title: NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure.
abstract: OBJECTIVE
  The study investigates how increased Ito, as mediated by the activator NS5806, affects excitation-contraction coupling in chronic heart failure (HF). We hypothesized that restoring spike-and-dome morphology of the action potential (AP) to a healthy phenotype would be insufficient to restore the intracellular Ca(2) (+) transient (CaT), due to HF-induced remodelling of Ca(2+) handling.
  
  
  RESULTS
  An existing mathematical model of the canine ventricular myocyte was modified to incorporate recent experimental data from healthy and failing myocytes, resulting in models of both healthy and HF epicardial, midmyocardial, and endocardial cell variants. Affects of NS5806 were also included in HF models through its direct interaction with Kv4.3 and Kv1.4. Single-cell simulations performed in all models (control, HF, and HF + drug) and variants (epi, mid, and endo) assessed AP morphology and underlying ionic processes with a focus on calcium transients (CaT), how these were altered in HF across the ventricular wall, and the subsequent effects of varying compound concentration in HF. Heart failure model variants recapitulated a characteristic increase in AP duration (APD) in the disease. The qualitative effects of application of half-maximal effective concentration (EC50) of NS5806 on APs and CaT are heterogeneous and non-linear. Deepening in the AP notch with drug is a direct effect of the activation of Ito; both Ito and consequent alteration of IK1 kinetics cause decrease in AP plateau potential. Decreased APD50 and APD90 are both due to altered IK1. Analysis revealed that drug effects depend on transmurality. Ca(2+) transient morphology changes-increased amplitude and shorter time to peak-are due to direct increase in ICa,L and indirect larger SR Ca(2+) release subsequent to Ito activation.
  
  
  CONCLUSIONS
  Downstream effects of a compound acting exclusively on sarcolemmal ion channels are difficult to predict. Remediation of APD to pre-failing state does not ameliorate dysfunction in CaT; however, restoration of notch depth appears to impart modest benefit and a likelihood of therapeutic value in modulating early repolarization.
authors.affiliation: Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, PO Box 134, Lysaker 1325, Norway mmaleck@simula.no.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Maleckar
authors.affiliation: Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, PO Box 134, Lysaker 1325, Norway Department of Informatics, University of Oslo, PO Box 1072, Oslo 0316, Norway.
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Lines
authors.affiliation: Simula Research Laboratory, Center for Cardiological Innovation and Center for Biomedical Computing, PO Box 134, Lysaker 1325, Norway.
authors.forename: Jussi T
authors.initials: JT
authors.lastname: Koivumäki
authors.affiliation: Department of Experimental Cardiology, Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.affiliation: Department of Veterinary Clinical and Animal Science, University of Copenhagen, Rm. 151, Dyrlægevej 100, Frederiksberg 1870, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
mesh_terms: D000200:Action Potentials; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D003198:Computer Simulation; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007700:Kinetics; D051665:Kv1.4 Potassium Channel / Q000819:agonists / Q000378:metabolism; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D051672:Shal Potassium Channels / Q000819:agonists / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C541204:1-(3,5-bis-trifluoromethylphenyl)-3-(2,4-dibromo-6-(1H-tetrazol-5-yl)phenyl)urea; D051665:Kv1.4 Potassium Channel; D010671:Phenylurea Compounds; D051672:Shal Potassium Channels; D013777:Tetrazoles
keywords: Excitation–contraction coupling; Heart failure; Ito; Modelling and simulation; Pharmacological therapy