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01-12-2017 | Original Article

Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension

Authors: Katarzyna Drozd, MSc, Ali Ahmadi, MD, PhD, Yupu Deng, MD, Baohua Jiang, MD, PhD, Julia Petryk, Stephanie Thorn, PhD, Duncan Stewart, MD, Rob Beanlands, MD, Robert A. deKemp, PhD, Jean N. DaSilva, PhD, Lisa M. Mielniczuk, MD

Published in: Journal of Nuclear Cardiology | Issue 6/2017

Abstract

Background

Altered myocardial energy metabolism has been linked to worsening of RV function in pulmonary arterial hypertension (PAH). The aim of this study was to evaluate RV glucose and fatty acid metabolism in vivo in a rat model of PAH using positron emission tomography (PET) and investigate the effects of Macitentan on RV substrate utilization.

Methods

PAH was induced in male Sprague-Dawley rats by a single subcutaneous injection of Sugen 5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% oxygen). At week 5 post-injection, the PAH rats were randomized to Macitentan (30 mg/kg daily) treatment or no treatment. Substrate utilization was serially assessed 5 and 8 weeks post-injection with 2-[¹⁸F]fluoro-2-deoxyglucose (FDG) and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) PET for glucose and fatty acid metabolism respectively and correlated with in vivo functional measurements.

Results

PAH induction resulted in a 2.5-fold increase in RV FDG uptake (standardized uptake value (SUV) of normal control: 1.6 ± 0.4, week 5: 4.1 ± 1.9, week 8: 4.0 ± 1.6, P < 0.05 for all groups vs. control). RV FTHA showed twofold increased uptake at week 5 (SUV control: 1.50 ± 0.39, week 5: 3.06 ± 1.10, P = 0.03). Macitentan significantly decreased RV FDG uptake at 8 weeks (SUV: 2.5 ± 0.9, P = 0.04), associated with improved RV ejection fraction and reduced RV systolic pressure, while FTHA uptake was maintained.

Conclusion

PAH is associated with metabolic changes in the RV, characterized by a marked increase in FDG and FTHA uptake. Macitentan treatment reduced PAH severity and was associated with a decrease in RV FDG uptake and improved RV function.

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Title: Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension
Authors: Katarzyna Drozd, MSc
Ali Ahmadi, MD, PhD
Yupu Deng, MD
Baohua Jiang, MD, PhD
Julia Petryk
Stephanie Thorn, PhD
Duncan Stewart, MD
Rob Beanlands, MD
Robert A. deKemp, PhD
Jean N. DaSilva, PhD
Lisa M. Mielniczuk, MD
Publication date: 01-12-2017
Publisher: Springer US
Published in: Journal of Nuclear Cardiology / Issue 6/2017
Print ISSN: 1071-3581
Electronic ISSN: 1532-6551
DOI: https://doi.org/10.1007/s12350-016-0663-4

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Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension

Abstract

Background

Methods

Results

Conclusion

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