title: Acetylcholine-induced shortening of the epicardial action potential duration may increase repolarization gradients and LQT3 arrhythmic risk.
abstract: Unlike other variants of long QT syndrome, LQT3 patients are particularly susceptible to cardiac events during sleep. Changes in heart rate alone fail to fully account for this phenomenon. We hypothesize that the parasympathetic nervous system may play a role in increasing arrhythmic risk in the mammalian ventricular myocardium via acetylcholine (ACh)-mediated effects on repolarisation gradients and, furthermore, that the effects of ACh exhibit rate dependency. Here, we investigate this hypothesis in a mathematical model of action potential generation and excitation-contraction coupling in a canine left ventricular epicardial myocyte, using a previously developed formulation for the muscarinic K(+) current I(K,ACh). Our model was able to reproduce an experimentally observed dose-dependent reduction in canine epicardial action potential duration(90) at 90% repolarization in response to application of ACh. Moreover, our model also predicts a rate-dependent reduction of epicardial APD(90) with the greatest effects occurring at slower rates. This is likely to be due to decreased repolarisation reserve at these rates. Our results suggest that ACh-mediated effects on epicardial myocytes may amplify already steep repolarisation gradients in the mammalian left ventricular wall of LQT3 patients and consequently increase the risk of arrhythmia formation.
authors.affiliation: Oxford University Computing Laboratory, University of Oxford, Oxford, United Kingdom. sarah.flaim@comlab.ox.ac.uk
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Flaim
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage*; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D003198:Computer Simulation; D004285:Dogs; D006801:Humans; D008133:Long QT Syndrome / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular; D032342:Muscle Cells / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D010496:Pericardium / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D000109:Acetylcholine