutes after 18FDG administration in IPAH patients. Patlak analysis was performed to calculate the metabolic rate of glucose uptake, which is the product of the influx rate constant (Ki) and serum glucose concentration.13 To obtain Ki, an image-derived input function from the ascending aorta blood pool was used.
Statistical analysis
SUVs for left and right lungs were compared using the paired Student t test. Differences in SUVs at different regions of interest were tested by one-way analysis of variance with Bonferroni post hoc analysis. IPAH and MI patients were compared using the unpaired Student t test. Correlations between SUV and clinical parameters were determined by Pearson linear regression. Kaplan-Meier survival was stratified by the median value of total lung SUV for all patients and compared by the log-rank test. Survival was measured from time of PET until cardiopulmonary death or the time of analysis (interquartile range, 24–50 months). Data are shown as mean ± standard deviation. 
was considered statistically significant.
Results
Clinical and hemodynamic characteristics of all patients are listed in Table 1. Figure 1 shows a typical example of an 18FDG scan in an IPAH patient, demonstrating low 18FDG uptake in the lungs compared with that in the heart. The mean injected dose of 18FDG was 
MBq in IPAH patients and 
MBq in MI patients. The mean left and right lung SUV was 
and 
(
), respectively, in IPAH patients and 
and 
(
), respectively, in MI patients (Fig. 2a). Total lung SUV was also similar in IPAH and MI patients (
vs. 
; 
). Analysis of four separate regions of interest in the lung fields of IPAH patients did not show regional differences in SUV (
; Fig. 2b). There was no correlation between mean total lung SUV and any of the following PAH parameters: 6-minute walk distance (
, 
), mean pulmonary artery pressure (
, 
), pulmonary vascular resistance (
, 
), and NT-proBNP (
, 
; Fig. 3). Patlak analysis to calculate the metabolic rate of glucose uptake gave negative results and therefore could not be performed. Four IPAH patients did not survive until the current analysis. Figure 4 shows that SUV did not predict survival in this cohort of IPAH patients (hazard ratio, 1.155; 95% confidence interval, 0.16–8.26; 
).
Table 1.
Patient characteristics at the time of 2-deoxy-2-[18F]-fluoro-d-glucose (18FDG) positron emission tomography
| Characteristic | IPAH patients | MI patients |
|---|---|---|
| Sex, no. | ||
| Male | 1 | 7 |
| Female | 15 | 0 |
| NYHA functional class, no. | ||
| II | 9 | … |
| III | 7 | … |
| Age, years | 46.1 ± 11.9 | 66.5 ± 12.2 |
| 6-minute walk distance, m | 466 ± 141 | … |
| Cardiac output, L min−1 | 4.9 ± 1.2 | … |
| Mean pulmonary arterial pressure, mmHg | 49 ± 13 | … |
| Mean right atrial pressure, mmHg | 6 ± 5 | … |
| Pulmonary vascular resistance, dyn s cm−5 | 628 ± 301 | … |
| Mixed venous saturation, % | 66 ± 8 | … |
| NT-proBNP, ng L−1 | 1,048 ± 1,644 | … |
| Serum glucose, mmol L−1 | 5.2 ± 0.8 | 5.6 ± 1.0 |
| Serum free fatty acids, mmol L−1 | 0.07 ± 0.02 | … |
Data are mean ± standard deviation, unless otherwise indicated. IPAH: idiopathic pulmonary arterial hypertension; MI: myocardial infarction; NYHA: New York Heart Association; NT-proBNP: N-terminal prohormone of brain natriuretic peptide.
Figure 2.
Standardized uptake values (SUVs) normalized to body weight, injected dose, and blood glucose level in left and right lungs of idiopathic pulmonary arterial hypertension (IPAH) and myocardial infarction (MI) patients (a) and in four separate regions of interest in lungs of IPAH patients (b). No differences were observed between the IPAH and MI patients or between different lung regions within IPAH patients. Ant: anterior part of the lung; post: posterior part of the lung. Data are shown as mean ± standard error of the mean.
Figure 3.
Scatterplots of standardized uptake values (SUVs) from idiopathic pulmonary arterial hypertension (IPAH) patients normalized to body weight, injected dose, and blood glucose level of both left and right lungs versus various PAH clinical parameters: 6-minute walk distance (6MWD; a), mean pulmonary artery pressure (mPAP; b), pulmonary vascular resistance (PVR; c), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP; d). Every dot represents a patient. No statistically significant correlations were found.
Figure 4.
Kaplan-Meier survival plot of all idiopathic pulmonary arterial hypertension (IPAH) patients. Patients were divided on the basis of the median value of total lung standardized uptake value (SUV; 0.34). Four patients died during the time between the positron emission tomography scan and the current analysis (2 patients with SUVs less than the median, and 2 patients with SUVs more than the median). When patients were clinically stable, total lung SUV did not predict survival in this cohort.
Discussion
This study is a first attempt to correlate pulmonary 18FDG uptake in IPAH patients with disease severity. The main results of this study show that pulmonary 18FDG uptake in treated IPAH patients is similar to that in MI patients without pulmonary hypertension and is not associated with severity of IPAH or survival.
Our data do not confirm the results of Xu et al.,6 who demonstrated higher 18FDG SUV in 4 IPAH patients compared with 3 healthy controls at 1.5 hours (
vs. 
; 
) and 3 hours (
vs. 
; 
) after 18FDG injection. In addition, Hagan et al.7 also observed a higher 18FDG lung parenchymal target-to-background ratio in a pilot study of 8 IPAH patients (7 treated, 1 untreated) compared with 6 chronic thromboembolic pulmonary hypertensive patients and healthy controls. A direct comparison to the present results is difficult because of differences in patient preparation, scanning time, and analysis of the PET data.5 However, comparing the present SUVs with those of Xu and colleagues shows that the quantitative differences are small. In addition, reported disease severity parameters in the previous pilot studies are limited. Although New York Heart Association functional class and NT-proBNP values are similar in the current population and the IPAH patients from the study of Hagan et al.,7 we cannot exclude that patients in the previous studies either had more severe PAH or were not receiving optimal treatment, explaining the higher pulmonary 18FDG uptake. More importantly, in the present study pulmonary 18FDG uptake was correlated directly with clinical and hemodynamic PAH parameters at the time of PET, which has not been done before. Unfortunately, although patients with variable IPAH severity were included, pulmonary 18FDG uptake was not associated with any clinical IPAH parameter or with survival.
In the present study, patients who had a MI were used as a comparison group. Because patient preparation was the same in IPAH and MI patients, a direct comparison of pulmonary SUV could be made. More importantly, we showed similar SUVs in IPAH and MI lungs, indicating that pulmonary glucose uptake in treated IPAH is indeed low. In addition, comparing the present results with data from the literature shows that the IPAH lung SUVs are comparable to those of healthy controls in the literature.6,12
A recent report showed that in vivo pulmonary 18FDG uptake was higher in a rat model of PAH than in control rats.3 These in vivo data were supported by increased glucose uptake in cultured rat PASMCs and increased glucose transporter 1 expression in both rat PASMCs and pulmonary artery endothelial cells (PAECs).3,14 In addition, previous reports have shown increased glycolytic rates in human PAH and IPAH PAECs.6 Increased 18FDG uptake in rat PAH may in part be due to the choice of the experimental model. Sugen-hypoxia and monocrotaline-injected rats used in the in vivo pulmonary 18FDG measurements are known to exhibit systemic vascular inflammation.3 Marsboom et al.3 carefully investigated the role played by inflammation in the lungs of these rats and did not observe an increase in pulmonary macrophages or glucose transporter 1 activity. However, these data did not exclude increased glycolytic rates of inflammatory cells or an increased number of inflammatory cells in the in vivo situation, accounting for higher 18FDG uptake.3 Interestingly, Hagan et al.7 did not find a correlation between inflammatory cytokines and lung parenchymal target-to-background ratio in IPAH patients, thereby showing that increased inflammation in human IPAH does not necessarily result in increased pulmonary 18FDG uptake. In light of these results from the literature, one might have expected increased pulmonary 18FDG uptake. However, results of the present study do not confirm this prediction. It should be noted, however, that PET provides a macroscopic measure of pulmonary 18FDG uptake, which in itself does not exclude the possibility that glycolytic rates at the cellular level are indeed increased.6 Another explanation for the present low pulmonary 18FDG uptake could be that pulmonary glycolytic rates are low because of optimal PAH treatment.
Limitations
First, the comparison group consisted of patients who had a MI and were thereby not completely healthy. Second, only parts of the lungs around the mediastinum were measured, although PAH is considered to be homogeneous throughout the lungs and the middle regions of the lungs should therefore be representative of the entire lungs. To underline this, separate regions of interest in both lungs did not show any differences in SUV. Third, a more accurate way to measure 18FDG uptake would be to calculate the metabolic rate of glucose uptake.15,16 However, in this study calculation of the metabolic rate of glucose uptake by Patlak analysis resulted in negative values and therefore could not be used. In addition, an image-derived input function from regions of interest over the ascending aorta was used to analyze the data. Because pulmonary blood supply comes from the right ventricle, blood values from the aorta may not be the best input function. However, it is technically challenging to obtain reliable regions of interest from the right ventricular blood pool because of spillover from the myocardium, movement of the heart, and the shape of the right ventricle. Consequently, it was not possible to generate reproducible results with the right ventricular blood pool as input function. Finally, it should be emphasized that the present results may not apply to untreated patients.
Conclusions
Pulmonary 18FDG uptake in treated IPAH patients is low and is not associated with disease severity or survival. Whether uptake is also low in untreated patients remains unknown; however, it is unlikely that 18FDG PET can be used as a tool for follow-up of these patients.
Source of Support: This research was funded by the Netherlands Organization for Scientific Research (NWO VIDI 329 grant 917.96.306).
Conflict of Interest: None declared.
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