- Utility of the JT Peak Interval and the JT Area in Determining the Proarrhythmic Potential of QT-Shortening Agents. [Journal Article]
- JCJ Cardiovasc Pharmacol Ther 2018 Aug 09; :1074248418791999
- Drug-induced long QT increases the risk of ventricular tachyarrhythmia known as torsades de pointes (TdP). Many biomarkers have been used to predict TdP. At present, however, there are few biomarkers...
Drug-induced long QT increases the risk of ventricular tachyarrhythmia known as torsades de pointes (TdP). Many biomarkers have been used to predict TdP. At present, however, there are few biomarkers for arrhythmias induced by QT-shortening drugs. The objective of the present study was to identify the best biomarkers for predicting arrhythmias caused by the 4 potassium channel openers ICA-105574, NS-1643, R-L3, and pinacidil. Our results showed that, at higher concentrations, all 4 potassium channel openers induced ventricular tachycardia (VT) and ventricular fibrillation (VF) in Langendorff-perfused guinea pig hearts, but not in rabbit hearts. The electrocardiography parameters were measured including QT/QTc, JT peak, Tp-e interval, JT area, short-term beat-to-beat QT interval variability (STV), and index of cardiac electrophysiological balance (iCEB). We found that the potassium channel openers at test concentrations shortened the QT/QTc and the JT peak interval and increased the JT area. Nevertheless, even at proarrhythmic concentrations, they did not always change STV, Tp-e, or iCEB. Receiver operating characteristic curve analysis showed that the JT peak interval representing the early repolarization phase and the JT area reflecting the dispersion of ventricular repolarization were the best predictors of VT/VF. Action potential recordings in guinea pig papillary muscle revealed that except for pinacidil, the potassium channel openers shortened APD30 in a concentration-dependent manner. They also evoked early or delayed afterdepolarizations at fast pacing rates. Patch-clamp recordings in guinea pig ventricular cardiomyocytes showed that the potassium channel openers enhanced the total outward currents during the early phase of action potential repolarization, especially at proarrhythmic concentrations. We concluded that the JT peak interval and the JT area are surrogate biomarkers identifying the risk of proarrhythmia associated with the administration of QT-shortening agents. The acceleration of early-phase repolarization and the increased dispersion of ventricular repolarization may contribute to the occurrence of arrhythmias.
- Electropharmacological characterization of microminipigs as a laboratory animal using anti-influenza virus drug oseltamivir. [Journal Article]
- JTJ Toxicol Sci 2018; 43(8):507-512
- We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking prop...
We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking properties, including Na+, Ca2+ and K+ channels (n = 4). Oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously infused over 10 min with an interval of 20 min, which provided peak plasma concentrations 1.4, 7.4 and 125.5 µg/mL, respectively. The low dose did not alter any of the cardiovascular variables. The middle dose decreased the heart rate at 30 min after the start of the infusion. The high dose transiently returned the heart rate toward the baseline for 10-15 min, but decreased it for 20-60 min; decreased the mean blood pressure for 5-60 min; prolonged the PR interval for 10-60 min, and the QRS width for 10-20 min; but shortened the QT interval for 10-30 min, and the QTc for 5-60 min. Thus, oseltamivir can suppress the sinus automaticity, and atrioventricular nodal and intraventricular conduction; and decrease the mean blood pressure, extents of which were greater in microminipigs than in beagle dogs in our previous observation in spite of similar plasma concentrations, reflecting higher sensitivity of microminipigs for Na+ and Ca2+ channel inhibition than that of beagle dogs. In contrast to beagle dogs, oseltamivir shortened the repolarization period in microminipigs, indicating that oseltamivir can more potently inhibit the inward currents than the outward ones in the hearts of microminipigs. This information may help improve utilizatione of microminipigs as a laboratory animal.
- QT instability, an indicator of augmented arrhythmogenesis, increases with the progression of myxomatous mitral valve disease in dogs. [Journal Article]
- JVJ Vet Cardiol 2018; 20(4):254-266
- CONCLUSIONS: Analyses of QT intervals demonstrated changes in STI, LTI, and TI. Increased QT prolongation and instability are significantly related to mortality and may be useful in determining prognosis of MMVD patients.
- Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects. [Journal Article]
- JPJ Pharmacol Sci 2018; 137(2):237-240
- We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and incr...
We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects.
- A new approach for analysis of heart rate variability and QT variability in long-term ECG recording. [Journal Article]
- BEBiomed Eng Online 2018 May 03; 17(1):54
- CONCLUSIONS: The ConceFT has the potential to provide a sharpened and stabilized spectrogram for the heart rate variability and QT variability in 14-day ECG recordings.
- Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. [Journal Article]
- CEClin Exp Rheumatol 2018 Jul-Aug; 36(4):545-551
- CONCLUSIONS: This study suggests an association between cumulative AM dose above the median (1207 g) and structural ECG abnormalities. More importantly, cumulative AM decreases the odds of ECG conduction abnormalities.
- Effects of moxifloxacin on the proarrhythmic surrogate markers in healthy Filipino subjects: Exposure-response modeling using ECG data of thorough QT/QTc study. [Journal Article]
- JPJ Pharmacol Sci 2018; 136(4):234-241
- Effects of moxifloxacin on QTc as well as proarrhythmic surrogate markers including J-Tpeakc, Tpeak-Tend and short-term variability (STV) of repolarization were examined by using both standard E14 ti...
Effects of moxifloxacin on QTc as well as proarrhythmic surrogate markers including J-Tpeakc, Tpeak-Tend and short-term variability (STV) of repolarization were examined by using both standard E14 time-based evaluation and exposure-response modeling. The study was conducted with a single-blind, randomized, single-dose, placebo-controlled and two-period cross-over design in healthy Filipino subjects. QT interval was corrected by Fridericia's formula (QTcF). In the E14 time-based evaluation of ECG data, the largest ΔΔQTcF with 90% confidence interval was 14.1 ms (11.2-16.9) with Cmax of 3.39 μg/mL at 3 h post-dose (n = 69; male: 35, female: 34), indicating a positive effect on the QTcF. Moxifloxacin significantly increased the ΔΔJ-Tpeakc and ΔΔTpeak-Tend, whereas the ΔΔSTV was not altered. Meanwhile in the exposure-response modeling of the same ECG data, the slope of moxifloxacin plasma concentration-ΔΔQTcF relationship was 4.84 ms per μg/mL and the predicted ΔΔQTcF with 90% confidence interval was 13.8 ms (13.1-15.1) at Cmax, also indicating a positive effect on the QTcF. Importantly, results in each proarrhythmic surrogate marker obtained by the exposure-response modeling also showed high similarity to those obtained by the E14 statistical evaluation. Thus, these results of moxifloxacin may become a guide to estimate proarrhythmic potential of new chemical entities.
- Pediatric Syncope: High-Risk Conditions and Reasonable Approach. [Review]
- EMEmerg Med Clin North Am 2018; 36(2):305-321
- Syncope is a common presentation to the emergency room. Unlike in the adult population, most pediatric syncope has non-life-threatening causes, and minimal evaluation in the emergency department is a...
Syncope is a common presentation to the emergency room. Unlike in the adult population, most pediatric syncope has non-life-threatening causes, and minimal evaluation in the emergency department is appropriate with parental reassurance. Despite this benign prognosis, care must be made to find uncommon and potentially fatal causes. The primary purpose of evaluation of the patient with syncope is to determine whether the patient is at increased risk for death and needs either admission to the hospital or an expedited outpatient evaluation. This article reviews some of the most dangerous causes of syncope in the pediatric patient.
- Maximum QTc on Holter electrocardiography in children. [Journal Article]
- PIPediatr Int 2018; 60(6):507-512
- CONCLUSIONS: The present method of analyzing QTc on Holter ECG, in which automatic and manual measurements are combined, is practical and may be useful for diagnosis and risk stratification of LQTS.
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- QTc prolongation in short-term treatment of schizophrenia patients: effects of different antipsychotics and genetic factors. [Journal Article]
- EAEur Arch Psychiatry Clin Neurosci 2018; 268(4):383-390
- Antipsychotics are effective in treating schizophrenia but may lead to a higher cardiovascular risk due to QTc prolongation. Besides drugs, genetic and clinical factors may contribute to QTc prolonga...
Antipsychotics are effective in treating schizophrenia but may lead to a higher cardiovascular risk due to QTc prolongation. Besides drugs, genetic and clinical factors may contribute to QTc prolongation. The aim of this study is to examine the effect of candidate genes known for QTc prolongation and their interaction with common antipsychotics. Thus, 199 patients were genotyped for nine polymorphisms in KCNQ1, KCNH2, SCN5A, LOC10537879, LOC101927066, NOS1AP and NUBPL. QTc interval duration was measured before treatment and weekly for 5 weeks while being treated with risperidone, quetiapine, olanzapine, amisulpride, aripiprazole and haloperidol in monotherapy. Antipsychotics used in this study showed a different potential to affect the QTc interval. We found no association between KCNH2, KCNQ1, LOC10537879, LOC101927066, NOS1AP and NUBPL polymorphisms and QTc duration at baseline and during antipsychotic treatment. Mixed general models showed a significant overall influence of SCN5A (H558R) on QTc duration but no significant interaction with antipsychotic treatment. Our results do not provide evidence for an involvement of candidate genes for QTc duration in the pathophysiology of QTc prolongation by antipsychotics during short-term treatment. Further association studies are needed to confirm our findings. With a better understanding of these interactions the cardiovascular risk of patients may be decreased.