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

Autor: Olivier Bernus, Ewan D. Fowler, Ed White, Rachel Stones, Olivier Cazorla, David A. Saint, Matthew E. L. Hardy, Alan P. Benson, Mark J. Drinkhill, David Benoist
Přispěvatelé: Bibliothèque interuniversitaire de santé (BIUS), Université Paris Descartes - Paris 5 (UPD5), University of Leeds, University of Manchester [Manchester], University of Adelaide, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), cazorla, olivier, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Rok vydání: 2014
Předmět:
medicine.medical_specialty
SERCA
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Hypertension
Pulmonary
Ventricular Dysfunction
Right
Biophysics
030204 cardiovascular system & hematology
Arrhythmias
Mechanotransduction
Cellular
Article
Mechanosensitivity
Ion Channels
TRPC1
03 medical and health sciences
0302 clinical medicine
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Heart Conduction System
Internal medicine
Elastic Modulus
Physical Stimulation
medicine
[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Ventricular outflow tract
Myocyte
Animals
Rats
Wistar
Ventricular remodeling
Pulmonary artery hypertension
Molecular Biology
Excitation Contraction Coupling
030304 developmental biology
0303 health sciences
Monocrotaline
Ventricular Remodeling
Chemistry
Systems Biology
Arrhythmias
Cardiac
medicine.disease
[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Rats
Heart failure
Cardiology
Mechanosensitive channels
Stress
Mechanical
Electrical conduction system of the heart
Ion Channel Gating
Zdroj: Progress in Biophysics and Molecular Biology
Progress in Biophysics and Molecular Biology, 2014, 115 (2-3), pp.162-172. ⟨10.1016/j.pbiomolbio.2014.06.008⟩
Progress in Biophysics and Molecular Biology, Elsevier, 2014, 115 (2-3), pp.162-172. ⟨10.1016/j.pbiomolbio.2014.06.008⟩
ISSN: 0079-6107
DOI: 10.1016/j.pbiomolbio.2014.06.008
Popis: International audience; 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.
Databáze: OpenAIRE
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