title: Modelling changes in transmural propagation and susceptibility to arrhythmia induced by volatile anaesthetics in ventricular tissue.
abstract: Volatile anaesthetics such as halothane, isoflurane and sevoflurane inhibit membrane currents contributing to the ventricular action potential. Transmural variation in the extent of current blockade induces differential effects on action potential duration (APD) in the endocardium and epicardium which may be pro-arrhythmic. Biophysical modelling techniques were used to simulate the functional impact of anaesthetic-induced blockade of membrane currents on APD and effective refractory period (ERP) in rat endocardial and epicardial cell models. Additionally, the transmural conduction of excitation waves in 1-dimensional cell arrays, the tissue's vulnerability to arrhythmogenesis and dynamic behaviour of re-entrant excitation in 2-dimensional cell arrays were studied. Simulated anaesthetic exposure reduced APD and ERP in both epicardial and endocardial cell models. The reduction in APD was greater in endocardial than epicardial cells, reducing transmural APD dispersion consistent with experimental data. However, the transmural ERP dispersion was augmented. All three anaesthetics increased the width of the tissue's vulnerable window during which a premature stimulus could induce unidirectional conduction block but only halothane reduced the critical size of ventricular substrates necessary to initiate and sustain re-entrant excitation. All three anaesthetics accelerated the rate of re-entrant excitation waves, but only halothane prolonged the lifespan of re-entry. These data illustrate in silico, that modest changes in ion channel conductance abbreviate rat ventricular APD and ERP, reduce transmural APD dispersion, but augment transmural ERP dispersion. These changes collectively enhance the propensity for arrhythmia generation and provide a substrate for re-entry circuits with a longer half life than in control conditions.
authors.affiliation: University of Manchester, UK.
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Tao
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kharche
authors.forename: Simon M
authors.initials: SM
authors.lastname: Harrison
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D003198:Computer Simulation; D004699:Endocardium / Q000187:drug effects / Q000503:physiopathology; D006221:Halothane / Q000494:pharmacology; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D007530:Isoflurane / Q000494:pharmacology; D008738:Methyl Ethers / Q000494:pharmacology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects; D010496:Pericardium / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D000077149:Sevoflurane
chemical_list: D000777:Anesthetics; D008738:Methyl Ethers; D000077149:Sevoflurane; D007530:Isoflurane; D006221:Halothane