Lung ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography for Diagnosis and Monitoring of Pulmonary Arterial Hypertension

Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer 18 F-fluorodeoxyglucose (FDG).Objectives: The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. Methods: PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. Measurements and Main Results: Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1a (HIF-1a), which underlies their glycolytic phenotype. Conclusions: HIF-1a-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.Keywords: hypoxia-inducible factor-1a (HIF-1a); glucose transporter-1 (Glut1); glycolysis; imatinib; Sugen 5416Pulmonary arterial hypertension (PAH) is a syndrome in which the mean pulmonary artery pressure exceeds 25 mm Hg because of obstruction and constriction of precapillary pulmonary resistance arteries. An important aspect of the pathophysiology of PAH is increased proliferation and reduced apoptosis of pulmonary arterial endothelial and smooth muscle cells (PASMCs) (1-8), leading to plexiform lesions and increased muscularization, respectively.Publications describe impaired glucose oxidation and/or a shift to glycolytic metabolism in PASMCs in rodents with experimental PAH (9), in endothelial cells of patients with PAH (10, 11), and in the pulmonary arteries of rats (12) and mice (13) exposed to chronic hypoxia. Aerobic glycolysis is also known as the Warburg effect and was shown to confer a growth advantage to proliferating cells (14). A crucial determinant of whether cells generate energy through glycolysis or aerobic mitochondrial respiration is the activity of pyruvate dehydrogenase complex (PDH). PDH catalyzes the conversion of pyruvate into acetyl coenzyme A...

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…One week after induction of PAH with MCT, a time point that corresponds to the onset of detectable pulmonary vascular disease but early in the course of evolution of PAH,21, 22 rats were treated with intraperitoneal injections of 0.5 mg/kg filter‐sterilized colchicine (Sigma‐Aldrich, St. Louis, MO) dissolved in PBS (n=24) or an equivalent volume of PBS (n=28) on Monday, Wednesday, and Friday for 3 weeks and were then analyzed. A sample size of 25 to 30 was targeted for 3 reasons: there were 3 groups in the analysis, to reduce effects of the heterogeneity with colchicine treatment, and to account for possible deaths during the experimental time frame.…”

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

“…It has been suggested that stimulating GO via FAO inhibition may be an effective pharmacological approach to improve cardiac function and efficiency, however a limited number of studies have thoroughly studied this in animal PAH models (Ussher et al, 2009;Sutendra et al, 2010;Marsboom et al, 2012). The Randle cycle may be exploited therapeutically by shifting the primary fuel source from FAs and stimulating GO.…”

“…There is increasing evidence that pathologic remodeling of the pulmonary vasculature is associated with abnormal cellular metabolism and studies with patients and animals have shown increased lung uptake with FDG PET (Hagan et al, 2011;Marsboom et al, 2012;Zhao et al, 2013;Ryan et al, 2013) Two studies using the monocrotaline rat model of severe PAH have shown that increased accumulation of FDG tracer may be detected in lung parenchyma and that there is an associated increased expression of GLUT1 and other glycolytic proteins Zhao et al, 2013) . Marsboom's group demonstrated that elevated lung FDG signals may be detected during early, mild PAH and that the signal progressively increases with evolving PAH.…”

“…There exists a pressing demand to better understand the pathophysiology of PAH and the contributing factors leading to the detriment of right ventricular (RV) function, to identify new therapeutic targets and accordingly develop more effective therapies. Recently, studies have revealed that metabolic perturbations may be an important mechanism of RV failure (Fang et al, 2012) and may be implicated in pathogenic pulmonary vascular remodeling Marsboom et al, 2012). Additionally, metabolic modulation has been shown to have beneficial effects on RV function by therapeutically improving metabolic efficiency and enhancing glucose oxidation (GO) Archer et al, 2010;Fang et al, 2012;Marsboom et al, 2012).…”

“…Recently, studies have revealed that metabolic perturbations may be an important mechanism of RV failure (Fang et al, 2012) and may be implicated in pathogenic pulmonary vascular remodeling Marsboom et al, 2012). Additionally, metabolic modulation has been shown to have beneficial effects on RV function by therapeutically improving metabolic efficiency and enhancing glucose oxidation (GO) Archer et al, 2010;Fang et al, 2012;Marsboom et al, 2012). This may provide a new treatment avenue to directly and selectively target the failing RV and improve prognosis in patients with PAH however, there have been limited studies evaluating in-vivo metabolism of the RV Fang et al, 2012).…”