Peter Smetana

Characterization of QT interval adaptation to RR interval changes and its use as a risk-stratifier of arrhythmic mortality in amiodarone-treated survivors of acute myocardial infarction

A new method is proposed to evaluate the dynamics of QT interval adaptation in response to heart rate (HR) changes. The method considers weighted averages of RR intervals (R~R~) preceding each cardiac beat to express RR interval history accounting for the influence on repolarization duration. A global optimization algorithm is used to determine the weight distribution leading to the lowest regression residual when curve fitting the [QT, R~R~] data using a patient- specific regression model. From the optimum weight distribution, a memory lag L/sub 90/ is estimated, expressing the delay in the QT adaptation to HR changes. On average, RR intervals of the past 150 beats (approximately 2.5 min) are required to model the QT response accurately. From a clinical point of view, the interval of the initial tens of seconds to one minute seems to be most important in the majority of cases. A measure of the optimum regression residual (r/sub opt/) has been calculated, discriminating between post-myocardial infarction patients at high and low risk of arrhythmic death while on treatment with amiodarone. A similar discrimination has been achieved with a variable expressing the character of QT lag behind the RR interval dynamics.

Sex differences in the rate dependence of the T wave descending limb

OBJECTIVE The interval from the peak to the end of the T wave (TpTe) has been proposed to reflect the heterogeneity of action potential durations within the ventricular wall. Several studies have previously described TpTe to be independent of heart rate, which contradicts the in vitro observation of marked changes in transmural repolarisation heterogeneity due to cycle length changes. Because of this inconsistency, we investigated heart rate related changes of TpTe interval. METHODS During 24-h recordings (SEER MC, Marquette GE) in healthy young women (n=25, 26+/-7 years) and men (n=25, 27+/-8 years), a 10-s 12-lead ECG was obtained every 30 s. Recordings were repeated after 1 day, 1 week, and 1 month and results in each subject were pooled together and grouped for women and men. The QT and QT(peak) intervals were obtained automatically using QT Guard software (Marquette) and TpTe was computed as the difference between QT and QT(peak). In each subject TpTe values were averaged over 10-ms RR interval bands from 550 to 1150 ms. RESULTS In both sexes, TpTe interval showed marked rate dependence with prolongation at long RR intervals. TpTe intervals in men were significantly longer over the entire range of investigated RR intervals (P=1.4x10(-25)). However, whereas the difference between sexes was marked at short cycle length (RR interval bin 540-550 ms: women 87+/-5 vs. men 95+/-9, P=5.1x10(-4)) it decreased at long cycle lengths (RR interval bin 1140-1150 ms: women 99+/-5 vs. men 106+/-6, P=9.3x10(-4)). CONCLUSION There is a marked rate dependence of TpTe interval, which differs between women and men. The finding is consistent with the TpTe interval being an approximate surrogate of the intraventricular repolarisation gradient. The rate dependent increase in transmural repolarisation heterogeneity might be one of the reasons for the increased propensity of torsades de pointes in women.

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).

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/RRα. 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)

Accurately measured and properly heart-rate corrected QTc intervals show little daytime variability

BACKGROUND Circadian QTc changes have been reported, with conflicting results. Spontaneous QTc variability is important for pharmaceutical cardiac safety studies. OBJECTIVE The purpose of this study was to investigate QTc variability in accurately measured and heart-rate corrected daytime data of healthy subjects. METHODS Continuous 12-lead ECGs were recorded in 53 healthy volunteers. For each recording, approximately 320 ECG samples of 10 seconds were obtained throughout the daytime period, all preceded by stable heart rates. In each ECG sample, QT interval was measured on superimposed 12 leads by two independent cardiologists and reconciled. Four RR-interval expressions were used: (a) average of the first three RR of the ECG sample, (b) RR average of the 10-second sample, (c) average of RR intervals in a 2-minute history, and (d) RR intervals of an independently established individual QT/RR hysteresis profile. For all RR-interval expressions, QT intervals were corrected using the Fridericia formula and individually optimized curvature correction. QTc variability was measured by intraindividual QTc standard deviations. RESULTS With Fridericia correction and the RR expressions (a) to (d), QTc variability obtained was (a) 9.45 +/- 1.70 ms, (b) 7.80 +/- 1.48 ms, (c) 6.37 +/- 1.64 ms, and (d) 5.81 +/- 1.75 ms. With individualized correction, QTc variability was (a) 8.16 +/- 1.71 ms, (b) 6.71 +/- 1.41 ms, (c) 5.22 +/- 1.13 ms, and (d) 4.56 +/- 1.18 ms. All differences (b) vs (a), (c) vs (b), and (d) vs (c) were highly statistically significant (P <10(-12) in all cases). CONCLUSION Previously reported large QTc variability largely results from methodologic imprecision. Little QTc variability is present in daytime recordings of healthy subjects. Consequently, QT-related pharmaceutical cardiac safety studies can be made smaller without decreasing their power.

Electrocardiographic QTc Changes Due to Moxifloxacin Infusion

Moxifloxacin (400‐mg single dose) is a frequent positive control in thorough QT/QTc studies. This investigation assessed baseline and placebo‐controlled QTc changes (ΔΔQTc, individualized correction for heart rate and rate hysteresis) at 126 data points before, during, and after 1‐hour moxifloxacin infusion in 44 healthy participants and in their sex‐, race‐, and age‐defined subgroups. Constant linear ΔΔQTc increase was found during the infusion. The postinfusion peak ΔΔQTc values (corresponding to maximum plasma levels) were not statistically different in women (16.1 ± 6.5 ms) and men (15.1 ± 5.3 ms), Africans (15.3 ± 5.3 ms) and whites (15.6 ± 6.6 ms), and participants younger (16.5 ± 4.8 ms) and older (14.7 ± 6.6 ms) than the median age of 35 years. The ΔΔQTc values were different in participants with a body mass index (BMI) below (16.8 ± 5.4 ms) and above 30 kg/m2 (10.8 ± 5.1 ms; P = .008). Although the population mean ΔΔQTc changes closely followed mean plasma‐level kinetics (4.8 ms per 1 μg/mL), the individual postinfusion peak ΔΔQTc was not related to individual peak plasma levels (P = NS) but was strongly related to BMI (P = .0007). Thus, the individual pharmacokinetic/pharmacodynamic effects are substantially variable; obese participants should be excluded from thorough QT/QTc studies.

Systematic Comparisons of Electrocardiographic Morphology Increase the Precision of QT Interval Measurement

Decreased intrasubject variability of QTc values is needed to increase the power and reduce the size of the so‐called thorough QT studies. One source of QTc variability is the lack of systematic measurements when electrocardiograms (ECG) with closely matching morphologies are not measured in an exactly corresponding way. The inaccuracy can be eliminated by postprocessing of QT measurements by ECG pattern matching. This study tested the effects of pattern matching in ECG measurements in two populations of healthy subjects (n = 48 + 56) and in a population of patients with advanced Parkinsons disease (n = 130) in whom both day‐time and night‐time data were available. Intrasubject QTc variability was measured by intrasubject standard deviations (SD) of QTc values obtained with manual measurements before and after pattern‐matching measurement alignments. In each subject, QT values (n = 230–320) in one drug‐free long‐term ECG recording were evaluated. The pattern‐matching adjustment of the QT measurement decreased the intrasubject QTc variability from 5.2 ± 1.0 to 4.5 ± 1.0 ms (P < 10−14) from 6.4 ± 1.7 to 5.5 ± 1.6 ms (P < 10−10) from 5.6 ± 1.5 to 4.6 ± 1.4 ms (P < 10−34) and from 6.1 ± 1.9 to 5.0 ± 1.7 ms (P < 10−33), in the two populations of healthy subjects and in the day‐time and night‐time recordings of Parkinsons disease patients, respectively. Hence, morphological pattern adjustment of QT interval measurements improves the quality of the QT data with substantial practical implications. Reductions in intrasubject QTc variability were reproducibly found in different populations and thus the technology might be recommended for every thorough QT/QTc study. Noticeable reductions of necessary study size are likely achievable in this way.

Sex differences in cardiac autonomic regulation and in repolarisation electrocardiography

The review summarises the present knowledge on the sex differences in cardiac autonomic regulations and in related aspects of electrocardiography with particular attention to myocardial repolarisation. Although some of the sex differences are far from fully established, multitude of observations show consistent differences between women and men. Despite more pronounced parasympathetic cardiac regulation, women have higher resting heart rate and lower baroreflex sensitivity. Of the electrocardiographic phenomena, women have longer QT interval duration, repolarisation sequence more synchronised with the inverse of the depolarisation sequence, and likely increased regional heterogeneity of myocardial repolarisation. Studies investigating the relationship of these sex disparities to hormonal differences led frequently to conflicting results. Although sex hormones seem to play a key role by influencing both autonomic tone and electrophysiological properties at the cellular level, neither the truly relevant hormones nor their detailed actions are known. Physiologic usefulness of the described sex differences is also unknown. The review suggests that new studies are needed to advance the understanding of the physiologic mechanisms responsible for these inequalities between women and men and provides key methodological suggestions that need to be followed in future research.

Correction for QT/RR Hysteresis in the Assessment of Drug-Induced QTc Changes—Cardiac Safety of Gadobutrol

Background: The so‐called thorough QT/QTc (TQT) studies required for every new pharmaceutical compound are negative if upper single‐sided 95% confidence interval (CI) of placebo and baseline corrected QTc prolongation is <10 ms. This tight requirement has many methodological implications. If the investigated drug has a fast action and ECGs cannot be obtained at stable heart rates, QT/RR hysteresis correction is needed.

Individual Patterns of Dynamic QT/RR Relationship in Survivors of Acute Myocardial Infarction and Their Relationship to Antiarrhythmic Efficacy of Amiodarone

Introduction: Amiodarone is an effective antiarrhythmic drug, but it has serious side effects and conducted trials did not support its prophylactic use in survivors of acute myocardial infarction. It is possible that the prophylactic use of the drug has not been tested effectively. To optimize therapy outcome, markers of drug efficacy might be developed to identify patients who, although at arrhythmic risk, would not benefit from amiodarone treatment. We investigated descriptors of QT/RR relationship for their potential value in predicting inefficient amiodarone treatment.