Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition.
Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.
Fossa
Anthony A
AA
Pfizer Global Research and Development, Eastern Point Rd., Bldg. 118, MS 4036, Groton, CT 06340, USA. anthony_a_fossa@groton.pfizer.com
Wisialowski
Todd
T
Magnano
Anthony
A
Wolfgang
Eric
E
Winslow
Roxanne
R
Gorczyca
William
W
Crimin
Kimberly
K
Raunig
David L
DL
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D004285:Dogs; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000503:physiopathology*; D009599:Nitroprusside / Q000009:adverse effects; D010656:Phenylephrine / Q000009:adverse effects; D010880:Piperidines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D013610:Tachycardia / Q000139:chemically induced
D000318:Adrenergic beta-Agonists; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C063968:E 4031; D009599:Nitroprusside; D010656:Phenylephrine; D007545:Isoproterenol