Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias.
OBJECTIVE
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.
INSERM UMR-S 769, LabEx LERMIT, DHU-Torino, Châtenay-Malabry, France.
Cristina E
CE
Molina
Jérôme
J
Leroy
Wito
W
Richter
Moses
M
Xie
Colleen
C
Scheitrum
Illkyu-Oliver
IO
Lee
Christoph
C
Maack
Catherine
C
Rucker-Martin
Patrick
P
Donzeau-Gouge
Ignacio
I
Verde
Anna
A
Llach
Leif
L
Hove-Madsen
Marco
M
Conti
Grégoire
G
Vandecasteele
Rodolphe
R
Fischmeister
D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000517:prevention & control*; D001281:Atrial Fibrillation; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D058988:Phosphodiesterase 4 Inhibitors; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D002118:Calcium