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T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization.

ABSTRACT: BACKGROUND:We present a new family of ECG biomarkers for assessing drug effects on ventricular repolarization. We show that drugs blocking inward (depolarizing) ion currents cause a relative increase of the T vector velocity (TVV) and accelerate repolarization, while drugs blocking outward ion currents cause a relative decrease of the TVV and delay repolarization. The results suggest a link between the TVV and the instantaneous change of the cellular action potentials that may contribute to bridge the gap between the surface ECG and myocardial cellular processes. METHODS:We measure TVV as the time required to reach X% of the total Trajectory length of the T vector loop, denoted as TrX. Applied to data from two FDA funded studies (22+22 subjects, 5232+4208 ECGs) which target ECG effects of various ion-channel blocking drugs, the TrX effect profiles indicate increasingly delayed electrical activity over the entire repolarization process for drugs solely reducing outward potassium current (dofetilide, moxifloxacin). For drugs eliciting block of the inward sodium or calcium currents (mexiletine, lidocaine), the TrX effect profiles were consistent with accelerated electrical activity in the initial repolarization phase. For multichannel blocking drugs (ranolazine) or drug combinations blocking multiple ion currents (dofetilide + mexiletine, dofetilide + lidocaine), the overall TrX effect profiles indicate a superposition of the individual TrX effect profiles. RESULTS:The parameter Tr40c differentiates pure potassium channel blocking drugs from multichannel blocking drugs with an area under the ROC curve (AUC) of 0.90, CI = [0.88 to 0.92]. This is significantly better than the performance of J-Tpeakc (0.81, CI = [0.78 to 0.84]) identified as the best parameter in the second FDA study. Combining the ten parameters Tr10c to Tr100c in a logistic regression model further improved the AUC to 0.94, CI = [0.92 to 0.96]. CONCLUSIONS:TVV analysis substantially improves assessment of drug effects on cardiac repolarization, providing a plausible and improved mechanistic link between drug effects on ionic currents and overall ventricular repolarization reflected in the body surface ECG. TVV contributes to an enhanced appraisal of the proarrhythmic risk of drugs beyond QTc prolongation and J-Tpeakc.

SUBMITTER: Bystricky W

PROVIDER: S-EPMC6613676 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization.

Bystricky Werner W Maier Christoph C Gintant Gary G Bergau Dennis D Kamradt Kent K Welsh Patrick P Carter David D

PloS one 20190708 7

<h4>Background</h4>We present a new family of ECG biomarkers for assessing drug effects on ventricular repolarization. We show that drugs blocking inward (depolarizing) ion currents cause a relative increase of the T vector velocity (TVV) and accelerate repolarization, while drugs blocking outward ion currents cause a relative decrease of the TVV and delay repolarization. The results suggest a link between the TVV and the instantaneous change of the cellular action potentials that may contribute ...[more]

PMID: 31283756

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Project description:AimTo use velocity vector imaging (VVI) technology to evaluate the correlation between the apical four-chamber view and short-axis myocardial movement in rats.MethodsWe used 25 10-week-old male Sprague-Dawley rats to measure the myocardium peak systolic velocity (Vs; cm/s), peak diastolic velocity (Vd; cm/s), peak systolic strain (SR; %), peak systolic strain rate (SRs; 1/s), and peak diastolic strain rate (SRd; 1/s) from the apical four-chamber view of the left ventricle (LV) and the parasternal mitral valve (PMV)-level short-axis view, and to analyze the correlation between myocardial motion in corresponding views of the two sections.ResultsComparing the myocardial motion between the lateral wall's basal segment in the apical four-chamber view of the LV and the lateral wall of the PMV-level short-axis view revealed that the Vd was positively correlated (r = 0.59, p<0.01), as was SRs (r = 0.68, p<0.05). Comparing the myocardial motion between the lateral wall's middle segment in the apical four-chamber view of the LV and the lateral wall of the PMV-level short-axis view demonstrated that Vd, SRs, and SRd were positively correlated (r = 0.63, 0.82, 0.79, respectively, all p<0.01). Our comparison of myocardial motion between the posterior septum's basal segment in the apical four-chamber view of the LV and the posterior septum of PMV-level short-axis view showed that Vd and SRs were positively correlated (r = 0.57, 0.68, respectively, both p<0.01). Comparing the myocardial motion between the posterior septum's middle segment in the apical four-chamber view of the LV and the posterior septum of the PMV-level short-axis view revealed that Vs, Vd, SR, and SRd were positively correlated (r = 0.89, 0.63, 0.64, 0.6, respectively, all p<0.01), and the SRs also had a significant positive correlation (r = 0.53, p<0.05).ConclusionVVI technology could be a valuable tool for evaluating the myocardial walls motion of the apical four-chamber view of the rat LV.

Project description:We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-Tpeak c and Tpeak -Tend , respectively, as well as Tpeak -Tend /QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n = 14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the seventh day, subjects received intravenous ibutilide 0.003 mg/kg, after which electrocardiograms were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-Tpeak c was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs. 227 ± 28 vs. 227 ± 21 ms, P = 0.002). Maximum post-ibutilide J-Tpeak c was also lower during the testosterone phase (233 ± 22 vs. 246 ± 29 vs. 248 ± 23 ms, P < 0.0001). Pre-ibutilide Tpeak -Tend was not significantly different during the three phases, but maximum post-ibutilide Tpeak -Tend was lower during the testosterone phase (80 ± 12 vs. 89 ± 18 vs. 86 ± 15 ms, P = 0.002). Maximum Tpeak -Tend /QT was also lower during the testosterone phase (0.199 ± 0.023 vs. 0.216 ± 0.035 vs. 0.209 ± 0.031, P = 0.005). Progesterone exerted minimal effect on drug-induced lengthening of J-Tpeak c, and no effect on Tpeak -Tend or Tpeak -Tend /QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.

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T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization.

Publications

T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization.

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