Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias
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Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. / Molina, Cristina E; Leroy, Jérôme; Richter, Wito; Xie, Moses; Scheitrum, Colleen; Lee, Illkyu-Oliver; Maack, Christoph; Rucker-Martin, Catherine; Donzeau-Gouge, Patrick; Verde, Ignacio; Llach, Anna; Hove-Madsen, Leif; Conti, Marco; Vandecasteele, Grégoire; Fischmeister, Rodolphe.
in: J AM COLL CARDIOL, Jahrgang 59, Nr. 24, 12.06.2012, S. 2182-90.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias
AU - Molina, Cristina E
AU - Leroy, Jérôme
AU - Richter, Wito
AU - Xie, Moses
AU - Scheitrum, Colleen
AU - Lee, Illkyu-Oliver
AU - Maack, Christoph
AU - Rucker-Martin, Catherine
AU - Donzeau-Gouge, Patrick
AU - Verde, Ignacio
AU - Llach, Anna
AU - Hove-Madsen, Leif
AU - Conti, Marco
AU - Vandecasteele, Grégoire
AU - Fischmeister, Rodolphe
N1 - Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
PY - 2012/6/12
Y1 - 2012/6/12
N2 - OBJECTIVES: This study was designed to examine whether a cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE), PDE4, is expressed in human atrium and contributes to the control of electrical stability.BACKGROUND: Atrial fibrillation is accompanied by a profound remodeling of membrane receptors and alterations in cAMP-dependent regulation of Ca(2+) handling. Being responsible for cAMP hydrolysis, PDEs are likely to play a role in this setting. In the rodent heart, PDE4 contributes up to 60% of total cAMP-hydrolytic activity. However, its role in the human heart remains controversial.METHODS: L-type Ca(2+) current and spontaneous Ca(2+) release were recorded in isolated human atrial myocytes. Intracellular cAMP was measured by live cell imaging using a fluorescence resonance energy transfer-based sensor. Contractile force and arrhythmias were recorded in human atrial trabeculae. PDE activity was measured in human atrial tissue from patients in sinus rhythm and permanent atrial fibrillation.RESULTS: PDE4 is expressed in human atrial myocytes and accounts for approximately 15% of total PDE activity. PDE4D represents the major PDE4 subtype. PDE4 inhibition increased intracellular cAMP and L-type Ca(2+) current and dramatically delayed their decay after a brief β-adrenergic stimulation. PDE4 inhibition also increased the frequency of spontaneous Ca(2+) release at baseline, as well as the contractile response and the incidence of arrhythmias in human atrial strips during β-adrenergic stimulation. Total PDE activity decreased with age, and the relative PDE4 activity was lower in patients with permanent atrial fibrillation than in age-matched sinus rhythm controls.CONCLUSIONS: PDE4 is critical in controlling cAMP levels and thereby Ca(2+) influx and release in human atrial muscle, hence limiting the susceptibility to arrhythmias.
AB - OBJECTIVES: This study was designed to examine whether a cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE), PDE4, is expressed in human atrium and contributes to the control of electrical stability.BACKGROUND: Atrial fibrillation is accompanied by a profound remodeling of membrane receptors and alterations in cAMP-dependent regulation of Ca(2+) handling. Being responsible for cAMP hydrolysis, PDEs are likely to play a role in this setting. In the rodent heart, PDE4 contributes up to 60% of total cAMP-hydrolytic activity. However, its role in the human heart remains controversial.METHODS: L-type Ca(2+) current and spontaneous Ca(2+) release were recorded in isolated human atrial myocytes. Intracellular cAMP was measured by live cell imaging using a fluorescence resonance energy transfer-based sensor. Contractile force and arrhythmias were recorded in human atrial trabeculae. PDE activity was measured in human atrial tissue from patients in sinus rhythm and permanent atrial fibrillation.RESULTS: PDE4 is expressed in human atrial myocytes and accounts for approximately 15% of total PDE activity. PDE4D represents the major PDE4 subtype. PDE4 inhibition increased intracellular cAMP and L-type Ca(2+) current and dramatically delayed their decay after a brief β-adrenergic stimulation. PDE4 inhibition also increased the frequency of spontaneous Ca(2+) release at baseline, as well as the contractile response and the incidence of arrhythmias in human atrial strips during β-adrenergic stimulation. Total PDE activity decreased with age, and the relative PDE4 activity was lower in patients with permanent atrial fibrillation than in age-matched sinus rhythm controls.CONCLUSIONS: PDE4 is critical in controlling cAMP levels and thereby Ca(2+) influx and release in human atrial muscle, hence limiting the susceptibility to arrhythmias.
KW - Arrhythmias, Cardiac
KW - Atrial Fibrillation
KW - Calcium
KW - Cyclic AMP
KW - Cyclic Nucleotide Phosphodiesterases, Type 4
KW - Fluorescence Resonance Energy Transfer
KW - Heart Atria
KW - Humans
KW - Myocytes, Cardiac
KW - Phosphodiesterase 4 Inhibitors
KW - Sarcoplasmic Reticulum
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1016/j.jacc.2012.01.060
DO - 10.1016/j.jacc.2012.01.060
M3 - SCORING: Journal article
C2 - 22676938
VL - 59
SP - 2182
EP - 2190
JO - J AM COLL CARDIOL
JF - J AM COLL CARDIOL
SN - 0735-1097
IS - 24
ER -