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Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes

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Abstract

Atrial fibrillation (AF) has been associated with increased spontaneous calcium release from the sarcoplasmic reticulum and linked to increased adenosine A2A receptor (A2AR) expression and activation. Here we tested whether this may favor atrial arrhythmogenesis by promoting beat-to-beat alternation and irregularity. Patch-clamp and confocal calcium imaging was used to measure the beat-to-beat response of the calcium current and transient in human atrial myocytes. Responses were classified as uniform, alternating or irregular and stimulation of Gs-protein coupled receptors decreased the frequency where a uniform response could be maintained from 1.0 ± 0.1 to 0.6 ± 0.1 Hz; p < 0.01 for beta-adrenergic receptors and from 1.4 ± 0.1 to 0.5 ± 0.1 Hz; p < 0.05 for A2ARs. The latter was linked to increased spontaneous calcium release and after-depolarizations. Moreover, A2AR activation increased the fraction of non-uniformly responding cells in HL-1 myocyte cultures from 19 ± 3 to 51 ± 9 %; p < 0.02, and electrical mapping in perfused porcine atria revealed that adenosine induced electrical alternans at longer cycle lengths, doubled the fraction of electrodes showing alternation, and increased the amplitude of alternations. Importantly, protein kinase A inhibition increased the highest frequency where uniform responses could be maintained from 0.84 ± 0.12 to 1.86 ± 0.11 Hz; p < 0.001 and prevention of A2AR-activation with exogenous adenosine deaminase selectively increased the threshold from 0.8 ± 0.1 to 1.2 ± 0.1 Hz; p = 0.001 in myocytes from patients with AF. In conclusion, A2AR-activation promotes beat-to-beat irregularities in the calcium transient in human atrial myocytes, and prevention of A2AR activation may be a novel means to maintain uniform beat-to-beat responses at higher beating frequencies in patients with atrial fibrillation.

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Acknowledgments

We would like to thank Mr. Andreu Ferrero-Gregori for invaluable help with the statistical analysis and greatly appreciate the collaboration of the surgeons at the Cardiac Surgery Department at Hospital de la Santa Creu i Sant Pau.

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  1. Cristina E. Molina

    Present address: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, 45122, Essen, Germany

Authors and Affiliations

  1. Cardiac Rhythm and Contraction, Cardiovascular Research Centre CSIC-ICCC and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, St Antoni Mª Claret 167, 08025, Barcelona, Spain

    Cristina E. Molina, Adela Herraiz-Martínez, Carmen Tarifa, Montserrat Barriga, Nuria Cabello & Leif Hove-Madsen

  2. Department of Cardiology and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Anna Llach, Rob F. Wiegerinck, Jacqueline Fernandes & Juan Cinca

  3. Department of Cardiac Surgery and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    José Montiel

  4. Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain

    Alex Vallmitjana & Raúl Benitéz

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  1. Cristina E. Molina
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Correspondence to Leif Hove-Madsen.

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This work has received funding from Spanish Ministry of Economía y Competitividad, Instituto de Salud Carlos III and Fondo Europeo de Desarollo Regional (FEDER): (SAF2011-30312), (SAF2014-58286-C2-1R), (CNIC2009-08) and (network RD12/0042/0002), Generalitat de Catalunya (2014SGR1465) and Marie Curie IEF Grant (PIEF-GA-2012-331241).

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Molina, C.E., Llach, A., Herraiz-Martínez, A. et al. Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes. Basic Res Cardiol 111, 5 (2016). https://doi.org/10.1007/s00395-015-0525-2

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