QTc Changes Research Articles

Abstract 9481: The Response of the Qt Interval and the T-wave Morphology to Sudden Tachycardia Provoked by Standing in Young Athletes

Background: the response of the QT interval to the sudden tachycardia provoked by standing can aid in the diagnosis of the long QT syndrome (LQTS). It is therefore important to know what is the normal response to this maneuver. The aim of this study was to characterise the response of the QT interval and the T-wave morphology following this provocation test in young healthy athletes. Methods: ECG was analysed as part of a prospective study about the impact of cardiovascular screening with ECG in young (14-35 years) athletes. ECG was performed after 5 minute of supine resting. Athletes without cardiac abnormalities, not taking drugs and with normal ECG (QTc for men < 450 msec, for women < 460 msec) were asked to stand up quickly with continuous ECG monitoring for 30”. Heart rate, QT, QTc (Bazett) and T-wave morphology [normal, biphasic, notched G1 (T2>T1), notched G2 (T2>>T1)] were analysed at baseline and at maximal tachycardia. Results: ECG of 289 athletes was analysed (76 % men, mean age 18.4 ± 5.6 years). Baseline parameters were following: heart rate 69 ± 11/min, QT 378 ± 27 msec, QTc 401 ± 21 msec. After standing, the maximal heart rate was 101 ± 13/min. QT was 361 ± 28 msec (shortening by 17 ±11 msec). In 4 % of athletes QT increased by 10-20 msec. QTc was 466 ± 30 msec (lengthening of 65 ± 24 msec). In 12 % of athletes QTc was ≥ 500 msec. T-wave morphology during tachycardia were notched G2 in 6% of athletes. During tachycardia, 15 % of athletes displayed a QTc ≥ 500 msec or QT lengthening or notched G2 morphology of T waves. Conclusions: During sudden tachycardia, a significant proportion of healthy young athletes demonstrated QTc interval and changes of T-wave morphology in the magnitude observed in patients with the LQTS. Caution should be applied in interpreting these parameters in ECG tracing and Holter monitoring displaying sudden oscillations of heart rate in this population.

Protracted QTc Prolongation following Treadmill Testing Identifies a Type 1 Long QT Mutation that is Resistant to PKA Activation

Background Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in KCNQ1, the gene that encodes the pore-forming α-subunit of the slowly activating delayed rectifier K + current (I Ks ). During β-adrenergic stimulation, protein kinase A (PKA) activation increases I Ks to prevent a dangerous prolongation of the ventricular action potential. LQT1 patients with mutations resistant to PKA activation are at greater risk for life-threatening arrhythmias. The purpose of this study is to identify LQT1 mutations resistant to PKA activation. Methods Retrospective analyses of the treadmill stress test results of LQT1 patients indicated that KCNQ1-I235N (p.Iso235Asn) exacerbated the delay in QTc latency recovery following treadmill stress testing. We used voltage-clamping techniques to study KCNQ1 current (I KCNQ1 ) in HEK293 cells expressing wild-type KCNQ1 (WT) or WT+I235N (to mimic the patients' genotype), the I Ks β-subunit KCNE1, and the I Ks PKA regulatory protein AKAP9 (Yotiao). Results LQT1 patients typically show a peak in QTc prolongation at 3 minutes during their recovery from treadmill stress testing. The change in QTc between the first and fifth minutes of recovery (ΔQTc) is typically KCNQ1 similar to native-like I Ks (n = 11). Compared with WT, cells coexpressing WT+I235N conducted maximal I KCNQ1 that was 32% smaller ( P P KCNQ1 in cells expressing WT by 64% (n = 4, P KCNQ1 only increased 23% in cells expressing WT+I235N (n = 4 each, P >.05). Conclusions LQT1 patients with delayed recovery in QTc prolongation following treadmill testing might indicate mutations that are resistant to PKA activation. These patients could be at high risk for life-threatening events but may derive a pronounced benefit from β-blocker therapy.

Corrected QT interval during treatment with methadone and buprenorphine—Relation to doses and serum concentrations

BackgroundMethadone and buprenorphine are widely used in the treatment of opioid addiction. Some study results suggest that methadone can be associated with QT interval prolongation and torsades de pointes ventricular arrhythmias, whereas no such risk has been observed for buprenorphine. The aim of this study is to determine the risk of corrected QT interval (QTc) increase among patients treated with these medications in an opioid maintenance treatment (OMT) programme, and to study possible associations between QTc changes and serum concentrations of methadone or buprenorphine. MethodsEighty patients enrolled in the OMT programme were followed after start of treatment with methadone (n=45) or buprenorphine (n=35). QTc interval was assessed by electrocardiography (ECG) at baseline and after 1 month (n=79) and 6 months (n=66) in the OMT programme. Blood samples were obtained for the analysis of serum concentrations of buprenorphine, (R)-methadone, (S)-methadone and total methadone. ResultsNo patients had QTc prolongation (defined as a QTc value above 450ms) at baseline or after 1 or 6 months. When analysed in a linear mixed effects model, QTc was not associated with the serum concentrations of buprenorphine or methadone. However, low serum potassium levels increased QTc significantly. ConclusionsThese results support and extend previous findings that treatment with methadone in modest doses (i.e. below 100mg/d) is not associated with clinically significant QTc increases, and that buprenorphine in commonly used doses is a suitable alternative to methadone with regard to the risk of QTc prolongation.

Thorough QT Studies and Indirect Causes of QTc Changes

Thorough QT Studies and Indirect Causes of QTc Changes

Assessment of Wall Motion Abnormality, Cardiac Function and QTc Change in Patients with Severe Heart Failure of Takotsubo Cardiomyopathy

The Takotsubo cardiomyopathy (TC) is characterized by transient wall-motion abnormality, mainly in apex of left ventricle (LV). The serious cases of heart failure (CHF, NYHA 3-4), shock, fatal arrhythmia (TdP, VT) associated with TC have not been fully investigated. Aim is to compare the LV function, size of wall motion abnormality (%WMA), QTc interval and clinical indicators (CK, CKMB, BNP) over time between TC patients in serious condition (Group A; CHF n=26, shock n=6) and stable condition (Group B; n=52).

Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction

AimsTo quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies. MethodsTwenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT–RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation. ResultsMoxifloxacin prolonged the QTc by 10.6±6.6ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87±0.13 vs. 0.82±0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91±0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7±1.1ms vs. 8.8±1.2ms for Fridericia). ConclusionThe ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.

Pharmacokinetics and Repolarization Effects of Intravenous and Transdermal Granisetron

The need for greater clarity about the effects of 5-HT(3) receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT(3) receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization.

Effect of Weight Loss After Bariatric Surgery on Left Ventricular Mass and Ventricular Repolarization in Normotensive Morbidly Obese Patients

To assess the effect of weight loss on ventricular repolarization in morbidly obese patients, 39 normotensive subjects whose baseline body mass indexes were ≥40 kg/m(2) before weight loss from bariatric surgery were studied. All patients were free of underlying organic heart disease, heart failure, and conditions that might affect ventricular repolarization. Twelve-lead electrocardiography and transthoracic echocardiography were performed just before surgery and at the nadir of postoperative weight loss. The corrected QT interval (QTc) was derived using Bazett's formula. QTc dispersion was calculated by subtracting the minimum from the maximum QTc on the 12-lead electrocardiogram. Echocardiographic left ventricular (LV) mass was indexed to height(2.7). The mean body mass index decreased from 42.8 ± 2.1 to 31.9 ± 2.2 kg/m(2) (p <0.0005). For the entire group, weight loss was associated with significant reductions in mean QTc (from 428.7 ± 18.5 to 410.5 ± 11.9 ms, p <0.0001) and mean QTc dispersion (from 44.1 ± 11.2 to 33.2 ± 3.3 ms, p <0.0005). Mean QTc and QTc dispersion decreased significantly with weight loss in patients with LV hypertrophy but not in subjects without LV hypertrophy. Multivariate analysis identified pre-weight loss LV mass/height(2.7) as the most important predictor of pre-weight loss QTc and QTc dispersion and also identified weight loss-induced change in LV mass/height(2.7) as the most important predictor of weight loss-induced changes in QTc and QTc dispersion. In conclusion, LV hypertrophy is a key determinant of QTc and QTc dispersion in normotensive morbidly obese patients. Regression of LV hypertrophy associated with weight loss decreases QTc and QTc dispersion.

Ziprasidone and the Corrected QT Interval

Prolongation of the corrected QT interval (QTc) is understood to be a predictor of risk for ventricular arrhythmia; consequently, data on QTc effects of drugs are used by regulatory bodies to evaluate potential safety risks. Clinical pharmacology studies in adults receiving oral ziprasidone demonstrated a dose-dependent mean increase (4.5-19.5 milliseconds [ms]) in QTc over the range of 40-160 mg/d with a small incremental increase (22.5 ms) at 320 mg/d. In a comparative study of ziprasidone versus five antipsychotics, the mean QTc increase at steady state maximum concentration (C(max)) for ziprasidone was 15.9 ms. Accordingly, the effects of ziprasidone on QTc were studied in phase II-IV randomized controlled trials (RCTs). The objective of this study was to provide clinicians and clinical researchers with a comprehensive analysis of QTc changes associated with ziprasidone based on data from Pfizer-sponsored phase II-IV RCTs in schizophrenia or bipolar disorder patients, safety reports and post-marketing surveillance. The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone: (i) post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies; (ii) post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults; (iii) post hoc analyses from phase II-IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and paediatric (5 studies) subjects; (iv) cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia; (v) a large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18 154 subjects with schizophrenia (the only previously reported results included here); and (vi) cardiac-related AEs presented in a ziprasidone post-marketing surveillance report created in 2007. A total of 4306 adults received ziprasidone in placebo- and active-comparator phase II-IV RCTs and had evaluable QTc data. One subject reached a QTc ≥480 ms; 33 (0.8%) had a QTc ≥450 ms. QTc prolongation ≥30 ms was observed in 389 subjects (9.0%); ≥60 ms in 30 (0.7%); and ≥75 ms in 12 (0.3%). In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (± 20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (± 20.6) ms. Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate or lamotrigine, demonstrated similar QTc effects. A scatter-plot of QTc prolongation against baseline QTc showed QTc prolongation ≥60 ms exclusively in adult subjects with a baseline QTc ≤400 ms. The final concentration-response analysis model, comprising 2966 data points from 1040 subjects, estimates an increase in QTc of 6 ms for each 100 ng/mL increase in ziprasidone concentration. The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use. Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs. These analyses provide the first comprehensive summary of QTc changes associated with ziprasidone based on Pfizer-sponsored phase II-IV RCTs, safety reports and post-marketing surveillance. The results of the analyses of pooled data from phase II-IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ≥60 ms (<1.0%) and rare observation of QTc ≥480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and post-marketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.

Thorough QT/QTc Study of Ritonavir‐Boosted Saquinavir Following Multiple‐Dose Administration of Therapeutic and Supratherapeutic Doses in Healthy Participants

The effect of saquinavir-boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double-blind, placebo- and positive-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT/QTc study. Least squares mean estimated study-specific QTc (QTcS) change from dense predose baseline (ddQTcS(dense)) was the primary endpoint. Greatest mean increase in ddQTcS(dense) occurred 12 hours postdose for the 1000/100-mg group (18.9 ms) and 20 hours for the 1500/10-mg group (30.2 ms). The upper 1-sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcB(dense) and ddQTcF(dense) were similar to ddQTcS(dense). No QTcS, QTcF, or QTcB measurements were >500 ms. One participant receiving 1000/100 mg and 3 receiving 1500/100 mg had a maximum ddQTcS(dense) >60 ms. More participants with ≥1 adverse event received saquinavir/ritonavir. PubMed search and Roche postmarketing data did not reveal publications or reports directly presenting the effect of saquinavir on QT/QTc or causing torsade de pointes.

Phase II Dose-Ranging Trial of the Early Bactericidal Activity of PA-824

PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.

Abstract P107: Association of Longitudinal Change and Fluctuation in QT Interval with Cardiovascular Outcomes: A Cohort Study in a Managed Care Setting

Purpose. Both long and short QT intervals are associated with life-threatening cardiac arrhythmias and adverse cardiovascular (CV) events, but prior studies have typically relied on a single baseline measure of the QT interval. We examined the prospective association of within-person change and fluctuation in QT length over time with subsequent CV outcomes and all-cause mortality in a managed care setting. Methods. We assembled a cohort of 187,901 Northern California Kaiser Permanente Medical Care Program (KPMCP) members who underwent three or more standard 12-lead ECGs as part of regular care between 1995 and 2008. Cohort-specific log-linear models stratified by gender, age and race/ethnicity were used to correct raw QT measurements for heart rate (QTc). Non-fatal and fatal CV outcomes and all-cause mortality were identified between the last ECG and right censoring event (CV event, death, termination of health plan membership or 12/31/2009; the median [SD] follow-up time was 4.1 [3.7] years). Cox regression models adjusting for age, gender, race/ethnicity, hypertension, diabetes, hyperlipidemia, smoking status and average QTc were used to simultaneously generate hazard ratios and 95% CI for tertiles 1 and 3 (versus tertile 2) of the linear slope of QTc (change in ms per year) and for tertiles 2 and 3 (versus tertile 1) of the root mean square error of QTc (RMSE, variability about the linear slope in ms). Results. The mean QTc slope and RMSE were +2.2 ms/year and 15.3 ms in men and +1.4 ms/year and 14.3 ms in women, respectively. In fully-adjusted models, the sex-specific tertile 3 of the QTc slope was associated with increased hazard of acute coronary syndrome (Number of events; Hazard Ratio; 95% Confidence Interval) (17,920; 1.34; 1.30-1.39), ischemic stroke (11,716; 1.30; 1.25-1.36), heart failure (42,909; 1.47; 1.44-1.51), cardiac arrest (4,700; 1.67; 1.55-1.79) and all-cause mortality (72,392; 1.43;1.40-1.45). In turn, the sex-specific tertile 3 of the RMSE was associated with increased hazard of heart failure (1.34;1.31-1.37), cardiac arrest (1.19;1,11-1.28) and all-cause mortality (1.06;1.04-1.08). Conclusions. In an insured population that underwent multiple ECGs, both linear increase and fluctuation of QTc over time were significantly and independently associated with adverse CV outcomes. Whether these associations are causal or represent confounding effects of medications warrant further research.

Response to “Vardenafil-Associated QTc Changes: Not Merely a Normal Autonomic Process”

Clinical Pharmacology & TherapeuticsVolume 91, Issue 4 p. 580-581 Letters to the Editor Response to “Vardenafil-Associated QTc Changes: Not Merely a Normal Autonomic Process” A A Fossa, Corresponding Author A A Fossa anthony.fossa@icardiac.com iCardiac Technologies, Rochester, New York, USASearch for more papers by this authorM Zhou, M Zhou iCardiac Technologies, Rochester, New York, USASearch for more papers by this author A A Fossa, Corresponding Author A A Fossa anthony.fossa@icardiac.com iCardiac Technologies, Rochester, New York, USASearch for more papers by this authorM Zhou, M Zhou iCardiac Technologies, Rochester, New York, USASearch for more papers by this author First published: 29 February 2012 https://doi.org/10.1038/clpt.2011.331Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume91, Issue4AutoimmunityApril 2012Pages 580-581 RelatedInformation

Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers

PurposeMidostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin’s effect on cardiac repolarization.MethodsThis phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate–corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers.ResultsThe maximum mean QTc change from baseline corrected using Fridericia’s correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported.ConclusionMidostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-012-1825-y) contains supplementary material, which is available to authorized users.

Effects of domperidone on QTc interval in infants

To prospectively evaluate the effects of oral domperidone on the QTc interval in infants. Infants (0-1 year) with a diagnosis of gastro-oesophageal reflux (GOR) disease were included. A 12-lead electrocardiography (ECG) was performed in all infants at baseline and 1 h after the intake of domperidone after 7-14 days; the corrected QTc interval was calculated by one investigator (MV) according to Bazett's formula. Forty-five infants were enrolled in this study. The mean gestational age was of 38.6 weeks (35.5-42.0), and the mean age at the start of domperidone was 75.3 days (19-218 days). No statistically significant difference in corrected QTc was observed between baseline and the second ECG (0.389 ± 0.02 vs. 0.397 ± 0.31; p 0.130)). A trend was observed regarding gender: Although there was no difference in QTc change in girls (p 0.622), there was a strong trend in boys (p 0.051). Two infants (both boys) had a clinically significant QTc prolongation (> 460 msec) without symptoms. The Spearman correlation test showed no relation between the QTc change and age (r: -0.05822; p 0.7284). There was no relation between domperidone dosage and QTc change. Overall, the group-analysis showed no statistical significant difference in QTc duration induced by domperidone. However, 2/45 (4.4%) infants had a prolonged QTc interval (> 460 msec) induced by domperidone. As a consequence, QTc measurement should be recommended in routine in infants when domperidone is started.

The effect of insulin therapy and plasma glucose levels on corrected QT intervals in patients with type 2 diabetes

This study aims is to investigate the effect of medium-term insulin therapy (3 months) and plasma glucose levels on corrected QT intervals (QTc) in patients with type 2 diabetes. The subjects were 17 patients with type 2 diabetes who had poor glycemic control and were changed to insulin therapy from sulfonylurea or diet therapy alone. QTc, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), serum potassium and body weight were measured at baseline and after 3 months of insulin therapy. A significant increase of QTc (0.406 ± 0.027 to 0.421 ± 0.025 s, P =0.0025) and a significant decrease in HbA1c (10.9 ± 1.9 to 7.9 ± 1.7%, P =0.0002) were found after 3 months of insulin therapy. QTc showed no correlation with FPG, HbA1c or body weight before insulin therapy and the change in QTc was not correlated with the change in FPG, HbA1c or body weight from before to after insulin therapy. In this study, insulin therapy for 3 months caused a significant increase of QTc in patients with type 2 diabetes. However, given the small size of the trial, further studies with larger number of patients are needed. Key words: QTc, type 2 diabetes, insulin therapy.

Qtc Changes in Smokers and Non Smokers - A Comparativestudy

Qtc Changes in Smokers and Non Smokers - A Comparativestudy

Electromagnetic energy radiated from mobile phone alters electrocardiographic records of patients with ischemic heart disease

Background:Electromagnetic energy radiated from mobile phones did not show significant effect on the blood pressure, heart rate, and electrocardiographic (ECG) parameters in animals and humans.Aim:This study aimed to investigate the effect of radiofrequency of mobile phone on the electrocardiographic parameters in patients with history of ischemic heart disease, taking into consideration the gender factor.Subjects and Methods:A total number of 356 participants (129 males and 227 females) were admitted in this study. They were grouped into: subjects without cardiac diseases (Group I), patients with ischemic heart disease (Group II), and patients with history of cardiac diseases not related to myocardial ischemia (Group III). Electrocardiogram was obtained from each patient when the mobile phone was placed at the belt level and over precordium in turn-off mode (baseline) and turn-on mode for 40 sec ringing. The records of ECG were electronically analyzed.Results:Prolongation of QTc interval was significantly observed in male gender of Groups I and III (P < 0.001). Male patients of Group II showed significant QTc interval prolongation (P = 0.01) and changes in the voltage criteria (P = 0.001). These changes were not observed in female patients with ischemic heart disease. The position of mobile at the belt level or over the precordium showed effects on the heart.Conclusions:The radiofrequency of cell phone prolongs the QT interval in human beings and it interferes with voltage criteria of ECG records in male patients with myocardial ischemia.

A randomized, crossover, placebo‐ and moxifloxacin‐controlled study to evaluate the effects of bosutinib (SKI‐606), a dual Src/Abl tyrosine kinase inhibitor, on cardiac repolarization in healthy adult subjects

Effects of therapeutic and supratherapeutic concentrations of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, on the corrected QT interval (QTc) in 60 healthy adults were assessed, according to ICH-E14 guidelines, in this 2-part, randomized, single-dose, double-blind, crossover, placebo- and open-label moxifloxacin-controlled study. Subjects received placebo, moxifloxacin and bosutinib 500 mg with food (therapeutic) in Part 1. In Part 2, subjects received placebo and bosutinib 500 mg plus ketoconazole (supratherapeutic). ANOVA compared baseline-adjusted QTc for bosutinib with placebo; and bosutinib plus ketoconazole with placebo plus ketoconazole. Primary endpoint was population-specific QT correction (QTcN). Secondary endpoints were Bazett QT correction (QTcB), Fridericia's formula QT correction (QTcF) and individual QT correction (QTcI). Upper bounds for 90% confidence intervals were <10 msec for the mean change in QTcN from placebo at all postdose time points, suggesting that mean therapeutic exposures (C(max) , 114 ng/mL; AUC, 2,330 ng · h/mL) and mean supratherapeutic exposures (C(max) , 326 ng/mL; AUC, 15,200 ng · h/mL) were not associated with QTc changes. Similar results were obtained for QTcB, QTcF and QTcI. No clinically relevant pharmacokinetic/pharmacodynamic relationship was observed between bosutinib concentrations and QTc. No subjects had QTcB, QTcF, QTcI or QTcN >450 msec or change from baseline >30 msec. In summary, therapeutic and supratherapeutic bosutinib exposures are not associated with QTc prolongation in healthy adults.

Cardiac QTc Interval Characteristics and Behavior in 995 Consecutive Hematopoietic Cell Transplantation Patients At a Single Institution

Abstract 1967 Introduction:The cardiac QT interval (QT) has gained deserved scrutiny among electrophysiologists. Reflecting the duration of the ventricular myocardial depolarization/repolarization cycle, the QT depends upon ion exchange across cardiomyocyte membranes. Ion flux perturbations (due to abnormalities of membrane-bound ion channel number, structure or function) can predispose to QT prolongation that, in turn, is associated with linearly increasing risks of ventricular tachy-arrhythmias and sudden death. As both polypharmacy and dys-electrolytemia have been reported to affect QT, we studied the interval's behavior in the potentially at-risk population of children and adults undergoing hematopoietic cell transplantation (HCT). Methods:We retrospectively reviewed over 2600 cardiologist-evaluated electrocardiograms (ECG) and transplant-related data for 995 consecutive children and adults undergoing HCT between 2006 and 2010, inclusive. Patients underwent routine pre-HCT ECG screening; repeat studies were obtained for various clinical indications. Corrected QT intervals (QTc) were noted; any study demonstrating non-sinus rhythm was disregarded. Multivariate regression models tested the association between QTc and other patient or transplant-related covariates (including age, gender, primary diagnosis, intensity of conditioning, and donor relatedness/graft-versus host disease prophylaxis for allograft recipients); reference groups representing fixed covariate characteristics were defined among the cohort for comparison. Student's t-test was used to determine the significance of aggregate intra-patient change in QTc from pre- to post-HCT. Results:Pre-HCT: 952 patients had an evaluable pre-HCT maximum QTc observed at a median Day −22. Median QTc was 428 ms (range, 330 to 569; interquartile range [IQR], 409 to 447). Statistically significant QTc variability with age was observed and reflected widely accepted age-dependent phenomena in the population-at-large. Factors predicting shorter QTc included male gender (-11 ms compared to reference group [CRG], p < 0.01) and inherited metabolic disorder (IMD) as HCT indication (-10 ms CRG, p = 0.03). Factors predicting longer QTc were myeloproliferative disorder (+22 ms CRG, p = 0.01) and acute myeloid leukemia (+7 ms CRG, p = 0.02) as HCT indications.Post-HCT: 578 patients had an evaluable post-HCT maximum QTc observed at a median Day +69. Median QTc was 454 ms (range, 367 to 619; IQR, 433 to 476). Age was not significantly predictive of maximum QTc post-HCT. Factors predicting shorter QTc were male gender (-7 ms CRG, p = 0.05) and no exposure to mycophenolate mofetil (MMF) for graft-versus-host disease (GvHD) prophylaxis (-11 ms CRG; p = 0.05). Patients diagnosed with acute lymphoblastic leukemia (ALL) demonstrated longer QTc (+17 ms CRG, p = 0.03).δQTc: 559 patients had at least one evaluable pre- and one evaluable post-HCT ECG. The median δQTc (defined per patient as [mean post-HCT QTc] - [mean pre-HCT QTc]) was 15.7 ms (range, −72 to 142; IQR, −2 to 32). A highly significant difference between post-HCT and pre-HCT QTc per patient was observed in this cohort (p < 0.01).Very Long QTc: 92 (15%) males demonstrated QTc ≥ 480 ms and 39 (10%) females demonstrated QTc ≥ 500 ms on any ECG. Of patients with ≥ 2 evaluable ECGs, 306 (50%) demonstrated prolongation ≥ 40 ms. Factors significantly predicting extreme prolongation included age < 1 year (+39 ms CRG, p < 0.01) and diagnosis of ALL (+15 ms CRG, p = 0.04); a trend toward more extreme prolongation was seen in patients with myelodysplastic syndrome (+14 ms CRG, p = 0.05). The factor protecting from extreme QTc prolongation was treatment with a related allograft (-9 ms CRG, p = 0.03); trends toward less extreme prolongation were also seen in autologous HCT and those not receiving MMF for GvHD prophylaxis. Conclusion:Prolonged QTc is associated with life-threatening ventricular tachy-arrhythmias. This retrospective analysis of a large, diverse HCT cohort shows statistically significant prolongation during transplantation. Too, we identify sub-populations demonstrating very-long QTc and/or experiencing marked QT prolongation during HCT. Further analysis regarding pharmacologic, electrolytic and HCT-related predictors as well as outcomes for the cohort is underway. Disclosures:No relevant conflicts of interest to declare.