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Mirabegron, a Clinically Approved β3 Adrenergic Receptor Agonist, Does Not Reduce Infarct Size in a Swine Model of Reperfused Myocardial Infarction

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Abstract

The administration of the selective β3 adrenergic receptor (β3AR) agonist BRL-37344 protects from myocardial ischemia/reperfusion injury (IRI), although the lack of clinical approval limits its translatability. We tested the cardioprotective effect of mirabegron, the first-in-class β3AR agonist approved for human use. A dose-response study was conducted in 6 pigs to select the highest intravenous dose of mirabegron without significant detrimental hemodynamic effect. Subsequently, closed chest anterior myocardial infarction (45 min ischemia followed by reperfusion) was performed in 26 pigs which randomly received either mirabegron (10 μg/kg) or placebo 5 min before reperfusion. Day-7 cardiac magnetic resonance (CMR) showed no differences in infarct size (35.0 ± 2.0% of left ventricle (LV) vs. 35.9 ± 2.4% in mirabegron and placebo respectively, p = 0.782) or LV ejection fraction (36.3 ± 1.1 vs. 34.6 ± 1.9%, p = 0.430). Consistent results were obtained on day-45 CMR. In conclusion, the intravenous administration of the clinically available selective β3AR agonist mirabegron does not reduce infarct size in a swine model of IRI.

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Abbreviations

AMI:

Acute myocardial infarction

β3AR :

β3 adrenergic receptor

CMR:

Cardiovascular magnetic resonance

IRI:

Ischemia/reperfusion injury

IS:

Infarct size

LV:

Left ventricle

LVEDV:

Left ventricular end-diastolic volume

LVEF:

Left ventricular ejection fraction

LVESV :

Left ventricular end-systolic volume

NOS:

Nitric oxide synthase

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Acknowledgments

The authors are greatly indebted to Gonzalo J Lopez-Martin and Angel Macias for image acquisition. The authors thank Tamara Cordoba, Oscar Sanz, Ruben Mota, Santiago Rodriguez, Eugenio Fernández, and the rest of the team at the CNIC Animal Facility and farm for providing outstanding animal care and support. The authors also thank Juan Pellico for the mirabegron purity check out with NMR.

Sources of Funding

Dr. Rossello has received support from SEC-CNIC CARDIOJOVEN Program. R. F-J is a recipient of funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No MSCA-IF-GF-707642. This study was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) through the Carlos III Institute of Health-Fondo de Investigación Sanitaria (PI10/02268, PI13/01979, and PI16/02110), and the Fondo Europeo de Desarrollo Regional (FEDER, RD: SAF2013-49663-EXP). This study forms part of a Master Research Agreement between the CNIC and Philips Healthcare. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).

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Authors and Affiliations

  1. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain

    Xavier Rossello, Rodrigo Fernández-Jiménez, Gonzalo Pizarro, Carlos Galán-Arriola, Manuel Lobo-Gonzalez, Jean Paul Vilchez, Jaime García-Prieto, Jose Manuel García-Ruiz, Ana García-Álvarez, David Sanz-Rosa & Borja Ibanez

  2. CIBER de Enfermedades CardioVasculares (CIBERCV), Madrid, Spain

    Xavier Rossello, Antonio Piñero, Rodrigo Fernández-Jiménez, Gonzalo Pizarro, Carlos Galán-Arriola, Manuel Lobo-Gonzalez, Jean Paul Vilchez, Jaime García-Prieto, Jose Manuel García-Ruiz, Ana García-Álvarez, David Sanz-Rosa & Borja Ibanez

  3. Cardiology Department, IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain

    Antonio Piñero & Borja Ibanez

  4. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, USA

    Rodrigo Fernández-Jiménez

  5. Philips Healthcare, Madrid, Spain

    Javier Sánchez-González

  6. Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea, Madrid, Spain

    Gonzalo Pizarro & David Sanz-Rosa

  7. Translational Laboratory for Cardiovascular Imaging and Therapy, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro, 3, 28029, Madrid, Spain

    Borja Ibanez

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  1. Xavier Rossello
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  2. Antonio Piñero
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  3. Rodrigo Fernández-Jiménez
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Correspondence to Borja Ibanez.

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Disclosures

Dr. Ibanez and Dr. García-Álvarez are inventors of the patent entitled “Use of selective beta-3 adrenergic agonists for the treatment of pulmonary hypertension” (PCT/ES2013/070611). Javier Sánchez-González is Philips employee.

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No human studies were carried out by the authors for this article.

Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

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Associate Editor Enrique Lara-Pezzi oversaw the review of this article

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Rossello, X., Piñero, A., Fernández-Jiménez, R. et al. Mirabegron, a Clinically Approved β3 Adrenergic Receptor Agonist, Does Not Reduce Infarct Size in a Swine Model of Reperfused Myocardial Infarction. J. of Cardiovasc. Trans. Res. 11, 310–318 (2018). https://doi.org/10.1007/s12265-018-9819-8

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