title: Calcium release near L-type calcium channels promotes beat-to-beat variability in ventricular myocytes from the chronic AV block dog.
abstract: Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca(2+) handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca(2+) handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca(2+) release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca(2+)]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca(2+) release increased both APD and BVR. Inhibition of Ca(2+) release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na(+)/Ca(2+) exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca(2+). Buffering of Ca(2+) transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca(2+) transients modulated BVR to a larger extent than the cytosolic Ca(2+) transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca(2+) release, which may act through modulation of the l-type Ca(2+) current in a subsarcolemmal microdomain.
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium; Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands; Department of Physiology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Johnson
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Eef
authors.initials: E
authors.lastname: Dries
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Demetrio J
authors.initials: DJ
authors.lastname: Santiago
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium; Department of Biophysics, Akdeniz University, Antalya, Turkey.
authors.forename: Semir
authors.initials: S
authors.lastname: Ozdemir
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Lenaerts
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Jet D M
authors.initials: JD
authors.lastname: Beekman
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Marien J C
authors.initials: MJ
authors.lastname: Houtman
authors.affiliation: Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven (University of Leuven), Leuven, Belgium. Electronic address: karin.sipido@med.kuleuven.be.
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.affiliation: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D054537:Atrioventricular Block / Q000378:metabolism* / Q000503:physiopathology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002908:Chronic Disease; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D002118:Calcium
keywords: Action potential; Calcium handling; Proarrhythmia; Remodeling; Repolarization variability