Clinical assessment of drug-induced QT prolongation in association with heart rate changes

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.     

Comparison of Formulae for Heart Rate Correction of QT Interval in Exercise Electrocardiograms

The study investigated the differences in five different formulae for heart rate correction of the QT interval in serial electrocardiograms recorded in healthy subjects subjected to graded exercise. Twenty-one healthy subjects (aged 37+/-10 years, 15 male) were subjected to graded physical exercise on a braked bicycle ergometer until the heart rate reached 120 beats/min. Digital electrocardiograms (ECG) were recorded on baseline and every 30 seconds during the exercise. In each ECG, heart rate and QT interval were measured automatically (QT Guard package, Marquette Medical Systems, Milwaukee, WI, USA). Bazett, Fridericia, Hodges, Framingham, and nomogram formulae were used to obtain QTc interval values for each ECG. For each formula, the slope of the regression line between RR and QTc values was obtained in each subject. The mean values of the slopes were tested by a one-sample t-test and the comparison of the baseline and peak exercise QTc values was performed using paired t-test. Bazett, Hodges, and nomogram formulae led to significant prolongation of QTc intervals with exercise, while the Framingham formula led to significant shortening of QTc intervals with exercise. The differences obtained with the Fridericia formula were not statistically significant. The study shows that the practical meaning of QT, interval measurements depends on the correction formula used. In studies investigating repolarization changes (e.g., due to a new drug), the use of an ad-hoc selected heart rate correction formula is highly inappropriate because it may bias the results in either direction.     

The imprecision in heart rate correction may lead to artificial observations of drug induced QT interval changes

Because of the known limitations of the Bazett and other heart rate correction formulas, it has been proposed that studies of drug induced QT interval changes should use several different heart rate correction formulas and that the consistency of findings by a majority of such formulas should be considered as valid. The aim of this article was to show that such an approach is inappropriate. Using the database of the EMIAT trial, data of QT and RR intervals were taken from electrocardiograms of the first postrandomization visit of 1,402 patients. Of these, 309 were on amiodarone and beta-blockers, 395 on amiodarone and off beta-blockers, 318 on beta-blockers and off amiodarone, and 380 off amiodarone and off beta-blockers. An investigation of drug induced QT interval changes was modeled by evaluating the corrected QT (QTc) interval differences between patients on and off amiodarone, and on and off beta-blockers. A set of 31 previously published heart rate correction formulas was used. In addition to calculating the QTc difference between on and off drug for each formula, the success of heart rate correction was judged by computing correlation coefficients between QTc and RR intervals (ideally corrected QTc values should be independent of heart rate). The difference between on and off drug QT intervals was also evaluated by logarithmic regression models between uncorrected QT and RR intervals in data taken from patients on and off treatment. The QTc interval prolongation on amiodarone was confirmed by all heart rate correction formulas but the extent of the prolongation differed from formula to formula and ranged from 13.6 to 30.9 ms. Of the 31 formulas, 3 reported QTc interval shortening on beta-blockers (up to -11.8 ms) and 28 reported QTc interval prolongation (up to +16.8 ms). The distribution of the results provided by the different formulas suggested that beta-blocker treatment led to a QTc interval prolongation by approximately 7 ms (e.g., +7.4 ms by the Fridericia formula, P = 0.002). The on treatment QTc changes obtained by different formulas were closely correlated to their correction success. Formulas that provided QTc intervals almost independent of the RR intervals estimated approximately 20 ms QTc prolongation on amiodarone and no QTc change on beta-blockers. QT/RR regression analysis confirmed that while amiodarone led to substantial QT prolongation, there was no change of QT interval on beta-blockers beyond the change in heart rate. The study showed that the concept of "majority voting" by different heart rate correction formulas is inappropriate and may lead to erroneous conclusions.     

Correlation between QTc interval and clinical severity of subarachnoid hemorrhage depends on the QTc formula used

OBJECTIVES: Subarachnoid hemorrhage (SAH) frequently prolongs QT interval in the acute phase. The purpose of our study is to investigate whether the correlation between electrocardiographic corrected QT interval and the clinical severity of SAH depends on QTc formula used. METHODS: We retrospectively studied 52 consecutive subjects with nontraumatic SAH (extravasation of blood into the spaces covering the central nervous system that are filled with cerebrospinal fluid) who were admitted within the first day of SAH. QT intervals were measured on a standard 12-lead electrocardiography and corrected by Bazett and Hodges formulae. All patients were evaluated according to clinical condition on admission by Hunt-Hess grades. The patients were grouped in two different categories according to QT interval corrected by Bazett and Hodges and scored by Hunt-Hess (HH) grades. RESULTS: Mean age of the study patients was 54 +/- 12 years and of those 31 (60%) were female. Mean values of heart rate and RR interval were 82 +/- 21 bpm and 777 +/- 163 msec, respectively. The mean QTc interval by Bazett and Hodges were 456 +/- 59 msec and 438 +/- 48 msec, respectively (P < 0.001). Twenty-three patients according to Bazett and fifteen according to Hodges had prolonged QTc. Correlation analyses showed relation between HH and QTc and prolonged QTc by Bazett (r = 0.278, P = 0.04 and r = 0.314, P = 0.024; respectively). There was no correlation between HH and QTc and prolonged QTc by Hodges (r = 0.204, P = 0.14 and r = 0.115, P = 0.41; respectively). CONCLUSIONS: In our study, correlation between QTc interval and clinical severity of SAH depended on the QTc formula used.     

Heart Rate‐Dependence of QTc Intervals Assessed by Different Correction Methods in Patients with Normal or Prolonged Repolarization

Background: There is a continuing debate about the optimal method for QT interval adjustment to heart rate changes. We evaluated the heart rate dependence of QTc intervals derived from five different QT correction methods. Methods: Study patients (n = 123, age 68 ± 11 years) were dual‐chamber device recipients with baseline normal or prolonged QT interval who had preserved intrinsic ventricular activation with narrow QRS complexes. Patients were classified to either Normal‐QT (n = 69) or Prolonged‐QT (n = 54) groups. Serial QT intervals were recorded at baseline (52 ± 3 beats per minute) and following atrial pacing stages at 60, 80, and 100 beats per minute. The QTc formulae of Bazett, Fridericia, Sagie‐Framingham, Hodges, and Karjalainen‐Nomogram were applied to assess the effect of heart rate on the derived QTc values by using linear mixed‐effects models. Results: Heart rate had a significant effect on QTc regardless of the formula used (P < 0.05 for all formulae). The Bazett's formula demonstrated the highest QTc variability across heart rate stages (highest F values) in both patient groups (in the total cohort, F = 175.9). In the following rank order, the formulae Hodges, Karjalainen‐Nomogram, Sagie‐Framingham, and Fridericia showed similar QTc heart rate dependence at both slower and faster heart rates in both patient groups (F = 21.8, 25.6, 28.8, 36.9, in the total cohort, respectively). Conclusions: Of the studied QTc formulae, the Bazett appeared the most heart rate dependent. Our results suggest the use of Hodges and the Karjalainen‐Nomogram secondly to ensure least heart rate dependence of QTc intervals in patients with either normal or prolonged repolarization. (PACE 2010; 553–560)     

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)     

Effects of three fluoroquinolones on QT interval in healthy adults after single doses

OBJECTIVE: A clinical trial was conducted in healthy adult volunteers to assess the effect of levofloxacin, moxifloxacin, and ciprofloxacin on the QT and QTc interval. METHODS: Electrocardiograms were recorded 24 hours before and after subjects took placebo, 1000 mg levofloxacin, 800 mg moxifloxacin, and 1500 mg ciprofloxacin in a double-blind, randomized, 4-period, 4-treatment, 4-sequence crossover trial. Changes in QT and QTc interval from baseline were assessed by several different methods. RESULTS: Increases in QT and QTc interval compared with placebo were consistently greater after moxifloxacin compared with either levofloxacin or ciprofloxacin. The mean postdose change from baseline QTc (Bazett) intervals for the 24-hour period after treatment with moxifloxacin ranged from 16.34 to 17.83 ms (P < .001, compared with placebo). For levofloxacin, this change ranged from 3.53 to 4.88 ms (P < .05, compared with placebo), and for ciprofloxacin, this change ranged from 2.27 to 4.93 ms (P < .05, compared with placebo, with the use of 3 of 5 baseline methods). CONCLUSIONS: A change in QTc (Bazett) interval from baseline can be demonstrated safely in healthy volunteers after single high doses of fluoroquinolones that achieve approximately 1.5 times the maximum plasma drug concentration that occurs after recommended doses. There is substantial daily variation in both QT and QTc interval, and the magnitude and frequency of changes in QTc interval can depend on the methods used. These factors need to be considered because clinical trials measuring the effects of drugs on QT intervals are used to estimate the risk of using these drugs. Greater changes in QT and QTc intervals after treatment with moxifloxacin compared with levofloxacin or ciprofloxacin are consistent with in vitro observations related to the effect of these drugs on rapid potassium (IK(r)) channels. The clinical relevance of these differences is not known.     

Multivariate analysis of risk factors for QT prolongation following subarachnoid hemorrhage

Background

Subarachnoid hemorrhage (SAH) often causes a prolongation of the corrected QT (QTc) interval during the acute phase. The aim of the present study was to examine independent risk factors for QTc prolongation in patients with SAH by means of multivariate analysis.

Method

We studied 100 patients who were admitted within 24 hours after onset of SAH. Standard 12-lead electrocardiography (ECG) was performed immediately after admission. QT intervals were measured from the ECG and were corrected for heart rate using the Bazett formula. We measured serum levels of sodium, potassium, calcium, adrenaline (epinephrine), noradrenaline (norepinephrine), dopamine, antidiuretic hormone, and glucose.

Results

The average QTc interval was 466 ± 46 ms. Patients were categorized into two groups based on the QTc interval, with a cutoff line of 470 ms. Univariate analyses showed significant relations between categories of QTc interval, and sex and serum concentrations of potassium, calcium, or glucose. Multivariate analyses showed that female sex and hypokalemia were independent risk factors for severe QTc prolongation. Hypokalemia (<3.5 mmol/l) was associated with a relative risk of 4.53 for severe QTc prolongation as compared with normokalemia, while the relative risk associated with female sex was 4.45 as compared with male sex. There was a significant inverse correlation between serum potassium levels and QTc intervals among female patients.

Conclusion

These findings suggest that female sex and hypokalemia are independent risk factors for severe QTc prolongation in patients with SAH.     

Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation

Regulatory authorities require new drugs to be investigated using a so-called "thorough QT/QTc study" to identify compounds with a potential of influencing cardiac repolarization in man. Presently drafted regulatory consensus requires these studies to be powered for the statistical detection of QTc interval changes as small as 5 ms. Since this translates into a noticeable drug development burden, strategies need to be identified allowing the size and thus the cost of thorough QT/QTc studies to be minimized. This study investigated the influence of QT and RR interval data quality and the precision of heart rate correction on the sample sizes of thorough QT/QTc studies. In 57 healthy subjects (26 women, age range 19-42 years), a total of 4,195 drug-free digital electrocardiograms (ECG) were obtained (65-84 ECGs per subject). All ECG parameters were measured manually using the most accurate approach with reconciliation of measurement differences between different cardiologists and aligning the measurements of corresponding ECG patterns. From the data derived in this measurement process, seven different levels of QT/RR data quality were obtained, ranging from the simplest approach of measuring 3 beats in one ECG lead to the most exact approach. Each of these QT/RR data-sets was processed with eight different heart rate corrections ranging from Bazett and Fridericia corrections to the individual QT/RR regression modelling with optimization of QT/RR curvature. For each combination of data quality and heart rate correction, standard deviation of individual mean QTc values and mean of individual standard deviations of QTc values were calculated and used to derive the size of thorough QT/QTc studies with an 80% power to detect 5 ms QTc changes at the significance level of 0.05. Irrespective of data quality and heart rate corrections, the necessary sample sizes of studies based on between-subject comparisons (e.g., parallel studies) are very substantial requiring >140 subjects per group. However, the required study size may be substantially reduced in investigations based on within-subject comparisons (e.g., crossover studies or studies of several parallel groups each crossing over an active treatment with placebo). While simple measurement approaches with ad-hoc heart rate correction still lead to requirements of >150 subjects, the combination of best data quality with most accurate individualized heart rate correction decreases the variability of QTc measurements in each individual very substantially. In the data of this study, the average of standard deviations of QTc values calculated separately in each individual was only 5.2 ms. Such a variability in QTc data translates to only 18 subjects per study group (e.g., the size of a complete one-group crossover study) to detect 5 ms QTc change with an 80% power. Cost calculations show that by involving the most stringent ECG handling and measurement, the cost of a thorough QT/QTc study may be reduced to approximately 25%-30% of the cost imposed by the simple ECG reading (e.g., three complexes in one lead only).     

Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram

BACKGROUND: Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined. AIM: To evaluate the performance of a QT nomogram in assessing the risk of TdP from QT-RR combinations. DESIGN: Systematic review. METHODS: We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QT-RR measurements available. The upper bound of a QT-RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT-HR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc = 440 ms and QTc = 500 ms for comparison (Bazett's correction). RESULTS: We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 30-90 bpm. Controls were more evenly distributed, with HR 40-160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9-99.9) and 98.7% (95%CI 96.8-100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3-100) and 66.7% (95%CI 58.6-74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6-98.0) and 97.2% (95%CI 94.3-100), respectively. DISCUSSION: The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed.     

Greater quinidine-induced QTc interval prolongation in women

BACKGROUND: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women. METHODS: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2). RESULTS: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval. CONCLUSIONS: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.     

Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.     

四硫化四砷对急性早幼粒细胞白血病患者心电图QTc问期的影响

目的探讨四硫化四砷(As4S4)对急性早幼粒细胞白血病(APL)患者心电图校正后QT(QTc)间期的影响.方法复方柏子仁(主要成分As4S4)治疗的90例患者分为诱导缓解组和巩固维持治疗组.诱导缓解组测定并记录患者服药前及缓解后的血砷浓度及同步12导联心电图;巩固维持治疗组测定并记录患者服药前及第2,4,6,8,10疗程后的血砷浓度及心电图.测量每份心电图的QT间期值,以Bazett公式校正,计算出QTc,观察血砷浓度与QTc间期的关系.结果无论诱导缓解组还是巩固维持治疗组,口服As4S4均能引起QTc间期的延长,QTc与As4S4的剂量及血砷浓度有关,随着As4S4的累积剂量或血砷浓度增大,QTc值及其延长的幅度也增大.在巩固维持治疗组服药的10个疗程中,QTc值异常(≥440 ms)率平均为 37.7%,随服用As4S4累积剂量的增加,各疗程血砷浓度缓慢上升,但各疗程之间的变化差异无显著性(P>0.05).各疗程中QTc间期虽逐步延长,但QTc值异常率在各疗程中无显著性差异(P>0.05).QTc异常的患者均无临床症状,未出现室性心动过速或尖端扭转型室性心动过速等病变,无一例患者因QTc间期延长而终止治疗.结论 As4S4治疗APL虽可引起QTc间期延长,且QTc间期的变化与血砷浓度呈正相关,但As4S4仍为一种安全的治疗APL的药物.     

Evaluation of a subject-specific transfer-function-based nonlinear QT interval rate-correction method

The QT interval in the electrocardiogram (ECG) is a measure of total duration of depolarization and repolarization. Correction for heart rate is necessary to provide a single intrinsic physiological value that can be compared between subjects and within the same subject under different conditions. Standard formulas for the corrected QT (QTc) do not fully reproduce the complexity of the dependence in the preceding interbeat intervals (RR) and inter-subject variability. In this paper, a subject-specific, nonlinear, transfer function-based correction method is formulated to compute the QTc from Holter ECG recordings. The model includes five parameters: three describing the static QT-RR relationship and two representing memory/hysteresis effects that intervene in the calculation of effective RR values. The parameter identification procedure is designed to minimize QTc fluctuations and enforce zero correlation between QTc and effective RR. Weighted regression is used to better handle unbalanced or skewed RR distributions. The proposed optimization approach provides a general mathematical framework for further extensions of the model. Validation, robustness evaluation and comparison with existing QT correction formulas is performed on ECG signals recorded during sinus rhythm, atrial pacing, tilt-table tests, stress tests and atrial flutter (29 subjects in total). The resulting average modeling error on the QTc is 4.9 ± 1.1 ms with a sampling interval of 2 ms, which outperforms correction formulas currently used. The results demonstrate the benefits of subject-specific rate correction and hysteresis reduction.     

Safety and efficacy of hydroxychloroquine in 152 outpatients with confirmed COVID-19: A pilot observational study

PurposeWe investigated the efficacy and safety of hydroxychloroquine for empirical treatment of outpatients with confirmed COVID-19.MethodsIn this prospective, single-center study, we enrolled ambulatory outpatients with COVID-19 confirmed by a molecular method who received hydroxychloroquine. The patients were divided into low- and moderate-risk groups based on the Tisdale risk score for drug-associated QT prolongation, and the QT interval was corrected for heart rate using the Bazett formula (QTc). The QTc interval was measured by electrocardiography both pretreatment (QTc1) and 4 h after the administration of hydroxychloroquine (QTc2). The difference between the QTc1 and QTc2 intervals was defined as the ΔQTc. The QTc1 and QTc2 intervals and ΔQTc values were compared between the two risk groups.ResultsThe median and interquartile range (IQR) age of the patients was 47.0 (36.2–62) years, and there were 78 men and 74 women. The median (IQR) QTc1 interval lengthened from 425.0 (407.2–425.0) to 430.0 (QTc2; 412.0–443.0) milliseconds (ms). However, this was not considered an increased risk of ventricular tachycardia associated with a prolonged QTc interval requiring drug discontinuation, because none of the patients had a ΔQTc of >60 ms or a QTc2 of >500 ms. Moreover, the median (quartiles; minimum-maximum) ΔQTc value was higher in patients in the moderate-risk group than those in the low-risk group (10.0 [−4.0–18.0; −75.0–51.0] vs. 7.0 [−10.5–23.5; −53.0–59.0 ms]) (p = 0.996). Clinical improvement was noted in 91.4% of the patients, the exceptions being 13 patients who presented with non-serious adverse drug reactions or who had severe COVID-19 and were hospitalized. Adverse effects related to hydroxychloroquine were non-serious and occurred in 52.8% (n = 80) of the patients.ConclusionsOur findings show that hydroxychloroquine is safe for COVID-19 and not associated with a risk of ventricular arrhythmia due to drug-induced QTc interval prolongation. Additionally, hydroxychloroquine was well tolerated, and there were no drug-related non-serious adverse events leading to treatment discontinuation in the majority of patients who were stable and did not require hospitalization.     

QT Interval Variability and Adaptation to Heart Rate Changes in Patients with Long QT Syndrome

Background: Increased QT variability (QTV) has been reported in conditions associated with ventricular arrhythmias. Data on QTV in patients with congenital long QT syndrome (LQTS) are limited.
Methods: Ambulatory electrocardiogram recordings were analyzed in 23 genotyped LQTS patients and in 16 healthy subjects (C). Short-term QTV was compared between C and LQTS. The dependence of QT duration on heart rate was evaluated with three different linear models, based either on the RR interval preceding the QT interval (RR₀), the RR interval preceding RR₀ (RR_-1), or the average RR interval in the 60-second period before QT interval (mRR).
Results: Short-term QTV was significantly higher in LQTS than in C subjects (14.94 ± 9.33 vs 7.31 ± 1.29 ms; P < 0.001). It was also higher in the non-LQT1 than in LQT1 patients (23.00 ± 9.05 vs 8.74 ± 1.56 ms; P < 0.001) and correlated positively with QTc in LQTS (r = 0.623, P < 0.002). In the C subjects, the linear model based on mRR predicted QT duration significantly better than models based on RR₀ and RR_-1. It also provided better fit than any nonlinear model based on RR₀. This was also true for LQT1 patients. For non-LQT1 patients, all models provided poor prediction of QT interval.
Conclusions: QTV is elevated in LQTS patients and is correlated with QTc in LQTS. Significant differences with respect to QTV exist among different genotypes. QT interval duration is strongly affected by noninstantaneous heart rate in both C and LQT1 subjects. These findings could improve formulas for QT interval correction and provide insight on cellular mechanisms of QT adaptation.     

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     

Temporary disturbances of the QT interval precede the onset of ventricular tachyarrhythmias in patients with structural heart diseases

An increase in sinus rate prior to ventricular tachyarrhythmias has been demonstrated in previous studies. There is no clear data available concerning changes in ventricular de- and repolarization prior to ventricular tachyarrhythmias, especially in patients with structural heart disease. Therefore, the aim of this study was to analyze the QT and QTc interval (Bazett's formula immediately before the onset of ventricular tachyarrhythmias in stored electrograms of patients with ICDs. The study analyzed 228 spontaneous ventricular tachyarrhythmia episodes in 52 patients (mean age 64 +/- 10 years, 49 men, 3 women) and compared them with 146 electrograms of baseline rhythm recorded during regular ICD follow-up. Mean ventricular cycle length (CL), QT interval, and QTc were measured before the onset of ventricular tachyarrhythmia and during baseline rhythm. Prior to ventricular tachyarrhythmias onset, CL was significantly shorter than during baseline rhythm (714 +/- 139 vs 828 +/- 149 ms, P < 0.0001). By contrast, the QT interval (430 +/- 67 ms) and QTc interval (518 +/- 67 ms) were significantly prolonged before the onset of ventricular tachyarrhythmias as compared to baseline rhythm (QT 406 +/- 67 ms, QTc 450 +/- 61 ms; P < 0.0001). CL, QT, and QTc changes were independent of concomitant treatment with antiarrhythmic drugs. Ventricular tachyarrhythmias are preceded by a significant prolongation of the QT and QTc intervals. This phenomenon may represent a greater than normal disparity of repolarization recovery times possibly facilitating the development of ventricular tachyarrhythmias.     

QT interval prolongation after oxytocin bolus during surgical induced abortion

BACKGROUND: Although oxytocin, a uterotonic agent, may cause short-term vasodilation that results in severe hypotension, it is still routinely given as an intravenous bolus injection during surgical suction curettage. Two reported cases of ventricular tachycardia after oxytocin bolus in patients with long QT interval syndrome led us to assess the effect of oxytocin on QT interval. METHOD: Thirty-eight healthy women scheduled for a surgical suction curettage with general anesthesia were enrolled. General anesthesia was induced by propofol and maintained by either propofol (n = 18) or sevoflurane (n = 20). Electrocardiographic recordings were obtained before and at 1, 2, 3, and 5 minutes after a 10-U intravenous bolus of oxytocin. RESULTS: Intravenous oxytocin induced a pronounced QTc interval prolongation of 41 +/- 21 ms ( P < .0001), which was maximal 1 minute after administration. The QTc interval returned to control values 3 minutes after oxytocin bolus. Oxytocin bolus also induced an increase in heart rate of 19 +/- 10 beats/min and a significant decrease in systolic arterial pressure of 11 +/- 9 mm Hg (both P < .0001). The drug used to maintain anesthesia was not an independent factor of QT interval prolongation in ANOVA analysis. CONCLUSIONS: Oxytocin intravenous bolus induced a large and transient QTc interval prolongation, suggesting that it may lead to proarrhythmia in circumstances favoring QTc interval increase.     

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.