Heterogeneity in Lung ¹⁸ FDG Uptake in Pulmonary Arterial Hypertension

Abstract

P ulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling characterized by dysregulated growth of pulmonary vascular cells and inflammation. [1][2][3][4] In the search for new medicines, the focus is moving toward therapies targeting these mechanisms, drawing on approved oncology interventions, such as tyrosine kinase inhibitors (eg, imatinib) 5,6 and metabolic modulators (eg, dichloroacetate), 7,8 and antiinflammatory treatments. 9 The evaluation of these antiremodeling and anti-inflammatory strategies in PAH patients poses a considerable challenge that may hamper their development. Background-Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterizedby dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models. Few data exist from patients with PAH. Methods and Results-Dynamic positron emission tomography imaging with fluorine-18-labeled 2-fluoro-2-deoxyglucose ( Clinical Perspective on p 1224Noninvasive molecular imaging with the use of positron emission tomography (PET) offers enormous potential for monitoring cellular and biochemical events in otherwise inaccessible tissue and has been used in oncology to assess antiproliferative therapeutics. Specifically, fluorine-18-labeled 2-fluoro-2-deoxyglucose ( 18 FDG), a glucose analogue, is widely used for the detection and staging of a variety of malignant lesions and can provide a quantitative assessment of response to treatment.10-13 18 FDG PET exploits the "Warburg effect," 14,15 the observation that many cancers use aerobic cytoplasmic glycolysis as opposed to mitochondrial glucose oxidation as a major energy source, a process that requires increased cellular glucose uptake.Aerobic glycolysis is also a characteristic of nonmalignant proliferating cells and is observed in human pulmonary endothelial cells isolated and cultured from idiopathic PAH (IPAH) patient lungs, 16 as well as in pulmonary arterial smooth muscle cells from rodent PAH models.17 Lung parenchymal glucose uptake, measured by 18 FDG PET, has been reported to be increased in IPAH patients compared with healthy controls. 16,18 Recently, Marsboom et al 19 showed an increased lung 18 FDG PET signal in animal PAH models that is reduced by treatment with imatinib and dichloroacetate. These data provide the foundation for further investigation of the utility of 18 FDG PET as a tool in the assessment of patients with PAH. We set out to explore 3 questions: (1) the utility of dynamic 18 FDG PET acquisition in discriminating between PAH patients and healthy controls; (2) the feasibility of 18 FDG PET in tracking the pathology of pulmonary hypertension in in vivo PAH models and their response to treatment; and (3) the impact of treatments on cellular 18 FDG uptake with the use of IPAH-derived cells in vitro. Our da...

Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

“…Thus, our results suggest that susceptibility to DNA damage is a widespread phenomenon in PAH, shared among multiple subtypes with seemingly disparate etiologies. Alterations in oxygen sensing and redox balance are now well recognized in pulmonary hypertension, including abnormal mitochondrial number and morphology, oxidative stress, and a shift to glycolytic metabolism (23)(24)(25)(26)(27)(28)(29)(30)(31). However, this study is the first to directly link increased ROS production in PAH cells to elevated levels of DNA damage.…”

The Crossroads of Iron with Hypoxia and Cellular Metabolism. Implications in the Pathobiology of Pulmonary Hypertension

“…These are supported by complementary human and experimental studies. Further contributing to the quasimalignancy paradigm of PH is evidence of clonal endothelial cell expansion in patients with IPAH (82), somatic chromosomal abnormalities in IPAH lungs (83), increased uptake of 18-fluorodeoxy-glucose in the lung fields of patients with IPAH (84), and the presence of DNA microsatellite instability within the IPAH vascular proliferative lesions (85). The metabolic switch toward aerobic glycolysis and mitochondrial dysfunction in PH is increasingly recognized as a key pathophysiologic feature shared with cancers.…”

Positron Emission Tomography Imaging with 18F-Labeled ZHER2:2891 Affibody for Detection of HER2 Expression and Pharmacodynamic Response to HER2-Modulating Therapies

“…Thirty-to sixty-minute cumulative images of the dynamic data were used to define 3-dimensional regions of interest (ROI). Arterial input function was estimated by drawing ROIs over the center of the heart cavity using cumulative images from 0.25 to 2 minutes of the dynamic series, a method, we previously validated for use in rodents (21). The count densities were averaged for all ROIs at each time point to obtain time versus radioactivity curves (TAC).…”