title: Prevention of adenosine A2A receptor activation diminishes beat-to-beat alternation in human atrial myocytes.
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.
authors.affiliation: 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.|Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, 45122, Essen, Germany.
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Molina
authors.affiliation: Department of Cardiology and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Llach
authors.affiliation: 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.
authors.forename: Adela
authors.initials: A
authors.lastname: Herraiz-Martínez
authors.affiliation: 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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Tarifa
authors.affiliation: 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.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Barriga
authors.affiliation: Department of Cardiology and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Rob F
authors.initials: RF
authors.lastname: Wiegerinck
authors.affiliation: Department of Cardiology and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fernandes
authors.affiliation: 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.
authors.forename: Nuria
authors.initials: N
authors.lastname: Cabello
authors.affiliation: Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Vallmitjana
authors.affiliation: Department of Automatic Control, Universitat Politècnica de Catalunya, Barcelona, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Benitéz
authors.affiliation: Department of Cardiac Surgery and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Montiel
authors.affiliation: Department of Cardiology and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Cinca
authors.affiliation: 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. lhove@csic-iccc.org.
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D002478:Cells, Cultured; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D034421:Sus scrofa
chemical_list: D043705:Receptor, Adenosine A2A
keywords: Adenosine receptor; Atrial myocyte; Electrophysiology; L-Type calcium current; Sarcoplasmic reticulum