title: Phosphodiesterase4D (PDE4D)--A risk factor for atrial fibrillation and stroke?
abstract: Mutations in the gene encoding phosphodiesterase 4D (PDE4D) enzyme are associated with ischemic stroke; however the functional implications of such mutations are not well understood. PDE4D is part of a complex protein family modulating intracellular signalling by cyclic nucleotides. The PDE4 family includes subtypes A-D, all of which show unique intracellular, cellular and tissue distribution. PDE4D is the major subtype expressed in human atrial myocytes and involved in the pathophysiology of arrhythmias, such as atrial fibrillation. The PDE4D enzyme hydrolyses cyclic adenosine monophosphate (cAMP). Though diverging results are reported, several population based studies describe association of various PDE4D single nucleotide polymorphisms (SNP) with cardio-embolic stroke in particular. Functionally, a down regulation of PDE4D variants has been reported in stroke patients. The anti-inflammatory and vasodilator properties of PDE4 inhibitors make them suitable for treatment of stroke and cardiovascular disease. PDE4D has recently been suggested as factor in atrial fibrillation. This review summarizes the possible function of PDE4D in the brain, heart, and vasculature. Further, association of the described SNPs, in particular, with cardioembolic stroke, is reviewed. Current findings on the PDE4D mutations suggest functionality involves an increased cardiac risk factor as well as augmented risk of atrial fibrillation.
authors.affiliation: Department of Neurology, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark; Lundbeck Foundation Center for Neurovascular Signaling, Glostrup Research Institute, Glostrup Hospital, Denmark.
authors.forename: Carina
authors.initials: C
authors.lastname: Jørgensen
authors.affiliation: Department of Neurology, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark; Dept. Neurology, Neurovascular Research Unit, Copenhagen, University Hospital Herlev, Denmark.
authors.forename: Saiqa
authors.initials: S
authors.lastname: Yasmeen
authors.affiliation: Department of Neurology, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark; Acute Stroke Unit, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark.
authors.forename: Helle K
authors.initials: HK
authors.lastname: Iversen
authors.affiliation: Lundbeck Foundation Center for Neurovascular Signaling, Glostrup Research Institute, Glostrup Hospital, Denmark; Dept. Neurology, Neurovascular Research Unit, Copenhagen, University Hospital Herlev, Denmark. Electronic address: ckruuse@dadlnet.dk.
authors.forename: Christina
authors.initials: C
authors.lastname: Kruuse
mesh_terms: D001281:Atrial Fibrillation / Q000235:genetics*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D012307:Risk Factors; D020521:Stroke / Q000235:genetics*
chemical_list: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human
keywords: Atrial fibrillation; Cerebrovascular disease; Gene; PDE4D; Phosphodiesterase inhibitors