Effect of age on diurnal changes of 24-hour QT interval variability.

QT interval on the surface electrocardiogram (ECG) reflects the time for repolarization of myocardium and prolongation of QTc is strongly associated with sudden cardiac death. Studies using novel techniques on beat-to-beat QT interval variability (QTV) have shown that it is influenced by the autonomic nervous system and is a predictor of sudden cardiac death. In this study, we examined the awake and sleep changes in QTV in 39 normal adults (mean age, 35 years) and 10 children (mean age, 11 years) using 24-hour ECG records. We obtained eight 5-minute segments of ECG sampled at 1000 Hz from the 24-hour records. Our results show that there is a diurnal variation of QTvm, detrended QT interval variance corrected for mean QT, and QTvi, an index of QTvm divided by heart rate variability corrected for mean heart rate. There was a significant increase in mean QT during sleep, whereas there was a significant decrease in QTvm and QTvi. QTvi significantly increased during the early morning hours. There were significant but modest correlations between the average 24-hour and awake QTvi and age (p < 0.01). There were also decreased low-frequency and high-frequency powers of QT during sleep. Coherence between heart rate and QT interval fluctuations in the range of 0-0.5 Hz, and especially in the high-frequency range (0.15-0.5 Hz), was significantly lower in adults than in children (p < 0.0002). These findings demonstrate diurnal fluctuations in ventricular repolarization lability. We speculate that these effects may relate to changes in cardiac autonomic function and may contribute to the well-known diurnal variation in the incidence of ventricular arrhythmias.

Effect of imipramine on linear and nonlinear measures of heart rate variability in children.

We investigated the effects of treatment with the tricyclic antidepressant (TCA) imipramine in eight children in supine and standing postures. We used 256 seconds of real-time data for the analyses. Spectral analysis showed a significant decrease of high-frequency (HF) power (0.15-0.5 Hz), especially in the standing posture. Low frequency (LF) HF ratios were significantly higher in the standing posture after treatment, suggesting increased sympathovagal interaction. We also obtained the nonlinear measures of fractal dimension (FD), and approximate entropy (APEN). Although the FD of heart rate was significantly lower in the standing posture, APEN was significantly decreased after treatment in either posture and was the most sensitive measure in this study. These findings suggest a decreased cardiac vagal function with a relative increase in sympathetic responsiveness, which may in part be related to the cardiotoxicity of these drugs. These findings are discussed in relation to the cardiovascular side effects of TCAs.

Daily exercise reduces measures of heart rate and blood pressure variability in hypertensive rats.

This study was designed to test the hypothesis that daily spontaneous running (DSR) reduces measures of heart rate and blood pressure variability in spontaneously hypertensive rats (SHR). After 8 weeks of DSR or sedentary control, rats were chronically instrumented with arterial catheters. Daily exercise reduced most measures of heart rate (HR) and blood pressure variability. Specifically DSR decreased heart rate, Low Frequency Power (LF: 0.19-0.61 Hz), and Low Frequency/High Frequency (HF: 1.2-2.5 Hz) ratio of HR. Furthermore, Total Power (TP), LF power, and LF/HF ratio of systolic blood pressure were reduced by daily spontaneous running. Finally, TP, LF and HF powers and LF/HF ratios of diastolic blood pressure were reduced by daily spontaneous running. These data demonstrate that daily exercise reduces sympathetic activity and possibly increases cardiac reserve in hypertensive animals.

Decreased chaos and increased nonlinearity of heart rate time series in patients with panic disorder.

In this study, we investigated measures of nonlinear dynamics and chaos of heart rate time series in 30 normal control subjects and 36 age-matched patients with panic disorder in supine and standing postures. We obtained minimum embedding dimension (MED), largest Lyapunov exponent (LLE) and measures of nonlinearity (NL) of heart rate time series. MED quantifies system's complexity, LLE predictability and NL, deviation from linear processes. There was a significant increase in complexity (p < 0.00001), an increase in predictability (decreased chaos) (p < 0.00001) and an increase in nonlinearity (Snet GS) (p = 0.00001), especially in supine posture in patients with panic disorder. Increased NL score in supine posture may be due to a relative increase in cardiac sympathetic activity and an overall decrease in LLE may indicate an impaired cardiac autonomic flexibility in these patients due possibly to a decrease in cardiac vagal activity. These findings may further explain the reported higher incidence of cardiovascular mortality in patients with anxiety disorders.

Heart rate and QT variability in children with anxiety disorders: a preliminary report.

This study compared beat-to-beat heart rate and QT variability in children with anxiety disorders (n = 7) and normal controls (n = 15) by using an automated algorithm to compute QT intervals. An increase in QT variability appears to be associated with a higher risk for sudden cardiac death. A decrease in heart rate variability is also linked to significant cardiovascular events. Supine detrended QT variability, QT variability corrected for mean QT interval, and QTvi (a log ratio of QT variance normalized for mean QT over heart rate variability normalized for mean heart rate) were significantly higher in children with anxiety compared to controls (P < 0.05). The largest Lyapunov Exponent (LLE) of heart rate time series was significantly lower (P < 0.05) in children with anxiety compared to controls. These findings suggest a relative increase in sympathetic activity and a relative decrease in cardiac vagal activity in children with anxiety disorders, and are discussed in the context of the effects of tricyclics on cardiac autonomic function in children, and the rare occurrence of sudden death during tricyclic antidepressant treatment.

Nonlinear measures of heart period variability: decreased measures of symbolic dynamics in patients with panic disorder.

Time series of heart period are not linear and recent studies illustrated the importance of using nonlinear methods to quantify the complexity of these time series. We compared different techniques to quantify the nonlinear complexity of these time series in patients with panic disorder and normal controls and correlated these measures with spectral powers in different bands of interest. Twenty-four hour ECG was recorded in 23 normal controls and 29 patients with panic disorder by using Holter records. Time series of heart period were analyzed by using approximate entropies, slopes of 1/f scaling, two algorithms to calculate fractal dimension, and word sequences using symbolic dynamics. Measures using symbolic dynamics, especially word count (WC-100), showed highly significant differences between the two groups similar to some of the frequency domain (spectral) measures, while the other techniques were relatively ineffective to distinguish between the two groups. Different nonlinear techniques may relate to different aspects of nonlinear complexity of the time series. These nonlinear techniques were also not uniform in showing the differences between awake and sleep periods. Some correlate with the measures of respiratory sinus arrhythmia and some measures obtained from symbolic dynamics may reflect not only the nonlinear complexity of the time series but also the total variability in the 24 hr HP time series, especially power in the ultra-low frequency band (< 0.0033 Hz). However, word count (WC-100) had only weak correlations with other measures and discriminated best between the two groups and showed that this nonlinear measure was of additional value to the linear measures in classifying the two groups.

Effect of age on QT variability.

Heart rate variability is influenced significantly by age. Recent studies have shown the utility of QT variability to study temporal repolarization lability, and increased QT variability is reportedly associated with sudden death. Because beat-to-beat QT interval variability appears to closely follow heart rate variability, this study investigated the relationship between age and QT variability. We obtained QT variability measures in 34 adults (22-55 years of age) and 15 children (6-14 years of age) using a novel algorithm to compute beat-to-beat QT intervals. QT variability corrected for mean QT interval was significantly inversely correlated with age. Coherence in the band of 0 to 0.5 Hz and high-frequency coherence (0.15-0.5 Hz) were also significantly inversely correlated with age. QTvi (QT variability corrected for mean QT interval over heart rate variability corrected for mean heart rate) was not significantly related to age in supine posture during spontaneous or controlled breathing, whereas there was a modest negative relationship in standing posture. These findings suggest that coherence between QT and heart rate time series appears to be modulated by cardiac vagal activity.

Effects of nortriptyline and paroxetine on QT variability in patients with panic disorder.

This study investigated beat-to-beat QT variability in patients with panic disorder before and after treatment with nortriptyline (n = 13) and paroxetine (n = 16), using an automated algorithm to compute QT intervals. An increase in QT variability appears to be associated with symptomatic patients with dilated cardiomyopathy and also with an increased risk for sudden cardiac death. QTvi (QT variability index: a log ratio of QT variance normalized for mean QT over heart rate variability normalized for mean heart rate) was significantly higher in supine posture in patients with panic disorder treated with nortriptyline (P = 0.006) but not paroxetine. Thus paroxetine may be a better drug of choice especially in patients with coexisting cardiac disease. These findings are important especially in view of the recent reports of increased risk for cardiovascular mortality and sudden death in patients with anxiety and depression. QTvi can be a valuable noninvasive measure of temporal repolarization lability, especially to study the side effects of medications which affect cardiac autonomic function.

Effect of posture and isoproterenol on beat-to-beat heart rate and QT variability.

RATIONALE: Recent literature emphasizes the utility of QT variability to study ventricular electrophysiologic function. In this investigation, we sought to test the hypothesis that beat-to-beat fluctuations in QT intervals are mediated by sympathetic activity in normal subjects using postural challenge and isoproterenol infusions. SUBJECTS AND METHODS: We obtained ECG in the supine and standing postures during spontaneous breathing, at 12, 15 and 20 per minute controlled breathing (n = 19), and before and after infusions of isoproterenol, a beta-adrenergic agent, in the supine posture during spontaneous breathing (n = 11) using lead II configuration in healthy human adult subjects. Heart rate (HR) and QT time series data were analyzed by spectral analysis of 256 s of real-time data. Beat-to-beat QT intervals were measured by automated analysis of ECG. A QT variability index (QT(vi)) was calculated for each subject as the logarithm of the ratio of normalized QT variance to normalized HR variance. We also calculated fractal dimensions of QT time series during spontaneous breathing. RESULTS: QT(vi) was significantly higher in the standing than in the supine posture (-1. 93 +/- 0.27 vs. -1.47 +/- 0.41; p = 0.0001), and also during isoproterenol infusions in the supine posture (-1.83 +/- 0.39 vs. -1. 27 +/- 0.43; p = 0.0001). Fractal dimensions of QT time series were also significantly higher during standing (p = 0.00001) and isoproterenol infusions (p = 0.0002). Respiratory rate or tidal volume did not account for the increased QT variability seen in the standing posture. CONCLUSIONS: A change from the supine to the standing posture as well as infusion of isoproterenol significantly increased the absolute as well as normalized QT variability, which appears to be due to an increase in sympathetic activity associated with these conditions.

Increased QT variability in patients with panic disorder and depression.

This study investigated beat-to-beat QT variability in patients with panic disorder and depression, and normal control subjects using an automated algorithm to compute QT intervals. An increase in QT variability appears to be associated with symptomatic patients with dilated cardiomyopathy and also with an increased risk for sudden death. QT(vm) (QT variability normalized for mean QT interval) and QT(vi) (a log ratio of QT variance normalized for mean QT over heart rate variability normalized for mean heart rate) were significantly higher in patients with panic disorder and depression in supine as well as standing postures (P=0.002 and 0.0001 for QT(vm) and QT(vi), respectively). In another analysis, QT(vi) was significantly higher in patients with panic disorder compared to control subjects in supine as well as standing postures during spontaneous breathing as well as 12, 15 and 20 per minute breathing (P=0.005). These findings are important especially in view of the recent reports of increased risk for cardiovascular mortality and sudden death in patients with anxiety and depression and the utility of QT(vi) as a noninvasive measure of temporal repolarization lability.

Heart period and QT variability, hostility, and type-A behavior in normal controls and patients with panic disorder.

OBJECTIVES: Excess cardiovascular morbidity has been reported in association with phobic anxiety as well as in association with hostility and type-A behavior. The aim of this study was to investigate the relationship between the measures of hostility and type-A behavior, and heart period (HP) and QT variability in normal controls and patients with panic disorder. METHODS: Data were obtained from Holter ECG records for HP and heart rate (HR) and QT variability measures were obtained from 5 min laboratory ECG records in normal controls (n=21) and patients with panic disorder (n=27). RESULTS: Patients with panic disorder were significantly more hostile, and had significantly higher scores on Jenkins Activity Survey (JAS) speed and impatience subscale (S scale). Hostility did not correlate with either HP variability or QT variability. Higher type-A scores were associated with higher low frequency (LF) and high frequency (HF) powers of HP variability and standing QT variability was associated inversely with type-A and S scores of the JAS in patients with panic disorder. CONCLUSIONS: Our results do not support the hypothesis that higher hostility and higher type-A scores are associated with decreased cardiac vagal function.

Nonlinear measures of heart rate time series: influence of posture and controlled breathing.

In this study, we investigated measures of nonlinear dynamics and chaos theory in regards to heart rate variability in 27 normal control subjects in supine and standing postures, and 14 subjects in spontaneous and controlled breathing conditions. We examined minimum embedding dimension (MED), largest Lyapunov exponent (LLE) and measures of nonlinearity (NL) of heart rate time series. MED quantifies the system's complexity, LLE predictability and NL, a measure of deviation from linear processes. There was a significant decrease in complexity (P < 0.00001), a decrease in predictability (P < 0.00001) and an increase in nonlinearity (P = 0.00001) during the change from supine to standing posture. Decrease in MED, and increases in NL score and LLE in standing posture appear to be partly due to an increase in sympathetic activity of the autonomous nervous system in standing posture. An improvement in predictability during controlled breathing appears to be due to the introduction of a periodic component.

Effects of paroxetine on heart period variability in patients with panic disorder: a study of holter ECG records.

We investigated cardiac autonomic function in 16 patients with panic disorder before and after treatment with paroxetine using Holter ECG records. Our previous data suggest a relative increase in sympathetic activity in patients with panic disorder, especially during sleep. Data for 20 h and awake and sleep periods were analyzed using spectral analysis to quantify absolute and relative heart period variability in ultra low (ULF: <0.0033 Hz), very low (VLF: 0.0033-0.04 Hz), low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.5 Hz) frequency bands. We also obtained fractal dimensions (FD) for the 20-hour, awake and sleep time series of RR intervals. Paroxetine treatment (19.7 +/- 4.7 mg/day for 105 +/- 37 days) resulted in a significant improvement in the frequency and intensity of panic attacks and also on the state anxiety inventory. Paroxetine treatment produced a significant decrease of 20-hour absolute HF power, awake absolute LF power and sleep absolute HF power. There was also a significant decrease of FDs after treatment with paroxetine for the sleep period. The decrease in LF and HF powers, and sleep FD is likely due to the antimuscarinic effect of paroxetine. The decrease in day-time LF power may also be due to a decrease in relative cardiac sympathetic activity after paroxetine treatment.

Fractal dimension and approximate entropy of heart period and heart rate: awake versus sleep differences and methodological issues.

1. Investigations that assess cardiac autonomic function include non-linear techniques such as fractal dimension and approximate entropy in addition to the common time and frequency domain measures of both heart period and heart rate. This article evaluates the differences in using heart rate versus heart period to estimate fractal dimensions and approximate entropies of these time series.2. Twenty-four-hour ECG was recorded in 23 normal subjects using Holter records. Time series of heart rate and heart period were analysed using fractal dimensions, approximate entropies and spectral analysis for the quantification of absolute and relative heart period variability in bands of ultra low (<0.0033 Hz), very low (0. 0033-0.04 Hz), low (0.04-0.15 Hz) and high (0.15-0.5 Hz) frequency.3. Linear detrending of the time series did not significantly change the fractal dimension or approximate entropy values. We found significant differences in the analyses using heart rate versus heart period between waking up and sleep conditions for fractal dimensions, approximate entropies and absolute spectral powers, especially for the power in the band of 0.0033-0.5 Hz. Log transformation of the data revealed identical fractal dimension values for both heart rate and heart period. Mean heart period correlated significantly better with fractal dimensions and approximate entropies of heart period than did corresponding heart rate measures.4. Studies using heart period measures should take the effect of mean heart period into account even for the analyses of fractal dimension and approximate entropy. As the sleep-awake differences in fractal dimensions and approximate entropies are different between heart rate and heart period, the results should be interpreted accordingly.

Decreased heart-period variability in patients with panic disorder: a study of Holter ECG records.

This study investigated cardiac autonomic function in patients with panic disorder and normal controls using Holter ECG records. A decrease in ultra-low frequency power (< 0.0033 Hz) is known to be associated with an increased risk for cardiovascular mortality in humans. Twenty-four-hour ECG was recorded in 29 patients with panic disorder and 23 normal controls using Holter records. Data for 20 h and also 20000 s of awake and 20000 s of sleep periods were analyzed using spectral analysis to quantify absolute and relative heart-period variability in ultra low (ULF: < 0.0033 Hz), very low (VLF: 0.0033-0.04 Hz), low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.5 Hz) frequency bands. The patients with panic disorder had significantly lower total and absolute ULF power, which was more pronounced during sleep. The patients also had significantly lower relative ULF power and significantly higher relative LF power during sleep. There was a significant increase of relative LF power from awake to sleep period only in the patient group. The decrease in total and ULF power may increase the risk of mortality and sudden arrhythmic death in patients with panic disorder if they experience a cardiac event. The higher relative LF power during sleep also suggests a possible higher sympathetic drive in the patients during sleep.

Effect of age on long-term heart rate variability.

OBJECTIVE: Previous studies on short-term time series of heart rage suggest an inverse relationship between age and spectral powers of heart rate variability in various frequency bands. In this study, we examined the relationship between age (6-61 years) and long-term heart rate variability. METHODS: We obtained 24-h Holter ECG in 33 healthy human subjects (11 children and 22 adults). The heart rate data were analyzed by using spectral analysis and fractal dimensions of the time series. RESULTS: We found a significant negative correlation between age and very low frequency (VLF, 0.0033-0.04 Hz), low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.5 Hz) powers and fractal dimensions during awake as well as sleep periods, and a positive correlation between age and LF/HF ratios. Age and ultra-low frequency (ULF, < 0.0033 Hz) were modestly and negatively correlated only during the awake period. CONCLUSIONS: Sleep ULF power is not significantly affected by age, whereas VLF, LF and HF powers and fractal dimensions of heart rate significantly decrease with age during awake as well as sleep periods.

Power spectrum of the QRS complex in patients with panic disorder and normal controls.

We performed spectral analysis on the QRS complex of the electrocardiogram obtained using standard limb leads, sampled at 500 Hz with 12 bit precision in 20 normal subjects and 15 patients with panic disorder. We divided the frequency range of the QRS into two bands based on spectral patterns before and after the postural challenge-mid frequency (MF): 7.8-20 Hz; and high frequency (HF): 21-250 Hz. Postural change from supine to standing produced a significant increase in absolute (P = 0.003) and relative HF power (P = 0.00001). Patients with panic disorder had a significantly decreased QRS HF power (P = 0.003). The increase in QRS HF power may have been due to the shortening of the QRS interval in standing posture. The decreased QRS HF power in patients with panic disorder should be further investigated due to the recent reports of an association of phobic anxiety and fatal coronary heart disease, and the possible association of decreased high frequency components of QRS in myocardial infarction.

Analysis of 24-hour ECG in patients with panic disorder.

Previous evidence suggests an increased cardiovascular morbidity in patients with panic disorder. In this study, we compared 24-hour ECG in patients with panic disorder (n = 22; age: 36.1 +/- 7.6 years) and healthy controls (n = 21; age: 34.6 +/- 10.0 years). The QTc intervals during the day or night were not significantly different between patients and controls. Ventricular ectopic beats were also not significantly different between the two groups. These results do not suggest any overt cardiac arrhythmias in this age group of patients with panic disorder.