Cyclic Adenosine Monophosphate Phosphodiesterase Type 4 Protects Against Atrial Arrhythmias

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• 作者：Cristina E. Molina ; PhD^鈦?/sup> ; ^&dagger ; ; Jé ; rô ; me Leroy ; PhD^鈦?/sup> ; ^&dagger ; ; Wito Richter ; PhD^&Dagger ; ; Moses Xie ; BSc^&Dagger ; ; Colleen Scheitrum ; BSc^&Dagger ; ; Illkyu-Oliver Lee ; MD^&sect ; ; Christoph Maack ; MD^&sect ; ; Catherine Rucker-Martin ; PhD^&dagger ; ; ^鈭?/sup> ; Patrick Donzeau-Gouge ; MD^¶ ; ; Ignacio Verde ; PhD^# ; Anna Llach ; PhD^鈦庘亷 ; Leif Hove-Madsen ; PhD^鈦庘亷 ; Marco Conti ; MD^&Dagger ; ; Gré ; goire Vandecasteele ; PhD^鈦?/sup> ; ^&dagger ; ; Rodolphe Fischmeister ; PhD^鈦?/sup> ; ^&dagger ; ; ^{rodolphe.fischmeister@inserm.fr}
• 关键词：arrhythmia ; atrial fibrillation ; PDE4 ; phosphodiesterase
• 刊名：Journal of the American College of Cardiology
• 出版年：2012
• 期刊代码：201_07351097
• 类别：med
• 出版时间：12 June, 2012
• 卷：59
• 期：24
• 页码：2182-2190
• 文件大小：1625 K

摘要

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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 Ca²⁺ 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 Ca²⁺ current and spontaneous Ca²⁺ 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 Ca²⁺ current and dramatically delayed their decay after a brief 尾-adrenergic stimulation. PDE4 inhibition also increased the frequency of spontaneous Ca²⁺ release at baseline, as well as the contractile response and the incidence of arrhythmias in human atrial strips during 尾-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 Ca²⁺ influx and release in human atrial muscle, hence limiting the susceptibility to arrhythmias.