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    Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline

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    Publication date
    2014-08
    Author
    Benoist, D.
    Stones, R.
    Benson, A.P.
    Fowler, E.D.
    Drinkhill, M.J.
    Hardy, Matthew E.
    Saint, D.A.
    Cazorla, O.
    Bernus, O.
    White, E.
    Keyword
    Systems biology
    Pulmonary artery hypertension
    Mechanosensitivity
    Arrhythmias
    Monocrotaline
    Right ventricular failure
    Peer-Reviewed
    yes
    
    Metadata
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    Abstract
    We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.
    URI
    http://hdl.handle.net/10454/16504
    Version
    No full-text in the repository
    Citation
    Benoist D, Stones R, Fowler ED, Drinkhill MJ, Hardy ME, Saint DA, Cazorla O, Bernus O and White E (2014) Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline. Progress in Biophysics and Molecular Biology. 115 (2–3): 162-172.
    Link to publisher’s version
    https://doi.org/10.1016/j.pbiomolbio.2014.06.008
    Type
    Article
    Collections
    Life Sciences Publications

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