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01.12.2017 | Original Article | Ausgabe 6/2017

Journal of Nuclear Cardiology 6/2017

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

Zeitschrift:
Journal of Nuclear Cardiology > Ausgabe 6/2017
Autoren:
MSc Katarzyna Drozd, MD, PhD Ali Ahmadi, MD Yupu Deng, MD, PhD Baohua Jiang, Julia Petryk, PhD Stephanie Thorn, MD Duncan Stewart, MD Rob Beanlands, PhD Robert A. deKemp, PhD Jean N. DaSilva, MD Lisa M. Mielniczuk
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s12350-016-0663-4) contains supplementary material, which is available to authorized users.
See related editorial, doi:10.​1007/​s12350-016-0695-9.
Katarzyna Drozd and Ali Ahmadi are co-first authors of this study.

Funding

This study was supported by grants from the Heart and Stroke Foundation of Ontario (HSFO) Grant# 000158 and unrestricted research funding from Actelion Pharmaceuticals.
The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarizes the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.​com.

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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