title: Interactive effect of beta-adrenergic stimulation and mechanical stretch on low-frequency oscillations of ventricular action potential duration in humans.
abstract: Ventricular repolarization dynamics are crucial to arrhythmogenesis. Low-frequency oscillations of repolarization have recently been reported in humans and the magnitude of these oscillations proposed to be a strong predictor of sudden cardiac death. Available evidence suggests a role of the sympathetic nervous system. We have used biophysically detailed models integrating ventricular electrophysiology, calcium dynamics, mechanics and β-adrenergic signaling to investigate the underlying mechanisms. The main results were: (1) Phasic beta-adrenergic stimulation (β-AS) at a Mayer wave frequency between 0.03 and 0.15Hz resulted in a gradual decrease of action potential (AP) duration (APD) with concomitant small APD oscillations. (2) After 3-4minutes of phasic β-AS, the mean APD adapted and oscillations of APD became apparent. (3) Phasic changes in haemodynamic loading at the same Mayer wave frequency (a known accompaniment of enhanced sympathetic nerve activity), simulated as variations in the sarcomere length, also induced APD oscillations. (4) The effect of phasic β-AS and haemodynamic loading on the magnitude of APD oscillations was synergistic. (5) The presence of calcium overload and reduced repolarization reserve further enhanced the magnitude of APD oscillations and was accompanied by afterdepolarizations and/or spontaneous APs. In conclusion, low-frequency oscillations of repolarization recently reported in humans were induced by phasic β-AS and phasic mechanical loading, which acted synergistically, and were greatly enhanced by disease-associated conditions, leading to arrhythmogenic events.
authors.affiliation: Biomedical Signal Interpretation and Computational Simulation (BSICoS) group, Aragón Institute of Engineering Research, IIS Aragón, University of Zaragoza, Edificio I+D+i, C/ Mariano Esquillor s/n, 50018 Zaragoza, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, pabellón 11, planta 0, 28029 Madrid, Spain. Electronic address: epueyo@unizar.es.
authors.forename: Esther
authors.initials: E
authors.lastname: Pueyo
authors.affiliation: Institute of Cardiovascular Science, University College London, Gower Street, WC1E 6BT London, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Orini
authors.affiliation: LaBS, Department of Chemistry, Materials and Chemical Engineering 'Giulio Nata', Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milano, Italy.
authors.forename: José F
authors.initials: JF
authors.lastname: Rodríguez
authors.affiliation: Institute of Cardiovascular Science, University College London, Gower Street, WC1E 6BT London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Taggart
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D055724:Electrophysiological Phenomena; D006352:Heart Ventricles / Q000187:drug effects*; D006439:Hemodynamics; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D013314:Stress, Mechanical; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium
keywords: Arrhythmogenesis; Calcium overload; Computer modeling.; Mechanical stretch; Ventricular repolarization oscillations; beta-Adrenergic stimulation