QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.105.095471v1 316/2/498    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fossa, A. A. Articles by Crimin, K. Search for Related Content PubMed PubMed Citation Articles by Fossa, A. A. Articles by Crimin, K.

CARDIOVASCULAR

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

Pfizer Global Research and Development, Groton, Connecticut

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.

Address correspondence to: Dr. Anthony A. Fossa, Pfizer Global Research and Development, Eastern Point Rd., Bldg. 118E, MS 4036, Groton, CT 06340. E-mail: anthony.a.fossa{at}pfizer.com

This article has been cited by other articles:

				M. Sala, M. Lazzaretti, G. De Vidovich, E. Caverzasi, F. Barale, G. d'Allio, and P. Brambilla Electrophysiological changes of cardiac function during antidepressant treatment Therapeutic Advances in Cardiovascular Disease, February 1, 2009; 3(1): 29 - 43. [Abstract] [PDF]

				E. Pueyo, J. P. Martinez, and P. Laguna Cardiac repolarization analysis using the surface electrocardiogram Phil Trans R Soc A, January 28, 2009; 367(1887): 213 - 233. [Abstract] [Full Text] [PDF]