Computer simulations to investigate the causes of T-wave notching.
Drugs that cause strong hERG potassium channel block (e.g., dofetilide, quinidine) cause T-wave notching. It has been suggested that this is due to prolongation of mid-myocardial (M) cells' action potential duration relative to endocardial and epicardial cells. However, the role of M cells in intact human hearts is debated. We simulated 2025 electrocardiograms representing changes in ventricular action potentials using the equivalent double layer mode that does not include M-cells. Action potential changes included prolongation, triangularization, squaring, and bumps in late repolarization, which have been observed experimentally and in single cell models with block of the hERG potassium channel. Changes were applied globally and spatially dispersed. Action potential bumps (slowing in late repolarization) produced T-wave notching similar to that observed clinically in healthy subjects receiving dofetilide or quinidine. Conversely, all other action potential changes (i.e., prolongation, triangularization, squaring), either global or spatially dispersed, resulted in T-wave changes, but did not cause T-wave notching. This study demonstrates that M-cells are not required to simulate T-wave notching.
US Food and Drug Administration, Silver Spring, MD, USA. Electronic address: Loriano.galeotti@fda.hhs.gov.
Loriano
L
Galeotti
Radboud University, Nijmegen, the Netherlands; UCLA, Los Angeles, CA, USA.
Peter M
PM
van Dam
US Food and Drug Administration, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Lars
L
Johannesen
US Food and Drug Administration, Silver Spring, MD, USA; BSICoS Group, I3A, IIS Aragón, University of Zaragoza, Zaragoza, Spain.
Jose
J
Vicente
US Food and Drug Administration, Silver Spring, MD, USA.
David G
DG
Strauss
D000200:Action Potentials / Q000502:physiology*; D003198:Computer Simulation; D004562:Electrocardiography / Q000379:methods*; D006329:Heart Conduction System / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000503:physiopathology*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology*
Action potential; ECG; M-cells; Simulation; T-wave notch; hERG block