Phosphodiesterase-4 Activity A Critical Modulator of Atrial Contractility and Arrhythmogenesis
Departments of Molecular Cardiology and Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.Journal of the American College of Cardiology (Impact Factor: 15.34). 06/2012; 59(24):2191-2. DOI: 10.1016/j.jacc.2012.03.027
Article: Highlights of the Year in JACC 2012Journal of the American College of Cardiology 01/2013; 61(3):357-385. DOI:10.1016/j.jacc.2012.12.002 · 15.34 Impact Factor
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ABSTRACT: -Atrial fibrillation (AF) risk has been associated with "leaky" ryanodine receptor (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca binding protein calsequestrin (Casq2) display an increased risk for AF. Here we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy. -Compared to wild-type mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2(-/-) mice and in isolated Casq2(-/-) hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein (PV) region. Ca and voltage mapping demonstrated sub-threshold diastolic Ca elevations (SCaE) and delayed afterdepolarizations (DADs) whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R-propafenone (3μM) significantly reduced frequency and amplitude of SCaE and DADs in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaE and DADs and failed to prevent AF. -Loss of Casq2 increases risk of AF by promoting regional SCaE and DADs in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF due to "leaky" RyR2 Ca channels with R-propafenone may be a more mechanism-based approach to treating this common arrhythmia.Circulation Arrhythmia and Electrophysiology 02/2014; 7(2). DOI:10.1161/CIRCEP.113.000994 · 5.42 Impact Factor
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