title: Persistent increases in Ca(2+) influx through Cav1.2 shortens action potential and causes Ca(2+) overload-induced afterdepolarizations and arrhythmias.
abstract: Persistent elevation of Ca(2+) influx due to prolongation of the action potential (AP), chronic activation of the β-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca(2+) influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the β2a subunit of Cav (Cavβ2a). DTG myocytes had increased L-type Ca(2+) current (ICa-L), myocyte shortening, and Ca(2+) transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca(2+) influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca(2+) overload, diastolic Ca(2+) sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca(2+) overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities.
authors.affiliation: Daping Hospital, The Third Military Medical University, Chongqing, China.|Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.|School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, 200240, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ai
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.affiliation: College of Medicine, University of Central Florida, Orlando, FL, 32827, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Harris
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Szeto
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.|The Second Artillery General Hospital, Beijing, 100088, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: MedThink SciCom, Raleigh, NC, 27609, USA.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
authors.affiliation: Center for Translational Medicine and Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, 45229, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Daping Hospital, The Third Military Medical University, Chongqing, China. xchen001@temple.edu.|Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA, 19140, USA. xchen001@temple.edu.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: C491528:Cacnb2 protein, mouse; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D002118:Calcium
keywords: Afterdepolarizations; L-type calcium channel or Cav1.2; Potassium currents; Short QT; β2a subunit