title: QT prolongation modifies dynamic restitution and hysteresis of the beat-to-beat QT-TQ interval relationship during normal sinus rhythm under varying states of repolarization.
abstract: The analysis of cardiac electrical restitution (the relationship between an action potential duration and its preceding diastolic interval) has been used to predict arrhythmia liability. However, the procedure to measure restitution is invasive and disrupts normal physiological autonomic balance. Dynamic analysis of sequential beat-to-beat ECG data was used to study restitution under normal sinus rhythm and to quantify changes in temporal hysteresis with heart rate acceleration/deceleration during QT prolongation. Congenital long QT (LQT) 1 and LQT2 syndromes during sympathetic stimulation were modeled because of their association with increased risk of ventricular arrhythmia. Temporal heterogeneity and hysteresis of restitution were examined in the conscious dog under varying conditions of delayed repolarization using either the selective inhibitors of the slowly activating delayed rectifier potassium current (R)-2-(4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide (L-768,673); the rapidly activating delayed rectifier potassium current (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methyl-sulfonylaminobenzoyl)-piperidine (E-4031); or a combination of both at rest and during heart rate acceleration with sympathetic stimulation using isoproterenol challenges. Impaired repolarization with the combination of E-4031 and L-768,673 increased heterogeneity of restitution at rest 55 to 91%, increased hysteresis during heart rate acceleration after isoproterenol challenge by approximately 40 to 60%, and dramatically reduced the minimum TQ interval by 72% to only 28 ms. Impaired repolarization alters restitution during normal sinus rhythm and increases hysteresis/heterogeneity during heart rate acceleration following sympathetic stimulation. Thus, dynamic beat-to-beat measurements of restitution could lead to clinically applicable ECG obtained biomarkers for assessment of changes associated with arrhythmogenic risk.
authors.affiliation: Pfizer Global Research and Development, Groton, CT 06340, USA. anthony.a.fossa@pfizer.com
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fossa
authors.forename: Todd
authors.initials: T
authors.lastname: Wisialowski
authors.forename: Kimberly
authors.initials: K
authors.lastname: Crimin
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D001570:Benzodiazepinones / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D008133:Long QT Syndrome / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000889:Anti-Arrhythmia Agents; D001570:Benzodiazepinones; C109598:L 768673; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C059983:potassium channel protein I(sk); C063968:E 4031