QT Interval

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Marek Malik - One of the best experts on this subject based on the ideXlab platform.

  • QT Interval duration and QT heart rate relationship
    2020
    Co-Authors: Marek Malik, Katerina Hnatkova
    Abstract:

    Abstract The chapter presents the methodology of QT Interval measurement and of the heart rate correction of the QT Interval. It stresses the importance of incorporating the QT/RR hysteresis correction into the analysis of heart rate underlying individual QT values. Based on the analysis of ECG data obtained in 335 healthy females and 416 healthy males, the chapter shows that compared to males, females have longer QT Interval duration especially at slow heart rates while with increasing heart rates, the sex difference in QT duration diminishes. Females also adapt the QT Interval to changing heart rate marginally faster than males and have the QT/RR profiles more curved and steeper than males.

  • errors and misconceptions in ecg measurement used for the detection of drug induced QT Interval prolongation
    Journal of Electrocardiology, 2004
    Co-Authors: Marek Malik
    Abstract:

    Drug-induced changes in cardiac repolarisation receive substantial attention by regulatory agencies. Since there are presently no established accurate possibilities of testing the propensity to torsade induction during clinical drug development, the regulators require drug-related QT Interval changes to be thoroughly investigated with almost all new pharmacological agents. Small QT Interval changes are easy to miss and the regulators therefore expect the relevant studies to be very precise. Such a precision is not easy to achieve and different strategies have been proposed. The purpose of this article is to review the most frequent misconceptions and errors in the electrocardiogram handling and measurements related to the detection to drug-induced QT Interval changes. Specifically, the article discusses (a) the possibilities of automatic measurement by standard electrocardiographic equipment, (b) the danger of casual measurement by central laboratories handling the electrocardiograms, (c) the selection of recording leads for QT Interval measurement, and (d) the problem of the so-called heart rate hysteresis of the QT Interval adaptation. Suggestions are made for drug developers of what study design and quality control aspects are needed to avoid the most frequent imprecisions.

  • the prognostic value of the QT Interval and QT Interval dispersion in all cause and cardiac mortality and morbidity in a population of danish citizens
    European Heart Journal, 1998
    Co-Authors: Hanne Elming, Marek Malik, Ellen Holm, L Jun, C Torppedersen, Lars Kober, M Kircshoff, John Camm
    Abstract:

    Aims. To evaluate the prognostic value of the QT Interval and QT Interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. Methods and results. The QT Interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30–60 years. QT Interval dispersion was calculated from the maximal difference between QT Intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT Interval (430ms or more) or prolonged QT Interval dispersion (80ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT Interval was less than 360ms, or whose QT Interval dispersion was less than 30ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2·9 for the QT Interval (95% confidence Interval 1·1–7·8) and 4·4 for QT Interval dispersion (95% confidence Interval 1·0–19·1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2·7 (95% confidence Interval 1·4–5·5) for the QT Interval and 2·2 (95% confidence Interval 1·1–4·0) for QT Interval dispersion. Conclusion. Prolongation of the QT Interval and QT Interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.

  • agreement and reproducibility of automatic versus manual measurement of QT Interval and QT dispersion
    American Journal of Cardiology, 1998
    Co-Authors: Irina Savelieva, Gang Yi, Katerina Hnatkova, Marek Malik
    Abstract:

    To determine whether the automatic measurement of the QT Interval is consistent with the manual measurement, this study evaluated the reproducibility and agreement of both methods in 70 normal subjects and 54 patients with hypertrophic cardiomyopathy. The mean, minimum, and maximum QT Interval and QT dispersion were computed in a set of 6 consecutive electrocardiograms (3 in the supine and 3 in the standing position) obtained from each subject. The automatic method determined the T-wave end as the intersect of the least-squares-fit line around the tangent to the T-wave downslope with the isoelectric baseline. Manual measurements were obtained using a high-resolution digitizing board. QT dispersion was defined as the difference between the maximum and minimum QT Interval and as standard deviations of the QT Interval duration in all and precordial leads. In patients with hypertrophic cardiomyopathy, the absolute values of the QT Interval and QT dispersion were significantly higher than those in normal subjects (p <0.0001). In both groups, the intrasubject variability of the QT Interval was significantly lower with automatic than with manual measurement (p <0.05). The agreement between automatic and manual QT Interval measurements was surprisingly poor, but it was better in patients with hypertrophic cardiomyopathy (r2 = 0.46 to 0.67) than in normal subjects (r2 = 0.10 to 0.25). In both groups, the reproducibility and agreement of both methods for QT dispersion were significantly poorer than for QT Interval. Hence, the automatic QT Interval measurements are more stable and reproducible than manual measurement, but the lack of agreement between manual and automatic measurement suggests that clinical experience gained with manual assessment cannot be applied blindly to data obtained from the automatic systems.

Rashmi R. Shah - One of the best experts on this subject based on the ideXlab platform.

  • drug induced QT Interval shortening potential harbinger of proarrhythmia and regulatory perspectives
    British Journal of Pharmacology, 2010
    Co-Authors: Rashmi R. Shah
    Abstract:

    ATP-dependent potassium channel openers such as pinacidil and levcromakalim have long been known to shorten action potential duration and to be profibrillatory in non-clinical models, raising concerns on the clinical safety of drugs that shorten QT Interval. Routine non-clinical evaluation of new drugs for their potential to affect cardiac repolarization has revealed that drugs may also shorten QT Interval. The description of congenital short QT syndrome in 2000, together with the associated arrhythmias, suggests that drug-induced short QT Interval may be proarrhythmic, and an uncanny parallel is evolving between our appreciation of the short and the long QT Intervals. Epidemiological studies report an over-representation of short QT Interval values in patients with idiopathic ventricular fibrillation. Therefore, as new compounds that shorten QT Interval are progressed further into clinical development, questions will inevitably arise on their safety. Arising from the current risk-averse clinical and regulatory environment and concerns on proarrhythmic safety of drugs, together with our lack of a better understanding of the clinical significance of short QT Interval, new drugs that substantially shorten QT Interval will likely receive an unfavourable regulatory review unless these drugs fulfil an unmet clinical need. This review provides estimates of parameters of QT shortening that may be of potential clinical significance. Rufinamide, a recently approved anticonvulsant, illustrates the current regulatory approach to drugs that shorten QT Interval. However, to further substantiate or confirm the safety of these drugs, their approval may well be conditional upon large-scale post-marketing studies with a focus on cardiac safety. This article is commented on by Malik, pp. 70–76 of this issue and is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010

  • refining detection of drug induced proarrhythmia QT Interval and triad
    Heart Rhythm, 2005
    Co-Authors: Rashmi R. Shah, Luc M. Hondeghem
    Abstract:

    QT Interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT Interval prolongation, but TdP can occur even in the absence of a prolonged QT Interval. Worse still, even shortening of the QT Interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling Interval and the duration of QT Interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT Interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT Interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or IKr, hERG blockade and the resulting prolongation of QT Interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT Interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT Interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT Interval prolongation alone.

  • The significance of QT Interval in drug development.
    British journal of clinical pharmacology, 2002
    Co-Authors: Rashmi R. Shah
    Abstract:

    The duration of QT Interval of the surface electrocardiogram (ECG) reflects the ventricular action potential duration (APD) which is determined mainly by the rapid component of the outward repolarizing current (IKr). This current is mediated primarily by the delayed rectifying potassium channel. Thus, the QT Interval is congenitally prolonged when this current is diminished as a result of genetic mutations of this channel as for example in the Romano–Ward syndrome [1]. Reduction in this current and hence, the prolongation of the QT Interval may also be acquired, resulting from electrolyte imbalance (especially hypokalaemia and/or hypomagnesaemia), endocrine dysfunction (e.g. hypothyroidism), autonomic imbalance, various disease states or most frequently, following clinical administration of drugs. Drug-induced prolongation of the QTc Interval may be followed by potentially fatal proarrhythmias. More than any other adverse drug reaction in recent times, it has been responsible for the withdrawal of many drugs from the market and yet as a surrogate of proarrhythmias, it is not well understood. Regulatory decisions have resulted in rejection of some new drugs or the restriction on the clinical use of many old and other new drugs over the last decade because of their potential to prolong the QTc Interval. Therefore, there are regulatory and clinical expectations of better preapproval characterization of new chemical entities (NCEs) for this potential risk which have had a very profound influence on drug development. This paper will focus on the issues that need to be addressed during drug development, strategies aimed at identifying this risk during early preclinical and clinical phases of drug development and the regulatory assessment of the potential risk, particularly the electrocardiographic data from the clinical trials. Because the actually measured QT Interval changes with heart rate in the absence of any intervention, it is usual to correct the measured Interval for changes in heart rates (RR Interval) to derive a rate-corrected (QTc) Interval, which is then used when evaluating the effect of an intervention. Clinically, the rate-correction applied most widely, and almost exclusively for years, is the Bazett’s correction (QTc = QT/RR0.50), which divides the measured QT Interval by the square root of the preceding RR Interval. A less frequently applied rate-correction is that of Fridericia (QTc = QT/RR0.33) which divides the measured QT Interval by the cube root of the preceding RR Interval. Both these corrections standardize the measured QT Interval to an RR Interval of 1 s (heart rate of 60 beats min−1). When corrected by Bazett’s formula, on historical and epidemiological grounds, the widely accepted upper limits of normal QTc Interval are 450 ms in adult males, 470 ms in adult females and 460 ms in children between 1 and 15 years of age (regardless of gender). Unless stated otherwise, the QTc Interval referred to in this paper is the Interval as corrected by Bazett’s formula. Drug-induced prolongation of QTc Interval is expected with class III antiarrhythmic drugs which are intended to produce their desired therapeutic benefit by blocking IKr, delaying ventricular repolarization and, therefore, increasing myocardial refractory period. Typical examples of these drugs include sotalol, bretylium, ibutilide, dofetilide, azimilide, sematilide, ambasilide, almokalant, N-acetyl-procainamide, fenoxedil and terikalant.

Raymond L Woosley - One of the best experts on this subject based on the ideXlab platform.

  • Bazett and Fridericia QT correction formulas interfere with measurement of drug-induced changes in QT Interval
    Heart rhythm, 2006
    Co-Authors: Julia H. Indik, Ellen C. Pearson, Karen Fried, Raymond L Woosley
    Abstract:

    Background The QT Interval on the ECG is prolonged by more than 50 marketed drugs, an effect that has been associated with syncope and/or sudden cardiac death due to an arrhythmia. Because changes in heart rate also change the QT Interval, it has become standard practice to use a correction formula, such as the Bazett formula, to normalize the QT Interval to a heart rate of 60 bpm, that is, the rate-corrected QT or QTc. Numerous other formulas have been devised to make this correction, including the Fridericia, Hodges, and Framingham formulas. Objectives The purpose of this study was to investigate how the Bazett formula and three other formulas influence assessment of the QT-prolonging effect of the potassium channel-blocking drug ibutilide. Methods Using a standardized physical activity protocol, the QT Interval was assessed over a broad range of heart rates before and after an infusion of ibutilide (4.75 microg/kg) that produced a stable 15- to 20-ms QT prolongation in consenting normal subjects (9 men and 9 women). The QT Interval was measured digitally over a range of heart rates from 60 to 120 bpm, and then four correction formulas (Bazett, Fridericia, Framingham, or Hodges) were applied. The uncorrected change in QT Interval due to ibutilide was compared with the change using each of the formulas by repeated measures analysis of variance. Results At heart rates from 60 to 120 bpm, the Bazett and Fridericia correction formulas overestimated the change in QT in both men and women (P Conclusion Rate correction of QT Intervals using the standard Bazett and Fridericia formulas can introduce significant errors in the assessment of drug effects on the QT Interval. This has implications for the clinical assessment of drug effects and for the safety assessment of new drugs under development.

  • sex hormones prolong the QT Interval and downregulate potassium channel expression in the rabbit heart
    Circulation, 1996
    Co-Authors: Milou D Drici, Thomas R Burklow, Vedanandam Haridasse, Robert I Glazer, Raymond L Woosley
    Abstract:

    Background Sex hormones are known to exert direct and indirect effects on cardiovascular function, but their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT Interval of the ECG is regulated largely by potassium channels such as the delayed rectifier currents HK2 and I sK . Methods and Results The effects of ovariectomy (OVX) and estradiol (E2) or dihydrotestosterone (DHT) treatment were evaluated on HK2, HERG , and I sK mRNA levels, QT duration, and quinidine-induced changes in QT Interval in isolated rabbit hearts. HK2 and 0.7-kilobase I sK mRNA were downregulated in cardiac ventricular tissue from OVX rabbits treated with either E2 or DHT. The QT Interval was prolonged in E2- and DHT-treated animals (OVX+vehicle, 223±6 ms; OVX+DHT, 236±10 ms; and OVX+DHT, 245±6 ms; P Conclusions The association between hormone-induced changes in baseline QT Interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT Interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4±4.6% and 19.3±4.6% increase in QT Interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4±3.8% increase; P

Christian Funckbrentano - One of the best experts on this subject based on the ideXlab platform.

  • QT Interval prolongation after oxytocin bolus during surgical induced abortion
    Clinical Pharmacology & Therapeutics, 2004
    Co-Authors: Beny Charbit, Christian Funckbrentano, Emmanuel Samain, Virginie Jannierguillou, Pierre Albaladejo, J Marty
    Abstract:

    Background Although oxytocin, a uterotonic agent, may cause short-term vasodilation that results in severe hypotension, it is still routinely given as an intravenous bolus injection during surgical suction curettage. Two reported cases of ventricular tachycardia after oxytocin bolus in patients with long QT Interval syndrome led us to assess the effect of oxytocin on QT Interval. Method Thirty-eight healthy women scheduled for a surgical suction curettage with general anesthesia were enrolled. General anesthesia was induced by propofol and maintained by either propofol (n = 18) or sevoflurane (n = 20). Electrocardiographic recordings were obtained before and at 1, 2, 3, and 5 minutes after a 10-U intravenous bolus of oxytocin. Results Intravenous oxytocin induced a pronounced QTc Interval prolongation of 41 ± 21 ms (P < .0001), which was maximal 1 minute after administration. The QTc Interval returned to control values 3 minutes after oxytocin bolus. Oxytocin bolus also induced an increase in heart rate of 19 ± 10 beats/min and a significant decrease in systolic arterial pressure of 11 ± 9 mm Hg (both P < .0001). The drug used to maintain anesthesia was not an independent factor of QT Interval prolongation in ANOVA analysis. Conclusions Oxytocin intravenous bolus induced a large and transient QTc Interval prolongation, suggesting that it may lead to proarrhythmia in circumstances favoring QTc Interval increase. Clinical Pharmacology & Therapeutics (2004) 76, 359–364; doi:10.1016/j.clpt.2004.06.005

  • influence of endogenous oestrogens on QT Interval duration
    European Heart Journal, 2003
    Co-Authors: Jeansebastien Hulot, Jeanlouis Demolis, Rachel Riviere, Soraya Strabach, Sophie Christinmaitre, Christian Funckbrentano
    Abstract:

    Aims Women have a longer QT Interval and a greater incidence of torsades de pointes than men. It has been suggested that oestrogens may influence the duration of cardiac repolarization. We thus investigated the influence of oestradiol (E2) on ventricular repolarization within the physiological concentration range of this hormone. Methods and results We studied QT Interval duration in 21 healthy women aged 18 to 35 years with regular menstrual cycle (mean duration: 29±1 days) during two periods associated with a wide range of oestradiol plasma levels: low level during menses (105±34pmol/l) and high level during the pre-ovulatory phase (750±277pmol/l). We used heart rate-independent assessment of QT. QT–RR pairs were measured over a wide range of RR Intervals obtained at rest and during a sub-maximal exercise test. Using a monoexponential nonlinear curve fitting for the QT–RR relation, the QT1000msduring nadir and peak oestradiol periods was then determined for each subject. QT1000msInterval was not different between both study periods: 382.1±18.4ms at peak versus 382.2±19.4ms at nadir oestradiol level ( P =0.98). Conclusion No significant change in QT Interval duration was observed within the large range of physiological E2 variations found during the menstrual cycle.

  • rate corrected QT Interval techniques and limitations
    American Journal of Cardiology, 1993
    Co-Authors: Christian Funckbrentano, Patrice Jaillon
    Abstract:

    The duration of the QT Interval on the surface electrocardiogram represents the time required for all ventricular depolarization and repolarization processes to occur. Among the many physiologic and pathologic factors that contribute to the QT Interval, heart rate plays a major role. Several approaches have been used to correct the QT Interval, all of which take into account the heart rate at which the Interval is measured. The simplest and most common approach to correcting the QT Interval is to divide its value by the square root of the preceding RR Interval expressed in seconds, i.e., by using Bazett's formula. This calculation provides a corrected QT (QTc) Interval that represents the QT Interval normalized for a heart rate of 60 beats/min. However, several studies have shown that Bazett's correction formula is not optimal. Fridericia's cube-root formula has been shown to perform better in correcting the QT Interval for heart rate. Other formulas require the measurement of several QT-RR pairs at various heart rates to obtain a reliable QTc Interval and are therefore not easily usable. Any correction formula is likely to introduce an error in assessing the QTc Interval. Although the importance of this error should not be minimized, the corrected QT Interval remains useful in assessing the effects of drugs on the duration of repolarization. For this purpose, Fridericia's cube-root formula is preferable to Bazett's square-root formula.(ABSTRACT TRUNCATED AT 250 WORDS)

Martin Borggrefe - One of the best experts on this subject based on the ideXlab platform.

  • drug induced QT Interval shortening following antiepileptic treatment with oral rufinamide
    Heart Rhythm, 2012
    Co-Authors: Rainer Schimpf, Christian Veltmann, Theano Papavassiliu, Boris Rudic, Turgay Goksu, Jurgen Kuschyk, Christian Wolpert, Charles Antzelevitch, A Ebner, Martin Borggrefe
    Abstract:

    Background The arrhythmogenic potential of short QT Intervals has recently been highlighted in patients with a short QT syndrome. Drug-induced QT-Interval prolongation is a known risk factor for ventricular tachyarrhythmias. However, reports on drug-induced QT-Interval shortening are rare and proarrhythmic effects remain unclear. Objective Recently, rufinamide, a new antiepileptic drug for the add-on treatment of Lennox-Gastaut syndrome, was approved in the European Union and the United States. Initial trials showed drug-induced QT-Interval shortening. The aim of our study was to evaluate the effects of rufinamide on QT Intervals in patients with difficult-to-treat epilepsies. Methods Nineteen consecutive patients with Lennox-Gastaut syndrome and other epilepsy syndromes were included (n = 12 men; mean age 41 ± 12 years). QRS, QT, and Tpeak-Tend Intervals were analyzed before and during rufinamide treatment. Results The mean QT Interval shortened significantly following rufinamide administration (QT Interval 349 ± 23 ms vs 327 ± 17 ms; corrected QT Interval 402 ± 22 ms vs 382 ± 16 ms; P = .002). Tpeak-Tend Intervals were 79 ± 17 ms before and 70 ± 20 ms on treatment (P = .07). The mean reduction of the corrected QT Interval was 20 ± 18 ms. During follow-up (3.04 ± 1.09 years), no adverse events including symptomatic cardiac arrhythmias or sudden cardiac deaths were observed. Conclusion QTc-Interval shortening following oral rufinamide administration in a small patient group was not associated with significant clinical adverse effects. These observations nothwithstanding, the ability of rufinamide to significantly shorten the QT Interval portends a potential arrhythmogenic risk that may best be guarded against by periodic electrocardiographic recordings.