title: Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline.
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, [Ca(2+)]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca(2+)-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.
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK; L'Institut de Rythmologie et Modelisation Cardiaque, INSERM U1045, Université de Bordeaux, France.
authors.forename: David
authors.initials: D
authors.lastname: Benoist
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Stones
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Benson
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Ewan D
authors.initials: ED
authors.lastname: Fowler
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Drinkhill
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK; Faculty of Life Sciences, University of Manchester, UK.
authors.forename: Matthew E L
authors.initials: ME
authors.lastname: Hardy
authors.affiliation: School of Medical Sciences, University of Adelaide, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Saint
authors.affiliation: INSERM U1046, Université Montpellier 1, Université Montpellier 2, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Cazorla
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK; L'Institut de Rythmologie et Modelisation Cardiaque, INSERM U1045, Université de Bordeaux, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bernus
authors.affiliation: Multidisciplinary Cardiovascular Research Centre, University of Leeds, UK. Electronic address: e.white@leeds.ac.uk.
authors.forename: Ed
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D055119:Elastic Modulus; D056966:Excitation Contraction Coupling; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D016686:Monocrotaline; D010812:Physical Stimulation / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D049490:Systems Biology / Q000379:methods; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000503:physiopathology*; D020257:Ventricular Remodeling
chemical_list: D007473:Ion Channels; D016686:Monocrotaline
keywords: Arrhythmias; Mechanosensitivity; Monocrotaline; Pulmonary artery hypertension; Systems Biology