Uncorrected QT Interval Research Articles

Physiological effects following administration of Citrus aurantium for 28 days in rats

BackgroundSince ephedra-containing dietary supplements were banned from the US market, manufacturers changed their formulations by eliminating ephedra and replacing with other botanicals, including Citrus aurantium, or bitter orange. Bitter orange contains, among other compounds, synephrine, a chemical that is chemically similar to ephedrine. Since ephedrine may have cardiovascular effects, the goal of this study was to investigate the cardiovascular effects of various doses of bitter orange extract and pure synephrine in rats. MethodFemale Sprague–Dawley rats were dosed daily by gavage for 28days with synephrine from two different extracts. One extract contained 6% synephrine, and the other extract contained 95% synephrine. Doses were 10 or 50mg synephrine/kg body weight from each extract. Additionally, caffeine was added to these doses, since many dietary supplements also contain caffeine. Telemetry was utilized to monitor heart rate, blood pressure, body temperature and QT interval in all rats. Results and conclusionSynephrine, either as the bitter orange extract or as pure synephrine, increased heart rate and blood pressure. Animals treated with 95% synephrine showed minimal effects on heart rate and blood pressure; more significant effects were observed with the bitter orange extract suggesting that other components in the botanical can alter these physiological parameters. The increases in heart rate and blood pressure were more pronounced when caffeine was added. None of the treatments affected uncorrected QT interval in the absence of caffeine.

Effect of Transient Myocardial Ischemia on QT Interval Dispersion Among Patients with Unstable Angina

Objective : Our aim was to examine the effect of transient myocardial ischemia on QT interval and QT interval dispersion in patients presenting with unstable angina. Methods : We studied 31 patients (mean age 64±10, 22 men, 16 with an old myocardial infarction, 6 with previous coronary bypass surgery) admitted with unstable angina manifestations. Patients with a history of complex ventricular ectopy, malignant ventricular arrhythmias, advanced congestive heart failure or antiarrhythmic drug therapy were excluded. The uncorrected and corrected QT interval and QT dispersion were measured during angina as well as after the relief of pain. Results: The RR intervals were not significantly changed by the ischemic event (879±121 ms at rest to 877±173 ms during angina). However, both the uncorrected and corrected QT intervals were significantly increased during angina (from 410±45 ms and 440±41 ms at rest to 425±53 ms and 460±42 ms during angina respectively, p<0.05 for both). Similarly, both the uncorrected (QTd) and the corrected (QTcd) QT dispersion values were significantly prolonged during ischemia (QTd: 58±23 ms at rest to 83±33 ms during ischemia, p<0.001, QTcd: 63±26 ms at rest to 95±36 ms during ischemia, p<0.001). The observed increment in the QTd and QTcd provoked by ischemia was not different among the unstable angina patients with and without old myocardial infarction. Conclusion: Transient myocardial ischemia besides an increase in the QT and QTc intervals provokes an increase in both the corrected and uncorrected QT interval dispersion. Under certain circumstances, this may contribute to the genesis of serious reentry ventricular arrhythmias.

Comparison of QTinno, a fully automated electrocardiographic analysis program, to semiautomated electrocardiographic analysis methods in a drug safety study in healthy subjects

Background Improved automated methods for electrocardiographic (ECG) analysis are needed, particularly for drug development purposes. Objectives This study compared a novel fully automated method for ECG analysis (QTinno; NewCardio, Santa Clara, CA) to 2 semiautomated digital methods: global measurement from the earliest QRS onset to the latest T-wave offset on representative superimposed beats (global) and tangent measurement on 3 consecutive beats in one lead (tangent). Methods All 3 methods were used to determine uncorrected and rate-corrected QT interval duration (QT and QTcF) and related metrics in 1422 digital 12-lead ECGs from a phase 1 drug study. Global and tangent annotations were manually adjusted by the same 3 cardiologists wherever necessary. No adjustments were made in QTinno determinations. Results QTinno returned QTcF change from time-matched baseline (ΔQTcF) that differed minimally from both global and tangent methods (mean pairwise difference: 0.1 millisecond between QTinno and global, 1.1 milliseconds between QTinno and tangent). The average absolute QT and QTcF intervals by QTinno were approximately 5 milliseconds longer than global and 25 milliseconds longer than by tangent. QTinno had lower intrinsic variability for ΔQTcF than either global or tangent (between-subject SD: QTinno 4.0 milliseconds, global 5.6 milliseconds, tangent 6.4 milliseconds; within-subject SD: QTinno 4.8 milliseconds, global 7.4 milliseconds, tangent 10.6 milliseconds). All methods were robust in detecting the largest placebo-adjusted mean time-matched ΔQTcF (15-25 milliseconds) induced by study drug. Conclusions The methods show good agreement for drug-induced QTc prolongation. Lower intrinsic variability of ΔQTcF by QTinno could facilitate smaller sample sizes or increase study power in thorough QTc studies.

QT Prolongation Following Ectopic Beats: Initial Data Regarding The Upper Limit Of Normal With Possible Implications For Antiarrhythmic Therapy And Concealed (Unexpressed) Long QT.

The QT interval in normal subjects may prolong following premature complexes but not to a value in excess of 480 ms.

Heritability of QT Interval: How Much Is Explained by Genes for Resting Heart Rate?

Objective of this study was to determine the optimal (most heritable) phenotype for gene finding studies of QT interval in the general population. We also studied the extent to which heritability of QT interval can be explained by genes that also influence resting heart rate. Subjects in this classic twin study were 105 monozygotic and 256 dizygotic female twin pairs (mean age: 49.9 +/- 11.5). ECG parameters were measured electronically using the Cardiofax ECG-9020. Quantitative genetic modeling was performed with Mx software. Best-fitting univariate models showed significant heritabilities for resting heart rate (0.55, 95% CI: 0.44-0.65), uncorrected QT interval (0.60, 95% CI: 0.49-0.69), and the Framingham QTc interval (0.50, 95% CI: 0.39-0.60). Familial resemblance of Bazett's QTc was best explained by shared environmental factors (0.34, 95% CI: 0.24-0.43) rather than genes. Simultaneously modeling heart rate and the uncorrected QT interval confirmed considerable heritabilities of 56% and 60%, respectively. Forty-four percent of the variance in QT interval was due to genes in common with heart rate, whereas 16% was due to genes specific to QT interval. The heritability of QT interval after the removal of effects shared with heart rate within the bivariate model (cf. QTc) was 51%. About a quarter of the QT interval heritability is due to genes specific for QT interval, while the majority is shared with genes for heart rate. Differences in QTc heritability estimates indicate that use of correction formulae is best avoided in gene finding studies to avoid erroneous results.

Cardiac repolarization abnormalities and potential evidence for loss of cardiac sodium currents on electrocardiograms of patients with Chagas heart disease

Some individuals with Chagas disease develop right precordial lead ST segment elevation in response to an ajmaline challenge test, and the prevalence of right bundle branch block (RBBB) is also high in Chagas disease. Because these same electrocardiographic abnormalities occur in the Brugada syndrome, which involves genetically defective cardiac sodium channels, acquired damage to cardiac sodium channels may also occur in Chagas disease. We studied several conventional and advanced resting 12-lead/derived Frank-lead ECG parameters in 34 patients with Chagas -related heart disease (mean age 39 14 years) and in 34 age-/gender-matched healthy controls. All ECG recordings were of 5-10 min duration, obtained in the supine position using high fidelity hardware/software (CardioSoft, Houston, TX). Even after excluding those Chagas patients who had resting BBBs, tachycardia and/or pathologic arrhythmia (n=8), significant differences remained in multiple conventional and advanced ECG parameters between the Chagas and control groups (n=26/group), especially in their respective QT interval variability indices, maximal spatial QRS-T angles and low frequency HRV powers (p=0.0006, p=0.0015 and p=0.0314 respectively). In relation to the issue of potential damage to cardiac sodium channels, the Chagas patients had: 1) greater than or equal to twice the incidence of resting ST segment elevation in leads V1-V3 (n=10/26 vs. n=5/26) and of both leftward (n=5/26 versus n=0/26) and rightward (n=7/26 versus n=3/26) QRS axis deviation than controls; 2) significantly increased filtered (40-250 Hz) QRS interval durations (92.1 8.5 versus 85.3 plus or minus 9.0 ms, p=0.022) versus controls; and 3) significantly decreased QT and especially JT interval durations versus controls (QT interval: 387.5 plus or minus 26.4 versus 408.9 plus or minus 34.6 ms, p=0.013; JT interval: 290.5 plus or minus 26.3 versus 314.8 plus or minus 31.3 ms; p=0.0029). Heart rates and Bazett-corrected QTc/JTc intervals were not significantly different between groups. Patients with Chagas heart disease have increased cardiac repolarization abnormalities, especially by advanced ECG. Moreover, as a group, they have decreased uncorrected JT and QT interval durations and increased filtered QRS interval durations (versus age/gender-matched controls), all suggesting a potential loss of cardiac sodium channel function that might be mediated, in part, by cardiac autonomic damage. Overall findings support Brugada et al's recent hypothesis that the pathway leading to sudden death may often be similar in Chagas' disease and Brugada syndrome i.e., damage to the sodium channel (infectious/immunologic/autonomic in Chagas' genetic in Brugada) with consequent loss of sodium currents may facilitate a phase II-reentry based arrhythmic substrate for ventricular fibrillation in both conditions. In general, JT interval-related results have been underreported in the Chagas literature.

Accuracy of Uncorrected versus Corrected QT Interval for Prediction of Torsade de Pointes Associated with Intravenous Haloperidol

To determine if the uncorrected QT interval (QT(u)) more accurately predicts drug-induced torsade de pointes than QT intervals corrected using the Bazett's (QT(B)), Fridericia (QT(Frid)), or Framingham (QT(Fram)) methods. Retrospective analysis of a previously reported case-control study of risk factors for haloperidol-induced torsade de pointes. Large tertiary care teaching hospital. Forty-six critically ill patients who received intravenous haloperidol for sedation; seven developed torsade de pointes. The QT intervals were measured manually by one investigator from electrocardiograms performed before and during haloperidol therapy. Logistic regression analysis for prediction of torsade de pointes was performed, incorporating QT(u), QT(B), QT(Frid), QT(Fram), and RR intervals measured during treatment. Receiver operating characteristics (ROC) curves were constructed. Primary outcome measures were proportion of explained variation (maximum-rescaled R2); area under the ROC curves for QT(u), QT(B), QT(Frid), QT(Fram), and RR interval; and sensitivity and specificity for prediction of haloperidol-induced torsade de pointes. The QT(u) was associated with the highest R2 compared with QT(Fram), QT(Frid), QT(B), and RR interval (0.77, 0.73, 0.68, 0.53, and 0.30, respectively). No significant differences in areas under the ROC curves were found between any of the QT-interval methods. Areas under the ROC curves for QT(u) and QT(Fram) trended toward being greater than that associated with the RR interval. All QT-interval methods were highly sensitive (100% for each), whereas the RR interval was less sensitive (86%); QT(u) and QT(Fram) were most specific (82%) compared with the QT(Frid) (72%), QT(B) (64%), and RR interval (36%). Compared with QT(B) and QT(Frid), the QT(u) and QT(Fram) best predicted haloperidol-induced torsade de pointes in critically ill patients; the QT(Fram) offered no advantage over the QT(u).

How does pure heart rate lowering impact on cardiac tolerability?

By selectively and specifically inhibiting the cardiac pacemaker If current, the If inhibitors lower heart rate without compromising myocardial contractility, haemodynamic status, or the electrophysiological properties of the heart. The first agent in this class, ivabradine, has completed its large clinical development programme, for which the cardiac tolerability data cover nearly 5000 patients, about 3500 of whom received the agent. Examination of the data shows that If inhibition with ivabradine constitutes an effective anti-anginal and anti-ischaemic therapy; cardiac adverse events were reported at a rate that is acceptable for a population with stable angina. Among the other adverse events, the most frequently reported were visual symptoms, which are related to retinal Ih inhibition and often resolve during treatment. Ivabradine is associated with significant increases in sinus node recovery time and uncorrected QT interval, which are related to heart rate, but had no significant effect on any other electrophysiological parameter. Correction of the QT interval using a population correction formula confirmed that ivabradine has no significant effect on the duration of ventricular repolarization, i.e. no proarrhythmic effect. Ivabradine produced no negative inotropic effect even in the presence of left ventricular (LV) systolic dysfunction. Preliminary clinical data suggest that ivabradine has a beneficial effect on cardiac performance and LV geometry. These results are currently being tested in the ongoing morBidity–mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study.

Human antibodies with muscarinic activity modulate ventricular repolarization: Basis for electrical disturbance

Introduction In chronic chagasic patients sudden death has been reported when QT interval dispersion is increased and antibodies with muscarinic-like activity have been demonstrated to trigger arrhythmias. The aims were to investigate, in vivo and in vitro, relation between these antibodies and heterogeneity of ventricular repolarization and to identify predictors of cardiac death in chronic chagasic patients. Methods and results Clinical, electrocardiograph and echocardiograph variables from 32 chronic chagasic patients with moderate to severe left ventricular dysfunction, followed-up for 10 years were analyzed. Sera from chronic chagasic patients with or without muscarinic activity were tested in isolated rabbit hearts to study ventricular repolarization. Stepwise multivariate logistic analysis was applied to identify independent predictors of cardiac death. QT interval dispersion of patients with muscarinic activity (75.9 ± 5.5 ms) was larger than that of patients without muscarinic activity (51.3 ± 4.0 ms, p < 0.001). Maximum uncorrected and corrected QT intervals were not significantly different between groups of patients. Sera from patients with muscarinic activity significantly and reversibly increased QT interval in isolated rabbit hearts ( p = 0.002). This effect was abolished in the presence of the muscarinic antagonist atropine. Multivariate analysis identified maximum corrected QT intervals and left ventricular end diastolic index as independent predictors of cardiac death ( p = 0.03 and p = 0.02, respectively). Conclusions Sera with muscarinic activity from chagasic patients have a strong contribution to evoke ventricular repolarization rhythm disorder. In these patients, ventricular repolarization heterogeneity is increased significantly. In vitro, muscarinic sera reversibly increased repolarization duration. Maximum corrected QT intervals and left ventricular end diastolic index are independent predictors of cardiac death.

Man Versus Machine: Is There an Optimal Method for QT Measurements in Thorough QT Studies?

Electrocardiographic (ECG) recordings from 3 placebo-controlled thorough QT healthy volunteer studies were used to compare QT intervals obtained by manual measurement with those generated by ECG machines. The effect of the positive control was compared to placebo at each time point for data obtained from both sources. Both manual and automated techniques consistently demonstrated statistically significant prolongation of QTcF with the positive controls. The proportion of outlier values was small for both methods. The pairwise comparison between manual and automated uncorrected QT intervals demonstrated clear differences, with intervals derived from one machine on average 16 to 19 milliseconds shorter and from the other 7 milliseconds longer than the manually measured QT intervals, but these differences disappeared when analyzing QT change from baseline. Both manual and automated, commercially available QT algorithms demonstrated small statistically significant effects on the QTc interval induced by positive controls.

Epinephrine QT Stress Testing in the Evaluation of Congenital Long-QT Syndrome

A paradoxical increase in the uncorrected QT interval during infusion of low-dose epinephrine appears pathognomonic for type 1 long-QT syndrome (LQT1). We sought to determine the diagnostic accuracy of this response among patients referred for clinical evaluation of congenital long-QT syndrome (LQTS). From 1999 to 2002, 147 genotyped patients (125 untreated and 22 undergoing beta-blocker therapy) had an epinephrine QT stress test that involved a 25-minute infusion protocol (0.025 to 0.3 microg.kg(-1).min(-1)). A 12-lead ECG was monitored continuously, and repolarization parameters were measured. The sensitivity, specificity, and positive and negative predictive values for the paradoxical QT response (defined as a > or =30-ms increase in QT during infusion of < or =0.1 microg.kg(-1).min(-1) epinephrine) was determined. The 125 untreated patients (44 genotype negative, 40 LQT1, 30 LQT2, and 11 LQT3) constituted the primary analysis. The median baseline corrected QT intervals (QTc) were 444 ms (gene negative), 456 ms (LQT1), 486 ms (LQT2), and 473 ms (LQT3). The median change in QT interval during low-dose epinephrine infusion was -23 ms in the gene-negative group, 78 ms in LQT1, -4 ms in LQT2, and -58 ms in LQT3. The paradoxical QT response was observed in 37 (92%) of 40 patients with LQT1 compared with 18% (gene-negative), 13% (LQT2), and 0% (LQT3; P<0.0001) of the remaining patients. Overall, the paradoxical QT response had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 status. Secondary analysis of the subset undergoing beta-blocker therapy indicated inferior diagnostic utility in this setting. The epinephrine QT stress test can unmask concealed type 1 LQTS with a high level of accuracy.

Comparison of Four Rate-Correction Algorisms for the Ventricular Repolarization Period in Assessing Net Effects of IKr Blockers in Dogs

The utility of corrected and uncorrected QT interval changes for assessing net repolarization delay by IKr (a rapid component of delayed rectifier K+ currents) blockers was assessed in halothane-anesthetized dogs using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of dl-sotalol (0.2 – 2 mg/kg) prolonged the MAP duration and RR interval, while terfenadine (3 mg/kg) increased the MAP duration but transiently shortened RR interval. The order of correlation coefficient between the MAP duration at a pacing cycle length of 400 ms and MAP duration itself or that with arithmetical correction was uncorrected > Van de Water = Matsunaga > Fridericia > Bazett. These results suggest that Matsunaga’s and Van de Water’s formulae would better predict the net repolarization delay in the in vivo canine model. Also, the risk of drug candidates that may prolong the QT interval should be judged by change in uncorrected QT interval as well as corrected QT interval.

Electrocardiogram, hemodynamics, and core body temperatures of the normal freely moving laboratory beagle dog by remote radiotelemetry

Introduction The objectives of this study were to provide baseline normative values for circadian changes in the time-series data collected over the course of a normal day in laboratory-housed dogs and to assess the relative efficiency of standard correction formulas to correct for the variations in QT intervals and heart rate functions. Methods One hundred and twenty-three beagle dogs (65 M, 58 F) were equipped with radiotelemetry transmitters and continuously monitored, while freely moving in their home cages. Electrocardiograms (ECGs), hemodynamic parameters (diastolic, systolic, and mean arterial pressures) as well as core body temperatures were recorded for 22 h. Results and discussion Blood pressures and core body temperatures demonstrated only very slight variations in their respective values over the 22-h monitoring period. ECGs were measured by a computerized waveform analysis program and quantitative elements reported as RR, PR, QRS, and QT intervals. Little circadian rhythmicity was demonstrated in the ECG intervals. Standard study-specific correction formulas appeared to satisfactorily normalize (i.e., compensate for) the relationship between heart rate and QT intervals in these beagle dogs but elevated the values of the QTc as compared to the uncorrected QT intervals. In sharp contrast, a subject-specific correction method based on analysis of covariance produced a more linear function between heart rates and QT intervals and, more importantly, provided QTc values within the normal range of actual, recorded QT interval data.

Obesity contributes to risk of SCD in the general population and prolongation of ventricular repolarization is a potential mechanism

heart rate. Objective: to investigate whether changes in the QT interval observed with IVA are entirely due to bradycardia or also to the direct effects of IVA on ventricular repolarisation. Methods: Because the non-linear relationship between the QT interval and the heart rate may often result in underor overestimation of the corrected QTc interval by the conventional Bazett (QTcB) and Fridericia (QTcF) formulae, respectively, a population correction formula (QTcP) was used. The QTcP formula was developed and validated in 23,997 QT/RR paired values from the ECGs in 1216 patients with coronary artery disease randomised to the placebo arm of several IVA efficacy studies. The QTcP formula was then used for rate correction of the QT interval in 995 patients randomised to treatment with IVA 10 mg bid. Eighty-three patients treated with atenolol 100 mg od served as active controls. Results: Based on the analysis of the QT/RR values in the placebo group, the QTcP formula resulted in a correction exponent of 0.384. Prolongation of the uncorrected QT interval was observed in patients treated with IVA or atenolol consistent with a reduction in heart rate (Figure). There were no changes in the corrected QTc interval throughout the follow-up period. Conclusion: The effects of IVA and atenolol on the QT interval is solely related to bradycardia with no evidence of any direct effect on repolarisation. The QTcP correction formula allows accurate QTc interval assessment.

Comparison of the effects of a selective I F current inhibitor ivabradine and atenolol on the QT interval in patients with coronary artery disease

Background: Ivabradine (IVA) is a novel antianginal agent which reduces the heart rate by selectively blocking the If ion current implicated in the slow depolarisation phase of the sinus node action potential. Prolongation of the uncorrected QT interval with IVA is associated with reduction in heart rate.

Drug Challenge with Epinephrine or Isoproterenol for Diagnosing a Long QT Syndrome: Should We Try This at Home?

Diagnosing a congenital long QT syndrome (LQTS) is straightforward when a prolonged QT is present in a patient with arrhythmia-related symptoms and documented torsade de pointes.1 More often, however, a clear-cut diagnosis is not possible because: (1) QT-related arrhythmias are only rarely documented (except for patients with arrhythmic storms), and cannot be reliably and safely provoked. (2) Accurate measurement of the QT interval is not always easy2 and the presence of respiratory sinus arrhythmia complicates the estimation of the rate corrected QTc because the response of the QT interval to heart rate oscillations is not instantaneous. Consequently, the QTc calculated during heart rate deceleration will be shorter than the QTc calculated, only a few beats later, when the heart rate accelerates.3 (3) The QTc intervals of healthy individuals and that of patients with genetically proven LQTS overlap to such extent that one third of LQTS gene carriers and a similar number of healthy individuals have “borderline QT,” that is, a QTc between 430 and 460 ms.4 (4) Genetic testing is obviously useful when mutations are found but, with present technology, no mutations are identified in ≥25% of patients with LQTS. Furthermore, genetic analysis is only available in selected centers and often takes months to perform. Therefore, diagnostic and therapeutic decisions are still based, at least initially, on clinical grounds. Since symptoms in the common types of LQTS are commonly triggered by stress, it is only logical to use sympathetic stimulation, in the form of adrenaline or isoproterenol infusion, as a challenge test to unravel a LQTS in questionable cases. In fact, physicians have used such tests sporadically without rigorous control.5 Two groups of investigators finally evaluated the effects of an epinephrine challenge in LQTS patients in a controlled fashion.6-8 First, Ackerman6 studied 37 patients with LQTS (19 with LQT1, 15 with LQT2, and 3 with LQT3) as well as 27 healthy controls. Epinephrine was started at “low doses” (0.05 μg/kg/min) and the infusion rate was gradually increased to a “high dose” of 0.3 μg/kg/min. The absolute (uncorrected) QT interval increased in all patients with LQT1, decreased in LQT2/3 and increased or decreased in different controls. Since epinephrine also increased the heart rate, the rate-corrected QTc actually increased in all patient groups. This increment in QTc was greatest for LQT1 patients, intermediate for controls and smallest for LQT2/3 patients. Yet, there was significant overlap between the QTc

Relationship of QT interval duration with carotid intima media thickness in a clinically healthy population undergoing cardiovascular risk screening

To investigate the relationship between cardiac repolarization (QT interval duration) and intima media thickness (IMT) of the carotid arteries as surrogate measures of subclinical atherosclerosis. Prospective study with consecutive subjects enrolled in the SAPHIR program (Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk). The analysis of the material was performed at the departments of medicine and neurology of a university hospital. The study cohort comprises a population-based sample of 1199 clinically healthy subjects (851 men and 348 women; age 39-66 years). Exclusion criteria were cardiovascular disease, diabetes, atrial fibrillation, bundle branch block and use of medication affecting QT interval duration. IMT of common (CCA) and internal carotid arteries (ICA) was measured by B-mode ultrasound. QT interval duration was determined in the resting 12-lead electrocardiogram by an automatic analysis program. The QT intervals were corrected for heart rate with five standard equations (QTc-Bazett, -Fridericia, -Framingham, -Hodges and -Rautaharju) and tested for their relationship with carotid IMT after adjustment for clinical and metabolic variables. Results. Females had higher heart rates than males (64 +/- 10 b min(-1) vs. 60 +/- 9 b min(-1), P <0.0005), with longer mean QT (410 +/- 28 ms vs. 404 +/- 28 ms, P=0.003) and QTc intervals in all correction formulae (P <0.0005). Significant correlations between QT/QTc and ICA IMT (r=0.14-0.16) were found in males. In the general linear model the association between QTc (except for Bazett) and ICA IMT remained significant after adjusting for age, BMI and further cardiovascular risk factors. In females the crude correlations between QT/QTc and ICA IMT were lower than those with CCA IMT. Only the correlation between uncorrected QT and CCA IMT (r=0.15, P=0.006) remained significant after adjustment for covariates. The results of the present study demonstrate that QT and QTc prolongation are in part associated with IMT of carotid arteries, which is an established risk marker of subclinical atherosclerosis. In men the data support the hypothesis of an association between QTc and ICA IMT. In women a statistically significant relationship was found between the uncorrected QT interval and CCA IMT. These findings suggest that differences in carotid IMT and ventricular repolarization between genders might be related to hormonal and nonhormonal effects.

Co‐administration of ketoconazole with H1‐antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects

Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines. In both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR(alpha) with special emphasis on individualized alpha values derived from each subject's own QT/RR relationship at baseline. No significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events. Ketoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms (-0.65 to 11.15 ms) over ketoconazole with placebo (6.96 ms) while ketoconazole plus loratadine resulted in a nonsignificant mean increase of 3.16 ms (-2.73 to 8.68 ms) over ketoconazole plus placebo (7.52 ms). Changes in uncorrected QT intervals for both antihistamines were not statistically different from those observed with ketoconazole alone. The greater effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly greater pharmacodynamic effect on cardiac repolarization.

Potent inhibition of human cardiac potassium (HERG) channels by the anti-estrogen agent clomiphene—without QT interval prolongation

The acquired form of the long-QT syndrome (LQTS) is a major safety consideration for the development and subsequent use of both cardiac and non-cardiac drugs; it is usually associated with pharmacological inhibition of cardiac HERG-encoded potassium channels. Clomiphene is an anti-estrogen agent used extensively in the treatment of infertility and is not associated with a risk of QT interval prolongation, in contrast to a structurally related compound tamoxifen. We describe here a potent inhibitory effect (IC 50=0.18 μM) of clomiphene on HERG ionic current ( I HERG) recorded from a mammalian cell line expressing HERG channels. Inhibition of I HERG by clomiphene showed voltage-dependence and developed quickly following membrane depolarisation, indicating contingency of block on HERG channel gating. At 100 nM, clomiphene and the related anti-estrogen tamoxifen produced similar levels of I HERG blockade ( p>0.05). Experiments on guinea-pig isolated perfused hearts revealed that, despite its inhibitory action on I HERG, clomiphene produced no significant effect at 1 μM on uncorrected QT interval ( p>0.1) nor on rate-corrected QT interval (QT c; p>0.1 for QT c determined using Van de Water’s formula). The disparity between clomiphene’s potent I HERG inhibition and its lack of effect on the QT interval underscores the notion that I HERG pharmacology may best be used alongside other screening methods when investigating the QT-prolonging tendency and related cardiotoxicity of non-cardiac drugs.

Quetiapine poisoning: A case series

Study objective We describe the effects of quetiapine in overdose. Methods Quetiapine poisonings were identified from a prospective database of poisoning admissions to a regional toxicology service. Data extracted included details of ingestion, clinical features, investigations (including ECG), and other outcomes (length of stay and ICU admission rate). Results There were 45 cases of quetiapine overdose, of which 18 patients with quetiapine assay results were included. Median length of stay was 35 hours (interquartile range [IQR] 14 to 42 hours) for the 18 patients, and 9 were admitted to the ICU. The median ingested dose was 3.5 g (IQR 1.7 to 6.2 g), and reported ingested dose was highly correlated with estimated peak drug concentration ( r 2=0.84; P<.0001), confirming patient-provided history of ingestion. Seizures occurred in 2 patients, delirium occurred in 3 patients, and mechanical ventilation was required in 4 patients. No arrhythmias or deaths occurred. Six of the 18 patients ingested quetiapine alone, with a median length of stay of 35 hours, and 3 were admitted to the ICU. In 1 patient who ingested 24 g, hypotension and seizures occurred. For 10 patients for whom ECGs were available and who had ingested no cardiotoxic drugs, tachycardia occurred in 8 patients. For these 10 patients, the mean corrected QT (QTc) interval was increased at 487 ms, but the mean uncorrected QT interval was 349 ms. Reported dose and peak quetiapine concentrations were significantly associated with ICU admission and length of stay more than 24 hours. A reported dose less than 3 g and a Glasgow Coma Scale score not less than 15 predicted patients not requiring ICU admission or length of stay more than 24 hours. Conclusion Quetiapine overdose causes central nervous system depression and sinus tachycardia. In large overdoses, patients may require intubation and ventilation for associated respiratory depression. Although a prolonged QTc occurs, its clinical significance is unclear because it is most likely caused by an overcorrection caused by the tachycardia. In our experience, a reported dose of less than 3 g for patients who are not drowsy (with a Glasgow Coma Scale score of 15) at least 4 hours after ingestion and who did not coingest another toxic agent defined a group not requiring ICU admission or inpatient admission greater than 24 hours.