title: Arrhythmogenic remodeling of β2 versus β1 adrenergic signaling in the human failing heart.
abstract: BACKGROUND
  Arrhythmia is the major cause of death in patients with heart failure, for which β-adrenergic receptor blockers are a mainstay therapy. But the role of β-adrenergic signaling in electrophysiology and arrhythmias has never been studied in human ventricles.
  
  
  RESULTS
  We used optical imaging of action potentials and [Ca(2+)]i transients to compare the β1- and β2-adrenergic responses in left ventricular wedge preparations of human donor and failing hearts. β1-Stimulation significantly increased conduction velocity, shortened action potential duration, and [Ca(2+)]i transients duration (CaD) in donor but not in failing hearts, because of desensitization of β1-adrenergic receptor in heart failure. In contrast, β2-stimulation increased conduction velocity in both donor and failing hearts but shortened action potential duration only in failing hearts. β2-Stimulation also affected transmural heterogeneity in action potential duration but not in [Ca(2+)]i transients duration. Both β1- and β2-stimulation augmented the vulnerability and frequency of ectopic activity and enhanced substrates for ventricular tachycardia in failing, but not in donor, hearts. Both β1- and β2-stimulation enhanced Purkinje fiber automaticity, whereas only β2-stimulation promoted Ca-mediated premature ventricular contractions in heart failure.
  
  
  CONCLUSIONS
  During end-stage heart failure, β2-stimulation creates arrhythmogenic substrates via conduction velocity regulation and transmurally heterogeneous repolarization. β2-Stimulation is, therefore, more arrhythmogenic than β1-stimulation. In particular, β2-stimulation increases the transmural difference between [Ca(2+)]i transients duration and action potential duration, which facilitates the formation of delayed afterdepolarizations.
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Di
authors: D
authors: Lang
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Katherine
authors: K
authors: Holzem
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Chaoyi
authors: C
authors: Kang
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Mengqian
authors: M
authors: Xiao
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Hye Jin
authors: HJ
authors: Hwang
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Gregory A
authors: GA
authors: Ewald
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.).
authors: Kathryn A
authors: KA
authors: Yamada
authors: From the Department of Biomedical Engineering (D.L., K.H., C.K., M.X., H.J.H., I.R.E.) and Department of Medicine (G.A.E., K.A.Y., I.R.E.), Washington University School of Medicine, St. Louis, MO; L'Institut de Rythmologie et Modélisation Cardiaque LIRYC, Université de Bordeaux, Bordeaux, France (I.R.E.); and Moscow Institute of Physics and Technology, Moscow, Russia (I.R.E.). igor@wustl.edu.
authors: Igor R
authors: IR
authors: Efimov
mesh_terms: D000200:Action Potentials; D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D016022:Case-Control Studies; D006333:Heart Failure / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D010766:Phosphorylation; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism*; D012307:Risk Factors; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D056969:Voltage-Sensitive Dye Imaging
chemical_list: C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2
keywords: arrhythmia (mechanisms); calcium; heart failure; receptors, adrenergic