Bazett's Correction Research Articles

Sex differences in the effect of four second‐generation antipsychotics on QTc interval in patients with schizophrenia

We examined sex differences in the effect of olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), or quetiapine (QTP) on mean corrected QT (QTc) intervals among 222 patients with schizophrenia. Subjects were patients with schizophrenia who were treated with either OLZ (n = 69), RIS (n = 60), ARP (n = 62), or QTP (n = 31). Electrocardiographic measurements were conducted, and the QT interval was corrected using Bazett's correction formula. The mean QTc interval of the QTP group was significantly longer than that of the RIS group (p = 0.002) or ARP group (p = 0.029). The mean QTc interval of the OLZ group was also significantly longer than that of the RIS group (p = 0.006). In female participants, the difference in the mean QTc interval among the four second-generation antipsychotic (SGA) groups was statistically significant (p = 0.002), whereas in male patients, there was no significant difference in the mean QTc interval among the four SGA groups. Post hoc analyses showed that sex differences in QTc interval were observed only in OLZ treatment group (p = 0.007). To our knowledge, this is the first study to demonstrate sex differences in the effect of four SGAs on the QTc interval.

Losmapimod concentration–QT relationship in healthy volunteers: meta-analysis of data from six clinical trials

The objective of this work was to describe the losmapimod concentration-QT relationship using meta-analysis of data from clinical trials with healthy volunteers and to evaluate the covariates that have significant impact on the QT prolongation. Losmapimod plasma concentration and QT interval data were collected from six early clinical studies with healthy volunteers. The electrocardiograms (ECGs) were collected at baseline and at a number of post-dose time points (losmapimod or placebo). The population pharmacokinetic/pharmacodynamic (PK/PD) modelling approach was applied to investigate the relationship between losmapimod concentration and QT prolongation. The dataset for analysis comprised 190 healthy adults who took at least one dose of losmapimod or placebo. Of the 2,494 QT observations collected, 1,532 observations had matched QT and losmapimod plasma concentration data. Population PK/PD analyses indicated that the model with the individual heart rate correction factor (α) fitted the data better than those using fixed α (0.33 for Fridericia's correction or 0.5 for Bazett's correction) and that there was no relationship between losmapimod concentration and QT interval. Female volunteers had about a 3 % higher QT interval at baseline than the male volunteers. No other covariates had a significant effect on the QT interval. It is appropriate to apply population PK/PD analysis to investigate the effect of drug concentration on QT prolongation. Our meta-analysis of healthy volunteer data indicated no relationship between systemic losmapimod concentration and QT interval in healthy volunteers.

Measurement and Rate Correction of the QT Interval

Measurement and Rate Correction of the QT Interval

QT Interval and Long‐Term Mortality Risk in the Framingham Heart Study

The association between QT interval and mortality has been demonstrated in large, prospective population-based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT-mortality relationship in the Framingham Heart Study (FHS). Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a reproducible digital caliper technique. Using Cox proportional hazards regression adjusting for age and sex, a 20 millisecond increase in QTc (using Bazett's correction; QT/RR(1/2) interval) was associated with a modest increase in risk of all-cause mortality (HR 1.14, 95% CI 1.10-1.18, P < 0.0001), coronary heart disease (CHD) mortality (HR 1.15, 95% CI 1.05-1.26, P = 0.003), and sudden cardiac death (SCD, HR 1.19, 95% CI 1.03-1.37, P = 0.02). However, adjustment for heart rate using RR interval in linear regression attenuated this association. The association of QT interval with all-cause mortality persisted after adjustment for cardiovascular risk factors, but associations with CHD mortality and SCD were no longer significant. In FHS, there is evidence of a graded relation between QTc and all-cause mortality, CHD death, and SCD; however, this association is attenuated by adjustment for RR interval. These data confirm that using Bazett's heart rate correction, QTc, overestimates the association with mortality. An association with all-cause mortality persists despite a more complete adjustment for heart rate and known cardiovascular risk factors.

Prevalence and determinants of QT interval prolongation in medical inpatients

QT interval prolongation carries an increased risk of torsade de pointes and death. We sought to determine the prevalence of QT prolongation in medical inpatients and to identify determinants of this condition. We enrolled consecutive patients who were admitted to the internal medicine ward and who had an electrocardiogram performed within 24 h of admission. We collected information on baseline patient characteristics and the use of QT-prolonging drugs. Two blinded readers manually measured the QT intervals. QT intervals were corrected for heart rate using the traditional Bazett formula and the linear regression-based Framingham formula. We used logistic regression to identify patient characteristics and drugs that were independently associated with QTc prolongation. Of 537 inpatients, 22.3% had a prolonged QTc based on the Bazett formula. The adjusted odds for QTc prolongation based on the Bazett correction were significantly higher in patients who had liver disease (OR 2.9, 95% CI: 1.5-5.6), hypokalaemia (OR 3.3, 95% CI: 1.9-5.6) and who were taking ≥1 QT-prolonging drug at admission (OR 1.7, 95% CI: 1.1-2.6). Overall, 50.8% of patients with QTc prolongation received additional QT-prolonging drugs during hospitalisation. The prevalence of QTc prolongation was high among medical inpatients but depended on the method used to correct for heart rate. The use of QT-prolonging drugs, hypokalaemia and liver disease increased the risk of QTc prolongation. Many patients with QTc prolongation received additional QT-prolonging drugs during hospitalisation, further increasing the risk of torsade de pointes and death.

Improvement in QTc prolongation induced by zotepine following a switch to perospirone

TO OUR KNOWLEDGE, there have been only two reports concerning the effect of zotepine on the QT interval.1, 2 We herein report the findings of a case of zotepine-induced QTc prolongation in a Japanese patient with schizophrenia. A 45-year-old woman was undergoing single-agent therapy for schizophrenia with a 200-mg intramuscular (i.m.) injection of haloperidol decanoate every 4 weeks. She received the i.m. injection of haloperidol decanoate 10 days before hospitalization. However, because her psychotic symptoms worsened, she was hospitalized on day 0. On the same day, electrocardiography showed a QTc of 419 msec at a heart rate (HR) of 64/min. We then started to switch the patient to 50 mg/day of zotepine. As a result of increasing the dosage of zotepine from 50 mg to 400 mg/day (on day 39), the patient's psychotic symptoms became stable. However, on day 61, electrocardiography showed a QTc of 483 msec at a HR of 98/min. Therefore, we started to switch the patient to 16 mg/day of perospirone on day 121. During the switch to perospirone treatment, her psychotic symptoms became unstable again. Therefore, the dosage of perospirone was increased from 16 mg to 32 mg daily on day 88, and then 48 mg/day on day 102. As a result of increasing the dosage of perospirone, the patient's psychotic symptoms became stable. On day 128, electrocardiography showed a QTc of 418 msec at a HR of 76/min. During the examinations, only benzodiazepines could be concomitantly used; zotepine and perospirone were administered once daily before sleep, and electrocardiographic measurements were conducted between 09.00 and 10.00 hours. The QT interval was corrected using Bazett's correction formula (QTc = QT/RR1/2). When electrocardiography was conducted at each time-point, biochemical examinations revealed no electrolyte abnormalities in the serum Na, K, Cl, or Mg levels, and no cardiac diseases, such as arrhythmia, or any other new physical disorders were observed. This patient provided written, informed consent. One cross-sectional study revealed that zotepine did not affect QTc in Japanese patients with schizophrenia.2 On the other hand, a dose-dependent effect of zotepine on QTc was also reported in a Han Chinese case.1 The results of the current case are in line with those reported by Lin et al.1 The QT interval can be affected by various factors, such as age, sex and drug–drug interactions. Hence, we believe that increased doses of zotepine should be given carefully, especially in patients who have other risk factors. In our case, a switch to perospirone from zotepine treatment normalized the QTc. However, the details regarding the correlation between perospirone and QTc prolongation still remain unclear. Further studies are needed to clarify the effect of zotepine or perospirone on QTc using longitudinal methods rather than with cross-sectional studies.

Abstract 9138: QT Interval Duration and Incident Mortality in the Framingham Heart Study

Background: The association between QT interval and mortality has been demonstrated in multiple large, prospective population-based studies using Bazett's heart rate correction, but the strength of the association varies considerably among studies. We examined this relationship in the Framingham Heart Study. Methods and Results: Participants in the first (original cohort, n = 2,415) and second generation (offspring cohort, n = 4,478) cohorts examined in the early 1970s were included in this study. Using Cox proportional hazards regression adjusting for age and sex, a 20 msec increase in QTc (using Bazett's correction; QT/RR 1/2 interval) was associated with increased risk of all-cause mortality (HR 1.15, 95% CI 1.12-1.19, p = 7.6x10 -17 ), CHD mortality (HR 1.18, 95% CI 1.08-1.30, p = 0.0003), and sudden cardiac death (HR 1.20, 95% CI 1.04-1.39, p = 0.01). However, additional adjustment for heart rate, either by additional adjustment of the QTc for RR interval, or use of linear regression of QT on RR interval, attenuated the associations with all-cause mortality (HR 1.10, 95% CI 1.06-1.15, p= 3.6x10 -6 , Figure), CHD mortality (HR 1.11, 95% CI 0.99-1.24, p= 0.07) and SCD (HR 1.16, 95% CI 0.97-1.40, p= 0.11). Conclusion: In the FHS (mean follow up 27.35 years), there is evidence for a graded relationship between QTc and all-cause mortality, CHD death, and SCD, however, this effect is considerably attenuated by additional adjustment for RR interval. These findings demonstrate that residual confounding by heart rate overestimates the effect on mortality when using Bazett's heart rate correction.

QT interval shortening in spontaneous reports submitted to the FDA: the need for consensus

QT interval shortening in spontaneous reports submitted to the FDA: the need for consensus

Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome

A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes. This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate. The independent contribution of 4 repolarization measures (the absolute QT interval, and Bazett's, Fridericia's, and Framingham's correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT). Multivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate × genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR⁰·⁸) than LQTS type 2 patients (improved QTc = QT/RR⁰·²). Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.

Normal reference values for QRS and T-wave non-dipolar components for adult Caucasian and African American men and women

the QTc is over 500 msec?” There is probably truth to both of these types of comments. It has been suggested that we state “Prolonged QT” whenever the QTc exceeds 460 milliseconds (Bazett correction). Although 460 milliseconds is above the 98th percentile of QTc for most age groups of normal subjects, large numbers of ECGs have QTc more than 460 milliseconds for which the mention of prolonged QT is not appropriate. For example, it is generally not useful to mention prolonged QT in the presence of intraventricular conduction defects such as right or left bundle-branch block. In an analysis of 44 896 ECGs representing all adult non–ventricular-paced ECGs in a major hospital ECG database over the course of 1 calendar year, the computerized interpretation program stated “Prolonged QT” on 9.8% of the ECGs. However, 36.2% of all ECGs had a QTc more than 460 milliseconds. A total of 5059 ECGs (11.3%) exhibited some form of intraventricular conduction block, 77.3% of those also had QTc more than 460 milliseconds. It should be evident that it would not be acceptable to state “Prolonged QT” on over a third of all ECGs. Clearly, exclusionary criteria are required so that “Prolonged QT” is stated only when meaningful. Our computerized interpretation program excludes ECGs with ventricular conduction blocks and with ventricular rates greater than 100 beats/min. We also have a tiered threshold that ranges from 460 to 510 milliseconds based on the presence or absence of infarction, ischemia, or nonspecific T-wave abnormality and on age and sex. Further discussion and standardization of the specific criteria for statement of “Prolonged QT” are warranted.

Effect of iodixanol and ioxilan on QT interval and renal function in patients with systolic heart failure

BackgroundContrast media (CM) exposure is associated with a substantial risk of arrhythmias and nephrotoxicity. These adverse effects may be exacerbated in high-risk conditions such as heart failure, although no studies have evaluated newer CM agents in this population. This study evaluated the electrophysiologic and renal effects of two newer CM agents, iodixanol and ioxilan, in heart failure patients undergoing angiography. MethodsEighty-seven consecutive systolic heart failure patients who received either iso-osmolar iodixanol (n=44) or low-osmolar ioxilan (n=43), stratified for concomitant amiodarone, were evaluated for QT interval and serum creatinine changes in comparison to baseline. QT values were corrected according to three formulae: Bazett's correction, Fridericia formula, and Framingham equation. ResultsBaseline patient characteristics were not significantly different in the iodixanol versus ioxilan groups, except for myocardial infarction and renal disease. No significant change in mean QTc was observed after exposure to either CM agent compared to baseline. These results were unaffected by amiodarone. A significant improvement in serum creatinine from baseline was observed in the iodixanol group compared to the ioxilan group (−0.121±0.35mg/dL vs. 0.033±0.23mg/dL, respectively; p=0.045). ConclusionsNo significant change in QTc interval was observed in patients receiving either iodixanol or ioxilan during angiography. Iodixanol appeared to improve short-term renal function in patients with heart failure and should be further investigated.

Facts, fancies and follies of drug‐induced QT/QTc interval shortening

Parallels exist between drug‐induced QT/QTc prolongation and shortening. However, these parallels are largely superficial and the experience with drug‐induced QTc prolongation and its potential proarrhythmic link cannot be directly applied to drug‐related QTc shortening. The congenital short QT syndrome (SQTS) is clearly much less prevalent than congenital, long QT syndrome, possibly some 1000 times. If the same discrepancy exists between arrhythmic susceptibility to drug‐induced QTc prolongation and shortening, it is questionable whether regulatory burden should be imposed on drugs that might cause serious arrhythmia, once in many millions of exposures. Further, majority of torsadegenic drugs block the IKr current which is susceptible to the drug blockade because of the corresponding channel geometry. There is no parallel known for drug‐induced QTc shortening. Also, all drugs that prolong QTc interval massively cause torsade de pointes tachycardia in more than exceptional isolated instances. On the contrary, digitalis that causes substantial QTc shortening is not known to trigger frequently ventricular arrhythmias. Moreover, most available population QTc data were obtained with Bazett's correction which produces erroneous QTc shortening at slow heart rates. Safety limits derived from such data are inappropriate. Because practically all new drugs undergo the so‐called thorough QT study, drug‐induced QTc shortening will not go unnoticed for any new pharmaceutical. Describing drug‐related QTc shortening in the label seems sufficient to avoid treatment of the rare SQTS subjects. Intensive investigations of QTc‐shortening drugs (similar to those of drugs with positive thorough QT studies) do not seem to be warranted.This article is a commentary on Shah, pp. 58–69 of this issue and is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010

Steady-state pharmacokinetics and tolerability of orally administered fampridine sustained-Release 10-mg tablets in patients with multiple sclerosis: A 2-week, open-label, follow-up study

Background: Fampridine sustained release (SR) has generally been well tolerated in clinical studies in patients with multiple sclerosis (MS) at doses ≤20 mg/d. The pharmacokinetics of single escalating doses of fampridine SR (5, 10, 15, and 20 mg) were evaluated in a companion study.Objectives: The primary objective of this study, which followed on from the single-dose pharmacokinetic study, was to assess the steady-state pharmacokinetics of fampridine in patients with MS over 2 weeks of oral administration of open-label fampridine SR 20 mg BID. Tolerability was also evaluated.Methods: The dose of fampridine SR was titrated upward to twice-daily administration over days 1 and 2, with 20 mg given in the morning and 10 mg in the evening. From days 3 to 14, patients received fampridine SR 20 mg BID (total daily dose, 40 mg). Fampridine pharmacokinetic parameters were determined on days 1, 8, and 15. The parameters of interest included Cmax, Tmax, Cmin, AUC, and apparent t½ These parameters were compared with those from the single-dose study. Tolerability was assessed based on adverse events, physical examinations, vital signs, laboratory tests, and ECGs.Results: Twenty-one white patients who participated in the single-dose study were enrolled in the steadystate study (52.4% female; mean [SD] age, 45.1 [7.4] years; weight range, 54–87 kg). Fampridine pharmacokinetic parameters on day 1 were consistent with those obtained in the single-dose study. The Tmax did not differ significantly between day 1, day 8, day 15, and the single-dose study (range, 3.25–3.78 hours). Cmax values on days 8 and 15 (66.7 and 62.6 ng/mL, respectively) were significantly higher than those on day 1 (48.6 ng/mL) and in the singledose study (50.5 ng/mL) (all, P < 0.001), reflecting accumulation of fampridine with multiple dosing. Values for Cmax/Cmin did not differ significantly between day 1 and the single-dose study (2.44 and 2.43, respectively) or between days 8 and 15 (2.90 and 2.88, respectively); however, the single-dose and day-1 values differed significantly from the day-8 and day-15 values (P ≤ 0.001). There were no significant differences with respect to any other pharmacokinetic parameters. One hundred adverse events were reported by 21 patients. With the exception of 1 case of severe nausea, all adverse events were of mild to moderate severity. Thirty-five events reported by 14 subjects were considered treatment related. Dizziness was the most common treatment-related adverse event, with 11 episodes reported by 8 patients. No clinically significant changes were found in clinical laboratory values, vital signs, or physical examination findings from baseline to the last visit, and there were no clinically significant changes in QTc intervals (Bazett's correction).Conclusions: In these patients with MS, the steady-state pharmacokinetic profile of fampridine SR 20 mg BID administered for 2 weeks appeared to support the use of twice-daily dosing in this population. This dosage was generally well tolerated.

Cardiac repolarization and striatal dopamine transporter function are interrelated

In Parkinson's disease, striatal dopamine transporter (DAT) binding and cardiac sympathetic function are disturbed. In addition, heart rate (HR)-corrected cardiac repolarisation time (QTc interval), which is partly under autonomic control, is prolonged. Whether there is physiological coupling between striatal DAT binding and QTc time (QTc-DAT relation) is not known. The purpose of this study is to evaluate QTc-DAT relation in healthy young adults. Thirty-five participants (18 women, age 26.4+/-1.8 years; mean+/-SD) were studied with iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single photon emission tomography. Signal-averaged ECG was recorded at rest from each participant. QTc interval was computed with Bazett's correction and with the approach by Karjalainen, getting QTc and QTk intervals, respectively. Mean striatal DAT binding, as (striatum-cerebellum)/cerebellum, was 2.63+/-0.31. Mean HR, QT, QTc and QTk intervals were 66+/-9 bpm, 340+/-25 ms, 354+/-18 ms and 351+/-16 ms, respectively. HR-QT correlation was -0.63, P value of less than 0.001. HR was not related to striatal DAT binding. QTc-DAT and QTk-DAT relations were significant, r = -0.50, P = 0.004 and r = -0.59, P = 0.0002, respectively. In linear regression model, striatal DAT binding explained 35% of the variance of QTk interval (95% confidence interval: -46.9 to -13.0, P = 0.0002). This study suggests significant physiological QTc-DAT relation in young healthy adults. QTc interval measurements might carry diagnostically important information in clinical conditions, which have an effect on both striatal DAT binding and cardiac sympathetic function.

Quinidine for Pharmacological Cardioversion of Atrial Fibrillation: A Retrospective Analysis in 501 Consecutive Patients

Although quinidine has been used to terminate atrial fibrillation (AFib) for a long time, it has been recently classified to be used as a third-line-drug for cardioversion. However, these recommendations are based on a few small studies, and there are no data available of a larger modern patient population undergoing pharmacological cardioversion of AFib. Therefore, we evaluated the safety of quinidine for cardioversion of paroxysmal AFib in patients after cardiac surgery and coronary intervention. In 501 consecutive patients (66 +/- 9 years, 32% women), 200-400 mg of quinidine were administered every 6 hours until cardioversion or for a maximum of 48 hours. Patients were included with QT interval < or =450 ms, ejection fraction (EF) > or =35%, and plasma potassium >4.3 mEq/L. Exclusion criteria were: unstable angina, myocardial infarction <3 months, and advanced congestive heart failure. Patients received verapamil, beta-blockers, or digitalis to slow down ventricular rate <100 bpm. Quinidine therapy did not have to be stopped due to adverse drug reactions (ADR), and no significant QTc interval prolongation (Bazett and Fridericia correction) and no life-threatening ventricular arrhythmia occurred. Mean quinidine dose was 617 +/- 520 mg and 92% of the patients received verapamil or beta-blocker to decrease ventricular rate. Cardioversion was successful in 84% of patients. All ADRs were minor and transient. Multivariate analysis revealed female gender (OR 2.62, CI 1.61-4.26, P < 0.001) and EF 45-54% (OR 1.97, CI 1.15-3.36, P = 0.013) as independent risk factors for ADRs. Quinidine for pharmacological cardioversion of AFib is safe and well tolerated in this subset of patients.

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.

Pharmacokinetics and Pharmacodynamics of Quetiapine in a Patient with a Massive Overdose

We present a case of massive overdose with the atypical antipsychotic quetiapine in a 34-year-old woman (body weight 65 kg). At admission, approximately 2 to 4 hours after ingestion of approximately 24 g of quetiapine, the patient was comatose (Glasgow Coma Scale score 5), requiring orotracheal intubation and transfer to the intensive care unit. Because of myoclonic jerks and generalized seizures, benzodiazepines were administered. In addition to transient mild hypotension after intubation, the main cardiovascular manifestation was sinus tachycardia. The QT interval was normal, and the QTc interval (Bazett's correction) was maximally prolonged to 620 ms. However, no malignant arrhythmias were observed. The patient recovered within 2 days but remained agitated and aggressive, for which she was transferred to the psychiatric clinic. The pharmacokinetics of quetiapine in such a large overdose could not be described by simple first-order kinetics. The initially observed rapid decline of the plasma concentrations of quetiapine could be simulated by first-order kinetics (half life = 4.1 hr) and can most probably be explained by rapid distribution into tissues. The final elimination of the drug from the body occurred after approximately 34 hours at much slower rate, most probably reflecting redistribution from tissues into blood and consecutive hepatic clearance of the drug.

Color M‐mode propagation velocity, but not its ratio to early diastolic inflow velocity, changes throughout gestation in normal human fetuses

Color M-mode propagation velocity (Vp) is a measure of diastolic function in adults and, when combined with early diastolic inflow velocity (E), the ratio E/Vp reflects ventricular filling pressure. Early detection of diastolic compromise may benefit fetal patients at risk for developing heart failure. The objectives of this study were to measure values for Vp and inflow peak E in a group of normal fetuses, to analyze age-dependent alterations in these measurements, and to evaluate the interobserver and intraobserver variability of the measurements. Thirty-two normal fetuses at between 20 and 35 weeks' gestation underwent echocardiography. Color M-mode Vp was measured from the four-chamber view for the right (RV) and left (LV) ventricles, and mitral and tricuspid inflow velocities were determined by pulsed-wave Doppler ultrasound. The values obtained were compared with previously reported findings in adults. Adequate tracings were obtainable in 23 patients for the RV and 29 for the LV. Mean Vp values for the RV (15.3 +/- 3.2 cm/s) and LV (20.8 +/- 5.6 cm/s) were lower than normal adult values, and Vp values were significantly lower for the RV than the LV (P < 0.001). Applying Bazett's heart rate correction, values for RV (23.4 +/- 4.8 cm/s) and LV (31.9 +/- 8.7 cm/s) remained lower than normal adult values. There was a linear correlation of Vp with gestational age for the RV (R = 0.69, P < 0.001), and the ratio of E/Vp corrected for heart rate for the RV (1.51 +/- 0.26) remained constant throughout gestation. Interobserver bias was high but intraobserver bias low, at 19 and 1.1%, respectively. Vp is lower in fetal than in adult life. Vp for the RV changes in a manner indicative of improving diastolic function throughout normal gestation, providing insight into the alterations in diastolic function with gestation that contribute to increases in cardiac output. The use of Vp to assess diastolic function disturbance in fetuses is feasible, but high interobserver variability is problematic.

Electrocardiographic Biomarkers of Ventricular Repolarisation in a Single Family of Short QT Syndrome and the Role of the Bazett Correction Formula

The definition of the short QT syndrome (SQTS) is based on QT duration, but thorough QT- and T-wave evaluation has not been performed to date. To evaluate the influence of QT rate-correction formulas in SQTS diagnosis, 12-lead electrocardiograms (ECGs) were recorded in 27 subjects from a single family with SQTS. Based on QT duration corrected by Bazett formula (QTc), 4 men were considered to have SQTS (QTc <or=340 ms), and 16 were classified to have "suspected" SQTS (QT <or=320 ms and/or QTc <or=380 ms). Holter ECGs were recorded in the 4 patients with SQTS, 8 with suspected SQTS, and 62 healthy volunteers. We evaluated QT duration at each RR interval and calculated individual alpha coefficient of the QT/RR relation. The QT interval duration at the mean Holter heart rate was corrected using an individual approach and 5 "universal" correction formulas (Bazett, Fridericia, Sagie-Framingham, Hodges, Rautaharju). Patients with SQTS and controls had lower alpha coefficients of the QT/RR relation when compared with Bazett and Fridericia formulas. The QT rate-dependence was lower in patients with SQTS (alpha 0.146 +/- 0.070) when compared with control subjects (alpha 0.203 +/- 0.039, p <0.05). The universal correction-formulas consistently provided higher values of corrected QT interval duration at the mean Holter heart rate than a subject-specific correction formula (p <0.05), which induced false negative diagnoses. In conclusion, the Bazett correction formula is not appropriate for making a diagnosis of SQTS. The subject-specific correction formula may provide a better cut-off value definition for the diagnosis of SQTS.

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.