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T WAVE INDICES OF DRUG INDUCED CHANGES IN REPOLARISATIONDr Tony Hunt: Managing Director and Chief Scientist Cardio-QT Ltde-mail: [email protected] Dr Tony Hunt
Managing Director and For the past decade prolongation of the QT Reverse use dependence, AP Instability and can be shown to be directly related to the wave morphology indices to predict TdP in seductive cost and time saving argument as measured by the slope method compared interval has been used by the Regulatory AP transmural Dispersion of repolarisation).
prolongation of the M cell AP and the other clinical settings. Invoking the which may lead us to proceed directly to the to the ‘gold standared' manual method, Agencies as the principal biomarker to global dispersion of repolarisation related to Amiodarone contradiction, this safe clinical cardiac safety studies.
particularly as the ECG isoelectric baseline investigate the arrhythmogenic potential of The seminal work by Antzelevitch the difference between the lumped M cell antiarrhythmic may produce morphological Accurate measurement of the true end of the new pharmaceutical compounds . It has demonstrated that the morphology of the T AP and epicardial AP timings. In the T wave changes indicating IKr inhibition QT interval, enables accurate measurement been suggested that torsade de pointes wave can be generated from the interplay of lumped model during IKr inhibition the but the incidence of TdP is very rare when of the changes in QT intervals during There are methods to measure the true end (TdP) is unlikely to occur if a drug prolongs the lumped action potentials within the triangulation of the APs will result in a thorough QT trials thereby reducing of the T wave as per the electrophysiological the mean QTc (in thorough QT studies) by epicardial, Mcell and endocardial layers of smaller instantaneous voltage differences standard error and measurement variability.
definition. Figure 2 represents such a
less than 5ms and that the risk of TdP is the myocardium. In the lumped model it has between the endocardial and M cell APs The preclinical TRIaD indices have been This results in higher statistical power with method. This method is based upon the substantially higher for prolongations of been shown that the peak T wave occurs generated at the time of cessation of the shown to be predictive of drug induced less subject recruitment. Accurate upright T wave and its inverted image being >20ms. With inherited long- QT syndromes when the epicardial AP returns to the prolonged epicardial AP therefore resulting arrhythmogenicity in over 700 animal measurement of QT interval enables virtually merged until there is best least there is a 5% exponential increase in the isoelectric line and that the time of the end in flattening of the delayed T wave peak and drug trials. The pathophysiological model accurate measurement of T wave squares fit between their common relative risk of a cardiac event for every 10 of T wave occurs when the M cell layer a skewness or asymmetry of the T wave interrelating these indices has shown that asymmetry, pT-Te, QT variability and isoelectric baselines. The first time point of ms increase in QTc duration beyond 440ms.
reaches isoelectric resting potential. In the develops. It can be shown by simple AP instability, AP triangulation and Reverse therefore accurate measurements of the intersection of the respective baselines Although it is accepted that prolongation of wedge preparation the timing between the geometric idealisation of a baseline ECG T use Dependence are in order of decreasing clinical equivalents of TRIaD.
being the end of the T wave.
QTc interval is associated with a significant end of the epicardial AP and M cell AP gave wave as an isosceles triangle that if the post relative importance. The index of spatial increased risk of arrhythmia there is concern is an index of the dispersion of transmural drug T wave peak were to be prolonged, the and temporal dispersion of repolarisation is Slope based automatic QT algorithms are that when using QTc prolongation as a sole repolarisation and the ECG clinical index of M cell AP would need to be prolonged by a product of these three phenomena.
ubiquitous and do not measure the true end arbiter of pro-arrhythmic risk there is a peak T wave to end T wave (pT-Te) has double that amount in order to maintain The problems of translating interspecies of the T wave as is illustrated in Figure 1. In
possibility that safe, beneficial candidate been shown to be an index of global symmetry of the triangular T wave. The physiological differences remain this figure, the blue and red traces represent drugs may not achieve regulatory approval dispersion of repolarisation and numerous prolongation of the M cell AP is very rarely insurmountable (eg the rabbit AP has the magnified curvilinear tail ends of T because of benign QTc prolongation.
studies have shown that a prolongation of double the prolongation of the epicardial inherent triangular morphology before drug waves from the same subject before and Amiodarone may not have been approved if this index is a strong predictor of TdP.
AP. M cell AP prolongation significantly induction of triangulation) and mandate that after sotolol, after alignment of the it had been subjected to a Thorough QT When the measurement of pT-Te is made beyond the endocardial AP duration will rigorous phase 1 human cardiac safety respective Q wave onsets. The yellow Trial and conversely some candidate manually it is significantly longer than result in a notch on the T wave downslope studies be performed. Fortunately, it is vertical makers represent the manually compounds which induce a shortened QTc when measured by the automated ECG as the M cell AP voltage is not attenuated by possible to translate the various preclinical measured end of the T waves. The blue interval may be potently arrhythmogenic slope QT algorithms which tend to ignore the endocardial AP for a significant indices within TRIaD to surrogate human oblique lines are projections of the (the short QT syndrome). Consequently the end of the T wave where the effects of proportion of the M cell AP downstroke.
ECG biomarkers some of which have maximum T wave tangents and where these much effort is being made to find drug induced inhibition of the rapid delayed Therefore combined scores of flatness, already been mentioned. In the presence of combinations of clinical ECG biomarker potassium rectifier current ( IKr) are most asymmetry and notching as measured by the IKr inhibition the phenomenon of AP indices which increase the sensitivity and pronounced. Therefore manual methods or various methods is in effect simply a triangulation is inevitably associated with specificity to predict the arrhythmogenic use of a automated QT algorithm which measure of the degree of IKr inhibition. The prolongation of the QTc interval, pT-Te is a potential of new compounds.
measures the true end of the T wave, as per use of the morphology indices flatness, surrogate marker of global dispersion of the electrophysiological definition, may asymmetry and notching has been inspired repolarisation, reverse use dependence is The purpose of this article is to discuss the prove more accurate. In conditions of drug by the Long QT syndrome (LQTS) 2 associated with a steep QT/R-R interval electrophysiological basis and potential induced IKr inhibition there is a phenotype and would not be as successful gradient and indices of increased short term shortcomings of some of the newer T wave triangulation (triangular morphology) of all applied to the ECG T waves of other LQTS QT variability measured by Poincare plots biomarkers which have been shown three myocardial layers, defined as a phenotypes. Nevertheless, this method of T have been shown to be predictive of TdP. It Innovation centre empirically to be potentially useful in a prolongation of phase 3 (AP)30 –AP(90).
wave morphology scoring has been shown is therefore possible to dynamically Hillington business park limited number of studies, relate these Because of the difference in the ratios of to be more sensitive in detecting IKr combine the human surrogate indices for newer indices to QTc prolongation and IKr to IKs (slow delayed potassium inhibition than prolongation of the QTc TRIaD with the morphological indices of cross some arbitrary threshold is deemed to discuss how these newer clinical rectifier) channel densities between the M interval. Currently there is some clinical the T wave to create a human TRIaD be the end of the T wave as measured by the biomarkers are a clinical expression of some cell and the other two layers, the M cell evidence in a small retrospective study that equivalent. With accumulating evidence slope method. Because of the divergence of of the indices within the preclinical TRIaD layer is prolonged by a proportionately morphology indices combined with QTc based clinical studies using these new these two tangents it can be seen that there Phone: +44 (0)7813 021061
biomarker of pro-arrhythmic risk. TRIaD greater degree that the other cell layers. In prolongation may be used to predict TdP in clinical biomarkers at our disposal, which in is the potential for a great deal of variability +44 (0)141 637 5535 stands for the combination of action the multicellular in silico models the a bradycardia model but we do not yet a species specific way may duplicate some between the difference in end of T wave potential (AP) indices: AP Triangulation, prolongation of the simulated QT interval know the sensitivity nor specificity of T of the important preclinical tests, there is a times (therefore difference in QT intervals) Pharmafile Research & Development Guide Pharmafile Research & Development Guide

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