Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension
Chinthaka B. Samaranayake, Marili Niglas, Nicoleta Baxan, Alexander Kempny, Ali Ashek, Michael Gatzoulis, Laura C. Price, Konstantinos Dimopoulos, Martin R. Wilkins, Stephen Wort, Christopher J. Rhodes, Lan Zhao, Colm McCabe
Chinthaka B. Samaranayake, Marili Niglas, Nicoleta Baxan, Alexander Kempny, Ali Ashek, Michael Gatzoulis, Laura C. Price, Konstantinos Dimopoulos, Martin R. Wilkins, Stephen Wort, Christopher J. Rhodes, Lan Zhao, Colm McCabe
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Research Article Cardiology Pulmonology

Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension

Abstract

Preclinical studies suggest beneficial effects of GLP-1 agonists in pulmonary arterial hypertension (PAH). This first-in-disease study evaluated acute hemodynamic effects of GLP-1 agonist, exenatide administered i.v. in patients with idiopathic PAH and CTEPH as well as in a PAH rodent model. Seventeen patients (9 idiopathic PAH) received an exenatide infusion during right heart catheterization, which included multisite sampling for circulating metabolites. Acute effects of exenatide were also assessed by cardiac magnetic resonance imaging in monocrotaline (MCT) PAH and control rats. In the clinical study, exenatide was well tolerated, reduced mean pulmonary artery pressure (45 ± 15 mmHg versus 40 ± 18 mmHg), and improved cardiac index (2.1 ± 0.6 L/min versus 2.4 ± 0.9 L/min/m2) and pulmonary vascular resistance (7.8 ± 8.0 WU versus 5.9 ± 5.0 WU) across all patients. Right ventricular (RV) contractility and afterload improved in a subset of patients undergoing pressure-volume measurements. In an exploratory metabolomics analysis, 47 metabolite levels changed after exenatide infusion, predominantly in free fatty acid pathways. Six metabolites with prognostic relevance in PAH within myocardial glycolytic and lipid oxidation pathways were also altered after exenatide. In MCT rats, exenatide improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling. These findings support the further evaluation of exenatide within chronic studies as a potentially novel pulmonary vasodilator therapy.

Authors

Chinthaka B. Samaranayake, Marili Niglas, Nicoleta Baxan, Alexander Kempny, Ali Ashek, Michael Gatzoulis, Laura C. Price, Konstantinos Dimopoulos, Martin R. Wilkins, Stephen Wort, Christopher J. Rhodes, Lan Zhao, Colm McCabe

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Figure 4

Change in metabolite gradients across sample sites before and after exenatide.

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Change in metabolite gradients across sample sites before and after exen...
(A–C) Shown are metabolite gradients between SVC-PA (A), PA-RA (B), RA-SVC (C) for 47 metabolites with significant change in level following exenatide infusion (FDR q < 0.05). (D and E) The metabolite levels at each sampling site for 2 free fatty acids — palmitate and oleate, respectively — known to be increased in PAH. Exenatide significantly reversed the direction of metabolite gradients across sampling sites. (F) The overlap in metabolite number demonstrating reversal of the direction of gradients with exenatide. Absolute difference in measurements reported (A–C). Data are shown as mean ± SEM (D and E).