Mode of QT correction for heart rate: Implications for the detection of inhomogeneous repolarization after myocardial infarction

Todt, Hannes; Krumpl, Günther; Krejcy, Kurt; Raberger, G.

doi:10.1016/0002-8703(92)90266-x

Cited by 22 publications

(4 citation statements)

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“…It should be noted that Bazett's formula overestimates the actual values at short RR intervals, while underestimating them at long RR intervals in humans (see 30 for review) and dogs. 45, 46 Without entering into the remaining controversies regarding which QTc correction to use in which experimental setting, the following should be noted: (1) the Matsunaga formula 32 has been found preferable to Bazett for testing QTc prolongation in beagle dogs and likely other breeds; (2) despite the first point, the QTc prolongation with the Bazett formula in the combined AC1/HCN2 biological pacemaker setting (at cycle lengths < 600 ms) should call for vigilance in evaluating the occurrence of proarrhythmia either spontaneously or induced via electrophysiological testing; (3) the occurrence of QTc prolongation with overexpressed HCN2/AC1 at low cycle lengths, but not with HCN2/AC1 at higher cycle lengths nor with sole overexpression of AC1 or HCN2 points out the complexity of events that may occur when various gene therapies are administered singly versus together in settings where their impact on a physiologic process is being assessed.…”

Section: Discussionmentioning

confidence: 99%

Ca ²⁺ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

et al. 2012

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Background Biological pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca2+-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes to those with single gene HCN2 transfer. Methods and Results We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches (LBB) of atrioventricular-blocked dogs. During steady-state gene expression (days 5-7), differences between AC1, HCN2/AC1 and HCN2 alone were evident in basal beating rate, escape time, and dependence on electronic back-up pacing. In HCN2, AC1, and HCN2/AC1, these parameters were, respectively: Basal beating rate: 50±1.5bpm, 60±5.0bpm, and 129±28.9bpm (P<0.05 for HCN2/AC1 vs. HCN2 or AC1 alone); Escape time: 2.4±0.2 sec, 1.3±0.2 sec, and 1.1±.0.4sec (P<0.05 for AC1 and HCN2/AC1 vs. HCN2); and % Electronic beats: 34±8%, 2±1%, and 6±2% (P<0.05 for AC1 and HCN2/AC1 vs. HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability (HRV) and circadian rhythm analyzed via 24h Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 as well as a high degree of sympathetic modulation in animals injected with HCN2/AC1. Conclusions AC1 or HCN2/AC1 overexpression in LBB provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.

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Section: Discussionmentioning

confidence: 99%

Ca ²⁺ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

et al. 2012

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“…However, it is also known that some of these correction formulae (e.g., Bazett's) yield misleading data, especially when differences in the heart rate between the treatment and control groups are large [16]. Two correction factors described by Todt et al [17] and Van de Water et al [9] have been identified that more adequately correct QT intervals for changes in heart rate. In this study, KUR-1246 at 10 and 100 µg/kg significantly reduced blood pressure with a concomitant increase in heart rate in conscious dogs.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Effects of KUR-1246, a New Tetrahydronaphthalen Derivative β2-Adrenoceptor Agonist and a Selective Uterine Relaxant

Furihata

Motokawa

Murata

et al. 2011

Arzneimittelforschung

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The aim of this study was to assess the cardiovascular effects of KUR-1246 (CAS 194785-31-4, (-)-bis(2-{[(2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl) phenyl] ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)monosulfate), a new beta2-adrenoceptor agonist tocolytic agent. In conscious dogs, the intravenous administration of KUR-1246 at 0.1 and 1 microg/kg had no effects on blood pressure, heart rate or femoral artery blood flow. KUR-1246 at 10 and 100 microg/kg significantly decreased blood pressure and increased heart rate. In the electrocardiograms, KUR-1246 did not affect QT intervals or QTc. In addition, the cardiac effects of KUR-1246 were evaluated in in vitro electrophysiological studies. KUR-1246 at 10 micromol/L did not affect action potential parameters (the maximal upstroke velocity, resting membrane potential, action potential amplitude and action potential durations) in isolated papillary muscles of guinea pigs or in the human ether-a-go-go related gene (HERG) tail current recorded from stably transfected human embryonic kidney (HEK) 293 cells. On the basis of these results, the effects of KUR-1246 in conscious dogs on the cardiovascular system appear to be limited to changes in blood pressure and heart rate. Therefore, KUR-1246 is unlikely to provoke ventricular arrhythmias by delaying the ventricular repolarization.

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“…(Aomine, 1989). Although the relationship between cardiac repolarization and cycle length becomes hyperbolic if cycle lengths > 1000 ms are included (Aomine, 1989;Surawicz, 1992), linear regression can be fitted equally well to the relationship if only the range of cycle lengths pertinent to this study are considered (Todt et al, 1992b). …”

Section: Analytical Proceduresmentioning

confidence: 96%

Kinetics of rate‐dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

Todt

Zojer

Raberger

1993

British J Pharmacology

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1 The effects of the class I antiarrhythmic agent, tocainide, on intraventricular conduction were assessed in guinea-pigs, anaesthetized with pentobarbitone sodium 60 mg kg', i.p. 2 After electrical ablation of the sinus node, heart rate was controlled by atrial pacing. His bundle electrograms were recorded by means of an epicardial bipolar electrode. administration of 30 mg kg-' tocainide, and 28.04 ± 0.64 ms versus 36.24 ± 1.31 ms (P<0.001), after addition of 20 mg kg-' tocainide. Thus, tocainide caused HV intervals to increase in a strictly ratedependent fashion. 4 In order to characterize the rate-dependent class I activity of tocainide in terms of its binding kinetics to sodium channels, fractional sodium channel block was estimated from drug induced reductions of intraventricular conduction velocity (AO). On abruptly changing the drive cycle length from 500 ms to 250 ms, AO reached a new steady state with rate constants of 1.23 ± 0.09 beat-' and 1.28 ± 0.09 beat ', after administration of 30 mg kg-' and addition of 20 mg kg-' tocainide, respectively. At a basic drive cycle length of 250 ms AO recovered with time constants of 250.29 ± 23.32 ms and 183.04 ± 8.03 ms after administration of 30 mg kg-' and addition of 20 mg kg-tocainide, respectively. 5 The experimentally determined kinetic parameters were implemented into a mathematical model that assumes drug binding to sodium channels in terms of a periodical two-state process. Rate-dependent reductions in conduction velocity during continuous stimulation after administration of tocainide were closely approximated by steady state reductions in sodium channel availability as calculated on the basis of the aforementioned model. 6 In agreement with previously published in vitro studies, our data, obtained in vivo, confirm the classification of tocainide as a class I antiarrhythmic agent with fast onset and offset kinetics. The kinetic parameters obtained in vivo can be used in order to predict steady state reductions in conduction velocity at a wide range of frequencies.

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Mode of QT correction for heart rate: Implications for the detection of inhomogeneous repolarization after myocardial infarction

Cited by 22 publications

References 50 publications

Ca ²⁺ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

Ca ²⁺ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

Cardiovascular Effects of KUR-1246, a New Tetrahydronaphthalen Derivative β2-Adrenoceptor Agonist and a Selective Uterine Relaxant

Kinetics of rate‐dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

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Mode of QT correction for heart rate: Implications for the detection of inhomogeneous repolarization after myocardial infarction

Cited by 22 publications

References 50 publications

Ca 2+ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

Ca 2+ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

Cardiovascular Effects of KUR-1246, a New Tetrahydronaphthalen Derivative β2-Adrenoceptor Agonist and a Selective Uterine Relaxant

Kinetics of rate‐dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo

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Product

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Ca ²⁺ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2

Ca ²⁺ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2