Effects of Celecoxib on the QTc Interval: A Thorough QT/QTc Study

PurposeCelecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go–related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines.MethodsThis randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method–corrected QT intervals (QTcF) were calculated and evaluated.FindingsTwenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 μg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects.ImplicationsCelecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.     

Systematic decrements in QTc between the first and second day of contiguous daily ECG recordings under controlled conditions

Background: Many thorough QT (TQT) studies use a baseline day and double delta analysis to account for potential diurnal variation in QTc. However, little is known about systematic changes in the QTc across contiguous days when normal volunteers are brought into a controlled inpatient environment. Methods: Two separate crossover TQT studies included 2 days of no treatment lead‐in days with ECG collection preceding periods of drug treatment . In the first study, there were two pairs of such contiguous days with 10 replicate electrocardiograms (ECGs) collected at six time points, and in the second study, there were four pairs of contiguous days with nine replicate ECGs collected at five time points. These lead‐in day pairs provided the opportunity to evaluate any systematic changes across contiguous first and second days of an inpatient environment. Within‐patient consistency of change across pairs of days as well as within day, diurnal variation could also be evaluated. Results: Modest (4.2 ms [range 1.9–6.5 ms]) but consistent decreases (significant [P < 0.05] for all 32 comparisons) were observed (probability: ≤5.4 × 10^?16). Although group behavior with respect to QTc was consistent, individual subjects demonstrated substantial variability across pairs of days. Evidence of diurnal variation was weak and inconsistent. Magnitude of any diurnal variation was less than magnitude of change across days. Conclusions: Subjects show a systematic decrease in QTc from first day to second day of inpatient status and do not demonstrate a significant diurnal pattern. The magnitude of this systematic change is sufficient to influence QTc study interpretation. (PACE 2011; 34:1116–1127)     

Difference in QT Interval Measurement on Ambulatory ECG Compared with Standard ECG

Measurement of the QT interval on standard ECG has diagnostic importance in the congenital long QT syndrome, in pharmacological therapy of arrhythmias, as well as in ischemic heart disease. It has been suggested that QT prolongation on ambulatory ECG (Holter) may have similar importance. To assess agreement between methods, QT interval measurement on standard ECG was compared to that on Holter. Simultaneously obtained ECG and Holter tracings (25 mm/s) of the same complexes in leads V₁ and V₅ were studied in 14 patients (age range 4–36 years). ECG pairs (n = 100, 49 V₁ and 51 V₅) were compared over a range of QT interval from 300–620 ms, as determined with the use of calipers by two observers blinded to pairing relationship. Correlation between methods was high for both observers (observer 1: r[V₁] = 0.872, r[V₅] = 0.973; observer 2: r[V₁] = 0.972, r[V₅] = 0.988), and interobserver variability was small (> 85% of measurements within 20 ms). As compared to ECG, Holter underestimated QT interval in V₁ mean difference (QT [Holter]—QT [ECG]) observer 1 (-23 ms, P < 0.001), observer 2 (-7 ms, P < 0.05), and overestimated QT in V5, mean difference observer 1 (+ 13 ms, P < 0.001), observer 2 (+13 ms, P < 0.001). However, individual variation between methods was wide, as expressed by the difference between individual measurements (95% confidence interval [V₁]: observer 1 [-99 to +53 ms] observer 2 [-47 to +33 ms]; [V₅]: observer 1 [-33 to +59 ms] observer 2 [-17 to +43 ms]). Furthermore, when using the QTA (interval from onset of Q wave to apex of T wave) similar variability was observed. In the assessment of QT interval, potential sources of error of this magnitude could limit the clinical utility of ambulatory monitoring in detecting prolongation of the QT interval for diagnostic purposes.     

Circadian Profile of QT Interval and QT Interval Variability in 172 Healthy Volunteers

BONNEMEIER, H., et al .: Circadian Profile of QT Interval and QT Interval Variability in 172 Healthy Volunteers. The limited prognostic value of QT dispersion has been demonstrated in recent studies. However, longitudinal data on physiological variations of QT interval and the influence of aging and sex are few. This analysis included 172 healthy subjects (89 women, 83 men; mean age   38.7 ± 15   years). Beat-to-beat QT interval duration (QT, QTapex [QTa], T_end[Te]), variability (QTSD, QTaSD), and the mean R-R interval were determined from 24-hour ambulatory electrocardiograms after exclusion of artifacts and premature beats. All volunteers were fully active, awoke at approximately 7:00 am , and had 6–8 hours of sleep. QT and R-R intervals revealed a characteristic day-night-pattern. Diurnal profiles of QT interval variability exhibited a significant increase in the morning hours (6–9 am ; P < 0.01) and a consecutive decline to baseline levels. In female subjects the R-R and T_end intervals were significantly lower at day- and nighttime. Aging was associated with an increase of QT interval mainly at daytime and a significant shift of the T wave apex towards the end of the T wave. The circadian profile of ventricular repolarization is strongly related to the mean R-R interval, however, there are significant alterations mainly at daytime with normal aging. Furthermore, the diurnal course of the QT interval variability strongly suggests that it is related to cardiac sympathetic activity and to the reported diurnal pattern of malignant ventricular arrhythmias. (PACE 2003; 26[Pt. II]):377–382)     

非典型抗精神病药物对精神分裂症患者心电图QT间期的影响

目的评价非典型抗精神病药物对精神分裂症患者心电图QT间期的影响。方法对153例单一口服非典型抗精神病药物治疗的精神分裂症患者,于治疗前及治疗药物达临床最大剂量时进行心电图检查,对心电图QT／QTc间期进行对比分析。结果非典型抗精神病药物喹硫平、利培酮、阿立哌唑治疗后QT／QTc间期与治疗前比较均无显著性差异（P〉0．05）;氯氮平治疗后QT／QTc间期均较治疗前显著缩短（t=5．294、3．243,P〈0．01）。治疗前不同药物组QT／QTc间期经方差分析均无显著性差异,治疗后不同药物组QT间期有显著性差异（F=8．759,P=0．000）;两两比较显示,治疗后QT间期平均值利培酮组、阿立哌唑组〉氯氮平组（P〈0．01）;不同药物治疗后QT间期平均值长短顺序依次为利培酮〉阿立哌唑〉喹硫平〉氯氮平。结论不同非典型抗精神病药物对心电图的QT／QTc间期有不同程度的影响,利培酮组的QT间期最长,氯氮平组最短。     

A Thorough QT Study of the Combination Glecaprevir + Pibrentasvir on Cardiac Repolarization in Healthy Subjects

PurposeFixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults.MethodsThis placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects. The doses of GLE 400 mg + PIB 120 mg were selected to provide exposures comparable to those with the doses that are therapeutic in the HCV-infected population, GLE 300 mg + PIB 120 mg. The doses of GLE 600 mg + PIB 240 mg were selected to provide supratherapeutic exposures without exceeding the exposures of the GLE + PIB maximal tolerated doses. Moxifloxacin 400 mg (active control/open label) was used for confirming the sensitivity of the ECG assay in detecting QTc prolongation. Time-matched plasma concentrations and triplicate ECGs were obtained on treatment days −1 and 1. The primary end point was time-matched, placebo-corrected, baseline-adjusted Fridericia-corrected QT interval (ΔΔQTcF). Pharmacokinetic–pharmacodynamic analyses characterized the relationship between GLE and PIB plasma concentrations and ΔΔQTcF using a linear regression model and linear mixed-effects model. Findings from categorical analyses of ECG-interval data were also summarized. Tolerability was evaluated through adverse-events monitoring, physical examination including vital sign measurements, ECGs, and laboratory tests.FindingsA total of 48 subjects (22 women [46%], 26 men [54%]), were enrolled in the study, and 47 subjects completed all 4 periods. None of the subjects had a change from baseline in QTcF interval of >30 msec or an absolute QTcF interval of >450 msec. Peak ΔΔQTcF values observed at 5 h postdose (T_max) were 2.9 msec (upper 95% confidence limit, 4.9 msec) with the therapeutic dose and 3.1 msec (upper 95% confidence limit, 5.1 msec) with the supratherapeutic dose, with both upper 95% confidence limits well below the 10-msec threshold. Assay sensitivity was confirmed by peak ΔΔQTcF in the positive control (12.8 ms at 2 h postdose). No statistically significant GLE or PIB concentration-dependent effects on ΔΔQTcF were observed. Headache and skin irritation from ECG electrodes were the most commonly reported AEs. No clinically significant vital sign measurements, ECG findings, or laboratory measurements were observed. There were no patterns of T- and U-wave morphologic abnormalities.ImplicationsThe fixed-dose combination regimen of GLE/PIB does not prolong the QTc interval. ClinicalTrials.gov identifier.     

Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized,Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults

Purpose

Nemonoxacin, a nonfluorinated quinolone, has been approved in Taiwan and mainland China for the treatment of bacterial infection. Whether nemonoxacin is associated with the adverse events of other quinolones, such as the risk for QT-interval prolongation, which has led to the withdrawal of several fluoroquinolones from the market, needs to be elucidated.

Precision of QT interval measurement by advanced electrocardiographic equipment

The costs of clinical investigations of drug-induced QT interval prolongation are mainly related to manual processing of electrocardiographic (ECG) recordings. Potentially, however, these costs can be decreased by automatic ECG measurement. To investigate the improvements in measurement accuracy of the modern ECG equipment, this study investigated QT interval measurement by the "old" and "new" versions of the 12SL ECG algorithm by GE Healthcare (Milwaukee, WI, USA) and compared the results to carefully validated and reconciled manual measurements. The investigation used two sets (A and B) of ECG recordings that originated from large clinical studies. Sets A and B consisted of 15,194, and 29,866 10-second ECG recordings, respectively. All the recordings were obtained with GE Healthcare recorders and were available in digital format compatible with ECG processing software by GE Healthcare. The two sets of recordings differed significantly in ECG quality with set B being substantially more noise polluted. Compared to careful manual QT interval readings in recording set A, the errors of the automatic QT interval measurement were (mean +/- SD) +3.95 +/- 5.50 ms, and +0.51 +/- 12.41 ms for the "new" and "old" 12SL algorithm, respectively. In recording set B, these numbers were +2.41 +/- 9.47 ms, and -0.17 +/- 14.89 ms, respectively (both differences were highly statistically significant, P < 0.000001). In recording set A, 95.9% and 76.6% of ECGs were measured automatically within 10 ms of the manual measurement by the "new" and "old" versions of the 12SL algorithm, In recording set B, these numbers were 83.9% and 59.5%. The errors made by the "new" and "old" version of 12SL algorithm were practically independent each of the other (correlation coefficients of 0.031 and 0.281 in recording sets A and B, respectively). The study shows that (a) compared to the "old" version of the 12SL algorithm, the QT interval measurement by the "new" version implemented in the most recent ECG equipment by GE Healthcare is significantly better, and (b) the precision of automatic measurement by the 12SL algorithm is substantially dependent on the quality of processed ECG recordings. The improved accuracy of the "new" 12SL algorithm makes it feasible to use modern ECG equipment without any manual intervention in selected parts of drug-development program.     

Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials

Objectives: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).

Methods: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).

Results: In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively.

?Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone.

Conclusions: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.     

Tp-e Interval, Tp-e/QT Ratio, and Tp-e/QTc Ratio are Prolonged in Patients with Moderate and Severe Obstructive Sleep Apnea

Background: Prolongation of the peak and the end of T wave (Tp-e) has been reported to be associated with ventricular arrhythmias. Tp-e/QT ratio and Tp-e/QTc ratio are used as an index of ventricular arrhythmogenesis. An increased incidence of ventricular arrhythmias has been reported in patients with obstructive sleep apnea (OSA). The aim of this study was to assess ventricular repolarization in patients with OSA by using Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio. Methods: We have studied 72 patients who underwent overnight polysomnography (PSG) between the years 2010-2011 at our institution. Patients with moderate and severe OSA (23 patients; mean age: 45±10), according to the apnea-hypopnea index, constituted the study group. Patients with normal PSG (23 patients; mean age: 42±11) were used as the control group. In all patients, Tp-e interval, Tp-e/QT ratio, Tp-e/QTc ratio, as well as some other electrocardiogram intervals were measured. Independent samples t-tests were used for comparison of continuous and categorical variables and correlations were calculated by Spearman rank correlation. Results: Although QT and QTc intervals were not different between the groups, mean Tp-e interval (81.6±11.1 msn; 63.9±7.3 msn; respectively; P < 0.001), Tp-e/QT ratio (0.21±0.03; 0.17±0.02; respectively; P < 0.001), and Tp-e/QTc ratio (0.20±0.03; 0.16±0.02; respectively; P < 0.001) were prolonged in the study group compared to the control group. Correlation analysis showed a significant positive correlation between the presence of moderate and severe OSA and Tp-e interval (r = 0.72; P < 0.001), Tpe/QT ratio (r = 0.70; P < 0.001), and Tp-e/QTc ratio (r = 0.70; P < 0.001). Conclusions: Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe OSA patients. There is a positive correlation between the presence of OSA and Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio. (PACE 2012; 35:966-972).     

Circadian Rhythm of the Corrected QT Interval: Impact of Different Heart Rate Correction Models

SMETANA, P., et al .: Circadian Rhythm of the Corrected QT Interval: Impact of Different Heart Rate Correction Models . A reduced circadian pattern in the QTc interval has been repeatedly reported to provide prognostic information in cardiac patients. However, the results of studies in healthy subjects in which different heart rate correction formulas were used are inconsistent regarding the presence and extent of diurnal variations in QTc. This study compared the diurnal variations in QTc obtained with four frequently used heart rate correction models with those based on individually optimized heart rate correction. In 53 subjects (25 men aged 27 ± 7 years and 28 women aged 27 ± 9 years) 12-lead digital ECGs were obtained every 30 seconds during 24 hours. The QT interval was measured automatically by six different algorithms provided by a commercially available device. The QT/RR relation was estimated by four common heart rate correction models and by an individually optimized correction model, QTc = QT/RR^α. In each 24-hour recording, RR, QT, and QTc intervals of separate ECG samples were averaged over 10-minute intervals. Marked differences were found in the extent of the circadian pattern of QTc obtained with different formulas for heart rate correction. Under and overcorrection of the QT interval resulted in significant over- or underestimation of the circadian pattern. Thus, the extent of circadian variation in QTc depends highly on the heart rate correction formula used. To obtain proper insight regarding diurnal variation in QTc prolongation during pharmacologic therapy and/or to assess higher risk due to impaired autonomic regulation of ventricular repolarization, individualized heart rate correction is necessary. (PACE 2003; 26[Pt. II]:383–386)     

Autonomic Effects of Dipyridamole Stress Testing on Frequency Distribution of RR and QT Interval Variability

Transient myocardial ischemia and associated changes in the autonomic nervous system may influence heart rate and ventricular repolarization to variable degrees. This study evaluated the effect of dipyridamole (DIP) induced ischemia on the autonomic balance by spectral analysis of RR and QT intervals variability. Patients with coronary artery disease undergoing DIP stress echocardiography were studied. From high resolution ECG recordings, RR and QT interval measurements were performed by a dynamic template-matching algorithm. A time-variant analysis was used to estimate power in the LF (0.05–0,15 Hz) and in the HF (0.15–0.4 Hz) band of RR and QT interval spectra. Patients were grouped in ischemic and nonischemic subgroups based on the echocardiographic detection of wall-motion abnormalities. In patients without ischemia (n = 28), DIP caused a decrease in LF power and an increase in HF power of the RR and QT interval variability, indicating concordant changes of both intervals. In contrast, patients with inducible ischemia (n = 11) showed a decrease in HF power of the RR interval spectra and an increase of HF power of QT interval spectra. Furthermore, LF power was increased for RR but decreased for QT interval spectra. Our study suggests that DIP induced ischemia causes a loss of autonomic coupling between heart rate and ventricular repolarization for sympathetic and parasympathetic activities. This lability in ventricular repolarization may constitute an arrhythmogenic substrate during acute ischemia in patients with coronary artery disease.     

Holter monitoring in the evaluation of congenital long QT syndrome

Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that affects one in 2,000 persons; causes syncope, seizures, and sudden death; and is both under‐ and overdiagnosed. LQTS diagnostic miscues have stemmed from assessment of ambulatory electrocardiographic monitoring (Holter) results. Objective: We sought to determine the prevalence of positive Holter monitor tests and its diagnostic significance in evaluating LQTS. Methods: We performed an institutional review board‐approved review of patients evaluated in our LQTS clinic from 2000 to 2009 who had Holter testing during their evaluation. Included patients (N = 473) were diagnosed with LQTS or dismissed as otherwise normal. Holters classified as positive had an episode of nonsustained ventricular tachycardia, supraventricular tachycardia, ≥4 couplets/day, ≥10 premature ventricular contractions/hour, or >5‐second sinus pause. Results: Among 209 patients dismissed as normal (128 females, average age 21 ± 15 years, average QTc 424 ± 39 ms), 27 (12.9%) had a positive Holter, while among 264 patients with LQTS (149 females, average age 22 ± 16 years, average QTc 472 ± 41 ms), 30 (11.3%) had a positive Holter (P = NS). Patients with LQT3 (5/23, 21%) and genotype‐negative LQTS (5/19, 26%) had a higher rate of positive Holter testing compared to LQT1 patients (7/124, 6%, P < 0.03). Among the 473 Holters, only one (0.2%) impacted clinical decision making. Conclusion: Routine Holter monitoring appears to be of minimal clinical utility from a diagnostic and prognostic perspective in evaluating LQTS, and may not be cost effective. Whether Holter monitoring aids in therapeutic decisions such as dosing or whether ambulatory QTc measurements, provided by some newer devices, might help in the diagnostic evaluation warrants further scrutiny. (PACE 2011; 34:1100–1104)     

Evaluation of Direct Respiratory Modulation of the QT Interval Variability

To investigate the direct respiration-mediated vagal modulation of the QT interval variability, spectral analyses of the RTp interval (from the R wave peak to the T wave peak) variability (RTpV) and the RR interval variability (RRV) were performed in 12 subjects with normal ventricular repolarization under three conditions while the respiration frequency was kept at 0.2 Hz: during sinus rhythm, during fixed atrial pacing, and during fixed atrial pacing with autonomic blockade. The cross-spectrum between the RRV and RTpV was quantified by the squared coherence. During sinus rhythm the RRV power spectrum showed two peaks: a broad peak in the low frequency (LF) band and a sharp peak at 0.2 Hz which corresponded to the controlled respiration frequency. The RTpV power spectrum showed corresponding peaks to the RRV peaks in both the LF and high frequency (HF) bands with high coherence (mean maximum values of the squared coherence in the LF band 0.59 ± 0.22, and in the HF band 0.74 ± 0.14). During atrial pacing mean total power of the RTpV decreased from during sinus rhythm (from 16.3 ± 5.6 ms² to 12.9 ± 5.4 ms², P < 0.05) and the RTpV spectral peaks were abolished in both the LF and HF bands concordant with disappearance of the RRV peaks. Autonomic blockade gave no additional change to the RTpV power spectrum independently of the RRV during fixed atrial pacing. The present study suggested that the direct respiration-mediated vagal modulation may not affect the short-term variability of the QT interval in subjects without repolarization abnormality.     

Effect of lead exclusion for the manual measurement of QT dispersion

To investigate the effect of different lead exclusion criteria for the manual measurement of QT dispersion (QTd). Simultaneous 12-lead ECGs from three groups of 25 subjects were studied; healthy normal subjects, subjects with a myocardial infarction, and subjects with arrhythmias. Leads were excluded with (1) small absolute T wave amplitudes, (2) small relative T wave amplitudes, and (3) small and/or large relative QT measurements. QTd was calculated as the QT range and assessed for its ability to differentiate between the normal and pathological groups. With exclusion of no leads or low absolute amplitude T waves (< 50 microV) significant differences were observed only between normal and myocardial infarct groups (P < 0.05). Significant differences between normal and both pathological groups were observed when excluding the lead with the smallest amplitude T wave or shortest QT (P < 0.05), or when two leads of either type were excluded (P < 0.005). There was good agreement between leads excluded by amplitude or QT (P < 0.01). Lead exclusion for QTd is important. Exclusion of the two smallest amplitude or two shortest QT leads from each subject produced the greatest differences between the normal and pathological groups.     

Evaluation of drug-induced QT interval modifications in dynamic electrocardiography: the case of bepridil

Summary— Drug-induced modifications of QT interval are usually assessed through formulae defining the corrected QT interval “QTc”. They are all based on the assumption that the correction is adequate, and that drug-induced heart rate variations and rate-dependent QT changes are proportional. Holler ECG allows to study the repolarization in selected RR cycles while controlling environmental rate-related and circadian influences. Repolarization duration was evaluated in 15 normal individuals and 13 patients with stable coronary artery disease and no heart failure who did not differ in terms of 24-hour heart rate, age and sex. The effects of a 3-month treatment with bepridil were assessed in the latter. Using the conventional evaluation through the corrected QT (Bazett formula), no difference was found between the two groups at baseline, and bepridil induced a non-significant 5% prolongation of QTc. At Holler recordings, the QTa (Q-T apex) duration was linearly correlated with the heart rate over 24 hours. To specifically study day-tonight variations and to exclude the rate-dependent and short-term autonomic influences. QTa was studied in populations of averaged QRS-T selected according to i) the last RR cycle length and ii) an identical mean RR interval during the preceding minute. Both RR values were fixed at 800 ms to obtain the “QTa-800” measured directly or extrapolated from linearly correlated, other RR values. Using this technique, the two groups differed at baseline in terms of dynamicity of QTa: the QTa/RR regression line slope was steeper in normals, and the strongly significant day-to-night difference of QTa-800 (P < 0.001) observed in them was absent in coronary patients. Bepridil, wliich did not significantly modify the 24-hour heart rate, lengthened the QTa-800 by 4–5%: although no more marked than with the QTc, this increase became significant at daytime (P = 0.04) and at night (P = 0.01) because of the inter-individual consistency of the modifications. These results suggest that the approach of QT evaluation in strictly comparable conditions of environmental rate and time allowed by the Hotter technique is better adapted than the conventional QTc method to assess limited drug-induced changes.     

Beat-To-Beat Behavior of QT Interval During Conducted Supraventricular Rhythm in the Normal Heart

To assess beat-to-beat behavior of QT interval under different conditions, high resolution recordings and computerized beat-to-beat analysis of the electrocardiogram were performed at rest, during recovery after short exercise, and during atrial pacing. Beat-to-beat variations of QT interval during sinus rhythm at rest and after short exercise were measured in ten healthy men. In an additional three patients with supraventricular tachycardia, beat-to-beat QT changes were studied after abrupt sustained acceleration and deceleration of heart rate by atrial pacing. Beat-to-beat changes in RH interval at rest are followed by minimal changes of the QT interval. The measured proportional change of the QT interval compared with the change in HR interval (Δ QT/A BR) was 0.02. This value represents 10% of the value expected for QT changes from Bazett's formula. Following short exercise QT interval did not change for 15 seconds and reached a maximal value 30 seconds later as compared to the RR interval (192 vs 115 sees, P < 0.001). The steady state of the QT interval during sustained atrial pacing was achieved after 132, 135, and 133 seconds for pacing intervals of 600, 500, and 600 msec, respectively. Our data indicate a relatively slow adaptation of the QT interval to changes in heart rate.     

Corrected QT interval in relation to the severity of diabetic autonomic neuropathy

The aim of this study was to investigate to what extent the existence of objective signs of diabetic autonomic neuropathy affects the corrected QT interval (QTc) in diabetic subjects. A total of 105 diabetic subjects (type 1, n  = 53; type 2, n  = 52) as well as 40 matched (by age and sex) control subjects were studied. All subjects underwent the battery of five Ewing tests. Autonomic neuropathy was diagnosed if two of the five tests were abnormal. In addition, the result of each test was considered as normal (grade = 0), borderline (grade = 1) or abnormal (grade = 2), and on the basis of the sum of the scores we calculated a total score for autonomic neuropathy. The QTc interval was measured at rest, and a value > 440 ms was considered abnormal. The QTc interval was significantly more prolonged in diabetic persons with autonomic neuropathy than in those without neutopathy and in control subjects: 408.4 ± 24.2 ms vs. 394.6 ± 27.9 ms and 393.6 ± 25.5 ms respectively ( P  = 0.001). Furthermore, multivariate analysis controlling for age, sex, systolic and diastolic blood pressure, body mass index (BMI), waist–hip ratio (WHR), smoking, type and duration of diabetes, type of treatment, HBA_1c and total score of autonomic neuropathy eliminated the role of all these factors as potential confounders except for the total score of autonomic neuropathy, which was found to affect QTc interval independently and significantly ( P  = 0.012). In summary, the present study confirmed the well-known relation between autonomic neuropathy and QTc interval; in addition, it showed that QTc prolongation is associated with major degrees of autonomic neuropathy.     

2型糖尿病患者心电图QT间期的变化及卡托普利对其影响

目的　探讨 2型糖尿病患者心电图QT间期的变化及卡托普利对其影响。方法　对 189例糖尿病患者心电图QT间期进行测量 ,并按Bazett公式进行校正 ,取其校正的QT间期QTc与 12 0例正常人进行对照。给糖尿病患者卡托普利治疗 ,观察治疗 1、2、3、6个月后QTc间期的变化。结果　正常人QTc间期 ,男性 396± 1.7ms ,女性 418± 2 .3ms。糖尿病患者QTc ,男性 40 7± 1.9ms、女性 42 7± 2 .2ms。糖尿病患者卡托普利治疗 3、6个月后QTc间期缩短 ,分别为 :男性40 3± 2 .1ms、40 2± 1.6ms ,女性 413± 2 .3ms、412± 1.9ms。与治疗前相比具有显著性差异。结论　 2型糖尿病患者QTc间期延长 ,卡托普利可使延长的QTc间期缩短。提示卡托普利有助于防治糖尿病心血管并发症