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Apelin Compared With Dobutamine Exerts Cardioprotection and Extends Survival in a Rat Model of Endotoxin-Induced Myocardial Dysfunction*

Chagnon, Frederic MSc; Coquerel, David PhD; Salvail, Dany PhD; Marsault, Eric PhD; Dumaine, Robert PhD; Auger-Messier, Mannix PhD; Sarret, Philippe PhD; Lesur, Olivier MD, MSc, PhD

doi: 10.1097/CCM.0000000000002097
Online Laboratory Investigations

Objective: Dobutamine is the currently recommended β-adrenergic inotropic drug for supporting sepsis-induced myocardial dysfunction when cardiac output index remains low after preload correction. Better and safer therapies are nonetheless mandatory because responsiveness to dobutamine is limited with numerous side effects. Apelin-13 is a powerful inotropic candidate that could be considered as an alternative noncatecholaminergic support in the setting of inflammatory cardiovascular dysfunction.

Design: Interventional controlled experimental animal study.

Setting: Tertiary care university-based research institute.

Subjects: One hundred ninety-eight adult male rats.

Interventions: Using a rat model of “systemic inflammation–induced cardiac dysfunction” induced by intraperitoneal lipopolysaccharide injection (10 mg/kg), hemodynamic efficacy, cardioprotection, and biomechanics were assessed under IV osmotic pump infusions of apelin-13 (0.25 μg/kg/min) or dobutamine (7.5 μg/kg/min).

Measurements and Main Results: In this model and in both in vivo and ex vivo studies, apelin-13 compared with dobutamine provoked distinctive effects on cardiac function: 1) optimized cardiac energy–dependent workload with improved cardiac index and lower vascular resistance, 2) upgraded hearts’ apelinergic responsiveness, and 3) consecutive downstream advantages, including increased urine output, enhanced plasma volume, reduced weight loss, and substantially improved overall outcomes. In vitro studies confirmed that these apelin-13–driven processes encompassed a significant and rapid reduction in systemic cytokine release with dampening of myocardial inflammation, injury, and apoptosis and resolution of associated molecular pathways.

Conclusions: In this inflammatory cardiovascular dysfunction, apelin-13 infusion delivers distinct and optimized hemodynamic support (including positive fluid balance), along with cardioprotective effects, modulation of circulatory inflammation and extended survival.

1Soins Intensifs Médicaux et Service de Cardiologie, Université de Sherbrooke, Sherbrooke, QC, Canada.

2Centre de Recherche du CHUS (CR-CHUS), Sherbrooke, QC, Canada.

3IPS Therapeutique Inc., Sherbrooke, QC, Canada

4Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.

5Institut de Pharmacologie de Sherbrooke (IPS), Université de Sherbrooke, Sherbrooke, QC, Canada.

6Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.

*See also p. 754.

Mr. Chagnon and Dr. Coquerel contributed equally.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Marsault received support for article research from the Natural Sciences and Engineering Research Council of Canada. Dr. Dumaine disclosed off-label product use (Apelin). Supported by grants from the Canadian Heart and Stroke Foundation (Drs. Lesur and Dumaine), a Merck Sharpe & Dhome FMSS grant (Drs. Lesur, Auger-Messier, Dumaine, Marsault, and Sarret), and a NSERC Engage grant (EGP 488509-15; Dr. Auger-Messier). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: Olivier.Lesur@USherbrooke.ca

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