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Monitoring of QTc interval is mandated in different clinical conditions. Nevertheless, intra-subject variability of QTc intervals reduces the clinical utility of QTc monitoring strategies. Since this variability is partly related to QT heart rate correction, 10 different heart rate corrections (Bazett, Fridericia, Dmitrienko, Framingham, Schlamowitz, Hodges, Ashman, Rautaharju, Sarma, and Rabkin) were applied to 452,440 ECG measurements made in 539 healthy volunteers (259 females, mean age 33.3 ± 8.4 years). For each correction formula, the short term (5-min time-points) and long-term (day-time hours) variability of rate corrected QT values (QTc) was investigated together with the comparisons of the QTc values with individually corrected QTcI values obtained by subject-specific modelling of the QT/RR relationship and hysteresis. The results showed that (a) both in terms of short-term and long-term QTc variability, Bazett correction led to QTc values that were more variable than the results of other corrections (p < 0.00001 for all), (b) the QTc variability by Fridericia and Framingham corrections were not systematically different from each other but were lower than the results of other corrections (p-value between 0.033 and < 0.00001), and (c) on average, Bazett QTc values departed from QTcI intervals more than the QTc values of other corrections. The study concludes that (a) previous suggestions that Bazett correction should no longer be used in clinical practice are fully justified, (b) replacing Bazett correction with Fridericia and/or Framingham corrections would improve clinical QTc monitoring, (c) heart rate stability is needed for valid QTc assessment, and (d) development of further QTc corrections for day-to-day use is not warranted., (© 2021. The Author(s).)

On standard electrocardiogram (ECG) PQ interval is known to be moderately heart rate dependent, but no physiologic details of this dependency have been established. At the same time, PQ dynamics is a clear candidate for non-invasive assessment of atrial abnormalities including the risk of atrial fibrillation. We studied PQ heart rate dependency in 599 healthy subjects (aged 33.5 ± 9.3 years, 288 females) in whom drug-free day-time 12-lead ECG Holters were available. Of these, 752,517 ECG samples were selected (1256 ± 244 per subject) to measure PQ and QT intervals and P wave durations. For each measured ECG sample, 5-minute history of preceding cardiac cycles was also obtained. Although less rate dependent than the QT intervals (36 ± 19% of linear slopes), PQ intervals were found to be dependent on underlying cycle length in a highly curvilinear fashion with the dependency significantly more curved in females compared to males. The PQ interval also responded to the heart rate changes with a delay which was highly sex dependent (95% adaptation in females and males after 114.9 ± 81.1 vs 65.4 ± 64.3 seconds, respectively, p < 0.00001). P wave duration was even less rate dependent than the PQ interval (9 ± 10% of linear QT/RR slopes). Rate corrected P wave duration was marginally but significantly shorter in females than in males (106.8 ± 8.4 vs 110.2 ± 7.9 ms, p < 0.00001). In addition to establishing physiologic standards, the study suggests that the curvatures and adaptation delay of the PQ/cycle-length dependency should be included in future non-invasive studies of atrial depolarizations.

To facilitate the precision of clinical electrocardiographic studies of J-to-Tpeak (JTp) and Tpeak-to-Tend (Tpe) intervals, the study investigated their differences between healthy females and males, and between subjects of African and Caucasian origin. In 523 healthy subjects (254 females; 236 subjects of African origin), repeated Holter recordings were used to measure QT, JT, JTp, and Tpe intervals preceded by both stable and variable heart rates. Subject-specific curvilinear regression models were used to obtain individual QTc, JTc, JTpc and Tpec intervals. Rate hysteresis, i.e., the speed with which the intervals adapted after heart rate changes, was also investigated. In all sex-race groups, Tpe intervals were not systematically heart rate dependent. Similar to QTc intervals, women had JTc, and JTpc intervals longer than males (difference 20-30 ms, p < 0.001). However, women had Tpec intervals (and rate uncorrected Tpe intervals) shorter by approximately 10 ms compared to males (p < 0.001). Subjects of African origin had significantly shorter QTc intervals than Caucasians (p < 0.001). Gradually diminishing race-difference was found for JTc, JTpc and Tpec intervals. JTc and JTpc were moderately increasing with age but Tpe/Tpec were not. Rate hysteresis of JTp was approximately 10% longer compared to that of JT (p < 0.001). In future clinical studies, Tpe interval should not be systematically corrected for heart rate and similar to the QT interval, the differences in JT, JTp and Tpe intervals should be corrected for sex. The differences in QT and JT, and JTp intervals should also be corrected for race.

Sex differences are known in several facets of cardiac electrophysiology, mostly concerning myocardial repolarisation. In this study, heart rate and heart rate variability (HRV) responses to postural provocations were compared in 175 and 176 healthy females and males, respectively (aged 33.1 ± 9.1 years). Two different postural provocative tests with position changes supine→sitting→standing→supine and supine→standing→sitting→supine (15-min standing, 10-min other positions) were performed up to 4 times in each subject. Heart rate and heart rate variability spectral indices were measured in 5-min windows before positional changes. At supine position, females had averaged heart rate approximately 5 beats per minute (bpm) faster than males and this sex difference was practically constant during the postural changes. In both sexes, change supine→sitting and supine→standing increased heart rate by approximately 10 and 30 bpm, respectively, with no statistical differences between the sex groups. At supine baseline, females had normalised high frequency components (nHF) of HRV approximately 7% larger compared to males (p < 0.001). While the same difference in nHF was found at sitting, the change to standing position lead to significantly larger nHF reduction in females compared to males (mean changes 22.5 vs 17.2%, p < 0.001). This shows that despite similar heart rate increase, females respond to standing by more substantial shifts in cardiac sympatho-vagal modulations. This makes it plausible to speculate that the differences in autonomic reactions to stress contribute to the known sex-differences in psychosocial responses to stressful situations and to the known difference in susceptibility to ventricular fibrillation between females and males., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Heart rate variability (HRV) reflects the autonomous nervous system modulation on heart rate and is associated with several pathologies, including cardiac mortality. While mechanistic studies show that smoking is associated with lower HRV, population-based studies present conflicting results., Methods: We assessed the mutual effects of active smoking status, cumulative smoking history, and current smoking intensity, on HRV among 4751 adults from the Cooperative Health Research In South Tyrol (CHRIS) study. The HRV metrics standard deviation of normal-to-normal (NN) inter-beat intervals (SDNN), square root of the mean squared differences of consecutive NN intervals (RMSSD), total power (TP), low (LF) and high frequency (HF) power, and their ratio (LF/HF), were derived from 20-minute electrocardiograms. Smoking status, pack-years (PY), and tobacco grams/day from standardized questionnaires were the main exposures. We fitted linear mixed models to account for relatedness, non-linearity, and moderating effects, and including fractional polynomials., Results: Past smokers had higher HRV levels than never smokers, independently of PY. The association of HRV with current smoking became apparent when accounting for the interaction between smoking status and PY. In current smokers, but not in past smokers, we observed HRV reductions between 2.0% (SDNN) and 4.9% (TP) every 5 PY increase. Furthermore, current smokers were characterized by dose-response reductions of 9.8% (SDNN), 8.9% (RMSSD), 20.1% (TP), 17.7% (LF), and 19.1% (HF), respectively, every 10 grams/day of smoked tobacco, independently of common cardiometabolic conditions and HRV-modifying drugs. The LF/HF ratio was not associated with smoking status, history, or intensity., Conclusions: Smoking cessation was associated with higher HRV levels. In current smokers, heavier smoking intensity appears gradually detrimental on HRV, corroborating previous evidence. By affecting both the sympathetic and parasympathetic nervous system indexes, but not the LF/HF balance, smoking intensity seems to exert a systemic dysautonomic effect., Competing Interests: The authors have declared that no competing interests exist.

Aims: Increased spatial angle between QRS complex and T wave loop orientations has repeatedly been shown to predict cardiac risk. However, there is no consensus on the methods for the calculation of the angle. This study compared the reproducibility and predictive power of three most common ways of QRS-T angle assessment., Methods and Results: Electrocardiograms of 352 healthy subjects, 941 survivors of acute myocardial infarction (MI), and 605 patients recorded prior to the implantation of automatic defibrillator [implantable cardioverter defibrillator (ICD)] were used to obtain QRS-T angle measurements by the maximum R to T (MRT), area R to T (ART), and total cosine R to T (TCRT) methods. The results were compared in terms of physiologic reproducibility and power to predict mortality in the cardiac patients during 5-year follow-up. Maximum R to T results were significantly less reproducible compared to the other two methods. Among both survivors of acute MI and ICD recipients, TCRT method was statistically significantly more powerful in predicting mortality during follow-up. Among the acute MI survivors, increased spatial QRS-T angle (TCRT assessment) was particularly powerful in predicting sudden cardiac death with the area under the receiver operator characteristic of 78% (90% confidence interval 63-90%). Among the ICD recipients, TCRT also predicted mortality significantly among patients with prolonged QRS complex duration when the spatial orientation of the QRS complex is poorly defined., Conclusion: The TCRT method for the assessment of spatial QRS-T angle appears to offer important advantages in comparison to other methods of measurement. This approach should be included in future clinical studies of the QRS-T angle. The TCRT method might also be a reasonable candidate for the standardization of the QRS-T angle assessment.

Aims: Twenty-four-hour deceleration capacity (DC24h) of heart rate is a strong predictor of mortality after myocardial infarction (MI). Assessment of DC from short-term recordings (DCst) would be of practical use in everyday clinical practice but its predictive value is unknown. Here, we test the usefulness of DCst for autonomic bedside risk stratification after MI., Methods and Results: We included 908 patients after acute MI enrolled in Munich and 478 patients with acute (n = 232) and chronic MI (n = 246) enrolled in Tuebingen, both in Germany. We assessed DCst from high-resolution resting electrocardiogram (ECG) recordings (<30 min) performed under standardized conditions in supine position. In the Munich cohort, we also assessed DC24h from 24-h Holter recordings. Deceleration capacity was dichotomized at the established cut-off value of ≤ 2.5 ms. Primary endpoint was 3-year mortality. Secondary endpoint was 3-year cardiovascular mortality. In addition to DC, multivariable analyses included the Global Registry of Acute Coronary Events score >140 and left ventricular ejection fraction ≤ 35%. During follow-up, 48 (5.3%) and 48 (10.0%) patients died in the Munich and Tuebingen cohorts, respectively. On multivariable analyses, DCst ≤ 2.5 ms was the strongest predictor of mortality, yielding hazard ratios of 5.04 (2.68-9.49; P < 0.001) and 3.19 (1.70-6.02; P < 0.001) in the Munich and Tuebingen cohorts, respectively. Deceleration capacity assessed from short-term recordings ≤ 2.5 ms was also an independent predictor of cardiovascular mortality in both cohorts. Implementation of DCst ≤ 2.5 ms into the multivariable models led to a significant increase of C-statistics and integrated discrimination improvement score., Conclusion: Deceleration capacity assessed from short-term recordings is a strong and independent predictor of mortality and cardiovascular mortality after MI, which is complementary to existing risk stratification strategies.

Aims: The study investigated healthy subjects to study sex and race differences in QRS durations and the dependency of QRS durations on heart rates and other physiologic correlates., Methods and Results: QRS duration and its heart rate dependency were evaluated in 420 615 electrocardiograms obtained in 523 healthy subjects including 111 females of African origin, 130 Caucasian females, 125 males of African origin, and 129 Caucasian males. The distributions of QRS/RR slopes and QRS durations at RR intervals of 1 and 0.5 s were compared between sex- and race-defined subgroups. At high heart rates, QRS duration was increased in ∼35% of all subjects, while in the others, QRS was shortened (no differences between the subgroups). At RR interval of 1 s, the QRS duration was 97.4 ± 4.6, 99.8 ± 6.0, 101.6 ± 5.3, and 104.8 ± 6.3 ms in African females, Caucasian females, African males, and Caucasian males, respectively (all differences P < 0.001). Similar statistical differences were found at an RR of 0.5 s. When accounting for the differences in lean body mass, the difference between African and Caucasian subjects was as large as the difference between females and males. Within each subgroup, the normal QRS durations differed by 15-20 and 18-25 ms at RR intervals of 1 and 0.5 s, respectively., Conclusion: The QRS widths are heart rate dependent and different not only between women and men but also between African and Caucasian individuals. Difference in cardiac resynchronization therapy efficacy might be expected between patients of African and Caucasian origin stratified by QRS duration., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Beat-to-beat variability of the QT interval (QTV) measured on surface ECG has emerged as a potential marker for ventricular repolarization instability and has been used along with heart rate variability (HRV) to predict arrhythmic risk. Since measurement modalities of QTV have not been standardized, the objective of this study was to investigate the effect of ECG recording duration on QTV as well as HRV. Using a database of 30 min ECG recorded from 500 patients with acute myocardial infraction during rest, we extracted RR and QT interval time series and estimated different HRV and QTV metrics over windows of varying length. Analysis of variance (ANOVA) and intra-class correlation analyses were computed to investigate the effect of recording length on consistency and short-term reproducibility of HRV and QTV variables. Good consistency (non-significant ANOVA results) and short-term reproducibility (intra-class correlation coefficients  >0.8) were demonstrated for all but standard deviation based metrics when at least 200 beats were included in the estimation. In conclusion, QTV can be quantified from resting ECG with good short-term consistency and reproducibility that is comparable to that of HRV.

Objective: The aim of this study was to investigate whether associations of acceleration capacity (AC) and deceleration capacity (DC) with metal-PM2.5 are mediated by inflammation., Methods: We obtained PM2.5, C-reactive protein, interleukin (IL)-6, 8, and 10, and electrocardiograms to compute AC and DC, from 45 male welders. Mediation analyses were performed using linear mixed models to assess associations between PM2.5 exposure, inflammatory mediator, and AC or DC, controlling for covariates., Results: The proportion of total effect of PM2.5 on AC or DC (indirect effect) mediated through IL-6 on AC was 4% at most. Controlling for IL-6 (direct effect), a 1 mg/m increase of PM2.5 was associated with a decrease of 2.16 (95% confidence interval -0.36 to 4.69) msec in AC and a decrease of 2.51 (95% confidence interval -0.90 to 5.93) msec in DC., Conclusion: IL-6 may be mediating the effect of metal particulates on AC.

Following the publication of the Task Force document on heart rate variability (HRV) in 1996, a number of articles have been published to describe new HRV methodologies and their application in different physiological and clinical studies. This document presents a critical review of the new methods. A particular attention has been paid to methodologies that have not been reported in the 1996 standardization document but have been more recently tested in sufficiently sized populations. The following methods were considered: Long-range correlation and fractal analysis; Short-term complexity; Entropy and regularity; and Nonlinear dynamical systems and chaotic behaviour. For each of these methods, technical aspects, clinical achievements, and suggestions for clinical application were reviewed. While the novel approaches have contributed in the technical understanding of the signal character of HRV, their success in developing new clinical tools, such as those for the identification of high-risk patients, has been rather limited. Available results obtained in selected populations of patients by specialized laboratories are nevertheless of interest but new prospective studies are needed. The investigation of new parameters, descriptive of the complex regulation mechanisms of heart rate, has to be encouraged because not all information in the HRV signal is captured by traditional methods. The new technologies thus could provide after proper validation, additional physiological, and clinical meaning. Multidisciplinary dialogue and specialized courses in the combination of clinical cardiology and complex signal processing methods seem warranted for further advances in studies of cardiac oscillations and in the understanding normal and abnormal cardiac control processes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: RR interval variations lead to beat-to-beat blood pressure differences through the myocardial force-interval relationship (FIR). In sinus rhythm, an altered FIR leads to post-extrasystolic potentiation (PESP) of systolic blood pressure, which has been shown to predict adverse outcome in survivors of acute myocardial infarction (MI). The purpose of this study was (1) to develop a parameter to assess the FIR in patients with atrial fibrillation (AF) and (2) to investigate its association with mortality in MI survivors suffering from AF., Methods and Results: Thirty-two patients with acute MI and AF underwent 30-min recordings of ECG and continuous blood pressure. Episodes of a short RR interval (<80% of mean interval, RRi) preceding a long interval (>140%, RRi+1) were identified. The systolic pressures of the pulse waves following RRi and RRi+1 were labeled Pi and Pi+1. PESPAfib was calculated as (Pi+1-Pi)/(RRi+1-RRi). During 5years of follow-up, 13 patients died. When PESPAfib was dichotomized at the median, mortality rates were 63% and 19% in patients with high and low PESPAfib. Hazard ratio for mortality was 4.88 for patients with high PESPAfib (1.33-17.84, p=0.004). The association of PESPAfib and mortality was independent from LVEF, age, diabetes mellitus or mean heart rate., Conclusions: PESPAfib, a measure for the FIR in patients with AF, can be derived from simultaneous ECG and blood pressure recordings. The results of this pilot study indicate that PESPAfib may be useful to predict adverse outcome in survivors of myocardial infarction suffering from AF., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Aims: The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodelled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyse the effects of the drugs in a computational model of atrial electrophysiology., Methods and Results: The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodelled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analysed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score., Conclusion: Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Schizophrenia is associated with increased cardiac mortality. A disturbed autonomic modulation of heart rate (HR) has been described in patients with schizophrenia in whom antipsychotic medication may represent an additional cardiac risk. The novel measure deceleration capacity (DC) of heart rate predicts cardiac mortality in patients with cardiovascular illnesses. The aim of the present paper was to calculate DC in patients with schizophrenia and to compare this measure with established parameters of heart rate variability (HRV)., Methods: HRV and DC were calculated in 24-hour electrocardiogram (ECG) recordings of 20 unmedicated, 40 medicated patients with schizophrenia and 40 controls. As activity has a major influence on HRV, 4-hour periods of "sleep-" and "wake-" ECG were evaluated as additional parameters. Actigraphy was used to ensure comparable levels of activity in patients and controls., Results: The DC as well as the other established HRV measures were not significantly different comparing unmedicated patients with schizophrenia to healthy controls. However, medicated patients showed a significant reduction of DC calculated from ECG recordings during 4 hour over night periods., Conclusion: Calculation of DC might contribute to a better monitoring and identification of an increased risk of cardiac mortality in patients with schizophrenia undergoing antipsychotic treatment., (Copyright © 2011. Published by Elsevier SAS.)

Unlabelled: A method for counting episodes of uninterrupted beat-to-beat heart rate decelerations was developed., Methods: The method was set up and evaluated using 24-hour electrocardiogram Holter recordings of 1455 (training sample) and 946 (validation sample) postinfarction patients. During a median follow-up of 24 months, 70, 46, and 19 patients of the training sample suffered from total, cardiac, and sudden cardiac mortality, respectively. In the validation sample, these numbers were 39, 25, and 15. Episodes of consecutive beat-to-beat heart rate decelerations (deceleration runs [DRs]) were characterized by their length., Results: Deceleration runs of 2 to 10 cycles were significantly less frequent in nonsurvivors. Multivariate model of DRs of 2, 4, and 8 cycles identified low-, intermediate-, and high-risk groups. In these groups of the training sample, the total mortalities were 1.8%, 6.1%, and 24%, respectively. In the validation sample, these numbers were 1.8%, 4.1%, and 21.9%., Conclusion: Infrequent DRs during 24-hour Holter indicate high risk of postinfarction mortality., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objective: Exposure to ambient particles has been shown to be responsible for cardiovascular effects, especially in elderly with cardiovascular disease. The study assessed the association between deceleration capacity (DC) as well as heart rate variability (HRV) and ambient particulate matter (PM) in patients with coronary artery disease (CAD)., Methods: A prospective study with up to 12 repeated measurements was conducted in Erfurt, Germany, between October 2000 and April 2001 in 56 patients with physician-diagnosed ischemic heart disease, stable angina pectoris or prior myocardial infarction at an age of at least 50 years. Twenty-minute ECG recordings were obtained every two weeks and 24-hour ECG recordings every four weeks. Exposure to PM (size range from 10 nm to 2.5 μm), and elemental (EC) and organic (OC) carbon was measured. Additive mixed models were used to analyze the association between PM and ECG recordings., Results: The short-term recordings showed decrements in the high-frequency component of HRV as well as in RMSSD (root-mean-square of successive differences of NN intervals) in association with increments in EC and OC 0-23 hours prior to the recordings. The long-term recordings revealed decreased RMSSD and pNN50 (% of adjacent NN intervals that differed more than 50 ms) in association with EC and OC 24-47 hours prior to the recordings. In addition, highly significant effects were found for DC which decreased in association with PM2.5, EC and OC concurrent with the ECG recordings as well as with a lag of up to 47 hours., Conclusions: The analysis showed significant effects of ambient particulate air pollution on DC and HRV parameters reflecting parasympathetic modulation of the heart in patients with CAD. An air pollution-related decrease in parasympathetic tone as well as impaired heart rate deceleration capacity may contribute to an increased risk for cardiac morbidity and sudden cardiac death in vulnerable populations.

Heart rate turbulence (HRT) denotes the baroreflex-mediated short-term oscillation of cardiac cycle lengths after spontaneous ventricular premature complexes. The physiological pattern of HRT consists of brief heart rate acceleration followed by more gradual heart rate deceleration before the heart rate returns to baseline. Physiological mechanisms of HRT are complex and require an intact interplay between both sympathetic and parasympathetic nervous systems. The strong and independent prognostic value of HRT in identifying postinfarction patients at high risk for death has been validated in six retrospective and three prospective studies together enrolling more than 8000 patients. This evidence qualifies HRT as a promising tool for selection of patients who might benefit from implantation of a cardioverter-defibrillator. Moreover, HRT predicts poor outcome in patients with heart failure. It is not only correlated with a patient's clinical status, but also recovers when heart failure treatment, including beta-blockers, angiotensin-converting enzyme inhibitors, or cardiac resynchronization therapy, is effective. Therefore, HRT might also be used as a treatment target to guide pharmacotherapy of heart failure.

Background: Twenty-four hour ambulatory electrocardiogram (AECG) monitoring is an established technique for integrated assessment of heart rhythm; however, comprehensive description of serial changes in cardiac electrophysiology over the first days of life in humans is lacking. The aim of this study was to determine the patterns of circadian heart rhythm based on AECG evaluation in newborns., Methods: Twenty healthy newborns (14 boys and 6 girls) were serially examined with AECG at days 1, 2, and 4 after birth. Heart rate (HR), arrhythmias, QT dynamicity, microvolt T-wave alternans, and various indices of HR variability (HRV) including deceleration/acceleration capacity analysis were analyzed., Results: There were no sex differences in HR. Supraventricular premature beats were noted in 35%, ventricular-in 15 % of newborns. Slope QT/RR was 0.35 (0.3-0.5); intercept QT/RR was 124 (93-148), QT/RR correlation coefficient (r) was 0.63 (0.53-0.85). Peak value of T-wave alternans was 32 +/- 8 (12-55) muV. Low level of HRV was typical for all parameters of time-domain analysis compared with normal limits for older children. The overall mean values of deceleration/acceleration capacity were 3.38 +/- 0.57 (2.16-4.13) and -3.58 +/- 0.67 (-2.13 to -4.38) milliseconds, respectively., Conclusion: The healthy newborns exhibit peculiarities of 24-hour cardiac rhythm with isolated premature beats, pauses of sinus rhythm less 1000 milliseconds, steep slope of QT/RR by analysis of QT dynamicity. There are low HRV, and symmetrical AC/DC capacity was typically for autonomic regulation of HR, probably due to high sympathetic activity at this age.

Background and Aim: In the Improved Stratification of Autonomic Regulation-Risk trial, postinfarction patients with severe autonomic failure (SAF)-defined as abnormal heart rate turbulence in the presence of abnormal deceleration capacity (DC)-were at high risk of subsequent death, even if left ventricular function was not particularly compromised. The aim of this study was to investigate SAF as a risk predictor in independent postinfarction cohorts., Methods and Results: The data of 3 postinfarction trials (ie, St George's Hospital Medical School Postinfarction Survey, Holter substudy of the European Myocardial Infarction Amiodarone Trial with both the placebo and the amiodarone arms, and Multiple Risk Factor Analysis Trial) were reanalyzed in a blinded fashion. The populations included a total of 2534 postinfarction patients. Heart rate turbulence and DC were obtained from 24-hour Holter recordings. Patients with both abnormal heart rate turbulence (slope < or =2.5 ms/R-R and onset > or =0%) and abnormal DC (< or =4.5 milliseconds) were considered suffering from SAF and prospectively classified as high risk. Primary end point was all-cause mortality. During follow-up, 291 of 2534 patients died. In all populations, SAF was a highly significant predictor of death in the subgroups of patients with preserved left ventricular ejection fraction (LVEF; >30%). The mortality risk of these patients was not statistically different from that of patients with impaired LVEF (< or =30%). The combined use of the criteria, LVEF of 30% or less and LVEF of more than 30% as well as SAF lead to a significant increase of sensitivity in all populations, whereas the positive predictive accuracies were preserved., Conclusion: In postinfarction patients with preserved left ventricular function, SAF identifies a subgroup with increased mortality risk equivalent to patients with LVEF of 30% or less.

Objectives: The purpose of this study was to analyze the impact of myocardial salvage on cardiac autonomic function in patients undergoing mechanical reperfusion therapy for acute myocardial infarction (MI)., Background: Heart rate deceleration capacity (DC) and heart rate turbulence slope (TS) are strong predictors of post-MI mortality. Salvage of jeopardized myocardium is the main mechanism by which patients benefit from reperfusion therapy. The impact of myocardial salvage on DC and TS is unknown., Methods: The study enrolled 854 consecutive patients undergoing mechanical reperfusion therapy for first MI. Paired (99m)Tc-sestamibi scintigraphy studies (acute and 7 to 14 days after reperfusion) were used to calculate myocardial salvage index. DC and TS were assessed from Holter recordings 7 to 14 days after reperfusion. Patients were categorized into 3 groups by salvage index: <30% (n = 244), 30% to 60% (n = 257), and > or =60% (n = 353)., Results: In the 3 groups, DC was 5.2 (interquartile range 3.5 to 7.1) ms, 5.7 (4.1 to 7.3) ms, and 6.4 (5.0 to 8.0) ms, whereas TS was 5.3 (2.6 to 8.4) ms/R-R interval, 6.9 (3.2 to 11.7) ms/R-R interval, and 7.8 (4.1 to 13.2) ms/R-R interval, respectively (p < 0.0001 for both). After adjustment for left ventricular ejection fraction (LVEF), initial perfusion defect, creatine kinase, age, diabetes mellitus, sex, and medical therapy, patients with salvage index <30% had a 2.6-fold risk (95% confidence interval: 1.8 to 3.9, p < 0.001) of having abnormal DC (< or =4.5 ms) or TS (< or =2.5 ms/R-R interval) compared with patients with salvage index > or =60%. However, patients who had autonomic dysfunction defined by abnormal DC and TS had a poor prognosis independent of whether or not the salvage index was <30% (5-year mortality rates of 16.5% and 17.3%, respectively). In contrast, prognosis was excellent when both factors were normal (5-year mortality rates of 2.9% and 4.0%, respectively). Predictive value of impaired LVEF (< or =40%) was also independent of salvage index. Multivariably, both autonomic dysfunction and impaired LVEF were independent predictors of 5-year mortality., Conclusions: In patients undergoing mechanical reperfusion therapy for acute MI, salvage index is an independent predictor of autonomic dysfunction but does not affect its prognostic value.

Aim of the study was to determine dynamics of main parameters of heart rhythm in children during first days of life. Material and methods. We examined 30 healthy newborns (14 boys and 16 girls) aged 1-4 days (2,6+/-1,3 days). Criteria of inclusion were healthy mother, normal course of pregnancy and delivery, gestational age at birth 38-40 weeks, body mass at birth 3200-3600 g; Algar score 8/9, no cardiovascular abnormalities at physical examination, informed consent of parents. On days 1-2 and 4 of life we carried out 12 lead ECG at rest and 24-hour Holter monitoring with assessment of heart rate (HR), arrhythmias, dynamics of QT-interval, HR variability (HRV) using methods "Time Domain" and "deceleration (DC)/acceleration capacity (AC)". Results. Average 24-hour HR was 138+/-17 beats/min, maximal pauses of sinus rhythm - 990 ms. Supraventricular extrasystoles (<10/24 hours) were registered in 35%, ventricular extrasystoles (<5/24 hours) in 15% of children. Values of HRV were as follows: N 442 (408-72) ms; SDNN 52 (43-75) ms; SDNNi 36 (35-61) ms; SDNNi24 (22-37) ms; SSD 14 (10-20) ms; NN50% 0,98(0-2,4)%. Analysis of D/ showed the following values: D = +3.43 +/- 0.54 (2.16-4.14),=-3.65+/-0.65 (from - 2.13 to - 4.38). Analysis of interval QT values: average 24-hour QT (QTo) - 293+/-10 (278-308) ms, maximal - 342+/-38 (328-360) ms; mean 24-hour QT 442+/-14 (428-470) ms; QT 204+/-11 (191-220) ms; QT - 308+/-17(284-337) ms, sl Q/RR 0.37 (0.304-0.505); intercept QT/RR 126 (92.0-151.0), correlation coefficient () QT/RR 0.65 (0.56-0.84). On day 4 compared with day 1 there were significantly higher values of correlation (r) QT/RR and lower values of sl QT/RR. Conclusions. During first days of life children can have supraventricular and ventricular extrasystoles (not more than 10 per 24 hours). First 24 hours of life are characterized by most pronounced signs of myocardial instability according to data of assessment of QT dynamics. HRV parameters of healthy newborns are characterized by high level of sympathetic activity, symmetry of deceleration capacity/acceleration capacity parameters.

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 Parkinson's 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 Parkinson's 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.

The time lag of the QT interval adaptation to heart rate changes (QT/RR hysteresis) was studied in 40 healthy subjects (18 females; mean age, 30.4+/-8.1 yr) with 3 separate daytime (>13 h) 12-lead electrocardiograms (ECG) in each subject. In each recording, 330 individual 10-s ECG segments were measured, including 100 segments preceded by 2 min of heart rate varying greater than +/-2 beats/min. Other segments were preceded by a stable heart rate. In segments preceded by variable rate, QT/RR hysteresis was characterized by lambda parameters of the exponential decay models. The intrasubject SDs of lambda values were compared with the intersubject SD of the individual means. The lambda values were also correlated to individually optimized parameters of heart rate correction. Intrasubject SDs of lambda were substantially smaller than the population SD of individual means (0.390+/-0.197 vs. 0.711, P<0.0001). The lambda values were unrelated to the QT/RR correction parameters. When compared with the corrected QT (QTc) for averaged RR intervals in 10-s ECGs and with the averaged RR intervals in 2-min history, QTc for QT/RR hysteresis led to a substantially smaller SD of QTc values (11.4+/-2.00, 6.33+/-1.31, and 4.66+/-0.85 ms, respectively, P<0.0001). Thus the speed with which the QT interval adapts to heart rate changes is highly individual with intrasubject stability and intersubject variability. QT/RR hysteresis is independent of the static QT/RR relationship and should be considered as a separate physiological process. The combination of individual heart rate correction with individual hysteresis correction of the QT interval is likely to lead to substantial improvements of cardiac repolarization studies.

Although heart rate dependency of QT interval is well known, the relationship of other electrocardiogram (ECG) parameters to heart rate has been researched less intensively. This study investigated the heart rate dependencies of QT interval, PQ interval, and QRS width in 40 healthy subjects (18 women; mean age, 30.4 +/- 8.1 years). In each subject, 3 long-term (approximately 13 hours) 12-lead ECGs were obtained for 3 day-time periods with gaps of 2 to 3 weeks between repeated recordings. In each recording, approximately 230 ECG measurements of QT interval, PQ interval, and QRS width were made, each preceded by stable heart rate. For each recording, linear regression slopes of QT/RR, PQ/RR, and QRS/RR relationships were obtained. Intrasubject SDs of individual values were compared with intersubject SDs of intrasubject means to test the individuality of the relationships. The intrasubject means of the slope values were also compared between sexes. The individual SDs of the QT/RR regression slopes were 0.0116 +/- 0.0065, whereas the population SD of intrasubject means was 0.0245 (P = 3.6 x 10(-15)). For the PQ/RR slopes and QRS/RR slopes, these values were 0.0085 +/- 0.0050 vs 0.0314 (P = 7.9 x 10(-28)) and 0.00189 +/- 0.00157 vs 0.00550 (P = 2.6 x 10(-17)), respectively. The QT/RR slopes were steeper in women than in men (0.194 +/- 0.019 vs 0.168 +/- 0.022, 0.0005), whereas the QRS/RR slopes were, on average, negative in women while positive in men (-0.00138 +/- 0.0045 vs 0.00335 +/- 0.0054, P = .005). There were no sex differences in the PQ/RR slopes (0.054 +/- 0.032 in women vs 0.055 +/- 0.031 in men, P = .95). Thus, not only the heart rate dependency of QT interval but also the rate dependencies of PQ interval and of QRS width show high intrasubject stability with substantial intersubject differences.

This consensus statement has been compiled on behalf of the International Society for Holter and Noninvasive Electrophysiology. It reviews the topic of heart rate turbulence (HRT) and concentrates on technologies for measurement, physiologic background and interpretation, and clinical use of HRT. It also lists suggestions for future research. The phenomenon of HRT refers to sinus rhythm cycle-length perturbations after isolated premature ventricular complexes. The physiologic pattern of HRT consists of brief heart rate acceleration (quantified by the so-called turbulence onset) followed by more gradual heart rate deceleration (quantified by the so-called turbulence slope) before the rate returns to a pre-ectopic level. Available physiologic investigations confirm that the initial heart rate acceleration is triggered by transient vagal inhibition in response to the missed baroreflex afferent input caused by hemodynamically inefficient ventricular contraction. A sympathetically mediated overshoot of arterial pressure is responsible for the subsequent heart rate deceleration through vagal recruitment. Hence, the HRT pattern is blunted in patients with reduced baroreflex. The HRT pattern is influenced by a number of factors, provocations, treatments, and pathologies reviewed in this consensus. As HRT measurement provides an indirect assessment of baroreflex, it is useful in those clinical situations that benefit from baroreflex evaluation. The HRT evaluation has thus been found appropriate in risk stratification after acute myocardial infarction, risk prediction, and monitoring of disease progression in heart failure, as well as in several other pathologies.

Background: Measurement of high-frequency (HF) spectral power of heart rate (HR) variability has not been able to identify the patients at risk of sudden cardiac death (SCD) despite the experimental evidence of protective role of vagal activity for fatal arrhythmias., Aim: We developed a novel respiratory sinus arrhythmia (RSA) analysis method and tested its ability to predict SCD after an acute myocardial infarction., Method: The RSA analysis method was developed in 13 subjects from simultaneous recordings of respiration and R-R intervals. An adaptive threshold was computed based on the zero-phase forward and reverse digital filtering in the analysis of RSA. With this method, only respiration-related R-R interval fluctuations are included. The prognostic power of RSA, analyzed from 24-hour electrocardiographic recordings, was subsequently assessed in a large postinfarction population including 1631 patients with mean follow-up of 40 +/- 17 months., Results: Depressed RSA was a strong predictor of SCD (hazard ratio 7.4; 95% CI 3.6-15.1; P 0.0001) but only a weak predictor of non-SCD. The RSA index remained an independent predictor of SCD after adjustments for ejection fraction and other clinical risk variables (RR 4.7; 95% CI 2.28-9.85)., Conclusions: Reduced respiratory-related HR dynamics, detected by RSA index, are a specific marker of an increased risk of SCD among postinfarction patients.

Background: Demonstration of a circadian rhythm in two parameters of heart rate turbulence--turbulence onset (TO) and turbulence slope (TS)--has been difficult., Objective: The aim of this study was to devise a new method for detecting circadian rhythm in noisy data and to apply it to selected Holter recordings from two postmyocardial infarction databases: Cardiac Arrhythmia Suppression Trial (CAST, n = 684) and Innovative Stratification of Arrhythmic Risk (ISAR, n = 327)., Methods: For each patient, TS and TO were calculated for each hour with >4 ventricular premature contractions (VPCs). An autocorrelation function Corr(Deltat) = then was calculated and averaged over all patients. Positive Corr(Deltat) indicates that TS at a given hour and Deltat hours later are similar. TO was treated likewise. Simulations and mathematical analysis showed that a circadian rhythm required Corr(Deltat) to have a U-shape consisting of positive values near Deltat = 0 and 23 and negative values for intermediate Deltat. Significant deviation of Corr(Deltat) from the correlator function of pure noise was evaluated as a Chi-square value., Results: Circadian patterns were not apparent in hourly averages of TS and TO plotted against clock time, which had large error bars. However, their correlator functions produced Chi-square values of approximately 10 in CAST (both P <.0001) and approximately 3 in ISAR (both P <.0001), indicating the presence of circadian rhythmicity., Conclusion: Correlator functions may be a powerful tool for detecting the presence of circadian rhythms in noisy data, even with recordings limited to 24 hours.

Objectives: Sudden cardiac death is a leading cause of mortality in patients with congenital cardiac disease after surgical correction and is potentially preventable. The identification of patients at risk is therefore of major interest. We sought to assess the prognostic value of impaired cardiac autonomic nervous activity in patients with congenital cardiac disease., Methods: Forty-three consecutive patients with congenital cardiac disease were included in this prospective study. Parameters of heart rate turbulence and heart rate variability were calculated from Holter electrocardiograms. In addition, serum brain natriuretic peptide levels were measured. A combined end point of sudden cardiac death or nearly missed sudden cardiac death was used., Results: During a mean follow up of 27 +/- 12.7 months, 5 patients died, and another 2 were successfully resuscitated. On univariate analysis, both brain natriuretic peptide levels and parameters of heart rate variability and heart rate turbulence were associated with impaired prognosis. On multivariate analysis, pathologic heart rate turbulence was found to be the strongest independent risk stratifier (hazard ratio, 61.5; P < .001)., Conclusions: Impaired cardiac autonomic nervous activity is associated with an increased risk of sudden cardiac death in congenital cardiac disease. Our results suggest that heart rate turbulence might be superior to established markers of cardiac autonomic dysfunction, such as heart rate variability. The combined use of heart rate turbulence, heart rate variability, and markers of neurohormonal activation, such as brain natriuretic peptide, might further improve the prognostic value.

Background: Decreased vagal activity after myocardial infarction results in reduced heart-rate variability and increased risk of death. To distinguish between vagal and sympathetic factors that affect heart-rate variability, we used a signal-processing algorithm to separately characterise deceleration and acceleration of heart rate. We postulated that diminished deceleration-related modulation of heart rate is an important prognostic marker. Our prospective hypotheses were that deceleration capacity is a better predictor of risk than left-ventricular ejection fraction (LVEF) and standard deviation of normal-to-normal intervals (SDNN)., Methods: We quantified heart rate deceleration capacity by assessing 24-h Holter recordings from a post-infarction cohort in Munich (n=1455). We blindly validated the prognostic power of deceleration capacity in post-infarction populations in London, UK (n=656), and Oulu, Finland (n=600). We tested our hypotheses by assessment of the area under the receiver-operator characteristics curve (AUC)., Findings: During a median follow-up of 24 months, 70 people died in the Munich cohort and 66 in the London cohort. The Oulu cohort was followed-up for 38 months and 77 people died. In the London cohort, mean AUC of deceleration capacity was 0.80 (SD 0.03) compared with 0.67 (0.04) for LVEF and 0.69 (0.04) for SDNN. In the Oulu cohort, mean AUC of deceleration capacity was 0.74 (0.03) compared with 0.60 (0.04) for LVEF and 0.64 (0.03) for SDNN (p<0.0001 for all comparisons). Stratification by dichotomised deceleration capacity was especially powerful in patients with preserved LVEF (p<0.0001 in all cohorts)., Interpretation: Impaired heart rate deceleration capacity is a powerful predictor of mortality after myocardial infarction and is more accurate than LVEF and the conventional measures of heart-rate variability.

Introduction: The prognostic value of heart rate turbulence for predicting mortality after acute myocardial infarction is well established. This study investigates a new measure of heart rate turbulence, termed turbulence dynamics, which quantifies the relationship between turbulence slope and underlying heart rate (HR(VPC))., Methods: Six hundred eight patients participating in the European Myocardial Infarction Amiodarone Trial had > or =25 ventricular premature complexes/24 h. During a follow-up period of 21 months (median), 120 patients died. Turbulence dynamics was assessed as the slope of the regression line between turbulence slope and HR(VPC). Survival analyses included age, history of previous myocardial infarction, presence of diabetes mellitus, mean normal-to-normal interval, heart rate variability index, presence of non-sustained ventricular tachycardia, left ventricular ejection fraction, turbulence onset and turbulence slope. All risk predictors were dichotomized at pre-defined cut-off points, turbulence dynamics was dichotomized at the median. Primary endpoint of the study was death of any cause., Results: In most patients, turbulence slope was inversely correlated to HR(VPC). Univariately, turbulence dynamics was the second strongest risk predictor of mortality (relative risk 2.4 (95% confidence interval 1.6-3.6), p<0.001). Multivariately, turbulence dynamics was the third strongest risk predictor (1.7 (1.1-2.7, p<0.01))., Conclusion: In the patient population studied, turbulence dynamics was an independent predictor of mortality. The results indicate that in addition to the overall level of autonomic function the loss of autonomic adaptability contributes to prognosis.

Objective: To assess the value for improving risk stratification of measures, unadjusted and adjusted for heart rate, of heart rate variability (HRV) and heart rate turbulence (HRT) based on 2- to 24-h ambulatory electrocardiographic recordings; and to relate this to the decision to use an implantable cardiac defibrillator (ICD) and the attendant consequences on effectiveness and cost-effectiveness., Background: Risk stratification for high risk or low risk of lethal ventricular arrhythmic events, and hence for a decision about defibrillator implant, most commonly utilizes the left ventricular ejection fraction (LVEF). Electrocardiographic (ECG) approaches include 24-h ambulatory ECG recordings, with counts of ventricular premature contractions (VPCs), measures of heart rate variability (HRV), and heart rate turbulence (HRT). HRT has two components: turbulence onset (TO) and turbulence slope (TS)., Methods and Results: We evaluated the qualifying ambulatory ECG recordings from 744 patients in the active treatment arms of the Cardiac Arrhythmia Suppression Trial (CAST). Beat characteristics, VPC counts, normal-to-normal beat intervals, and time-domain measures of HRV and HRT were calculated. Tachograms were rescaled to a heart rate of 75 and the resulting "normalized" measures evaluated as risk predictors for death, compared to unnormalized measures. Measures based on 2-h ECGs were also evaluated as risk predictors. The most powerful univariate predictor of survival was the normalized turbulence slope. The best multivariate prediction model had six components: history of angina, hypertension, diabetes, and absence of post-myocardial infarction revascularization, the log of LVEF, normalized TS, HR, and an interaction term of HR and normalized TS. Gains in effectiveness from use of this model cost between $0 and $4000 per year of life saved., Conclusions: Turbulence slope substantially exceeded other ECG-based measures in improving prediction of subsequent death in models which included LVEF, and other clinical parameters. Use of this model would improve the effectiveness and cost-effectiveness of the ICD.

Psychiatric disorders are associated with autonomic dys-regulations. There is evidence that these dys-regulations are partly responsible for the increased mortality in patients with psychiatric disorders. The determination of the heart rate variability (HRV) is a method easily applicable and allows the assessment of the autonomic control of the heart rate regulation. A multitude of HRV parameters with different physiological meanings have been introduced, the most widely used parameters are presented and characterized in this paper. Many studies have shown a reduced HRV in patients with major depression. Most studies found a reduced parasympathetic activity. However some authors discuss an elevated sympathetic activity. The magnitude of HRV reduction correlates to the severity of the depression. In patients with coronary diseases, major depression is an independent risk factor of mortality. Antidepressive therapy with serotonin reuptake inhibitors has failed to improve the prognosis of this patients. Patients with panic disorders also have a reduced HRV due to an elevated sympathetic control and reduced vagal control. In schizophrenic patients a reduced HRV was found in long term electrocardiogram recordings, whereas short term recordings did not show a reduced HRV. Patients with Alzheimer's disease also have a reduced HRV, which is limited to the low frequency component. Therapy with cholinesterase inhibitors further influences HRV by reducing the high frequency component and might increase the risk for arrhythmias. HRV analysis and integration in the assessment and monitoring of psychiatric patients before and during therapy elucidate the role of autonomic disturbances in such diseases and may help to optimize treatment.

Initial acceleration and a subsequent deceleration of sinus rhythm following a ventricular ectopic beat with a compensatory pause has been termed heart rate turbulence (HRT). The changes in sinus rhythm are thought to be mediated by a baroreflex response to the lower stroke volume of the ectopic beat. HRT is vagally mediated and abolished by atropine, whereas beta-blockers have no effect. HRT has been shown to be an independent and powerful predictor of mortality after myocardial infarction. In patients on beta-blockers, it scores better than left ventricular ejection fraction (LVEF) in its predictive value. Two common measures of HRT are turbulence onset and turbulence slope. When both these measures are abnormal, it is as powerful a predictor of mortality as LVEF. HRT correlates with other indices of cardiac autonomic functions like baroreflex sensitivity and heart rate variability. A composite autonomic index including all these three has been shown to be a powerful predictor of mortality. In patients undergoing direct percutaneous intervention for myocardial infarction, HRT improves in those attaining successful reperfusion. Abnormal values for HRT have been noted in patients with dilated cardiomyopathy and Chagas disease. Diabetic and elderly individuals are more likely to have blunted HRT. HRT cannot be measured in patients lacking ventricular ectopic beats and in patients presenting with atrial fibrillation.

April 2004 marks the fifth anniversary of the first heart rate turbulence (HRT) publication, which demonstrated the usefulness of HRT in predicting cardiac death in postmyocardial infarction patients. Since then, HRT has been shown to predict prognosis of patients with dilated cardiomyopathy and of patients with heart failure of mixed etiology. HRT also has been shown to be predictive even in the current lower-mortality era of acute revascularization therapy for myocardial infarction. We discuss the latest criteria for obtaining reliable measurements of HRT, review factors that influence HRT values, and consider recent clinical studies.

Decreased left ventricular ejection fraction is the most commonly used risk factor for identification of patients at high-risk for lethal ventricular arrhythmic events. Twenty-four-hour electrocardiographic (ECG) approaches to risk stratification include: counts of ventricular premature contractions (VPCs), measures of heart rate variability (HRV), and heart rate turbulence (HRT) which has two components, turbulence onset and turbulence slope (TS). Refinement of these ECG risk stratifiers could enhance their clinical utility. We explored the structural relationships between heart rate (HR) and HRV and HRT measures. Our goal was to separate out the component of these measures due to the underlying average heart rate (HR), thus potentially reducing the variability of the measures and increasing their power to stratify risk. We proposed re-scaling tachograms of heart-beat intervals so that the re-scaled tachogram has a HR of 75 (or equivalently an average interval of 800 ms) and calculating HRV and HRT from the rescaled time series. We also explored the relationship between the number of VPCs and HRT. We showed that TS is structurally related to the number of VPCs (and hence to the length of the ECG recording). We proposed an adjusted TS that is independent of the number of VPCs. We also addressed the ability of shorter ECG recording to estimate HRV and HRT measures. We evaluated standard and rescaled HRV and HRT measures using qualifying ambulatory ECG recordings from 744 patients in the Cardiac Arrhythmia Suppression Trial. We found that measures based on the rescaled tachogram had reduced variance (20% to 40%). Correlations between measures were also substantially reduced. We also found substantial circadian effects on some, but not all HRV indices, not explained by the circadian pattern in HR and possibly pointing to additional measures for risk prediction. In conclusion, we found that adjusting for HR and the number of VPCs in heart-beat related ambulatory ECG measures has the potential to significantly improve the power of these measures to risk stratify cardiac patients.

Background: Retrospective postinfarction studies revealed that decreased heart rate turbulence (HRT) indicates increased risk for subsequent death. This is the first prospective study to validate HRT in a large cohort of the reperfusion era., Methods and Results: One thousand four hundred fifty-five survivors of an acute myocardial infarction (age <76 years) in sinus rhythm were enrolled. HRT onset (TO) and slope (TS) were calculated from Holter records. Patients were classified into the following HRT categories: category 0 if both TO and TS were normal, category 1 if either TO or TS was abnormal, or category 2 if both TO and TS were abnormal. The primary end point was all-cause mortality. During a follow-up of 22 months, 70 patients died. Multivariately, HRT category 2 was the strongest predictor of death (hazard ratio, 5.9; 95% CI, 2.9 to 12.2), followed by left ventricular ejection fraction (LVEF) < or =30% (4.5; 2.6 to 7.8), diabetes mellitus (2.5; 1.6 to 4.1), age > or =65 years (2.4; 1.5 to 3.9), and HRT category 1 (2.4; 1.2 to 4.9). LVEF < or =30% had a sensitivity of 27% at a positive predictive accuracy level of 23%. The combined criteria of LVEF < or =30%, HRT category 2 or LVEF >30%, age > or =65 years, diabetes mellitus, and HRT category 2 had a sensitivity of 24% at a positive predictive accuracy level of 37%. The combined criteria of LVEF < or =30% or LVEF >30%, age > or =65 years, diabetes mellitus, and HRT category 1 or 2 had a sensitivity of 44% at a positive predictive accuracy level of 23%., Conclusions: HRT is a strong predictor of subsequent death in postinfarction patients of the reperfusion era.

Background: Heart rate turbulence (HRT) has recently been described as a strong, independent risk stratifier in postinfarct patients. To date, however, the incidence of false positive HRT findings in adults is unknown. Therefore, we performed a blinded, retrospective analysis of HRT in a prospectively collected database of 110 apparently healthy persons to determine the prevalence and clinical significance of abnormal HRT findings in healthy controls using previously published cut-off values., Methods and Results: The study included 43 out of 110 apparently healthy adults, in whom a sufficient number of ventricular premature beats were available for HRT analysis on 24-hour Holter recordings. The HRT slope was dichotomized at 2.5 ms per R-R interval and HRT onset was dichotomized at 0% using previously established criteria to define an abnormal HRT analysis in postinfarct patients. Using these definitions, abnormal HRT results were found in 2 out of 43 controls (5%) for HRT slope and in 8 out of 43 controls (19%) for HRT onset without any cardiac deaths during 32 +/- 15 months follow-up., Conclusions: The incidence of false positive HRT results in healthy middle-aged volunteers is low for HRT slope (5%), but not for HRT onset (19%) when previously published cut-off values are used to define abnormal HRT results. Thus, HRT slope dichotomized at 2.5 ms per R-R interval, but not HRT onset dichotomized at 0%, may be used as a relatively specific tool for risk stratification in middle-aged persons.