Abstract
Aim: Previous studies have demonstrated increased glucose uptake by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in lung parenchyma in animal models or small pulmonary arterial hypertension (PAH) cohorts. However, it is not well known whether increased FDG uptake in the lung is a unique phenomenon in PAH or whether elevated pulmonary artery pressure (PAP) induces FDG uptake.
Methods and results: Nineteen patients with PAH, 8 patients with pulmonary hypertension due to left heart disease (PH-LHD), and 14 age matched control subjects were included. All PH patients underwent right heart catheterization and FDG-PET. The mean standard uptake value (SUV g/mL) of FDG in each lung was obtained and average values of both lungs were calculated as mean lung FDG SUV. The correlation between hemodynamics and mean lung FDG SUV was also analyzed in PH patients. Mean PAP (mPAP) was not significantly different between PAH and PH-LHD (45 ± 11 vs 43 ± 5 mmHg, p=0.51). PAH patients demonstrated significantly increased mean lung FDG SUV compared with PH-LHD and controls (PAH: 0.76 ± 0.26 vs PH-LHD: 0.51 ± 0.12 vs controls: 0.53 ± 0.16, p=0.0025). The mean lung FDG SUV did not correlate with mPAP either in PAH or PH-LHD.
Conclusion: PAH is associated with increased lung FDG uptake indicating increased glucose utilization in the lung. This may represent metabolic shift to glycolysis and/or active inflammation in the remodeled pulmonary vasculature, and is observed to a greater extent in PAH than in patients with PH secondary to LHD and control subjects without PH.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling of the intima and media with proliferation of endothelial and smooth muscle cells leading to narrowing and obliteration of small pulmonary arteries and arterioles, and progressive increases in pulmonary vascular resistance (PVR) (1). A specific morphological feature in advanced PAH is the so-called plexiform lesions which are complex, glomeruloid-like vascular structures originating from pulmonary arteries (2, 3). In contrast pulmonary hypertension (PH) secondary to left heart disease (LHD) (PH-LHD, or group 2 PH) occurs secondary to passive transmission of elevated venous pressures due to the underlying LHD, where pulmonary vascular remodeling may not be present, especially in patients with isolated post capillary PH (4–6). Recent studies have shown increased glucose metabolism in the PAH endothelial cell and pulmonary artery smooth muscle cell (PASMC) cultures (7, 8), which may reflect underlying metabolic abnormalities in the remodeled pulmonary vasculature.
This increased glucose uptake can be demonstrated in-vivo with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging (8–11). Whether the glucose uptake visualized in the lungs of PAH patients (with primary pulmonary vascular remodeling) is different from patients with PH from LHD (and passive venous congestion) has not been previously evaluated. This study was designed to determine whether FDG lung imaging can identify increased glucose uptake in the lungs of patients with PH, and whether differences exist across different pathophysiologic groups of PH (PAH vs PH-LHD).
Methods
Study populations
All study subjects were recruited at the University of Ottawa Heart Institute (UOHI). The study subjects consisted of the following groups; 1) group I PH (PAH), 2) Group 2 PH (PH-LHD) and 3) controls without a diagnosis of PH. We retrospectively recruited patients from 2 different cohorts including an earlier pilot study and ongoing previous prospective study for PAH (12, 13). Patients with PH-LHD were recruited from a registry of subjects who underwent cardiac 18F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) in Ottawa between September of 2008 and September of 2009, for assessment of myocardial viability in the setting of heart failure due to ischemic heart disease (IHD) and who also had undergone right heart catheterization (RHC) and met criteria for PH. For the control population without PH, we included healthy volunteers from our previous prospective study for PAH, those who had been referred for cardiac sarcoidosis (CS) but not found to have CS, and patients with coronary artery disease (CAD) and no evidence to suggest PH from viability registry. We stratified PAH patient cohorts for subgroup analyses (idiopathic PAH or connective tissue disease associated PAH) (CTD-PAH). We excluded subjects with interstitial lung disease (ILD) since the presence of ILD can increase lung FDG uptake.
All PH patients underwent RHC to obtain pulmonary hemodynamics including pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP), mean right atrial pressure (mRAP), and cardiac output (CO) using Swan-Ganz catheter. CO was measured by the thermodilution method. Cardiac index (CI) was calculated as CO divided by body surface area (L/min/m2). Pulmonary vascular resistance (PVR) was calculated as mean PAP (mPAP) minus PAWP and divided by CO, expressed in woods units. Pulmonary arterial capacitance was estimated by the formula stroke volume/pulmonary artery pulse pressure (14–16). The diagnosis of PAH or PH-LHD was determined based on the 6th World Symposium on Pulmonary Hypertension in 2018 (17). We reclassified PH-LHD into 2 subgroups including isolated post-capillary PH (Ipc-PH) (mPAP >20, PAWP >15 and PVR <3 WU ) or combined post-capillary and pre-capillary PH (Cpc-PH) (mPAP >20, PAWP >15 and PVR ≥3 WU) (17).
All study subjects underwent FDG-PET/CT. The study was approved by Ottawa Health Science Network Research Ethics Board (OHSN-REB) and informed consents were obtained from all patients and volunteers.
FDG-PET/CT imaging protocol
All patients were instructed to fast overnight prior to the PET study. Patients were positioned in the GE Discovery 600 PET/VCT scanner (Waukesha, WI). Following a scout scan to confirm patients positioning, a low dose x-ray CT scan was performed at normal end-expiration to correct for photon attenuation. A static FDG uptake scan was initiated 40 minutes after injection of 5 MBq/kg of FDG. We used FDG-PET/CT protocols; fasting and glucose load. On the glucose load protocol, the tracer was injected at 30 minutes after the glucose load.
Both fasting and glucose loading protocols were used in this analysis. In our earlier pilot study for PAH, we performed FDG-PET/CT with a glucose load protocol as with prior studies (11, 13, 18–20). In our ongoing previous prospective study for PAH (12), we performed FDG-PET/CT under fasting condition in order to investigate both glucose and free fatty acid uptake (PAH and controls). In patients with PH-LHD (group 2 PH) and CAD patients with no PH (controls), a glucose load protocol was used because FDG-PET/CT studies were performed to assess myocardial viability. Patients who investigated for sarcoidosis underwent FDG-PET/CT under fasting condition (controls). In addition, since July 2012, all patients who underwent FDG-PET/CT for the evaluation of suspected CS were prescribed a low-carbohydrate, high-fat and protein-permitted diet as dinner the day before the test. Hence, fasting protocols were classified into fasting-only protocol (fasting) and fasting with dietary modification protocol (fasting with low-carb). Thus, we used three FDG-PET protocols; fasting, fasting with low-carb and glucose load.
Image processing
PET images of activity concentration (Bq/cc) were reconstructed using an iterative algorithm (VuePoint HD) with 8 mm Hann post-filter. CT image alignment was verified against PET using a fusion display program (ACQC) to ensure accurate attenuation correction. Patient body weight and injected activity were used to convert the PET image units to standardized uptake values (SUV g/cc) according to standard methods (12).
PET imaging data analysis
Regions of interest (ROIs) were drawn to include the lateral one-third of the lungs on the sagittal images to avoid including major blood vessels and airways and fibrotic lesions (appendix). The mean lung FDG SUV was obtained by the following formula: mean lung FDG SUV = [mean SUV (Rt) + mean SUV (Lt)]/2.
Statistical analysis
PAH (entire PAH, IPAH, or CTD-PAH), PH-LHD and controls were compared using one-way ANOVA. Comparison among 3 subgroups in terms of those different FDG-PET/CT protocols (fasting, fasting with low-carb or glucose load) were performed using one-way ANOVA. Correlations between PET data and hemodynamics were evaluated using Spearman correlation coefficients. Statistical significance was defined as p <0.05. Data are described as mean ± SD. All analyses were performed using SAS software version 9.3.
Results
Patient characteristics
Nineteen patients with PAH, 8 patients with PH-LHD and 14 control subjects were enrolled in the study (Table 1). In the PAH group, 13 patients were diagnosed with idiopathic PAH (IPAH) and 6 were PAH associated with connective tissue disease (CTD-PAH). Of the 6 patients with CTD-PAH, five had scleroderma and one had mixed connected disease.
In the PH-LHD group, all patients were diagnosed with heart failure with reduced ejection fraction (HFrEF) due to ischemic heart disease (IHD). All patients had moderately or severely reduced left ventricular ejection fraction. Of these, 3 patients were categorized into Ipc-PH and the remaining 5 patients were categorized into Cpc-PH. In the control group, 4 patients also had coronary artery disease (CAD), 3 were healthy subjects, and 7 patients were investigated for CS due to arrhythmia, which was ruled out after the examinations. Control subjects did not any evidence of PH by physical examination, chest X-ray, electrocardiogram and transthoracic echocardiogram.
There were no significant differences in the mean age amongst 3 groups (p = 0.65). In the PAH group, patients were predominantly female (p = 0.0004).
Seventeen of the 19 PAH patients were treated with PAH specific medications. The mean pulmonary arterial pressure (mPAP) was not significantly different between PAH and PH-LHD groups (45 ± 11 vs 43 ± 5 mmHg, p = 0.51). Compared with the PAH group, the PH-LHD group had a significantly higher PAWP (9 ± 3 vs 30 ± 6 mmHg, p <0.0001). There was no significant difference in the mean pulmonary arterial capacitance (PAC) between the PAH cohort and the PH-LHD cohort (1.2 ± 0.6 vs 1.2 ± 0.5 ml/mmHg, p = 0.95). In the PAH and control groups, fasting, fasting with low-carb or glucose load protocol was used for FDG-PET/CT studies (PAH: 12/0/7 [fasting/fasting with low-carb/glucose]; control 4/5//5 [fasting/fasting with low-carb/glucose]) (Table 1). All patients with PH-LHD underwent FDG-PET/CT with a glucose load (Table 1).
Lung FDG uptak
The mean lung FDG SUV was greater in the group with PAH when compared to the other groups (entire PAH group vs PH-LHD and control groups; 0.76 ± 0.26 vs 0.51 ± 0.12 vs 0.53 ± 0.16, p = 0.0025) (Figure 1). There were no statistically significant differences in mean lung FDG uptake when PAH patients were divided into IPAH and CTD-PAH, but CTD-PAH patients showed slightly higher lung FDG uptake but this doesn’t not reach statistical significance (IPAH vs CTD-PAH; 0.72 ± 0.26 vs 0.85 ± 0.24, p = 0.31).
Patients with IPAH showed higher lung FDG SUV than the other 2 groups (IPAH group vs PH-LHD and control groups, p = 0.025) (Figure 1). There were no significant differences in mean lung FDG SUV between fasting and glucose load protocols in the PAH. Also, no significant differences were present in mean lung FDG SUV among fasting, fasting with low-carb and glucose load in controls (Figure 2).
The mean lung FDG SUV did not correlate with mPAP either PAH or PH-LHD group (r = 0.07, p = 0.77 for PAH; r = 0.08, p = 0.85 for PH-LHD) (Figure 3). Mean lung FDG SUV did not correlate with PAP, PVR or mRAP in either the PAH nor the PH-LHD group. PAC was not related to mean lung FDG SUV when the entire population was studied together. There was a nonsignificant trend for decreased PAC to be related to increased lung FDG uptake in the CTD-PAH, entire PH-LHD and Cpc-PH (r = -0.68, p = 0.14 for CTD-PAH; r = -0.55, p = 0.15 for PH-LDH; r = -0.77, p = 0.13 for Cpc-PH). Mean lung FDG-SUV was not significantly different between the IpC-PH and the CpC-PH cohorts from the PH-LHD group (p = 0.25). Figure 4 shows a representative case of each group.
Discussion
This study evaluated the relationship between pulmonary hemodynamics, type of PH and lung FDG uptake in patients with PH and controls. We demonstrated that PAH was associated with a significantly higher mean lung FDG SUV than PH-LHD and control groups. The mean lung FDG SUV did not significantly correlate with pulmonary hemodynamics and PVR either in PAH or PH-LHD. There was a nonsignificant trend towards increased lung FDG uptake and decreased PAC in patients with PH-LHD.
In the pathobiology of PAH, disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors have been reported to induce the vascular remodeling (21–23). Several studies have demonstrated that PAH pulmonary artery smooth muscle cells (PASMCs) mitochondria have increased glycolysis as a result of suppressed glucose oxidation, which has been considered to be similar behavior to a cancer cell in order to compensate ATP synthesis in the cytoplasm (7, 8, 24–27). Also this increased glucose uptake could be visualized using FDG-PET (8–10, 28). Xu et al. reported that the elevated aerobic glycolysis was observed in pulmonary endothelial cells derived from IPAH patients and demonstrated increased FDG uptake in the lungs of IPAH patients compared to controls (7). Marsboom et al. demonstrated increased lung FDG uptake in 2 experimental small animal models (monocrotaline or SU5416/hypoxia rat) (8). They found that the lung FDG uptake was increased in the early stage of PAH, and the effective therapies (dichloroacetate and imatinib) decreased the increased FDG intensity. Furthermore, they also showed that the glucose transporter 1 (Glut 1) mRNA was upregulated in both endothelium and PASMCs, however, not airway cells or macrophages. They successfully revealed the origins of FDG-PET signal intensity. Zhao et al. reported that mean lung FDG uptake was increased in patients with IPAH (n = 18) compared with healthy controls (n = 5) and found heterogeneity in lung FDG signal intensity both in the lungs of individual patient and among patients (9). More, recently, Michelakis et al. performed a 4-month phase I clinical trial and demonstrated that dichloroacetate administration led to improvement in hemodynamics and exercise capacity in IPAH patients. However, the response to DCA varied. The patients who showed a hemodynamic response showed an overall decrease in lung FDG uptake, whereas those without a response had an increase in lung FDG uptake (29).
The mechanism of the development of group 2 PH is mainly a passive backward transmission of LV filling pressures (passive PH) (30, 31). However, some group 2 PH patients have disproportionally high PVR. In these patients, the venous congestion may trigger PAH like vascular remodeling (30, 31). The precise characterization of this cohort has been a challenge and has changed over time. Historically, transpulmonary pressure gradient (TPG = mPAP – PAWP)) was used to distinguish between ‘passive PH’ and ‘reactive PH’ (32). The 2015 ESC guidelines proposed the use of the diastolic pressure gradient (DPG = diastolic PAP- PAWP) in order to distinguish “Ipc-PH” from “Cpc-PH” (6, 30). However, the latest hemodynamic definitions proposed to distinguish between Ipc-PH and Cpc-PH based on PVR (17). Hemodynamic-biomarker correlates can help to further the understanding of the pathobiology of this complex disease.
We hypothesized that patients with Cpc-PH may have more advanced remodeling of the arterioles, thus they may have higher lung FDG SUV than those with Ipc-PH. In our patient cohorts, patients with Cpc-PH did not have higher mean lung FDG SUV. There was a trend observed between increased lung FDG uptake and decreased PAC in patients with PAH-LHD, and the finding remained a trend even after limiting Cpc-PH. But these findings may have been limited by the small sample size. Previous studies have suggested that PAC is an important predictor of mortality in patients with PH-LHD, and may be a better marker of RV afterload than PVR (14).
Several studies have reported increased lung FDG uptake in patients with idiopathic pulmonary fibrosis (IPF) and other diffuse parenchymal pulmonary diseases (33–35). Interestingly, Win et al. showed that patients with IPF had increased lung FDG uptake on FDG-PET/CT in normal areas on high resolution computed tomography (HRCT) (36). These results indicate that increased FDG uptake in the lung reflects the inflammatory activity in the lung parenchyma. The spatial resolution of the current PET/CT system is not enough to distinguish between lung vasculature and airways, thus excluding patients with significant parenchymal lung disease helped to confirm that the increased lung FDG uptake seen in patients with PAH was originating from lung vasculature.
There are limitations to the current study. First, the sample size is relatively small, especially in patients with PH-LHD. Additionally, we included 3 different FDG-PET protocols such as fasting, fasting with low-carb and glucose load. FDG is taken up by glucose transporter 1 (GLUT-1) in the endothelial cells and PASMCs. In theory, GLUT-1 is insulin independent, thus insulin secretion induced by oral glucose intake might not affect FDG uptake in the pulmonary vasculature. Despite this, the results were consistent when the data were stratified by study protocol. Lastly, we currently cannot identify if the origin of the increased FDG uptake is in the vascular tissue or the airway. However, animal studies have demonstrated that GLUT-1 mRNA was up-regulated in both endothelium and PASMCs, but not in the airway cells or macrophages, and the results of this study are consistent whether patients with concomitant lung disease are included in the analysis or not.
FDG-PET cannot be used for the diagnosis of PH as it does not have specificity. As shown in the animal studies by Marsboom et al. (8) and Zhao et al. (9), it is expected that FDG-PET may be a tool to investigate the molecular pathology of PAH and may also be able to monitor therapeutic changes in the vasculature. In the current clinical setting, the disease severity of PAH is evaluated by exercise capacity such as WHO functional class or cardiopulmonary exercise tests, pulmonary hemodynamics, cardiac morphology and RV function. FDG-PET may be a complementary imaging test to evaluate the pathologic metabolic changes in PAH, and further studies are needed to evaluate whether FDG PET imaging can be used to assess therapeutic response or guide prognosis in the evaluation of patients with PH.
In conclusion, increased FDG uptake is a unique phenomenon in patients with PAH in our study cohorts. This may reflect underlying metabolic abnormalities in the remodeled pulmonary vasculature itself not by passive elevation of pulmonary arterial pressure. Further prospective studies are needed to evaluate the assessment of lung FDG uptake in PAH.
Acknowledgments
H.O. was supervised by Drs. Mielniczuk and Beanlands.
The authors would like to thank and acknowledge the collaboration, and mentorship of the late Dr. Keiichiro Yoshinaga with whom we all had the sincere pleasure to work and are sad that he has passed. He has inspired us to complete and submit this work.
Sources of funding
LM is a clinician scientist supported by the Heart and Stroke Foundation of Ontario (HSF)) and a University of (u)Ottawa Tier 2 Research Chair . RB was a career investigator supported by the HSFO, the UOHI Vered Chair in Cardiology and a uOttawa Distinguished Research Chair. Funding for this study was obtained by grants from the Ottawa Heart Institute ORACLE Research Cluster grant and the Heart and Stroke Foundation of Ontario.
Conflicts of interest
L.M. has research grants and advisory board fees from Actelion and Bayer; R.B. is a consultant and has received grant funding from Lantheus Medical Imaging, Jubilant DRAX Image (JDI) and GE Healthcare; R.d.K. and R.K are consultants for and receive research funding from JDI. R.d.K., R.K., and J.R. receive royalty revenues from rubidium generator technology and from FlowQuan tsoftware licenses;D.J.S.has equity with Northern Therapeutics and research funding from United Therapeutics; C.P.has speakers fees from Actelion and Pfizer; R.A.D. has unrestricted educational grants from Actelion and Bayer and speakers fees from Actelion; G.C. has participated in advisory board meetings for Bayer and Actelion.
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