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  1. Article: Measurement, interpretation and clinical potential of QT dispersion.

    Malik, M / Batchvarov, V N

    Journal of the American College of Cardiology

    2000  Volume 36, Issue 6, Page(s) 1749–1766

    Abstract: ... of both automatic and manual measurement of QT dispersion is low and significantly lower than that of the QT ... without adverse outcome. In reality, QT dispersion is a crude and approximate measure of abnormality ... dispersion indices, as well as between different lead systems for their measurement. Reported values of QT ...

    Abstract QT dispersion was originally proposed to measure spatial dispersion of ventricular recovery times. Later, it was shown that QT dispersion does not directly reflect the dispersion of recovery times and that it results mainly from variations in the T loop morphology and the error of QT measurement. The reliability of both automatic and manual measurement of QT dispersion is low and significantly lower than that of the QT interval. The measurement error is of the order of the differences between different patient groups. The agreement between automatic and manual measurement is poor. There is little to choose between various QT dispersion indices, as well as between different lead systems for their measurement. Reported values of QT dispersion vary widely, e.g., normal values from 10 to 71 ms. Although QT dispersion is increased in cardiac patients compared with healthy subjects and prognostic value of QT dispersion has been reported, values are largely overlapping, both between healthy subjects and cardiac patients and between patients with and without adverse outcome. In reality, QT dispersion is a crude and approximate measure of abnormality of the complete course of repolarization. Probably only grossly abnormal values (e.g. > or =100 ms), outside the range of measurement error may potentially have practical value by pointing to a grossly abnormal repolarization. Efforts should be directed toward established as well as new methods for assessment and quantification of repolarization abnormalities, such as principal component analysis of the T wave, T loop descriptors, and T wave morphology and wavefront direction descriptors.
    MeSH term(s) Animals ; Electrocardiography ; Heart Conduction System/physiology ; Heart Conduction System/physiopathology ; Heart Diseases/physiopathology ; Heart Rate ; Humans ; Hypertrophy, Left Ventricular/physiopathology ; Myocardial Infarction/physiopathology ; Prognosis
    Language English
    Publishing date 2000-11-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 605507-2
    ISSN 1558-3597 ; 0735-1097
    ISSN (online) 1558-3597
    ISSN 0735-1097
    DOI 10.1016/s0735-1097(00)00962-1
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1846: Show issues Location:
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    Zs.MO 196: Show issues

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  2. Article: In vivo measurement of QT prolongation, dispersion and arrhythmogenesis: application to the preclinical cardiovascular safety pharmacology of a new chemical entity.

    De Clerck, Fred / Van de Water, André / D'Aubioul, Jan / Lu, Hua Rong / van Rossem, Koen / Hermans, An / Van Ammel, Karel

    Fundamental & clinical pharmacology

    2003  Volume 16, Issue 2, Page(s) 125–140

    Abstract: ... on temporal and transmural dispersion of ventricular repolarization and on incidences of early after ... conduction disturbances) are readily identified. Drug-induced QT dispersion rather than a 'simple' QTc ... activity and ventricular repolarization). Nevertheless, correction of QT with Bazett's formula usually ...

    Abstract In addition to in silico and in vitro measurements, cardiac electrophysiology in experimental animals plays a decisive role in the selection of a potential 'cardio-safe' new chemical entity (NCE). The present synopsis critically reviews such in vivo techniques in experimental animals. In anaesthetized guinea-pigs, surface ECG recordings readily identify the typical effects of Class I to IV anti-arrhythmic compounds and of If blockers such as zatebradine on ECG intervals and morphology, but also of non-cardiovascular NCEs affecting cardiac electrical activity via ion channels or neurogenic mechanisms. QT/RR plots indicate that bradycardia is a dominant effect of IKr blockers (dual modulation by IKr of sinus node activity and ventricular repolarization). Nevertheless, correction of QT with Bazett's formula usually distinguishes between drug-induced heart rate reduction and real prolongation of ventricular repolarization (QTc). The anaesthetized guinea-pig model thus is a useful tool for first line in vivo testing of an NCE for effects on cardiac electrophysiology, in particular when combined with measurements of drug levels in plasma and heart tissues. In anaesthetized dogs, advanced ECG analyses identify drug-induced effects on atrial and ventricular intervals, on temporal and transmural dispersion of ventricular repolarization and on incidences of early after-depolarizations. This can be combined with complete haemodynamic, pulmonary and pharmacokinetic analyses in one preparation. However, compound doses/plasma levels needed for effects on ventricular repolarization in this model are substantially higher than those identified in guinea-pigs, at least for IKr blocking compounds. Therefore, we use this 'information-rich' canine model as a second line approach. In awake, trained and appropriately instrumented dogs, readings of surface ECG in combination with cardio-haemodynamic and behavioural assessments can be performed after the administration of an NCE via the expected therapeutic route, including oral medication. However, at higher doses the compound under scrutiny may induce overall behavioural side-effects, related to its primary pharmacological action, such as gastrokinetic repercussions or CNS-mediated sedation or excitation. Such primary pharmacological effects are bound to compromise the evaluation of real drug-induced changes on cardiac electrophysiology, readily identified by resource-friendly setups in smaller animals. Therefore, we use such paradigms as an imperative, final cardiovascular check-up, before a 'First in Man' administration of the NCE. In anaesthetized, methoxamine-challenged rabbits, arrhythmogenic effects of IKr blockers (torsades de pointes) and of dual channel INa/IKr blockers (conduction disturbances) are readily identified. Drug-induced QT dispersion rather than a 'simple' QTc prolongation determines the ventricular arrhythmogenic effect of IKr blockers. The latter effect also depends on the rate of drug delivery (plasma levels vs. heart level, equilibrium throughout the myocardium). Therefore, we use models sensitized for arrhythmogenesis to document further the profile of a comparatively 'cardio-safe' NCE. We conclude that the interpretation of an integrated profile of activity of an NCE on in vitro and in vivo cardiovascular parameters, in comparison with the characteristics of its primary pharmacology and target disease, determines its eventual selection via a scientific, rather than a 'checklist' or 'menu' approach to cardiovascular safety pharmacology. Appropriate tests in experimental animals play a key role in this process.
    MeSH term(s) Animals ; Anti-Arrhythmia Agents/adverse effects ; Drug Evaluation, Preclinical/methods ; Drugs, Investigational/adverse effects ; Electrophysiology/methods ; Long QT Syndrome/chemically induced ; Models, Animal ; Torsades de Pointes/chemically induced
    Chemical Substances Anti-Arrhythmia Agents ; Drugs, Investigational
    Language English
    Publishing date 2003-02-21
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 639134-5
    ISSN 1472-8206 ; 0767-3981
    ISSN (online) 1472-8206
    ISSN 0767-3981
    DOI 10.1046/j.1472-8206.2002.00081.x
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    Zs.A 2247: Show issues Location:
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  3. Article ; Online: Predicting drug-induced QT prolongation and torsades de pointes: a review of preclinical endpoint measures.

    Townsend, Claire / Brown, Barry S

    Current protocols in pharmacology

    2013  Volume Chapter 10, Page(s) Unit 10.16

    Abstract: ... variability, transmural dispersion of repolarization, and field potential duration, are described ... Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and ... this unit discusses approaches that can predict QT effects prior to undertaking clinical ...

    Abstract Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpretation is also discussed. In addition, endpoint measures of the integrated activity of cardiac ion channels at the single-cell, tissue, and whole-animal level, including for example the well-established action potential to the more recent beat-to-beat variability, transmural dispersion of repolarization, and field potential duration, are described in the context of their ability to predict QT prolongation and torsadogenicity in humans.
    MeSH term(s) Drug Evaluation, Preclinical/methods ; Heart/drug effects ; Humans ; Long QT Syndrome/chemically induced ; Predictive Value of Tests ; Prescription Drugs/adverse effects ; Torsades de Pointes/chemically induced
    Chemical Substances Prescription Drugs
    Language English
    Publishing date 2013-06
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1934-8290
    ISSN (online) 1934-8290
    DOI 10.1002/0471141755.ph1016s61
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  4. Article: The added diagnostic value of automated QT-dispersion measurements and automated ST-segment deviations in the electrocardiographic diagnosis of acute cardiac ischemia.

    Aufderheide, T P / Xue, Q / Dhala, A A / Reddy, S / Kuhn, E M

    Journal of electrocardiology

    2000  Volume 33, Issue 4, Page(s) 329–339

    Abstract: ... This study supports a potential clinical role for automated QT dispersion when combined with other diagnostic ... The purpose of this study was to determine the added value of automated QT dispersion and ST ... the clinical use of QT dispersion. Twelve-lead ECGs (n = 1,161) from the Milwaukee Prehospital Chest Pain ...

    Abstract The purpose of this study was to determine the added value of automated QT dispersion and ST-segment measurements to physician interpretation of 12-lead electrocardiograms (ECGs) in patients with chest pain. To date, poor reproducibility of manual measurements and lack of shown added value have limited the clinical use of QT dispersion. Twelve-lead ECGs (n = 1,161) from the Milwaukee Prehospital Chest Pain Database were independently classified by 2 physicians into 3 groups (acute myocardial infarction (AMI), acute cardiac ischemia (ACI), or nonischemic), and their consensus was obtained. QT-end and QT-peak dispersions were measured by a computerized system. The computer also identified ST-segment deviations. Sensitivity, specificity, and positive predictive values (PPVs) and negative predictive values (NPV) for AMI and ACI were evaluated independently and in combinations. For AMI, physicians' consensus classification was remarkably good (sensitivity, 48%, specificity, 99%). Independent classification by QT-end and QT-peak dispersions or ST deviations was not superior to the physicians' consensus. Optimal classification occurred by combining automated QT-end dispersion and ST deviations with physicians' consensus. This combination increased sensitivity for the diagnoses of AMI by 35% (65% vs 48%, P < .001) and ACI by 55% (62% vs 40%, P < .001) compared with physicians' consensus, while maintaining comparable specificity. This study supports a potential clinical role for automated QT dispersion when combined with other diagnostic methods for detecting AMI and ACI.
    MeSH term(s) Adolescent ; Adult ; Angina Pectoris/diagnosis ; Chest Pain/diagnosis ; Data Interpretation, Statistical ; Diagnosis, Differential ; Electrocardiography/methods ; Female ; Humans ; Male ; Middle Aged ; Myocardial Infarction/diagnosis ; Myocardial Ischemia/diagnosis ; Sensitivity and Specificity ; Signal Processing, Computer-Assisted
    Language English
    Publishing date 2000-02-23
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 410286-1
    ISSN 1532-8430 ; 0022-0736
    ISSN (online) 1532-8430
    ISSN 0022-0736
    DOI 10.1054/jelc.2000.18358
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    Zs.A 701: Show issues Location:
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