The Time Course of New T‐Wave ECG Descriptors Following Single‐ and Double‐Dose Administration of Sotalol in Healthy Subjects

Abstract

Introduction:The aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation.Methods: Twelve-lead digital ECG Holter was recorded in 38 healthy subjects (27 males, mean age = 27.4 ± 8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d-l sotalol. For each 24-hour period and each subject, ECGs were extracted every 10 minutes during the 4-hour period following drug dosage. Ventricular repolarization was characterized using three biomarker categories: conventional ECG time intervals, principal component analysis (PCA) analysis on the T wave, and fully automatic biomarkers computed from a mathematical model of the T wave.Results: QT interval was significantly prolonged starting 1 hour 20 minutes after drug dosing with 160 mg and 1 hour 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol-induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes.The duration of manual QT and automatic surrogate QT were strongly correlated (R 2 = 0.92, P < 0.001). The Bland and Altman plot revealed a nonstationary systematic bias (bias = 26.5 ms ± 1.96 * SD = 16 ms).Conclusions: Changes in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies.

The genetic makeup of the electrocardiogram

“…Drugs (off-) targeting ion channels are well established examples, including Na v 1.5 ( SCNSA ), which is targeted by different drugs with cardiac safety concerns 24 . Another example are I kr channels ( KCNH2 ) targeted by class Ia anti-arrythmic drugs including quinidine and the class III anti-arrythmic drug sotalol, both known to prolong QT interval 25 , a feature also observed in our data ( Extended Fig. 1a ; http://www.ecgenetics.org), or drugs targeting Ca v 3.1 ( CACNA1G ) known to affect the PR-interval 26 , a feature also observed in our data ( Extended Fig.…”

Morphological analysis of T-wave in vectorcardiographic leads system by a bi-Gaussian approach in patients under effect of salbutamol

“…3). Therefore, it was performed a mathematical analysis of the parameters needed to model this curve [4], [15]. The bi-gaussian function (BGF) is a five-parameter function made of two half-Gaussian functions in this case with the same mean but with two different amplitudes.…”

“…For a given T-wave, the five parameters of the bi-gaussian model produced are WKH IROORZLQJ RXWSXWV ³D´ DV WKH 7wave amplitude for the first-half Gaussian measured at Tpeak (mV), ³D´DVWKH7-wave amplitude for the secondhalf gaussian (mV), LVWKH³HDUO\-7´ILWWLQJ the ascending phase of the T-wave and LV WKH ³ODWH-7´ GHVFULELQJ WKH descending phase of the T wave DQG LV WKH WLPH ZKen Tpeak is reached [4], [15].…”

“…There is currently great interest in studying ventricular repolarization, due to the fact that, pathologically, a long QT interval is related to the onset of a cardiac event. The European Society of Cardiology and the Food and Drug Administration (FDA) have recommended measuring the QT interval during the evaluation of new drugs [3], [4].…”

“…In fact, the evaluation of the end of the QT interval is not a straightforward task, particularly for hypoglycaemic ECG morphologies [4], [5], [6]. Salbutamol (INN) or albuterol (USAN) is a short-acting 2 -adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease [7].…”