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ARTICLE CONTRIBUTORS

Journal of the American College of Cardiology

Clinical Articles, News & Views

PDE4 limits susceptibility to arrhythmias

Cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE), PDE4, can help limit susceptibility to arrhythmias, according to a study1 published recently in the Journal of the American College of Cardiology.

Researchers examined whether PDE4 is expressed in the human atrium and contributes to the control of electrical stability, thus affecting the likelihood of developing atrial fibrillation (AF).

AF 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, though its role in the human heart remains controversial, say the authors.

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.

PDE4 inhibition increased intracellular cAMP and L-type Ca2+ current and dramatically delayed their decay after a brief b-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 b-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.

In an accompanying editorial Drs David Van Wagoner and Bruce Lindsay state that, in light of the study, it “seems likely that loss of PDE4 activity contributes to AF risk, and that the presence of AF is associated with a further reduction in PDE4 activity. Although a number of pro-arrhythmic pathways (sympathetic tone, hypertension, fibrosis, and so on.) also increase in prevalence with age, the results of Molina et al. are intriguing”.

The study “suggests the intriguing hypothesis that novel agents that selectively enhance PDE4D activity might simultaneously prevent atrial contractile dysfunction, limit atrial energy demands associated with Ca2+ cycling, help to prevent AF, and decrease stroke risk. Efforts to test this hypothesis would represent a significant step toward more effective management of AF,” they continue.

References

1. Molina CE, Leroy J, Richter W, et al. Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias.  JACC 2012:59;2182–90. doi: 10.1016/j.jacc.2012.01.060

2. Van Wagoner DR, Lindsay BD. Phosphodiesterase-4 activity: a critical modulator of atrial contractility and arrhythmogenesis. JACC 2012:59;2191–2. doi: 10.1016/j.jacc.2012.03.027

Published on: June 25, 2012

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ENDORSED BY

  • ArrhythmiaAlliance
  • Stars
  • Anticoagulation Europe
  • Atrial Fibrillation Association
 

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