QT Interval Variability Research Articles

T Wave Amplitude Correction of QT Interval Variability for Improved Repolarization Lability Measurement.

Objectives: The inverse relationship between QT interval variability (QTV) and T wave amplitude potentially confounds QT variability assessment. We quantified the influence of the T wave amplitude on QTV in a comprehensive dataset and devised a correction formula.Methods: Three ECG datasets of healthy subjects were analyzed to model the relationship between T wave amplitude and QTV. To derive a generally valid correction formula, linear regression analysis was used. The proposed correction formula was applied to patients enrolled in the Evaluation of Defibrillator in Non-Ischemic Cardiomyopathy Treatment Evaluation trial (DEFINITE) to assess the prognostic significance of QTV for all-cause mortality in patients with non-ischemic dilated cardiomyopathy.Results: A strong inverse relationship between T wave amplitude and QTV was demonstrated, both in healthy subjects (R2 = 0.68, p < 0.001) and DEFINITE patients (R2 = 0.20, p < 0.001). Applying the T wave amplitude correction to QTV achieved 2.5-times better group discrimination between patients enrolled in the DEFINITE study and healthy subjects. Kaplan-Meier estimator analysis showed that T wave amplitude corrected QTVi is inversely related to survival (p < 0.01) and a significant predictor of all-cause mortality.Conclusion: We have proposed a simple correction formula for improved QTV assessment. Using this correction, predictive value of QTV for all-cause mortality in patients with non-ischemic cardiomyopathy has been demonstrated.

QT interval variability in body surface ECG: measurement, physiological basis, and clinical value: position statement and consensus guidance endorsed by the European Heart Rhythm Association jointly with the ESC Working Group on Cardiac Cellular Electrophysiology.

This consensus guideline discusses the electrocardiographic phenomenon of beat-to-beat QT interval variability (QTV) on surface electrocardiograms. The text covers measurement principles, physiological basis, and clinical value of QTV. Technical considerations include QT interval measurement and the relation between QTV and heart rate variability. Research frontiers of QTV include understanding of QTV physiology, systematic evaluation of the link between QTV and direct measures of neural activity, modelling of the QTV dependence on the variability of other physiological variables, distinction between QTV and general T wave shape variability, and assessing of the QTV utility for guiding therapy. Increased QTV appears to be a risk marker of arrhythmic and cardiovascular death. It remains to be established whether it can guide therapy alone or in combination with other risk factors. QT interval variability has a possible role in non-invasive assessment of tonic sympathetic activity.

Beat-to-beat determinants of the beat-to-beat temporal and spatial variability of repolarization

BackgroundThe goal of this study was to compare the time series predictors of beat-to-beat variability in repolarization in healthy individuals. MethodsSpatial QRS- and T-vector amplitudes, spatial QRS-T, RR′ and TT′ angles, RR′ and QT intervals, and QRS- and T-loop roundness were measured on 453 consecutive sinus beats in 168 healthy subjects (mean age 39.8±15.6years; 50% men; 93% white). Panel time-series regression models were adjusted by age, sex, and race. Appropriate time series of ECG metrics served as predictors and outcomes. ResultsIncrease in T-loop roundness index by 0.1 was associated with 1.1° (95%CI 0.9–2.2; P=0.048) increase in corresponding TT′ angle. One unit increase in a respiration index was associated with 4ms (95%CI 0.6–7.0; P=0.021) increase in QT interval. ConclusionsSpatial TT′ angle and beat-to-beat variability in T-loop roundness represent intrinsic measures of repolarization variability. QT interval variability characterizes the effect of respiration and heart rate variability.

Effects of ECG sampling rate on QT interval variability measurement

Abstract Beat-to-beat variability of the QT interval (QTV) has been used as a marker of repolarization lability and sympathetic activation. The aim of this study was to establish ECG sampling rate requirements for reliable QT interval variability measurement. We measured QTV in high resolution simulated (1000 Hz) and real ECG (1600 Hz; in the supine position during rest and during sympathetic activation upon standing), using time and frequency domain metrics as well as measures of symbolic dynamics for complexity assessment. We successively halved the sampling rate and investigated its effect on the QTV metrics. Reduction in sampling rate below 400 Hz and 500 Hz, respectively, resulted in a significant overestimation of QTV variability and also affected complexity measurement of QTV. QTV increased during standing compared to the supine measurement. At 100 Hz, the posture related change in QTV was completely masked by the measurement noise introduced by the low sampling rate. In conclusion, ECG sampling rates of 500 Hz yields a reliable QTV measurement, while sampling rates of 200 Hz and below should be avoided.

Contractile function assessment by intraventricular balloon alters the ability of regional ischaemia to evoke ventricular fibrillation.

In drug research using the rat Langendorff heart preparation, it is possible to study left ventricular (LV) contractility using an intraventricular balloon (IVB), and arrhythmogenesis during coronary ligation-induced regional ischaemia. Assessing both concurrently would halve animal requirements. We aimed to test the validity of this approach. The electrocardiogram (ECG) and LV function (IVB) were recorded during regional ischaemia of different extents in a randomized and blinded study. IVB-induced proarrhythmia was anticipated, but in hearts with an ischaemic zone (IZ) made deliberately small, an inflated IVB reduced ischaemia-induced ventricular fibrillation (VF) incidence as a trend. Repeating studies in hearts with large IZs revealed the effect to be significant. There were no changes in QT interval or other variables that might explain the effect. Insertion of an IVB that was minimally inflated had no effect on any variable compared with 'no IVB' controls. The antiarrhythmic effect of verapamil (a positive control drug) was unaffected by IVB inflation. Removal of an inflated (but not a non-inflated) IVB caused a release of lactate commensurate with reperfusion of an endocardial/subendocardial layer of IVB-induced ischaemia. This was confirmed by intracellular (31) phosphorus ((31) P) nuclear magnetic resonance (NMR) spectroscopy. IVB inflation does not inhibit VF suppression by a standard drug, but it has profound antiarrhythmic effects of its own, likely to be due to inflation-induced localized ischaemia. This means rhythm and contractility cannot be assessed concurrently by this approach, with implications for drug discovery and safety assessment.

QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome.

BackgroundIncreased variability of QT interval (QTV) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long QT syndrome (LQTS), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and QTV.Methods and ResultsTwenty‐four‐hour Holter monitor tracings from 78 genotyped congenital LQTS patients (52 females; 51 LQT1, 23 LQT2, 2 LQT5, 2 JLN, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer‐assisted annotation of RR and QT intervals. Several models of RR‐QT relationship were tested in all patients. A model assuming exponential decrease of past RR interval contributions to QT duration with 60‐second time constant provided the best data fit. This model was used to calculate QTc and residual “intrinsic” QTV, which cannot be explained by heart rate change. The intrinsic QTV was higher in patients with long QTc (r=0.68; P<10−4), and in LQT2 than in LQT1/5 patients (5.65±1.28 vs 4.46±0.82; P<0.0002). Both QTc and intrinsic QTV were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively).ConclusionsIn LQTS patients, QT interval adaptation to heart rate changes occurs with time constant ≈60 seconds, similar to results reported in control subjects. Intrinsic QTV correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of LQTS.

Early Economic Evaluation of Short-Term Variability of Qt Intervals As A Potential Test for Predicting The Effectiveness of Icd Implantation In Patients With Heart Failure

Objectives: Implantable cardioverter-defibrillators (ICD) improve survival in heart failure patients with New York Heart Association Functional Classification (NYHA) class III/IV symptoms and a left ventricular ejection fraction (LVEF) of ≤ 35%. Therefore, the current clinical guidelines recommend the implantation of the ICD in all the patients that fulfill the above conditions. However, as the costs of the ICD devices are relatively high, the prophylactic implantation of ICDs as per the guideline is not particularly cost-effective. A previous study demonstrated that short-term variability of QT (STVQT) may in fact reflect the increased susceptibility to SCD in patients with DC since it was shown that patients with DC and HF had the highest STVQT. The objective of this study was to explore the cost-effectiveness of shortterm variability of QT (STVQT) as a biomarker for implanting ICDs as secondary prevention of SCDs in heart failure patients and assess the societal value (headroom) of a hypothetical perfect STVQT biomarker for risk assessment and subsequent treatment decision in implanting ICDs . Methods: The study uses a decision analytical model. Results: The use of the QT (STVQT) as a biomarker for implanting ICDs as secondary prevention of SCDs in heart failure patients is a cost-effective healthcare intervention. The headroom (societal willingness to pay multiplied by incremental quality-adjusted life years) available for the hypothetical perfect biomarker ranged from € 483 to € 3,868. Conclusions: The use of the QT (STVQT) as a biomarker for implanting ICDs is cost effective. Identification of patients with high-risk for SCD and implantation of ICDs only on those patients could potentially save substantial costs. However, further research of risk stratifying biomarkers test accuracy is needed to support and strengthen the results of this modeling study.

Relation between QT interval variability and muscle sympathetic nerve activity in normal subjects.

Beat-to-beat variability of the QT interval (QTV) is sought to provide an indirect noninvasive measure of sympathetic nerve activity, but a formal quantification of this relationship has not been provided. In this study we used power contribution analysis to study the relationship between QTV and muscle sympathetic nerve activity (MSNA). ECG and MSNA were recorded in 10 healthy subjects in the supine position and after 40° head-up tilt. Power spectrum analysis was performed using a linear autoregressive model with two external inputs: heart period (RR interval) variability (RRV) and MSNA. Total and low-frequency power of QTV was decomposed into contributions by RRV, MSNA, and sources independent of RRV and MSNA. Results show that the percentage of MSNA power contribution to QT is very small and does not change with tilt. RRV power contribution to QT power is notable and decreases with tilt, while the greatest percentage of QTV is independent of RRV and MSNA in the supine position and after 40° head-up tilt. In conclusion, beat-to-beat QTV in normal subjects does not appear to be significantly affected by the rhythmic modulations in MSNA following low to moderate orthostatic stimulation. Therefore, MSNA oscillations may not represent a useful surrogate for cardiac sympathetic nerve activity at moderate levels of activation, or, alternatively, sympathetic influences on QTV are complex and not quantifiable with linear shift-invariant autoregressive models.

Time, frequency and information domain analysis of heart period and QT variability in asymptomatic long QT syndrome type 2 patients.

This study was designed to characterize in time, frequency and information domains heart period (HP) and QT interval variabilities in asymptomatic (ASYMP) long QT syndrome type 2 (LQT2) subjects. HP, approximated as the temporal distance between two consecutive R-wave peaks, and QT, approximated as the temporal distance between the R-wave peak and the T-wave offset, were automatically derived from 24h Holter recordings in 10 ASYMP LQT2 patients and 13 healthy non mutation carriers (NMC) subjects. All analyses were carried out during DAY (from 2 to 6 PM) and NIGHT (from 12 to 4 AM). Mean, variance, spectral power and complexity indices at short, medium and long time scales were assessed over HP and QT beat-to-beat series. Circadian rhythmicity was evident in both NMC and ASYMP LQT2 but ASYMP LQT2 subjects were characterized by higher HP, QT interval and HP variability during both DAY and NIGHT. In addition, multiscale complexity analysis was able to differentiate the groups by showing a higher HP complexity and a lower QT complexity at long time scales in ASYMP LQT2 during DAY. ASYMP LQT2 exhibited a different autonomic control compared to NMC and such a differentiation could be protective and assure them a lower risk profile.

A novel technique to investigate the effect of ageing on ventricular repolarization characteristics in healthy and LQTS subjects.

Ventricular repolarization(VR) characteristics is affected by ageing alongside several other factors like Heart rate(HR),respiration, modulation of autonomic nervous system, different drug effects, genetical factors affecting the cardiac ion channel characteristics, gender etc. Therefore, total VR variability (i.e. QT interval variability in surface ECG) consists of two components: one dependent on HR variability (HRV) and another independent of HRV. Analysis of QT interval variability (QTV) is crucial for both healthy and pathological conditions as increase in VR variability measured by QTV increases cardiac repolarization instability, which might lead to arrhythmogenesis. Analyzing the effect of ageing using a widely used measure of QTV (i.e. QTVI) is reported inconsistently in Healthy subjects whereas the same for Long QT Syndrome (LQTS) subjects is not widely reported. In this study, we propose a novel time domain measure from beat-tobeat QT-RR distribution to analyze how ageing affects VR in both Healthy and a group of genotyped LQTS1 subjects. A total of 139 Healthy subjects and 134 LQTS1 subjects of three different age groups (i.e. Young: age 20-35, Middle-aged: 40-55 and Old: age<;60) were analyzed for this study. The proposed measure is also compared with other existing widely used measures of QTV like SDQT and QTVI in differentiating different age groups. The proposed measure stands out to be more discriminatory than other existing variability measures of QT interval.

Effects of energy drink consumption on corrected QT interval and heart rate variability in young obese Saudi male university students.

BACKGROUND AND OBJECTIVESConsumption of energy drinks has adverse effects on the heart that might be potentiated in obese individuals. Since the incidence of obesity and use of energy drinks is high among Saudi youth, we used non-invasive tests to study hemodynamic changes produced by altered autonomic cardiac activity following consumption of energy drinks in obese male students.DESIGN AND SETTINGThis cross-sectional study was carried out at Department of Physiology, College of Medicine, University of Dammam, Saudi Arabia, over a one-year period from December 2013 to December 2014.SUBJECTS AND METHODSIn Saudi male university students we measured continuous ECG recordings and a one-minute deep breathing maneuver to measure the expiratory-to-inspiratory ratio, the mean heart rate range (MHRR), the mean percentage variability. (M%VHR) and the corrected QT interval (QTc) at 0, 30 and 60 minutes after consumption of energy drink.RESULTSWe enrolled 31 students (18 overweight/obese and 13 normal weights. QTc was significantly increased at 60 min as compared with the resting state in overweight/obese subjects (P=.006). Heart rate variability was significantly less in obese as compared with normal weight subjects at 60 minutes as indicated by E:I ratio, (P=.037), MHRR (P=.012), M%VHR (P=.040) after energy drink consumption. Significant increases in diastolic (P= .020) and mean arterial blood pressure (P=.024) were observed at 30 minutes in the obese group.CONCLUSIONHemodynamic changes after intake of energy drinks in obese subjects indicate that obesity and energy drinks could synergistically induce harmful effects. This finding warrants efforts to caution the obese on intake of energy drinks and timely intervention to motivate changes in life style.

Short-term beat-to-beat variability of the QT interval is increased and correlates with parameters of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy.

Stratification models for the prediction of sudden cardiac death (SCD) are inappropriate in patients with hypertrophic cardiomyopathy (HCM). We investigated conventional electrocardiogram (ECG) repolarization parameters and the beat-to-beat short-term QT interval variability (QT-STV), a new parameter of proarrhythmic risk, in 37 patients with HCM (21 males, average age 48 ± 15 years). Resting ECGs were recorded for 5 min and the frequency corrected QT interval (QTc), QT dispersion (QTd), beat-to-beat short-term variability of QT interval (QT-STV), and the duration of terminal part of T waves (Tpeak-Tend) were calculated. While all repolarization parameters were significantly increased in patients with HCM compared with the controls (QTc, 488 ± 61 vs. 434 ± 23 ms, p < 0.0001; QT-STV, 4.5 ± 2 vs. 3.2 ± 1 ms, p = 0.0002; Tpeak-Tend duration, 107 ± 27 vs. 91 ± 10 ms, p = 0.0015; QTd, 47 ± 17 vs. 34 ± 9 ms, p = 0.0002), QT-STV had the highest relative increase (+41%). QT-STV also showed the best correlation with indices of left ventricular (LV) hypertrophy, i.e., maximal LV wall thickness normalized for body surface area (BSA; r = 0.461, p = 0.004) or LV mass (determined by cardiac magnetic resonance imaging) normalized for BSA (r = 0.455, p = 0.015). In summary, beat-to-beat QT-STV showed the most marked increase in patients with HCM and may represent a novel marker that merits further testing for increased SCD risk in HCM.

Increased Short-Term Beat-To-Beat Variability of QT Interval in Patients with Acromegaly.

Cardiovascular diseases, including ventricular arrhythmias are responsible for increased mortality in patients with acromegaly. Acromegaly may cause repolarization abnormalities such as QT prolongation and impairment of repolarization reserve enhancing liability to arrhythmia. The aim of this study was to determine the short-term beat-to-beat QT variability in patients with acromegaly. Thirty acromegalic patients (23 women and 7 men, mean age±SD: 55.7±10.4 years) were compared with age- and sex-matched volunteers (mean age 51.3±7.6 years). Cardiac repolarization parameters including frequency corrected QT interval, PQ and QRS intervals, duration of terminal part of T waves (Tpeak-Tend) and short-term variability of QT interval were evaluated. All acromegalic patients and controls underwent transthoracic echocardiographic examination. Autonomic function was assessed by means of five standard cardiovascular reflex tests. Comparison of the two groups revealed no significant differences in the conventional ECG parameters of repolarization (QT: 401.1±30.6 ms vs 389.3±16.5 ms, corrected QT interval: 430.1±18.6 ms vs 425.6±17.3 ms, QT dispersion: 38.2±13.2 ms vs 36.6±10.2 ms; acromegaly vs control, respectively). However, short-term beat-to-beat QT variability was significantly increased in acromegalic patients (4.23±1.03 ms vs 3.02±0.80, P<0.0001). There were significant differences between the two groups in the echocardiographic dimensions (left ventricular end diastolic diameter: 52.6±5.4 mm vs 48.0±3.9 mm, left ventricular end systolic diameter: 32.3±5.2 mm vs 29.1±4.4 mm, interventricular septum: 11.1±2.2 mm vs 8.8±0.7 mm, posterior wall of left ventricle: 10.8±1.4 mm vs 8.9±0.7 mm, P<0.05, respectively). Short-term beat-to-beat QT variability was elevated in patients with acromegaly in spite of unchanged conventional parameters of ventricular repolarization. This enhanced temporal QT variability may be an early indicator of increased liability to arrhythmia.

Asymptomatic ST-depression during exercise testing in children and adolescents with type 1 diabetes mellitus and autonomic dysfunction

Aim. The aim of this study was to investigate cardiac autonomic function as assessed by ST dynamics during and post-exercise in children and adolescents with type 1 diabetes mellitus (T1DM). Materials and methods. The study included 71 young patients with T1DM. The patients were aged 9?18 years and had no history of macrovascular disease or renal disease, including microalbuminuria. Cardiac autonomic function was assessed using cardiovascular tests and 24-h ECG monitoring with automatic calculation of QT interval and heart rate variability parameters. Each patient underwent the physical working capacity 170 test. Results. The prevalence of cardiovascular autonomic neuropathy (CAN) was 30.9%. The frequency of asymptomatic ST-segment depression increased during exercise in 10 (45.5%) patients with CAN (CAN+) compared with 9 (18.4%) patients without CAN (CAN-; p=0.042). During the recovery period, asymptomatic ST-segment depression was present in the first minute in 8 (36.4%) CAN+ patients compared with 1 (2%) CAN- patient (p=0.0003) and in the second minute in 5 (22.7%) CAN+ patients compared with 1 (2%) CAN- patient (p=0.0095). Conclusion. Children and adolescents with T1DM and impaired autonomic function have increased prevalence of asymptomatic ST-segment depression during and post-exercise. The presence of cardiovascular risk factors in children and adolescents with T1DM and CAN may contribute to the increased cardiovascular morbidity and mortality during adulthood in patients with T1DM.

Usefulness of Signal-averaged ECG, Short-term Heart Rate Variability, QT Interval and T Loop Criteria in Predicting 2 Years Lethal Outcome after Myocardial Infarction

For evaluation of prognostic power usefulness of parameters of signal averaged ECG, short-term heart rate variability (HRV), QT interval and T loop morphology 116 patients with myocardial infarction were enrolled to a follow up study. During follow up of 2 years 16 patients died. A signal-averaged ECG was obtained 5 to 7 days after hospitalization. QT interval variables were measured automatically by means of appropriate computer software. HRV characteristics were assessed from rhythmograms. Vectorcardiographic 3D T loop was projected onto a vertical plane and parameters of T loop morphology were evaluated. Using logistic regression there was established the complex of informative parameters for lethal outcome. Hereby we could define a “high risk” group of patients with αQRS-T>96, QRSd>109, CV 111 ms2, LVEF≤40%. The proposed model is simple and could be applied in the clinical practice to evaluate risk of death, to screen patients with unfavourable prognosis and to choose the best treatment for these patients. Ill.1, bibl. 7 (in English; summaries in English, Russian and Lithuanian).

Аrterial stiffness and cardiovascular autonomic neuropathy relationship in children and adolescents with type 1 diabetes mellitus

Aim. To evolve the association between cardiac autonomic function and arterial stiffness in children and adolescents with type 1 diabetes mellitus (T1DM). Materials and methods. 72 T1DM patients aged 7?18 years without history of macrovascular complications or renal disease, including microalbuminuria, were involved in the study. Cardiac function was assessed by the cardiovascular tests and 24-hour ECG monitoring with automatic calculation of QT interval and heart rate variability (HRV) parameters. Artery stiffness was assessed by measurement of pulse wave velocity (PWV) and augmentation index (AI) obtained from arterial blood pressure monitoring for 24 hours. Results. Estimated prevalence of cardiovascular autonomic neuropathy (CAN) was 31,9%. CAN+ patients had significantly higher PWV and AI than those without CAN. A negative correlation between PWV and AI with some cardiovascular tests and HRV parameters was observed. In multivariable analysis, AI was independent predictor of autonomic dysfunction defined as number of positive cardiovascular tests, HRV parameters below normal values and prolongation of QT interval (?. =0,18; p=0,035). Conclusion. Cardiac autonomic function is an independent predictor of arterial stiffness, in children and adolescents with T1D without macrovascular and renal complications. The presence of cardiovascular risk factors and arterial stiffness in children and adolescents with T1DM may contribute to the increased cardiovascular morbidity and mortality in adulthood in patients with CAN.

QT interval variations and mortality risk: is there any relationship?

Abnormal prolongation and shortening of the electrocardiographic QT interval duration, which occur in the hereditary forms of long and short QT syndromes, are associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Even within the normal range, these altered durations are associated with an increased mortality risk in the general population. While extreme prolongation or reduction of the QT interval predisposes patients to malignant ventricular arrhythmias and sudden cardiac death, the precise dose-response relationship between the QT interval and cardiovascular disease mortality is still unknown. This paper describes the need for more standardized methods for measuring and reporting the QT interval and the need for more precise assessments of the risk associated with QT interval variation.

Qt Interval in Patients with Ischemic Stroke with or Without Cognitive Impairment

Introduction Ischemic stroke can lead to heart injury via dysfunction of the autonomic nervous system. QT intervals on electrocardiography (ECG) are susceptible to autonomic influences and their prolongation was associated with increased mortality after stroke. Aims We aimed to study QT intervals in patients with ischemic stroke in chronic phase with and without cognitive impairment. Methods ECGs were recorded in 50 patients with ischemic stroke. QT interval corrected for heart rate (QTc), QT dispersion (QTd), and QT interval variability (QTIV) were measured. The QTVI was calculated as the logarithm of the ratio between the variances of the normalized QT and RR intervals. Using Mini Mental State Examination and Hachinski's ischemic scale we identified vascular dementia (VaD) in 17 patients. Twenty age-matched healthy subjects were examined for comparison. Results We identified QTc, QTd prolongation in patients with ischemic stroke. Comparing patients with ischemic stroke vs. VaD, QTc (412 ±75.2 ms vs 456± 115 ms, p Conclusion Prolongation of QT intervals and increased QTVI occurs frequently after ischemic stroke but most significant changes were found in patients with cognitive impairment. Early detection of cognitive impairment in stroke patients provides better prevention of possible dementia.

Symbolic dynamics to discriminate healthy and ischaemic dilated cardiomyopathy populations: an application to the variability of heart period and QT interval

Myocardial ischaemia is hypothesized to stimulate the cardiac sympathetic excitatory afferents and, therefore, the spontaneous changes of heart period (approximated as the RR interval), and the QT interval in ischaemic dilated cardiomyopathy (IDC) patients might reflect this sympathetic activation. Symbolic analysis is a nonlinear and powerful tool for the extraction and classification of patterns in time-series analysis, which implies a transformation of the original series into symbols and the construction of patterns with the symbols. The aim of this work was to investigate whether symbolic transformations of RR and QT cardiac series can provide a better separation between IDC patients and healthy control (HC) subjects compared with traditional linear measures. The variability of these cardiac series was studied during daytime and night-time periods and also during the complete 24 h recording over windows of short data sequences of approximately 5 min. The IDC group was characterized by an increase in the occurrence rate of patterns without variations (0 V%) and a reduction in the occurrence rate of patterns with one variation (1 V%) and two variations (2 V%). Concerning the RR variability during the daytime, the highest number of patterns had 0 V%, whereas the rates of 1 V% and 2 V% were lower. During the night, 1 V% and 2 V% increased at the expense of diminishing 0 V%. Patterns with and without variations between consecutive symbols were able to increase the separation between the IDC and HC groups, allowing accuracies higher than 80%. With regard to entropy measures, an increase in RR regularity was associated with cardiac disease described by accuracy >70% in the RR series and by accuracy >60% in the QTc series. These results could be associated with an increase in the sympathetic tone in IDC patients.

Pharmacokinetic-pharmacodynamic analysis to evaluate the effect of moxifloxacin on QT interval prolongation in healthy Korean male subjects.

A single 400 mg dose of moxifloxacin has been the standard positive control for thorough QT (TQT) studies. However, it is not clearly known whether a 400 mg dose is also applicable to TQT studies in Asian subjects, including Koreans. Thus, we aimed to develop a pharmacokinetic (PK)-pharmacodynamic (PD) model for moxifloxacin, to evaluate the time course of its effect on QT intervals in Koreans. Data from three TQT studies of 33 healthy male Korean subjects who received 400 and 800 mg of moxifloxacin and placebo (water) were used. Twelve-lead electrocardiograms were taken for 2 consecutive days: 1 day to record diurnal changes and the next day to record moxifloxacin or placebo effects. Peripheral blood samples were also obtained for PK analysis. The PK-PD data obtained were analyzed using a nonlinear mixed-effects method (NONMEM ver. 7.2). A two-compartment linear model with first-order absorption provided the best description of moxifloxacin PK. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian variation of QT intervals was described by two mixed-effect cosine functions. The effect of moxifloxacin on QT interval prolongation was well explained by the nonlinear dose-response (Emax) model, and the effect by 800 mg was only slightly greater than that of 400 mg. Although Koreans appeared to be more sensitive to moxifloxacin-induced QT prolongation than were Caucasians, the PK-PD model developed suggests that a 400 mg dose of moxifloxacin is also applicable to QT studies in Korean subjects.