Medicine (Baltimore). 2016 Jun;95(25):e3976.
Thoracic [18F]fluorodeoxyglucose uptake measured by positron emission tomography/computed tomography in pulmonary hypertension
Armin Frille1, Karen Geva Steinhoff2, Swen Hesse2,3, Sabine Grachtrup1, Alexandra Wald1, Hubert Wirtz1, Osama Sabri2, and Hans-Juergen Seyfarth1.
1Department of Respiratory Medicine; 2Department of Nuclear Medicine; 3Integrated Research and Treatment (IFB) Centre Adiposity Diseases,
University of Leipzig, Leipzig, Germany.
Positron emission tomography (PET) visualizes increased cellular [18F]fluorodeoxyglucose ([18F]FDG) uptake. Pulmonary hypertension (PH) is conceived of a proliferative disease of the lung vessels. Increased glucose uptake can be quantified as pulmonary [18F]FDG uptake via PET imaging.
Because the angioproliferative mechanisms in PH are still in need of further description, the aim of the present study was to investigate whether [18F]FDG PET/CT imaging can elucidate these pathophysiologic mechanisms in different etiologies of PH.
Patients (n = 109) with end-stage pulmonary disease being evaluated for lung transplant were included in this observational study. Mean standardized uptake value (SUVmean) of predefined regions of interest in lung parenchyma (LP), left (LV), and right ventricle (RV) of the heart, and SUVmax in pulmonary artery (PA) were determined and normalized to liver uptake. These SUV ratios (SUVRs) were compared with results from right heart catheterization (mean pulmonary artery pressure [mPAP], pulmonary vascular resistance [PVR]), and serum N-terminal pro-brain natriuretic peptide. Group comparisons were performed and Pearson correlation coefficients (r) were calculated.
The [18F]FDG uptake ratios in LP, RV, RV/LV, and PA, but not in LV, were found to be significantly higher in both patients with mPAP ≥25 mm Hg (P = 0.013, P = 0.006, P = 0.049, P = 0.002, P = 0.68, respectively) and with PVR ≥480 dyn·s/cm5 (P < 0.001, P = 0.045, P < 0.001, P < 0.001, P = 0.26, respectively). The [18F]FDG uptake in these regions positively correlated also with mPAP, PVR, and N-terminal pro-brain natriuretic peptide. The SUVR of PA positively correlated with the SUVR of LP and RV (r=0.55, r=0.42, respectively).
Pulmonary and cardiac [18F]FDG uptake in PET imaging positively correlated with the presence and severity of PH in patients with end-stage pulmonary disease. Increased glucose metabolism in the central PAs seems to play a certain role in terms of severity of PH. These results suggest that [18F]FDG-PET imaging can help understand the pathophysiology of PH as a proliferative pulmonary disease.
Pulmonary hypertension (PH) is a complex disease progressively involving the thoracic compartments such as the lungs with its vessels, and the heart. PH is characterized by both elevated resistance to the pulmonary blood flow and pressure within the pulmonary arteries leading to right-heart failure and death (1, 2). The symptoms are quite nonspecific and comprise shortness of breath, fatigue, weakness, angina, and syncope. Altogether, an early diagnosis is therefore often hampered. Biomarkers such as N-terminal pro-brain natriuretic peptide (NT-proBNP) have the potential to estimate cardiopulmonary impairment and prognosis (3).
The underlying diseases leading to PH arise from the different thoracic compartments (1):
- pulmonary arteries such as pulmonary arterial hypertension (PAH),
- heart such as ventricular dysfunctions or valvular diseases,
- lungs with or without hypoxia such as chronic lung diseases,
- recurrent obstruction of pulmonary arteries by peripheral venous clots, or
- unclear multifactorial mechanisms.
PH occurs frequently in most chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD) and its presence is associated with increased morbidity and mortality (4).
The mechanisms leading to the increase of pulmonary vascular resistance (PVR) and subsequently to PH in chronic lung diseases are largely based on the combination of (5, 6):
– loss of peripheral pulmonary vessels due to destruction of the lung parenchyma,
– hypoxic pulmonary vasoconstriction due to chronic or recurrent hypoxia, and
– vascular remodeling.
The latter consists for one of proliferation of the pulmonary vessel wall cells. These proliferative processes are mediated by an altered expression of vascular, inflammatory, and growth factors as well as a modified cellular metabolism of the components of the pulmonary vessel wall cells including mitochondrial dysfunction (7).
In this respect, PH seems to share some functional common features with a cancer-like disease as a proliferative non-neoplastic process, even though obvious major differences between PH and cancer exists including absence of invasion and metastasis, the degree of angiogenesis impairment, and genetic instability (8).
However, the major similarities comprise altered crosstalk between cells from different tissue types, unexplained proliferation and survival of pulmonary smooth muscle and endothelial cells, association with the immune system, and metabolic shifts.
Like cancer cells, proliferating pulmonary vessel wall cells have made crucial changes in their energy metabolism leading to increased glucose consumption. Intracellular glucose is subsequently not converted into complete mitochondrial glucose oxidation to water and carbon dioxide even in the presence of oxygen via the Krebs cycle. Instead, the increased glucose uptake is turned into an incomplete cytoplasmic degradation of glucose into lactate via glycolysis yielding a sixteenth of energy per molecule glucose in comparison with the complete mitochondrial oxidation (9).
At a first glance, it does not seem comprehensible why glycolysis is largely performed in those cells without mitochondrial oxidation in the presence of oxygen. This metabolic shift is termed aerobic glycolysis, which is an important metabolic starting point of de-novo synthesis of nucleic acids and lipids via pentose phosphate pathway (10). This metabolic detour enables those cells to perform the synthesis of fundamental elements necessary for cell division and survival.
In summary, proliferating cells such as cancer cells and cells of the pulmonary vessel wall in patients with PH tend to engage in an increased glucose uptake with aerobic glycolysis at the expense of reduced energy production. This mechanism is termed Warburg effect after German physician and biochemist Otto Warburg who first described aerobic glycolysis in cancer cells (11).
Positron emission tomography (PET) is a noninvasive nuclear imaging technique that visualizes cellular metabolic processes throughout the whole body. In conjunction with radiolabeled glucose, such as fluorodeoxyglucose (FDG), PET has already been established in oncology as a cornerstone of diagnostic and therapy monitoring (10).
In this view, FDG-PET appears an attractive method quantifying the amount of glucose metabolism of proliferating cell within lung parenchyma, pulmonary arteries and heart in order to assess the severity of pulmonary hypertension.
We intended to investigate whether FDG-PET imaging is able to measure and visualize these proliferative mechanisms in patients with PH due to chronic lung diseases.
Figure 1. Exemplary overview of selected regions of interest (ROI) delineated in FDG-PET/CT fusion images. ROIs of lung parenchyma in different planes: transverse (A–B), coronal (C-D), sagittal planes not depicted, of left and right ventricular myocardium (E), and of right central pulmonary artery (F). Volume of interest (VOI) of liver parenchyma (D) as reference (SUVR) for semiquantitative analysis. FDG-PET = fluorodeoxyglucose positron emission tomography, CT= computed tomography.
Therefore, we performed a retrospective analysis of 109 patients with end-stage pulmonary disease including mainly COPD and ILD, who were referred for lung transplant evaluation. All patients underwent right heart catheterization to invasively assess pulmonary hypertension as well as FDG-PET/ computed tomography to rule out malignant diseases as strictly demanded by local lung transplant evaluation protocol. As a useful biomarker in PH, we considered serum concentration of NT-proBNP as well.
The main two subgroups were COPD (62.4%) and ILD (30.3%) including idiopathic pulmonary fibrosis (58% of ILD). The distribution of pulmonary hypertension among all patients was fairly even: 56% of patients suffered from pulmonary hypertension with a mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, while 44% did not. More than 75% of patients with ILD and about 44% of patients with COPD were invasively measured with manifest pulmonary hypertension.
In order to assess the amount of glucose uptake in a specific thoracic compartment, the radioactivity of a chosen region or volume of interest (ROI, VOI) was measured, compared with radioactivity initially injected and calculated as standardized uptake value (SUV).
We accurately measured the region of interests within the lungs (14 planes), the heart (right and left ventricle) and the central pulmonary artery (Figure 1). Each thoracic SUV was related to the SUV of liver parenchyma within the respective patient, in order to obtain a better comparability between the datasets and was termed SUVR.
Figure 2. Significant group differences between pulmonary and right ventricular FDG uptake ratios (SUVR) compared with the mean pulmonary artery pressure (A) and the pulmonary vascular resistance (B). Median with interquartile range. * P < .05, ** P < .01, *** P < .001. LP = lung parenchyma; PA = pulmonary artery; RV = right ventricular myocardium; RV/LV = ratio of right to left ventricular myocardium.
Our key findings were that patients with an end-stage pulmonary disease due to mainly COPD or ILD who were invasively measured with pathologically elevated mPAP or PVR presented with a higher glucose uptake in the lung parenchyma, the central pulmonary arteries and the right ventricle of the heart, while this circumstance did not hold true for the left ventricle (Figure 2). Moreover, glucose uptake in those regions of lung, pulmonary arteries, and right ventricle positively correlated with the severity of PH assessed by mPAP, PVR, and NT-proBNP, while none was found for the left ventricle (Figure 3).
The strength of this study includes the considerably large number of patients investigated by right heart catheterization and FDG-PET. Patients were evaluated for lung transplantation due to end-stage pulmonary disease. The local lung transplant evaluation protocol strictly included right heart catheterization and FDG-PET. A certain selection bias therefore exists towards advanced pulmonary diseases with no healthy control group (emphysema vs. interstitial lung diseases).
In conclusion, pulmonary and cardiac FDG uptake in PET imaging positively correlated with the presence and severity of PH in patients with end-stage pulmonary disease. These results suggest that FDG-PET imaging can help understand the pathophysiology of PH as a proliferative pulmonary disease. Nevertheless, the role of FDG-PET imaging as a helpful tool in diagnosing PH and monitoring therapeutic effects still needs to be defined.
Figure 3. Positive correlations between FDG uptake in lung parenchyma (LP), central pulmonary arteries (PA), right ventricle (RV) and hemodynamic parameters (mPAP, PVR, NT-proBNP). Scatterplots of standardized uptake value ratios (SUVR) from 109 patients with pulmonary end-stage disease. Ordinate and labeling in the first column applies to each row, respectively. r = Pearson’s correlation coefficient; ln = natural logarithm to the base e.
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All authors thank the radiopharmacy staff, the technologists, and the administrative staff of both Division of Respiratory Medicine and Department of Nuclear Medicine at the University Hospital of Leipzig for the patient management and their help in acquiring the data. The authors highly appreciate the fruitful collaboration between respiratory and nuclear medicine.
Armin Frille, MD
Department of Respiratory Medicine,
University of Leipzig,
04103 Leipzig, Germany.