Changes In QT Interval Research Articles

Comparison of Manual and Automated Measurements of the QT Interval in Healthy Volunteers: An Analysis of Five Thorough QT Studies

We analyzed five crossover, thorough QT (TQT) studies to compare automated, manual, and computer-assisted (CA) measurement methods. All the methods detected moxifloxacin-induced, baseline-adjusted, placebo-subtracted mean changes in Fridericia-corrected QT interval (QTcF), with peak effect ranging from 10 to 21 ms. The variability associated with manual and CA measurements was generally 5-28% greater than that associated with automated methods. The performances of automated, manual, and CA measurements were comparable for the purpose of demonstrating assay sensitivity in TQT studies with healthy volunteers.

Effect of different intra-abdominal pressure levels on QT dispersion in patients undergoing laparoscopic cholecystectomy

Hemodynamic changes caused by carbon dioxide (CO(2)) insufflation occur frequently in patients who undergo laparoscopic surgery. One indicator of these changes is corrected QT dispersion (QTcd), an index of myocardial function. Prolongation of QTcd has been associated with cardiovascular morbidity and mortality. We compared the effects of high-pressure (15 mmHg) and low-pressure (7 mmHg) CO(2) pneumoperitoneums on the QT interval, the rate-corrected QT interval (QTc), the QT dispersion (QTd), and the corrected QT dispersion (QTcd) during laparoscopic cholecystectomy. Twenty consecutive patients were in a low-pressure pneumoperitoneum group and 32 were in a high-pressure pneumoperitoneum group. A 12-lead electrocardiogram was used to monitor cardiac variables. In all patients, serial electrocardiograms were recorded before anesthesia induction (baseline), immediately after the pneumoperitoneum had been created, every 15 minutes during CO(2) insufflation, and 5 minutes after deflation. Two observers measured the QT intervals independently, and the QTcd was calculated using Bazett's formula. The QT interval and the QTc interval did not change significantly during the study in either group. The QTd and QTcd in the high-pressure pneumoperitoneum group increased significantly during CO(2) insufflation and were significantly higher in the high-pressure pneumoperitoneum group compared with the low-pressure pneumoperitoneum group. Changes caused by CO(2) insufflation were reversible. Statistically significant increases of QTd and QTcd, which are associated with an increased risk of arrhythmias and cardiac events, occur during CO(2) insufflation in both high-pressure and low-pressure pneumoperitoneums. QTd and QTcd were significantly higher in the high-pressure pneumoperitoneum group than they were in the low-pressure pneumoperitoneum group. QT interval changes were not related to anesthetic agents, surgical stress, hypercapnia, or duration of CO(2) insufflation. Increased intra-abdominal pressure may have caused these changes.

Effects of Standard and Supratherapeutic Doses of Nelfinavir on Cardiac Repolarization: A Thorough QT Study

This was a randomized, 4-way crossover, third-party-blinded study in 68 healthy subjects to assess the effect of nelfinavir on QTc interval. Treatments included (A) nelfinavir 1250 mg every 12 hours on days 1-4, (B) nelfinavir 1250 mg every 12 hours on days 1-3 plus 3125 mg on day 4, (C) placebo, and (D) moxifloxacin 400 mg every 24 hours on days 1-4. Pharmacokinetics and triplicate 12-lead electrocardiograms were performed over 12 hours on days 1 and 4. Time-matched, placebo-subtracted, baseline-adjusted changes in QT intervals with Fridericia's (QTcF) correction were determined following nelfinavir and moxifloxacin administration. Neither dose of nelfinavir had a clinically relevant effect on the QTcF interval on day 4 (primary endpoint) and day 1 because at every time point the upper 90% confidence limit was below 10 milliseconds and, furthermore, the mean difference was below 5 milliseconds. Additionally, there was no clinically relevant effect on QTcB (Bazett's correction), uncorrected QT, or the RR interval on days 1 or 4. Pharmacokinetics confirmed adequate systemic exposure to nelfinavir and moxifloxacin. While nelfinavir exposure was higher in poor compared with extensive metabolizers of CYP2C19 isozyme, there were no corresponding significant differences in QTcF change from placebo. At clinically relevant, doses nelfinavir is unlikely to cause QTc prolongation.

Epinephrine-Induced Polymorphic Ventricular Tachycardia in a Patient With Congenital Long QT Syndrome

A 24-year-old woman presented to the department of plastic surgery for surgical excision of a nevus on her nose. Although her history failed to reveal any cardiac disease, her pre-operative electrocardiogram (ECG) showed an extremely prolonged QT interval of up to 528 msec. Repeated history-taking after admission revealed three syncopal episodes associated with both physical and emotional stress, and because the two-dimensional echocardiography and exercise ECG test were normal except for the prolonged QT interval, an epinephrine test was done to assess QT interval changes after an epinephrine infusion. Immediately after a bolus injection of epinephrine (0.1 µg/kg), marked prolongation of the QT interval developed, followed by polymorphic ventricular tachycardia which was immediately terminated with direct current shock, resulting in the diagnosis of a long QT syndrome (LQTS), probably type 1. Gene studies were recommended, but declined by the patient and her family. She was instructed to avoid competitive sports, and a β-blocker was prescribed after which she remained symptom-free.

Prolongation in QT interval is not predictive of Ca2+-dependent arrhythmias: implications for drug safety

Background: Voltage-gated ion channels are the main providers of drug-induced delayed repolarization and, therefore, first line targets in cardiac safety assessments. Objectives/methods: We review mechanisms of drug-induced ventricular arrhythmias that may be associated with sudden cardiac death. We focus on Ca2+-dependent mechanisms with drug safety concerns. Results: Early afterdepolarizations occur during abnormally prolonged action potential repolarization. QT interval measurement is commonly used to assess the proarrhythmic risk of a drug. However, delayed afterdepolarizations are triggered by intracellular Ca2+ overload and/or abnormal spontaneous openings of ryanodine receptors in diastole. A drug promoting alterations of Ca2+ handling may be pro-arrhythmogenic without QT interval change at rest. Conclusion: Ca2+-dependent arrhythmia should be investigation matter in drug safety evaluation.

Can we prevent ondansetron induced fatal ventricular tachycardia?

Sir, We have read with interest the article ‘Ondansetron induced fatal ventricular tachycardia’ by Chandrakala et al., published in the Indian Journal of Pharmacology, August 2008. We would like you to give us the opportunity to discuss some of our observations on the same. Ondansetron is a racemic compound having one chiral centre. Racemic Ondansetron is a 50:50 mixture of two enantiomers, R-Ondansetron and S-Ondansetron. In one animal study (in dogs), effects of R-Ondansetron, S-Ondansetron and racemic Ondansetron on cardiac arrhythmias (cardiotoxicity) were evaluated. QTc interval was most prolonged among animals receiving S-Ondansetron and racemic Ondansetron and was shortest among animals receiving R-Ondansetron. Based on these results it was reported that R-Ondansetron has less cardiotoxicity than S-Ondansetron or racemic Ondansetron.[1] Bodhankar et al. in 2006 studied the effect of racemic Ondansetron, R-Ondansetron and S-Ondansetron on QTc interval in electrocardiograms of rats. The Ondansetron and its enantiomers were administered IV in a dose of 3 mg/Kg and changes in QT and RR interval and heart rate were calculated. The results of this study showed that racemic Ondansetron and S-Ondansetron significantly prolonged QTc interval, while R-Ondansetron did not prolong QTc interval as compared to the vehicle treated group. They concluded that R-Ondansetron is safer on the heart. Authors reported that S-Ondansetron might have higher inhibitory effects on Bezold-Jarisch reflex and this might be the reason for QTc prolongation with S-Ondansetron and racemic Ondansetron.[2] A multicentric, randomized, double-blind, parallel group, comparative study on efficacy and safety of R-Ondansetron 4 mg versus racemic Ondansetron 8 mg in 240 Indian patients with nausea and vomiting concluded that R-Ondansetron 4 mg BID was equally effective compared to racemic Ondansetron 8 mg BID with a slightly better safety profile compared to racemic Ondansetron.[3] This suggests that the S-Ondansetron component can be omitted without loss of efficacy. Efficacy and safety of R-Ondansetron solution was also studied in 410 pediatric patients confirming R-Ondansetron solution is safe and effective in pediatric patients with nausea and vomiting.[4] From the above discussion it is clear that R-Ondansetron 4 mg alone is sufficient for its anti-emetic potential and is preferable without its counterpart – the S-isomer which can prolong the QTc. So switching from racemic Ondansetron to R-Ondansetron is a rational therapeutic approach. R-Ondansetron has been approved by the DCGI on 15th April 2005 and is available as tablets (2 mg/4 mg), solution (1 mg/5 ml) and injection (1 mg/ml).

Regadenoson, a Novel Pharmacologic Stress Agent for Use in Myocardial Perfusion Imaging, Does Not Have a Direct Effect on the QT Interval in Conscious Dogs

Our goal was to determine the effect of regadenoson (a novel A2A adenosine receptor agonist) on the QT interval in conscious dogs. Sixteen mongrel dogs were chronically instrumented for measurements of blood pressure and ECG. Regadenoson (2.5, 5, and 10 microg/kg, IV) caused a dose-dependent QT interval shortening (DeltaQT: 14 +/- 3, 24 +/- 5, and 27 +/- 5 ms, mean +/- SEM; n = 7 to 11; all P < 0.05) associated with significant increases in HR (Peak HR: 114 +/- 9, 125 +/- 6, and 144 +/- 7 bpm). Atrial pacing (135, 150, and 165 bpm) also caused a frequency-dependent shortening of the QT interval (DeltaQT: 15 +/- 3, 22 +/- 3, and 39 +/- 5 ms; n = 6 to 7; all P < 0.05). Regadenoson- and pacing-induced shortenings in the QT interval were significantly correlated with the R-R interval (r = 0.67 and 0.8, both P < 0.05). Regadenoson at 5 and 10 microg/kg did not cause a significant change in HR or QT interval either during atrial pacing at 165 bpm or after administration of propranolol and atropine to prevent HR from changing or after treatment of dogs with hexamethonium to block autonomic ganglia. Regadenoson (5 to 10 microg/kg) caused no significant changes of QT interval in the heart in which HR was kept constant via physiological or pharmacological procedures, indicating that regadenoson has no direct effect on the QT interval.

Abstract 2965: QT Interval Prolongation during Severe Acute Rejection is Predictive of Sudden Cardiac Death in Heart Transplant Recipients

Background. QT interval prolongation is considered a risk factor for sudden cardiac death (SCD) in various non-transplant populations. Since acute allograft rejection is associated with a prolonged QT interval, we sought to investigate the effects of rejection-induced QT interval changes on SCD in heart transplant recipients. Methods. Of all patients who underwent heart transplantation between 1998 and 2007, we enrolled those with severe acute cellular rejection episodes (ISHLT grade 3A or higher, accompanied with hemodynamic compromise). In this cohort, baseline ECGs were obtained within 7 days after transplantation; follow-up ECGs were recorded at the time of the rejection episode. On all ECGs, QT interval was defined as the mean duration QT interval measurements in all leads, and corrected for heart rate with Bazett formula. A significant increase of QTc during rejection (dQTc) was defined as a relative change in QTc ≥10%. Patients were followed for SCD for 1 year after the rejection episode. Results. Of 80 patients with a severe rejection episode, 9 (11%) were excluded because of the inadequate quality of ECG recordings. Within the 1-year follow-up, 21 of 71 (30%) patients died. Of these, 14 (67%) died of SCD, and 7 (23%) died of other causes. Patients who died of SCD and survivors did not differ with regards to age (44 ± 12 years in SCD group vs. 46 ± 16 years in survivors, P = 0.61), gender (male: 83% vs. 58%, P = 0.06), incidence of infections (0.21 ± 0.43 vs. 0.20 ± 0.40, P = 0.91), malignancy (0% vs. 8%, P = 0.84), or allograft vasculopathy (29% vs. 26%, P = 0.85). No difference in Qtc prolonging drug was noted. During acute rejection, QTc interval was significantly longer in SCD group than in survivors (475 ± 57 ms vs. 437 ± 36 ms, P = 0.01), and the same was true for the incidence of dQTc &gt; 10% (50% vs. 16%, P = 0.008). SCD-free survival as evaluated by Kaplan-Meier analysis was significantly lower in patients with dQTc &gt; 10% (P = 0.013). On multivariate analysis, dQTc &gt; 10% was the only independent predictor of SCD (P = 0.02). The multivariate model included left ventricular dysfunction (LVEF &lt; 30%) and dQTc. Conclusion. Heart transplant recipients who display a significant (&gt; 10%) prolongation of QT interval during a severe acute rejection episode may be at increased risk for SCD.

Effect of follicle stimulating hormone and clomiphehne citrate on heart rate and QT intervals in women undergoing ovulation induction

OBJECTIVE: This study was designed to evaluate the effect of rising estradiol concentration on QT interval in women undergoing ovulation induction. DESIGN: 87 cycles received FSH alone, 59 cycles FSH plus clomiphene citrate (FSH/CC), and 49 cycles CC alone. MATERIALS AND METHODS: In patients receiving FSH, an EKG and E2 value were obtained at the onset of menses. FSH was begun on day 2. At follicular maturation a follow-up EKG and E2 were obtained. In the CC group an EKG was obtained at the onset of menses. Clomiphene was begun on day 3 for five days. At follicular maturity a follow-up EKG was obtained. Patients receiving FSH/CC had a baseline EKG and E2 level. CC was administered days 3-7 with FSH days 8, 9, 10. A follow-up EKG and E2 determined at follicular maturity. RR and QT intervals were measured and QTc was calculated using Bazett's formula QTc= QT/(R-R)1/2. RESULTS: In the FSH group the RR interval shortened after treatment (836+/−87 vs 791+/−87; p=.01). No change in heart rate was found in the other two groups. In the FSH group, a small but significant increase in the QTc was noted after treatment (pre-treatment 402+/−18 vs post-treatment 409+/−15; p=.002). No significant change was seen in the other two treatment groups. No significant change in the QT interval was seen in any of the three groups. There was no difference in age or maximum E2 concentration achieved between the FSH group and the FSH/CC group. However, the amount of FSH administered per patient was significantly greater in the FSH group compared to the FSH/CC group (1718 units vs. 741 units). In addition, the number of days exposed to FSH was greater in the FSH group compared to the FSH/CC group (9.2 days vs. 5.7 days). In the FSH group, no correlation was found between the change in QTc and the maximum E2 achieved. Similarly, no correlation was found between the change in QTc and the dose of FSH administered nor in days exposed to FSH. CONCLUSIONS: This study demonstrated a mild increase in heart rate, a minimal increase in QTc interval, and no change in QT interval in women treated with FSH. This effect was not seen in either group of patients treated with CC. Inhibition of estrogen receptors by CC prior to administration of FSH may explain the absence of the heart rate effect in the group who received both CC and FSH. These findings suggest that estrogen causes a mild increase in heart rate resulting in an increase in the QTc without affecting the QT interval.

Predicting drug‐induced changes in QT interval and arrhythmias: QT‐shortening drugs point to gaps in the ICHS7B Guidelines

Background and purpose:The regulatory guidelines (ICHS7B) recommending inhibition of the delayed rectifier K+ current (IKr), carried by human ether-a-go-go-related gene (hERG) channels in cardiac cells (the hERG test), as a ‘first line' test for identifying compounds inducing QT prolongation, have limitations, some of which are outlined here.Experimental approach:hERG current was measured in HEK293 cells, stably transfected with hERG channels; action potential duration (APD) and arrhythmogenic effects were measured in isolated Purkinje fibres and perfused hearts from rabbits.Key results:576 compounds were screened in the hERG test: 58% were identified as hERG inhibitors, 39% had no effect and 3% were classified as stimulators. Of the hERG inhibitors, 92 were tested in the APD assay: 55.4% of these prolonged APD, 28.3% had no effect and 16.3% shortened APD. Of the 70 compounds without effect on hERG channels, 54.3% did not affect APD, 25.7% prolonged, while 20% significantly shortened APD. Dofetilide (hERG inhibitor; IC50, 29 nM) prolonged QT and elicited early after-depolarizations and/or torsade de pointes (TdP) in isolated hearts. Mallotoxin and NS1643 (hERG current stimulators at 3 μM), levcromakalim and nicorandil (no effect on hERG current), all significantly shortened APD and QT, and elicited ventricular fibrillation (VF) in isolated hearts.Conclusion and implications:The hERG assay alone did not adequately identify drugs inducing QT prolongation. It is also important to detect drug-induced QT shortening, as this effect is associated with a potential risk for ventricular tachycardia and VF, the latter being invariably fatal, whereas TdP has an ∼15–25% incidence of death.

Effect of Aldehyde Dehydrogenase‐2 Genotype on Cardiac Autonomic Nervous Responses to Moderate Alcohol Ingestion

Asian people are divided into the individuals who can ingest alcohol and cannot because of the difference of aldehyde dehydrogenase-2 (ALDH2) genotype. The purpose of the present study was to investigate the effect of ALDH2 genotype on cardiac autonomic nervous responses to moderate alcohol ingestion. Subjects were 17 healthy male students at Kyoto University. According to the difference of ALDH2 genotype, they were divided into two groups: the STRONG (n = 10) and WEAK (n = 7) group. The subjects ingested 10 (the LITTLE trial) or 30 g (the MUCH trial) of pure alcohol on a separate day randomly. We collected ECG data and analyzed QT interval. ECG QT interval, the important marker for sudden cardiac death in cardiac patients as well as healthy people, of the STRONG group were not prolonged after alcohol ingestion, but that of the WEAK group were significantly prolonged, compared to control. Moreover, with respect to the comparison of the change of QT interval between the LITTLE and MUCH trials, there were also no significant differences in the STRONG group. In the WEAK group, however, the change was more marked at MUCH trial. It is concluded that the cardiovascular response to alcohol ingestion is influenced by ALDH2 genotype and that the drinking assumed to be in moderation puts a strain on the hearts for the ALDH2-deficient individuals. The results of this investigation show that moderate drinking does not have a good effect on everybody with respect to QT interval. This study also shows that moderate alcohol intake does not have a bad effect on the immune system regardless of ALDH2 genotype.

Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction

KAI-9803, a delta-protein kinase C inhibitor, has been shown to ameliorate injury associated with ischemia and reperfusion in animal models of acute myocardial infarction (MI). Direct Inhibition of delta-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) was a "first-in-human," dose-escalation study that evaluated the safety, tolerability, and activity of KAI-9803 for patients with acute anterior ST-segment elevation MI undergoing primary percutaneous coronary intervention. Patients who presented within 6 hours of symptom onset and had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion to receive 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. Safety and biomarker end points were assessed. Overall, 154 patients were randomized and treated with study drug (37 in cohort 1, 38 in cohort 2, 38 in cohort 3, 41 in cohort 4). The incidence of serious adverse events was similar between patients treated with KAI-9803 versus placebo. Other safety end points, including changes in QT intervals and standard laboratory values after study drug administration, were similar between treatment groups. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in creatine kinase-MB area under the curve and ST-recovery area under the curve values across all dosing cohorts with KAI-9803 compared with concurrent placebo, and similar trends were demonstrated for improvements in (99m)technetium sestamibi infarct size values with active study drug in cohorts 1, 2, and 3. KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation MI. Signs of potential drug activity were demonstrated with biomarker end points in this small exploratory study, indicating that further testing of KAI-9803 as an adjunctive therapy for ST-segment elevation MI is warranted.

Twelve-lead electrocardiogram monitoring of subjects before and after voluntary exposure to the Taser X26

Objectives The Taser (Taser International, Scottsdale, Ariz) uses high-voltage electricity to incapacitate subjects. We sought to evaluate cardiac rhythm changes during deployment of the Taser on healthy volunteers. Methods This prospective study was performed on 32 healthy volunteer subjects receiving a Taser X26 discharge. The subjects had baseline 12-lead electrocardiogram (ECG) monitoring performed immediately before and within 1 minute after the Taser discharge. Changes in cardiac rhythm, morphology, and interval duration were evaluated. Descriptive statistics and paired-sample t test comparisons are reported. Results All 32 subjects had an interpretable 12-lead ECG obtained before and after the Taser activation, although 1 subject's post–PR interval could not be determined. The mean age and body mass index were 33 years and 26.5 kg/m 2, respectively. Overall, there was a significant increase in heart rate (2.4; 95% confidence interval [CI], 0.0-4.9) and a decrease in PR interval (−6.5; 95% CI, −9.7 to −3.3). When stratified by sex, only the PR interval in men significantly decreased (−5.9; 95% CI, −9.2 to −2.5). There were significant changes in heart rate (4.0; 95% CI, 1.3-6.7), PR interval (−6.0; 95% CI, −11.3 to −0.7), and QT interval (−18.8; 95% CI, −33.2 to −4.3) among those with a normal body mass index, and in PR interval among those who were overweight/obese (−6.7; 95% CI, −10.8 to −2.5). None of the statistically significant differences between ECG measures were clinically relevant. Conclusions There were no cardiac dysrhythmia and interval or morphology changes in subjects who received a Taser discharge based on a 12-lead ECG performed immediately before and within 1 minute after a Taser activation.

Effect of calcium-channel antagonist on repolarization heterogeneity of ventricular myocardium in an in vitro rabbit model of long QT syndrome

Intracellular Ca(2+) and Ca(2+)-dependent signaling molecule play an essential role in the genesis of long-QT (LQT) syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repolarization heterogeneity of ventricular myocardium was assessed in an in vitro rabbit model of LQT syndrome. By using the monophasic action potential (MAP) recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall in rabbit hearts perfused by Langendorff method with standard Tyrode's solution. Bradycardia was induced by complete ablation of atrioventricular node. A catheter was introduced into the right ventricle to pace at the cycle lengths (CLs) of 1500, 1000, and 500 ms, successively. Quinidine (2 micromol/L) prolonged QT interval and ventricular MAP duration (MAPD), and increased transmural dispersion of repolarization (TDR) in a reverse rate-dependent fashion in isolated rabbit heart. No polymorphic ventricular tachycardias were induced under this condition. The effective free therapeutic plasma concentrations of verapamil (0.01-0.05 micromol/L) used in this experiment had no effect on quinidine-induced changes of QT interval, MAPD and TDR. This study demonstrated that, in this model of LQT syndrome, blockade of calcium-channel with verapamil had no effect on quinidine-induced changes of repolatiation heterogeneity of ventricular myocardium.

Aging-related changes of QT and RR intervals in conscious guinea pigs

Introduction Although guinea pigs are suitable for in vivo QT assessment of newly discovered drugs at the pre-clinical stage because of the similarity of the ion channels between the guinea pig heart and the human, there is limited data available regarding the characteristics of QT interval in conscious guinea pigs. Aging is one of several factors which have been shown to affect the QT interval in humans and animals. In the present study, we examined the influence of age on QT and RR intervals in conscious guinea pigs. Methods Electrocardiograms were recorded from female Hartley guinea pigs at the age of 6 weeks (young; n = 6) and 23 months (old; n = 4) via a telemetry system. The QT and RR intervals were measured during daytime and nighttime, and following intravenous bolus injection of E-4031 (0.1 mg/kg) or terfenadine (4 mg/kg). Comparisons were made to determine group differences in: (1) the normal values of the QT and RR intervals, (2) the best-fit QT-correction formula, (3) the circadian rhythm of QT and RR intervals, and (4) drug effects on repolarization. Results The normal values of QT and RR intervals in the old group were significantly longer than those in the young group. The best-fit formula for correcting QT interval was a modified Bazett's formula for both young and old groups. The old group did not show the nocturnal variation of either QT or RR interval. Terfenadine caused significantly greater QTc prolongation in the old group compared to the young. Discussion Aging affects resting QT and RR intervals in conscious female guinea pigs, a factor which should be considered when examining the effects of compounds on cardiac repolarization. Also, the present study suggests a possibility that age can affect QTc prolongation induced by some IKr blockers.

Haloperidol is as effective as ondansetron for preventing postoperative nausea and vomiting

Recent warnings regarding the safety of droperidol have limited use of this drug as an antiemetic. Haloperidol, a butyrophenone derivative similar to droperidol, has not been rigorously evaluated as an antiemetic. The aim of this study was to compare the prophylactic antiemetic efficacy of haloperidol vs ondansetron for the prevention of postoperative nausea and vomiting (PONV) after general anesthesia. Ninety non-smoking female patients were eligible to participate in this randomized double-blinded study. Approximately 30 min before the end of surgery, patients were randomly assigned to receive either haloperidol 2 mg iv, or ondansetron 4 mg iv, respectively. The incidence of PONV, average pain and sedation scores, recovery times, and changes of the rate-corrected QT (QTc) interval were observed postoperatively. The proportion of patients who experienced PONV in the first 24 hr was similar in the two groups (28% and 26% for haloperidol and ondansetron groups, respectively). The incidence of PONV was significantly less in both groups than predicted according to the patients' underlying risks (53% for the haloperidol group, P=0.016; 51% for the ondansetron group, P=0.015). Pain scores, sedation scores, and recovery times were similar in the two groups, and no prolongation of the QTc interval was observed in either group. Haloperidol 2 mg iv given 30 min before the end of surgery is effective in preventing PONV, with efficacy comparable to ondansetron 4 mg iv for the first 24 hr after general anesthesia.

Biventricular Pacing and QT Interval Prolongation

The purpose of this study was to examine BiV pacing-dependent changes in QT interval and the related potential for proarrhythmia. Biventricular (BiV) pacing has emerged as a promising therapy for patients with advanced congestive heart failure (CHF) and bundle branch block (BBB). One hundred and seventy-six consecutive patients (123 men and 53 women; mean age 67 +/- 16 years) with ischemic (n = 128) or nonischemic (n = 48) cardiomyopathy in New York Heart Association Class II (8%) or III (92%) CHF (ejection fraction 24 +/- 9%) underwent atrial synchronous BiV pacing. The QRS, QT, and JT intervals were measured at 30 minutes after initiation of BiV pacing, at 24 hours, and at 1 month postimplant. QT interval was defined as the time interval between the initial deflection of the QRS complex and the point at which the T wave crossed the isoelectric line. At baseline, the average QRS duration was 178 +/- 10 ms, attributable to left BBB (n = 158) or intraventricular conduction delay (n = 18). BiV pacing resulted in a small but statistically significant reduction in QRS duration (148 +/- 9 ms during BiV pacing vs 178 +/- 10 ms at baseline [P < 0.0001]), yet the QT increased to 470 +/- 34 ms with BiV pacing versus 445 +/- 32 ms at baseline [P < 0.0001]). The JTc interval during BiV pacing was significantly shorter than during LV pacing (290 +/- 9 ms vs 320 +/- 20 ms, P < 0.0001). During a mean follow-up of 24 +/- 6 months, one patient developed recurrent torsade de pointes. That was eliminated once left ventricular pacing was discontinued. Biventricular pacing prolongs QT interval. However, the occurrence of torsade de pointes is uncommon.

The Prokinetic Cinitapride Has No Clinically Relevant Pharmacokinetic Interaction and Effect on QT during Coadministration with Ketoconazole

The present clinical trial was designed to evaluate the possible pharmacokinetic and electrocardiographic interactions of the gastroenteric prokinetic drug cinitapride with ketoconazole. The safety and tolerability of the study treatments were also evaluated. After a placebo-controlled, double-blind, crossover design, 16 healthy male (n = 8) and female (n = 8) volunteers were randomized into four treatment groups of four subjects (two males and two females): cinitapride (CTP; 1 mg t.i.d.) + ketoconazole (KET; 200 mg b.i.d.), CTP + placebo (PL), PL+KET, and PL+PL. Treatments were given for 7 days with a washout period of 14 days between crossover treatments. Cinitapride is rapidly absorbed after oral administration and is metabolized by the cytochrome P450 CYP3A4 and CYP2C8 isozymes. At steady state, coadministration with ketoconazole, a potent CYP3A4 inhibitor, increased mean C(max,ss) and AUC(tau) by 1.63- and 1.98-fold, respectively. Measurement of mean QTc interval or baseline-corrected QTc intervals on day 7 showed small increases that were due to the effects of ketoconazole alone. Comparing CTP+KET versus PL+KET, the differences between mean increases in the QTc parameters were always less than 2 ms. Finally, no outlier increase of the QTc interval versus baseline >60 ms was identified after any treatment. The study showed that cinitapride, either given alone or after coadministration with ketoconazole 200 mg b.i.d., had no effect on cardiac repolarization as measured by changes in the heart rate-corrected QT interval on the surface electrocardiogram.

Chronic Arsenic Exposure and Cardiac Repolarization Abnormalities with QT Interval Prolongation in a Population-based Study

BackgroundChronic arsenic exposure is associated with cardiovascular abnormalities. Prolongation of the QT (time between initial deflection of QRS complex to the end of T wave) interval and profound repolarization changes on electrocardiogram (ECG) have been reported in patients with acute promyelocytic leukemia treated with arsenic trioxide. This acquired form of long QT syndrome can result in life-threatening arrhythmias.ObjectiveThe objective of this study was to assess the cardiac effects of arsenic by investigating QT interval alterations in a human population chronically exposed to arsenic.MethodsResidents in Ba Men, Inner Mongolia, have been chronically exposed to arsenic via consumption of water from artesian wells. A total of 313 Ba Men residents with the mean arsenic exposure of 15 years were divided into three arsenic exposure groups: low (≤ 21 μg/L), medium (100–300 μg/L), and high (430–690 μg/L). ECGs were obtained on all study subjects. The normal range for QTc (corrected QT) interval is 0.33–0.44 sec, and QTc ≥ 0.45 sec was considered to be prolonged.ResultsThe prevalence rates of QT prolongation and water arsenic concentrations showed a dose-dependent relationship (p = 0.001). The prevalence rates of QTc prolongation were 3.9, 11.1, 20.6% for low, medium, and high arsenic exposure, respectively. QTc prolongation was also associated with sex (p < 0.0001) but not age (p = 0.486) or smoking (p = 0.1018). Females were more susceptible to QT prolongation than males.ConclusionsWe found significant association between chronic arsenic exposure and QT interval prolongation in a human population. QT interval may potentially be useful in the detection of early cardiac arsenic toxicity.

The changes of electrocardiography and signal-averaged electrocardiography after surgical repair of Tetralogy of Fallot

Purpose : The purpose of this study was to analyze the changes of the late potential of Signal- averaged electrocardiography (SAECG) and Electrocardiography (ECG) parameters during follow up of those who had taken surgical repair of Tetralogy of Fallot (TOF). Methods : Nine patients who had taken surgical repair of TOF since 1985 checked SAECG and standard 12 leads ECG twice in 1999 and 2005 in Kyungpook national university hospital. We evaluated changes of QRS duration, QT interval and JT interval, QRS dispersion, QT dispersion and JT dispersion of standard 12 leads ECG and Filtered QRS (f-QRS), High frequency low amplitude potential (HFLA), Root mean square in terminal 40 ms (RMS) and Mean voltage in terminal 40 ms (MV) of SAECG between in 1999 and 2005. Results : There were significant decrease of JT dispersion (101.11±50.11 vs 71.11±22.61 ms, P