Beat-to-beat ECG restitution: A review and proposal for a new biomarker to assess cardiac stress and ventricular tachyarrhythmia vulnerability.

BACKGROUND: Cardiac restitution is the ability of the heart to recover from one beat to the next. Ventricular arrhythmia vulnerability can occur when the heart does not properly adjust to sudden changes in rate or in hemodynamics leading to excessive temporal and/or spatial heterogeneity in conduction or repolarization. Restitution has historically been used to study, by invasive means, the dynamics of the relationship between action potential duration (APD) and diastolic interval (DI) in sedated subjects using various pacing protocols. Even though the analogous measures of APD and DI can be obtained using the surface ECG to acquire the respective QT and TQ intervals for ECG restitution, this methodology has not been widely adopted for a number of reasons. METHODS: Recent development of more advanced software algorithms enables ECG intervals to be measured accurately, on a continuous beat-to-beat basis, in an automated manner, and under highly dynamic conditions (i.e., ambulatory or exercise) providing information beyond that available in the typical resting state. RESULTS: Current breakthroughs in ECG technology will allow ECG restitution measures to become a practical approach for providing quantitative measures of the risks for ventricular arrhythmias as well as cardiac stress in general. CONCLUSIONS: In addition to a review of the underlying principles and caveats of ECG restitution, a new approach toward an advancement of more integrated restitution biomarkers is proposed.

Use of continuous ECG for improvements in assessing the standing response as a positive control for QT prolongation.

BACKGROUND: Standing invoked change in QT interval has been identified as a promising autonomic maneuver for the assessment of QT/QTc prolongation in patients with underlying heart abnormalities or as a positive control in healthy volunteers for drug studies. Criticism for its more widespread use is the high variability in reported results and the need for a more standardized methodology with defined normal ranges. METHODS: Forty healthy male subjects underwent continuous ECG collection on the day before dosing in a double-blind, placebo-controlled, randomized, single ascending dose trial. A brisk supine to standing (3 minutes) response was conducted at three time points. Results were grouped by treatment cohort or assessed as a pooled group at each time point. Maximum time and median change from baseline (ΔTmax QTcF, ΔQTcF) were calculated for each individual over sequential 30-second periods staggered by 5 seconds. RESULTS: Maximum ΔQTcF at all time points and in all groups was significant (i.e., the lower bound of 90% CI was > 5 milliseconds) which is the ICH E14 regulatory requirement for a positive control. Variability of the time to maximum response was also reduced 9-fold by the third time period. CONCLUSIONS: Standing invoked ΔQTcF can be utilized to validate the sensitivity of a study for assessment of the QT interval effect of drugs in early development. The methodology may be used to further improve its diagnostic use of long QT syndromes by reducing the variability and allowing adequate definition of normal limits.

Use of ECG restitution (beat-to-beat QT-TQ interval analysis) to assess arrhythmogenic risk of QTc prolongation with guanfacine.

BACKGROUND: Guanfacine (Intuniv) is a centrally active alpha-2A adrenergic agonist for the new indication of attention-deficit/hyperactivity disorder. QTc (QTcF and QTcNi) was prolonged at both therapeutic (4 mg) and supratherapeutic (8 mg) doses of a thorough QT study even though guanfacine has had a safe clinical history of over 3 million prescriptions for the treatment of hypertension. In an attempt to understand this disparity, retrospective evaluation of the continuous ECG data utilized dynamic beat-to-beat and ECG restitution analyses was performed. METHODS: Sixty healthy subjects using 24-hour Holters were examined in a 3-arm, placebo- and positive-controlled, double-blind crossover study for effects on beat-to-beat QT, TQ, and RR intervals. RESULTS: ECG restitution analyses indicated that, at all time points, a disproportionate effect to increase the TQ interval (rest) occurred more in relationship to each QT interval lengthening resulting in a placebo-adjusted reduced QT/TQ ratio of 21% after 4 mg and 31% after 8 mg (both antiarrhythmic responses). Additionally, the percentage of time and magnitude of stress on the heart, as measured by the upper limits of the QT/TQ ratio, were reduced with guanfacine by 22% to 24%. In contrast to guanfacine, moxifloxacin did not show a significant improvement in any restitution parameters but reflected a trend toward proarrhythmia with an increase in the QT/TQ ratio of up to 11%. CONCLUSION: These results indicate that guanfacine causes a stabilizing effect on cardiac restitution that helps reconcile the clinical evidence for a lack of arrhythmia liability despite apparent increases in typical QT/QTc prolongation measures.

Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects.

This White Paper, written collaboratively by members of the Cardiac Safety Research Consortium from academia, industry, and regulatory agencies, discusses different methods to characterize the QT effects for drugs that have a substantial direct or indirect effect on heart rate. Descriptions and applications are provided for individualized QT-R-R correction, Holter bin, dynamic QT beat-to-beat, pharmacokinetic-pharmacodynamic modeling, and QT assessment at constant heart rate. Most of these techniques are optimally performed using continuous electrocardiogram data obtained in clinical studies designed to characterize a drug's effect on the QT interval. An important study design element is the collection of drug-free data over a range of heart rates seen on treatment. The range of heart rates is increased at baseline by using ambulatory electrocardiogram recordings in addition to those collected under semisupine, resting conditions. Discussions in this study summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further increase our knowledge and understanding of this topic.

Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine.

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure of arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure-response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment.

Transmural dispersion of repolarization as a preclinical marker of drug-induced proarrhythmia.

Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.

Assessing QT prolongation in conscious dogs: validation of a beat-to-beat method.

A model of sling-trained, conscious mongrel dogs instrumented with telemetric arterial pressure transmitters and ECG leads was validated for assessment of the QT-RR interval relationship at clinically used free and total plasma concentrations of positive and negative standards with known outcomes. The beat-to-beat technique for assessing the dynamic boundaries of the individual cardiac cycles was compared to the same data with typically used averaging techniques and corrections applied. Positive standards E-4031, cisapride, terodiline, and terfenadine showed increased sensitivity toward detection at clinically relevant levels when an outlier analysis of beats beyond the normal autonomic boundary is applied. Since methods to correct the QT interval for heart rate are often confounded with changes in autonomic state, a validation of the changes with reflex tachycardia induced by vasodilatation after nitroprusside and reflex bradycardia induced by sudden vasoconstriction with phenylephrine where shown to be differentiated from direct effects of repolarization with E-4031. These changes were also demonstrated to be identical to effects observed in humans after standing or challenged with a similar dose of phenylephrine. The conscious dog is also a sensitive model for studying the arrhythmia liability induced by beat-to-beat changes in cardiac ECG restitution (the relationship between QT and TQ intervals) and hysteresis. However, some caveats based on observations may need to be considered due to inherent differences in QT intervals and sinus arrhythmia between canines and humans.

Assessing QT prolongation in conscious dogs: validation of a beat-to-beat method.

A model of sling-trained, conscious mongrel dogs instrumented with telemetric arterial pressure transmitters and ECG leads was validated for assessment of the QT-RR interval relationship at clinically used free and total plasma concentrations of positive and negative standards with known outcomes. The beat-to-beat technique for assessing the dynamic boundaries of the individual cardiac cycles was compared to the same data with typically used averaging techniques and corrections applied. Positive standards E-4031, cisapride, terodiline, and terfenadine showed increased sensitivity toward detection at clinically relevant levels when an outlier analysis of beats beyond the normal autonomic boundary is applied. Since methods to correct the QT interval for heart rate are often confounded with changes in autonomic state, a validation of the changes with reflex tachycardia induced by vasodilatation after nitroprusside and reflex bradycardia induced by sudden vasoconstriction with phenylephrine where shown to be differentiated from direct effects of repolarization with E-4031. These changes were also demonstrated to be identical to effects observed in humans after standing or challenged with a similar dose of phenylephrine. The conscious dog is also a sensitive model for studying the arrhythmia liability induced by beat-to-beat changes in cardiac ECG restitution (the relationship between QT and TQ intervals) and hysteresis. However, some caveats based on observations may need to be considered due to inherent differences in QT intervals and sinus arrhythmia between canines and humans.

Comparison of Two Highly Automated ECG Algorithms for Detection of Drug-Induced Cardiac Ion Channel Block.

US Food and Drug Administration (FDA) investigators recently demonstrated in a crossover study that early (J-Tpeak c) and late (Tpeak -Tend ) repolarization duration can differentiate selective potassium block with a high arrhythmia risk from multichannel block with lower risk in subjects receiving dofetilide, verapamil, quinidine, or ranolazine. The purpose of this study was to determine if the findings by the FDA using their published software algorithm could be corroborated using an alternative software algorithm for the same metrics and to determine if methodological differences resulted in clinically meaningful differences in interpretation. Exposure-response relationships computed with linear mixed effects models and mean maximal effects on ECG intervals measured by the two algorithms were similar, corroborating the FDA findings, but with some differences in the modeled slopes and magnitude of changes. The alternative software resulted in an average 25% reduction in the 95% confidence intervals of the mixed effects models with generally lower Akaike Information Criterion values.

Points to consider emerging from a mini-workshop on cardiac safety: assessing torsades de pointes liability.

A mini-workshop on cardiac safety focusing on assessing drug-induced Torsades de Pointes (TdP) liability was convened as part of the 6th Annual Meeting of the Safety Pharmacology Society. The purpose of this brief publication is to disseminate the salient points emanating from this workshop as a means of engaging the scientific community in the appropriate discussions needed to advance this important field of human safety. The recommendations in this publication extend those of the workshop on "Moving Towards Better Predictors of Drug-Induced Torsades de Pointes" held in November 2005 under the auspice of the International Life Sciences Institute, Health and Environmental Sciences Institute; they fall into four key areas: molecular and cellular biology underlying TdP, dynamics of periodicity, models of TdP proarrhythmia and key considerations for demonstrating utility of non-clinical models. The reader is encouraged to consider the recommendations emanating from the two workshops and align these with ongoing studies in their laboratories. The authors intend to convene a workshop in 2009/2010 to judge advancements in the field of study of drug-induced TdP and make recommendations for a focused validation of those methods holding the greatest promise of improving the predictivity of this unwanted human cardiac risk.

Electrical alternans and hemodynamics in the anesthetized guinea pig can discriminate the cardiac safety of antidepressants.

INTRODUCTION: The arrhythmogenic risk of fluoxetine, citalopram, and venlafaxine were evaluated through preclinical assays measuring hERG, blood pressure and electrical alternans over their respective clinical unbound concentration ranges. METHODS: Anesthetized guinea pigs were instrumented with jugular and carotid cannulae for drug infusion and blood pressure monitoring respectively; a thoracotomy was performed for placement of a monophasic action potential probe on the left ventricle and for placement of pacing wires on the left ventricular apex. Drugs were infused as a 5-min loading dose immediately followed by a 10-min maintenance dose to achieve clinically relevant plasma concentrations; blood samples were taken at the end of each maintenance dose. Ventricular pacing was performed twice at baseline and at each dose level as follows: 50 preconditioning-beats at S1=220 (or 240) ms immediately followed by 30 test-beats at S2=200 ms. This S1-S2 protocol was repeated for S2=190 to 140 ms. HERG and calcium current measurements were recorded in HEK-293 cells stably expressing hERG potassium currents and freshly isolated guinea pig cardiac myocytes using the whole-cell configuration of the patch clamp technique. RESULTS: Physiologically relevant inhibition (IC(20)) of hERG occurred at concentrations 22-fold (fluoxetine), 9-fold (citalopram), and 11-fold (venlafaxine) beyond their respective clinically effective concentration (C(eff)). At the highest achievable levels, fluoxetine (20-fold C(eff)) and citalopram (28-fold C(eff)) significantly decreased heart rate and/or blood pressure as well as increasing electrical alternans by 5 and 18 ms respectively. Venlafaxine increased blood pressure at only 1.3-fold C(eff), but did not increase electrical alternans at the highest achievable dose (3.1-fold C(eff)). DISCUSSION: These data suggest that evaluating other dose limiting side effects in relation to a drug's therapeutic range may be crucial for accurate assessment of arrhythmia liability.

The impact of drug-induced QT interval prolongation on drug discovery and development.

During the past decade, a number of non-cardiovascular drugs have had their label revised or have been withdrawn from the market because of unexpected post-marketing reports of sudden cardiac death associated with a prolongation of the QT interval, and an increased propensity to develop a ventricular tachyarrhythmia called Torsades de Pointes. Although a direct link between QT interval prolongation and arrhythmogenesis is still unclear, QT prolongation is now the subject of increased regulatory review and is considered a significant risk factor for predicting human safety of New Chemical Entities. Consequently, pharmaceutical companies are striving to improve the drug discovery and development process to identify, as early as possible, the risk of novel agents, or their metabolites, of causing QT interval prolongation and to make appropriate go/no-go decisions or modify their development programme accordingly.

Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig.

Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies

Improving the precision of QT measurements.

BACKGROUND: Accurate and precise QT interval measurement is very important for both regulatory and drug developmental decision making. These measurements are often made using a manual or semi-automated technique, and the associated variability necessitates sample sizes of around 50 to 70 subjects in thorough QT/QTc studies. The purpose of this study was to compare the reproducibility and precision of a semi-automated (SA) method and a high-precision (HPQT) technique for ECG extraction and QT interval measurement on two thorough QT/QTc (TQT) studies conducted in compliance with ICH E14. METHODS: Data from 35 healthy subjects from two different crossover TQT studies on treatment with placebo and moxifloxacin was analyzed. Both methods examined the RR and QT intervals measured in lead II or the lead with the highest quality T-wave on a single beat basis using the QT algorithm included in the COMPAS software package. ECGs were measured at a protocol-specific timepoint. RESULTS: The effect of moxifloxacin on the QTc interval was highly reproducible in the two studies, and assay sensitivity was met with both methods. Pairwise comparison of QTcF values between methods demonstrated high agreement with no bias, small mean differences (below 1.5 ms) and narrow limits of agreement. HPQT improved the precision of the QTc measurement by 31% in Study I (standard deviation of DQTcF: SA 8.9 ms; HPQT 6.3 ms) and by 15% in Study II (SD: SA 9.7 ms; HPQT 8.3 ms). CONCLUSIONS: The HPQT QT measurement technique detected the effect induced by moxifloxacin with the same accuracy as SA techniques, and with clearly improved precision. More precise QTc measurement has important implications in terms of lowering the likelihood of false positive results and/or reducing the sample size in TQT studies, as well as improving the utility of QT assessment in early clinical development.

Assessing QT prolongation and electrocardiography restitution using a beat-to-beat method.

Historically, the heart rate corrected QT (QTc) interval has been the standard method to assess for impaired ventricular repolarization, particularly for drug development. However, QTc does not reflect changes in autonomic state or QT-RR hysteresis which can also affect the interpretation of arrhythmogenic risk. With the advent of more accurate algorithms to automatically measure the QT interval from continuously collected digital ECG data, usage of heart rate corrected functions is no longer necessary. The dynamic beat-to-beat QT interval method compares the QT interval to individual cardiac cycles from all normal autonomic states at similar RR intervals, thus eliminating the need for correction functions. The upper 97.5% reference boundary of these beat-to-beat QT interval values is defined across the entire 24-hour RR interval range. Beats with QT intervals exceeding this limit are flagged as outlier beats for further arrhythmia vulnerability assessment. The same beat-to-beat technique can also be used to assess the QT-TQ interval relationship known as ECG restitution. This analysis potentially provides an additional means to quantify cardiac stress or arrhythmia vulnerability as the heart works more in relationship to each rest cycle.

Azithromycin/chloroquine combination does not increase cardiac instability despite an increase in monophasic action potential duration in the anesthetized guinea pig.

Prolongation of the electrocardiogram QT interval by some, but not all drugs, has been associated with increased incidence of sudden cardiac death. Current preclinical regulatory assays cannot discriminate the arrhythmia liability of these drugs. Consequently, many new medications that prolong the QT interval are not developed despite their potential therapeutic benefit. Alternans (action potential duration alternations) is a measure of cardiac instability in humans and animals associated with the onset of ventricular fibrillation. Due to potential arrhythmia risk from observed QT prolongation, alternans was assessed in the anesthetized guinea pig after azithromycin or chloroquine alone and after combination treatment at clinically relevant concentrations proposed for the management of malaria. Chloroquine alone, but not azithromycin, caused a profound increase in action potential duration but with only minimal effects on alternans (approximately 10 ms). Azithromycin alone and in combination with chloroquine showed no increase in alternans beyond vehicle baseline responses indicating no additional arrhythmia liability.

Analyses of dynamic beat-to-beat QT-TQ interval (ECG restitution) changes in humans under normal sinus rhythm and prior to an event of torsades de pointes during QT prolongation caused by sotalol.

BACKGROUND: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat-to-beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm. METHODS: The QT, R-R and TQ intervals were examined 22.5 hour Holter monitoring before and after oral sotalol in normal male and female volunteers. Additionally, comparisons were made to those observed in the time-matched dataset prior to torsades de pointes in a heart diseased patient that received a single dose of sotalol. RESULTS: Sotalol increased QT, R-R and TQ intervals 71, 101, and 125 ms after 160 mg (n = 38) and 194, 235, and 135 ms after 320 mg (n = 19) during maximum plasma concentrations, respectively. The percentage of beats with a QT/TQ ratio >1 was reduced 25% over the entire 22.5 hours after sotalol and the lower TQ interval boundary (5th quantile) was increased 22-30%. In contrast, 99% of the beats prior to torsades de pointes had a QT/TQ ratio > 1 and the median TQ interval was below the lower 98% confidence bounds of normals before and after sotalol. CONCLUSIONS: ECG restitution changes are quantifiable under varying states (nocturnally, beta-adrenergic blockade, QT prolongation) in healthy subjects.

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.

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.

Differentiation of arrhythmia risk of the antibacterials moxifloxacin, erythromycin, and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability.

Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á-go-go-related gene (hERG) with IC20 concentrations of 31 microM (moxifloxacin), 21 microM (erythromycin), and 11 microM (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 microM). Erythromycin also increased MAPD at its highest free drug concentration (58 microM), but alternans occurred at a relatively lower therapeutic multiple (13.9 microM), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 microM). The relative risk at therapeutic concentrations is erythromycin>moxifloxacin>telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

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.