Problems of heart rate correction in assessment of drug-induced QT interval prolongation

INTRODUCTION: Estimation of QT interval prolongation belongs to safety assessment of every drug. Among unresolved issues, heart rate correction of the QT interval may be problematic. This article proposes a strategy for heart rate correction in drug safety studies and demonstrates the strategy using a study of ebastine, a nonsedating antihistamine. METHODS AND RESULTS: Four-way cross-over Phase I study investigated 32 subjects on placebo, ebastine 60 mg once a day, 100 mg once a day, and terfenadine 180 mg twice a day. Repeated ECGs were obtained before each arm and after 7 days of treatment. The changes in heart rate-corrected QTc interval were investigated using (A) 20 published heart rate correction formulas, (B) a correction formula optimized by QT/RR regression modeling in all baseline data, and (C) individual corrections optimized for each subject by drug-free QT/RR regression modeling. (A) Previously published correction formulas found QTc interval increases on terfenadine. The results with ebastine were inconsistent. For instance, Bazett's and Lecocq's correction found significant QTc increase and decrease on ebastine, respectively. The results were related (absolute value(r) > 0.95) to the success of each formula (independence of drug-free QTc and RR intervals). (B) The pooled drug-free QT/RR regression found an optimized correction QTc = QT/RR(0.314). QTc interval changes on placebo, ebastine 60 mg, ebastine 100 mg, and terfenadine were -1.95 +/- 6.87 msec (P = 0.18), -3.91 +/- 9.38 msec (P = 0.053), 0.75 +/- 8.23 msec (P = 0.66), and 12.95 +/- 14.64 msec (P = 0.00025), respectively. (C) Individual QT/RR regressions were significantly different between subjects and found optimized corrections QTc = QT/RR(alpha) with alpha = 0.161 to 0.417. Individualized QTc interval changes on placebo, ebastine 60 mg, ebastine 100 mg, and terfenadine were -2.76 +/- 5.51 msec (P = 0.022), -3.15 +/- 9.17 msec (P = 0.11), -2.61 +/- 9.55 msec (P = 0.19), and 12.43 +/- 15.25 msec (P = 0.00057, respectively. Drug-unrelated QTc changes up to 4.70 +/- 8.92 msec reflected measurement variability. CONCLUSION: Use of published heart rate correction formulas in the assessment of drug-induced QTc prolongation is inappropriate, especially when the drug might induce heart rate changes. Correction formulas optimized for pooled drug-free data are inferior to the formulas individualized for each subject. Measurement imprecision and natural variability can lead to mean QTc interval changes of 4 to 5 msec in the absence of drug treatment.     

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval

Objective

A statistical modelling study investigated whether incorporating the curvatures of QT/RR patterns into the individual-specific QT heart rate correction increases QTc data accuracy.

Methods

Repeated ECG readings were available from 4 different drug-free recordings made in 176+176 healthy female and male subjects (aged 32 ± 10 and 33 ± 8 years, respectively). In each subject, up to 1440 ECG readings were made of QT intervals and of the corresponding QT/RR hysteresis corrected RR intervals. The QT/RR patterns of each study participant was fitted with 12 different regression formulae that corresponded to differently curved physiologically plausible QT/RR profiles. In each subject, each of the regression fits was converted into a QT heart rate correction formula and the optimum model that fitted the data of the subject best was identified. Correction formulae were applied to modelled QT/RR data with RR intervals between 400 ms and 1600 ms. Differences in QTc intervals calculated by the correction formulae corresponding to the individually optimum QT/RR regression models and by the same type of regression in all study subjects were statistically summarised in females and males.

Results

Compared to the individually curvature optimised QTc heart rate correction formulae, formulae of the different regression models overestimated or underestimated the QTc values when applied on all study subjects. At RR of 500 ms, the model assuming linear QT/RR relationship led to errors of − 5.01 ± 6.63 ms and of − 4.80 ± 7.23 ms in females and males, respectively. At the same RR interval level, the model assuming the linear relationship between the logarithms of QT and RR intervals led to errors of + 11.51 ± 6.36 ms and of + 15.09 ± 7.61 ms in females and males, respectively.

Conclusion

The differences in the curvatures of QT/RR patterns should be considered in the optimisation of subject-specific heart rate corrections. Forcing an arbitrary simple regression model on the QT/RR patterns of different subjects may lead to appreciable errors in QTc estimates. The frequently used linear and log-linear regression models were among the least precise if used without checking their appropriateness in individual subjects.     

肝硬化患者QTc间期与QT离散度变化机制及临床意义

目的 探讨肝硬化患者QTc间期及QT离散度(QTd)变化的机制与临床意义.方法 116例肝硬化患者与50例对照组行同步12导联心电图,测定QTc及QTd,同时检测凝血酶原活动度(PTA)、白蛋白(Alb)、总胆红素(Tbil),观察腹水和肝性脑病情况.结果 肝硬化组的QTc延长发生率显著高于对照组(41.4%Vg 4.0%,P＜0.01),肝硬化组QTd显著高于对照组(48.7±18.6ms Vg 34.6±11.1ms,P＜0.05),QTc延长的发生率与Child分级、Tbil、腹水量呈正相关,与PTA、Alb、肝性脑病无相关性.结论 肝硬化患者QTc延长及QTd增加是多因素共同作用的结果,QTc延长及QTd增加是引起室性心律失常的常见诱因,可能也是肝硬化患者出现猝死的原因之一.     

Comparison of formulae for heart rate correction of QT interval in exercise ECGs from healthy children

OBJECTIVE—To investigate the differences in four formulae for heart rate correction of the QT interval in serial ECG recordings in healthy children undergoing a graded exercise test.
SUBJECTS—54 healthy children, median age 9.9 years (range 5.05-14.9 years), subjected to graded physical exercise (on a bicycle ergometer or treadmill) until heart rate reached > 85% of expected maximum for age.
DESIGN—ECG was recorded at baseline, at maximum exercise, and at one, two, four, and six minutes after exercise. For each stage, a 12 lead digital ECG was obtained and printed. In each ECG, QT and RR interval were measured (lead II), heart rate was calculated, and QTc values were obtained using the Bazett, Hodges, Fridericia, and Framingham formulae. A paired t test was used for comparison of QTc, QT, and RR interval at rest and peak exercise, and analysis of variance for all parameters for different stages for each formula.
RESULTS—From peak exercise to two minutes recovery there was a delay in QT lengthening compared with RR lengthening, accounting for differences observed with the formulae after peak exercise. At peak exercise, the Bazett and Hodges formulae led to prolongation of QTc intervals (p < 0.001), while the Fridericia and Framingham formulae led to shortening of QTc intervals (p < 0.001) until four minutes of recovery. The Bazett QTc shortened significantly at one minute after peak exercise.
CONCLUSIONS—The practical meaning of QT interval measurements depends on the correction formula used. In studies investigating repolarisation changes (for example, in the long QT syndromes, congenital heart defects, or in the evaluation of new drugs), the use of an ad hoc selected heart rate correction formula may bias the results in either direction. The Fridericia and Framingham QTc values at one minute recovery from exercise may be useful in the assessment of long QT syndromes.


Keywords: paediatric exercise testing; QT interval; QTc formulae     

Relationship of QT interval variability to heart rate and RR interval variability

The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 ± 9.1 years, 176 females) while they underwent postural provocative tests involving supine, unsupported sitting and unsupported standing positions. Each recording was processed as a sequence of overlapping 10-second segments. In each segment, the mean RR interval, the coefficients of variance of the RR intervals (RRCV) and the QT intervals (QTCV) were obtained. In each subject, these characteristics, corresponding to different postural positions, were firstly averaged and secondly used to obtain within-subject correlation coefficients between the different characteristics at different postural positions. While the within-subject means of RRCV generally decreased when changing the position from supine to sitting and to standing (4.53 ± 1.95%, 4.12 ± 1.51% and 3.26 ± 1.56% in females and 3.99 ± 1.44%, 4.00 ± 1.24% and 3.53 ± 1.32% in males respectively), the means of QTCV systematically increased during these position changes (0.96 ± 0.40%, 1.30 ± 0.56% and 1.88 ± 1.46% in females and 0.85 ± 0.30%, 1.13 ± 0.41% and 1.41 ± 0.59% in males, respectively). The intra-subject relationship between QTCV, RRCV and mean RR intervals was highly dependent on postural positions. The study concludes that no universally applicable normalization of the QT interval variability for the heart rate and/or the RR interval variability should be assumed. In future studies of the QT variability, it seems preferable to report on the absolute values of QT variability, RR variability and mean heart rate separately.     

Factors associated with a prolonged QT interval in liver cirrhosis patients

Aim

The aim of this study was to identify factors associated with prolonged QT interval in liver cirrhosis patients.

Materials and Methods

Thirty-eight patients with liver cirrhosis were enrolled in this study. The maximal QT interval (QTmax), heart rate-corrected QT interval (QTc), QT interval in lead DII (QTII), and mean QT interval (QTm) were determined manually, using 12-lead electrocardiogram. Additional laboratory tests were also performed.

Results

The following values were obtained: QTmax, 435 ± 43 milliseconds; QTc, 493 ± 46 milliseconds; QT interval in lead DII, 405 ± 46 milliseconds; and mean QT interval, 400 ± 40 milliseconds. Ten (6%) patients had a prolonged QTmax, and 27 (71%) had a prolonged QTc. The highest values were obtained for QTc and QTmax in patients with alcoholic cirrhosis and Child-Pugh class C, respectively. A moderate correlation was observed between QTmax and serum uric acid (URCA; r = 0.504), and multiple linear regression analysis revealed that URCA was significantly associated with QTc and heart rate.

Conclusions

Liver disease severity, alcoholic etiology, and URCA are associated with prolonged QT interval in patients with liver cirrhosis.     

QT correction methods in children and adolescents

INTRODUCTION: Accurate determination of the QTc interval has become increasingly important in the assessment of a drug's ability to prolong cardiac repolarization. Previous work suggests the most appropriate correction formula for adults is QTc=QT/RR0.40, but little on correction methods for children and adolescents has been published. METHODS AND RESULTS: In this study, ECG data were obtained from a meta-analysis of seven clinical trials for attention deficit/hyperactivity disorder (ADHD) involving 2,288 children and adolescents. The most appropriate formula for children and adolescents included in this database was found to be QTc=QT/RR0.38. Adjustments of the correction factor specifically for males and females of different ages also are reported. CONCLUSION: QT correction methods developed for adults do not apply to children. As accurate QTc determination plays a larger role in assessing a drug's potential to retard repolarization, use of age- and gender-specific correction formulas becomes more important.     

正常中国人QT间期及QTLC与QTC比较

目的探讨中国人正常ＱＴ间期并建立依心率校正ＱＴ的线性公式模型。方法对４３２２例从出生到８５岁健康婴儿、儿童和成人心电图ＱＴ间期进行分析统计，用直线回归方法拟合依心率校正ＱＴ的线性公式模型ＱＴＬＣ，并与Ｂａｚｅｔ的ＱＴｃ比较。结果研究证明，ＱＴ间期有心率、年龄、性别和种族差别，但影响ＱＴ的主要因素是心率，用直线回归方法拟合成依心率校正ＱＴ的线性回归方程：Ｙ（ＱＴＬＣ）＝ＱＴ＋０．２１６×（１－ＲＲ），Ｒ＝０．８９１３，ＳＸ．Ｙ＝０．０２１。在校正ＱＴ的功能方面能克服Ｂａｚｅｔ的ＱＴｃ随心率快而出现过高校正ＱＴ的现象。结论心率是影响ＱＴ间期的主要因素，用心率校正ＱＴ的线性公式（（ＱＴＬＣ）明显优于Ｂａｚｅｔｔ的ＱＴｃ。（ＱＴＬＣ）校正公式在临床上可用于任何年龄     

肺动脉高压患者心率校正QT间期和QT离散度的研究

目的:检测肺动脉高压(pulmonary hypertension,PH)患者的心率校正的QT间期(heartrate-corrected QT interval,QTc)和QTc离散度(QTc dispersion,QTcd),并评价其与肺动脉压力的关系。方法:入选2003年12月至2008年7月因初步诊断为PH而进行右心导管术的患者。记录静息12导联心电图,手工测量QT间期并用Bazett公式进行校正。根据平均肺动脉压,将患者分为对照组,轻-中度PH组和重度PH组。结果:共入选201例患者。男性患者的QTc和QTcd在3组间差异无统计学意义。女性患者中,重度PH组的QTc比对照组高〔(436.1±39.4)msvs.(407.6±24.8)ms,P=0.037〕,重度PH组的QTcd(68.5±20.9)ms高于对照组(45.1±12.6)ms和轻-中度组(58.6±14.7)ms(P=0.002;P=0.003)。此外,女性患者的QTc和QTcd与平均肺动脉压正相关(r=0.207,P=0.03;r=0.236,P=0.012)。结论:本组资料中女性PH患者的QTc和QTcd与平均肺动脉压正相关,且在重度PH患者中显著增高,有待于进一步探讨。     

心动过缓患者QT与RR间期的相关变化

分析33名病窦综合症和高度房室传导阻滞所致心动过缓患者的24小时动态心电图。用直线回归方程计算QT和RR间期回归直线的斜率(slode).分为RR间期≤1.4s(slopeL)和>1.4s(slope2)。发现所有患者的slope_2(0.0086±0.0039)明显小于sIope_1(0.0785±0.0057;P<0.001)。12名校正后QT间期(QT_c)≥0.44s患者(B组)的slope_1(0.0969±0.0083)和slope_2(0.0198±0.0049)均明显大于QT_c<0.44s患者(A组)的slope_1(0.063±0.0063;P<0.01)和slope_2(0.0022±0.0028;P<0.01)。slope_1和slope_2与QT_c呈正相关。表明心动过缓患者.随着心率的减慢,QT间期延长的量逐渐减少,与QT间期正常组相比,QT延长组当RR间期延长时.QT间期有较大的延长。     

QT interval in cardiac amyloidosis

The aim of the study was to investigate whether cardiac amyloidosis is associated with QT interval abnormalities and ventricular arrhythmias. A controlled study of 30 patients was undertaken at a university cardiology department in a large referral hospital. Thirty patients (18 men, 12 women, mean age 56 ± 12 years) with systemic amyloidosis verified by biopsy and strong indications of cardiac amyloidosis comprised the study group, with 30 healthy age- and sex-matched individuals serving as controls. Complete M-mode and two-dimensional echocardiographic study was undertaken and QT interval and QT_c were calculated. All patients and controls underwent 24-h Holter monitoring for arrhythmias. Left ventricular (LV) wall thickening was found in all patients with cardiac amyloidosis. The LV mass in the patients with cardiac amyloidosis was significantly greater than that of the control group, as was the ratio LVmass/body surface area (p < 0.001). There was no significant difference in the max QT interval or in QT_c dispersion between the two groups, although the max QT_c was greater in the patients with cardiac amyloidosis. Patients with cardiac amyloidosis did not have a higher incidence of arrhythmias than the controls. Although patients with thickened cardiac walls due to cardiac amyloidosis have a prolonged QT_c in comparison with controls, they do not show an increase in interlead QT_c dispersion which might suggest the possibility of regional disturbances of the uniformity of repolarization. Patients with cardiac amyloidosis do not have a higher incidence of arrhythmias than controls.     

临终患者伴发QT间期缩短的心电图分析

目的:探讨临终患者伴发QT间期缩短的心电图特征和临床意义。方法:常规测量10例临终患者的QT间期实测值(QT),通过QT间期换算公式计算QT间期预测值(QTp)、校正后QT间期值(QTc)以及QT/QTp比值。结果:10例临终患者心电图除出现各型传导阻滞、心室停搏等心电异常外,均伴随QT间期缩短(QTc<0.32～0.34s、QT/QTp<0.88)。结论:继发性QT间期缩短可能是出现于临终患者的一种罕见心电图表现,在一定程度上反映了心脏电活动衰竭,其预后不良,应引起临床高度重视。     

QT interval measurements

The QT interval, which represents duration of ventricular electrical systole, i.e., the time required forcompletion of both ventricular depolarization and repolarization, has been a parameter of particular interest incardiology. However, the relationship between duration of cellular action potentials and the QT interval recordedat the body surface is very complex. As a result, the QT interval is difficult to measure with precision. First,there is inherent imprecision in identifying the end of the T wave because of incomplete understanding of therecovery process and its projection on the body surface. Second, significant variation both in the onset of theQRS complex and the end of the T wave among some ECG leads provides different QT values depending on the leadsselected for measurement. Third, technical factors such as paper speed and sensitivity influence QT measurementswith higher paper speed leading to shorter interval values and higher sensitivity resulting in QT prolongation.The above problems do not appear to be solved by automatic QT measurement techniques, which have been found to beless accurate in cardiac patients than in healthy controls.In conclusion, we should accept that QT interval remains merely a gross measure of ventricular electricalsystole and/or repolarization and we should not expect significant improvement in accuracy of traditional QTinterval measurements. Rather, in clinical research, methods examining the shape or amplitude of the T wave andits changes related to heart rate should be exploited.     

心肌缺血与QT与QTc间期的动态变化

目的观察ＱＴ和ＱＴｃ与心肌缺血和自主神经状态之间的关系。方法５２例动态心电图中见发作性ＳＴ段下移的病例被列为分析病例,男３７例,女１５例,平均年龄６０±１０（４１～８２）岁。结果显示ＳＴ段下移前和最大下移时,ＱＴ和心率的ＲＲ间期均有相关性（ｒ均＝０．７５,Ｐ＜０．０１）,但ＱＴ与ＲＲ间期直线回归方程的截距有显著性差异（ｔ检验,Ｐ＜０．０５）;ＳＴ段下移前５分钟和ＳＴ段最大下移时,ＱＴｃ和心率有显著性差异,ＱＴｃ的差值与心率（ｒ＝０．３４,Ｐ＜０．０５）和最大ＳＴ段下移的程度（ｒ＝０．３１,Ｐ＜０．０５）呈正相关。结论心肌缺血是影响ＱＴ和ＱＴｃ的主要因素。     

A new physiological method for heart rate correction of the QT interval

AIM: To reassess QT interval rate correction. BACKGROUND: The QT interval is strongly and inversely related to heart rate. To compare QT intervals between different subjects with different heart rates requires the application of a QT interval rate correction formula. To date these formulae have inappropriately assumed a fixed relation between QT interval and heart rate. An alternative method of QT interval rate correction that makes no assumptions about the QT interval-heart rate relation is needed. PROPOSAL: A QT heart rate correction method should maintain or accentuate biological QT interval variability, should totally remove the dependence of the rate corrected QT interval on heart rate, and should be applicable over a wide range of conditions with a wide range of differing autonomic states. METHODS: QT intervals were obtained at rest and during exercise from subjects expected to have different QT intervals and different QT interval-heart rate relations. A linear regression line was obtained from the exercise test data, and the QT interval at a notional heart rate of 60 and 0 beats/min, termed the QT(60) interval, and the QT y intercept obtained by back calculation. RESULTS: QT(60) and QT y intercept values were prolonged in heart failure compared with either left ventricular hypertrophy or controls. There was no relation between heart rate and either QT(60) or QT y intercept CONCLUSIONS: This new physiologically based method of correcting QT interval for heart rate removes the dependence of the corrected QT interval on heart rate, and maintains biological differences.     

QT correction using Bazett’s formula remains preferable in long QT syndrome type 1 and 2

BackgroundThe heart rate (HR) corrected QT interval (QTc) is crucial for diagnosis and risk stratification in the long QT syndrome (LQTS). Although its use has been questioned in some contexts, Bazett''s formula has been applied in most diagnostic and prognostic studies in LQTS patients. However, studies on which formula eliminates the inverse relation between QT and HR are lacking in LQTS patients.We therefore determined which QT correction formula is most appropriate in LQTS patients including the effect of beta blocker therapy and an evaluation of the agreement of the formulae when applying specific QTc limits for diagnostic and prognostic purposes.MethodsAutomated measurements from routine 12‐lead ECGs from 200 genetically confirmed LQTS patients from two Swedish regions were included (167 LQT1, 33 LQT2). QT correction was performed using the Bazett, Framingham, Fridericia, and Hodges formulae. Linear regression was used to compare the formulae in all patients, and before and after the initiation of beta blocking therapy in a subgroup (n = 44). Concordance analysis was performed for QTc ≥ 480 ms (diagnosis) and ≥500 ms (prognosis).ResultsThe median age was 32 years (range 0.1–78), 123 (62%) were female and 52 (26%) were children ≤16 years. Bazett''s formula was the only method resulting in a QTc without relation with HR. Initiation of beta blocking therapy did not alter the result. Concordance analyses showed clinically significant differences (Cohen''s kappa 0.629–0.469) for diagnosis and prognosis in individual patients.ConclusionBazett''s formula remains preferable for diagnosis and prognosis in LQT1 and 2 patients.     

Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus.

AIMS: To evaluate prolonged QTc interval and QT dispersion as predictors of all-cause and cardiovascular mortality after adjustment for well-established risk factors in Type 1 diabetic patients. METHODS: From a cohort of all adult Type 1 diabetic patients, duration of diabetes >or= 5 years, attending the clinic in 1984 and followed in an observational study for 10 years (n = 939), all subjects with resting baseline electrocardiograms were identified (n = 697, 360 males). The QT length was measured and corrected for heart rate (QTc). Maximal QTc length (QTc max) and QT dispersion were determined. RESULTS: At baseline, 431 had normoalbuminuria (< 30 mg/24 h), 138 had microalbuminuria (30-299 mg/24 h) and 128 had macroalbuminuria (>or= 300 mg/24 h) of whom 66 (15%), 35 (25%) and 61 (48%) died during follow-up, respectively (26 (6%), 14 (10%), 21 (16%) from cardiovascular disease). QTc max. was 442 (1.2) ms (mean (SEM)) for survivors and 457 (3.7) in patients who died (P < 0.001). In a Cox proportional hazards model including baseline values of putative risk factors, independent predictors of death were QTc max (P = 0.03), age (P < 0.001), presence of hypertension (P = 0.001), male sex (P < 0.001), log urinary albumin excretion (P < 0.001), smoking (P = 0.04), log serum-creatinine (P < 0.001), height (P < 0.001), low social class (P = 0.04), whereas QT dispersion, heart rate, and HbA1c were not included. In the subgroup with macroalbuminuria, but not for all patients, QTc max was an independent risk factor for cardiovascular mortality. CONCLUSION: QTc prolongation, but not increased QT dispersion, is an independent marker of increased mortality in patients with Type 1 diabetes mellitus.