title: Computational modeling of Takotsubo cardiomyopathy: effect of spatially varying β-adrenergic stimulation in the rat left ventricle.
abstract: In Takotsubo cardiomyopathy, the left ventricle shows apical ballooning combined with basal hypercontractility. Both clinical observations in humans and recent experimental work on isolated rat ventricular myocytes suggest the dominant mechanisms of this syndrome are related to acute catecholamine overload. However, relating observed differences in single cells to the capacity of such alterations to result in the extreme changes in ventricular shape seen in Takotsubo syndrome is difficult. By using a computational model of the rat left ventricle, we investigate which mechanisms can give rise to the typical shape of the ventricle observed in this syndrome. Three potential dominant mechanisms related to effects of β-adrenergic stimulation were considered: apical-basal variation of calcium transients due to differences in L-type and sarco(endo)plasmic reticulum Ca(2+)-ATPase activation, apical-basal variation of calcium sensitivity due to differences in troponin I phosphorylation, and apical-basal variation in maximal active tension due to, e.g., the negative inotropic effects of p38 MAPK. Furthermore, we investigated the interaction of these spatial variations in the presence of a failing Frank-Starling mechanism. We conclude that a large portion of the apex needs to be affected by severe changes in calcium regulation or contractile function to result in apical ballooning, and smooth linear variation from apex to base is unlikely to result in the typical ventricular shape observed in this syndrome. A failing Frank-Starling mechanism significantly increases apical ballooning at end systole and may be an important additional factor underpinning Takotsubo syndrome.
authors.affiliation: Department of Biomedical Engineering, King's College London, London, United Kingdom;
authors.forename: Sander
authors.initials: S
authors.lastname: Land
authors.affiliation: Department of Biomedical Engineering, King's College London, London, United Kingdom;
authors.forename: Steven A
authors.initials: SA
authors.lastname: Niederer
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway;
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway;
authors.forename: Åsmund T
authors.initials: ÅT
authors.lastname: Røe
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway; KG Jebsen Cardiac Research Center and Center for Heart Failure Research, University of Oslo, Oslo, Norway;
authors.forename: Jan Magnus
authors.initials: JM
authors.lastname: Aronsen
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Stuckey
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Markus B
authors.initials: MB
authors.lastname: Sikkel
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom;
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Tranter
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom; National Insitute of Health Research Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom; and.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Lyon
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, United Kingdom; National Insitute of Health Research Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom; and.
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
authors.affiliation: Department of Biomedical Engineering, King's College London, London, United Kingdom; Faculty of Engineering, University of Auckland, Auckland, New Zealand np.smith@auckland.ac.nz.
authors.forename: Nicolas P
authors.initials: NP
authors.lastname: Smith
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D003198:Computer Simulation; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology*; D016014:Linear Models; D019028:Magnetic Resonance Imaging, Cine; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D054549:Takotsubo Cardiomyopathy / Q000378:metabolism / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol
keywords: Takotsubo cardiomyopathy; cardiac modeling; catecholamine overload