Exaggerated differences in pulse wave velocity between left and right sides among patients with anxiety disorders and cardiovascular disease.

OBJECTIVE: To compare the left-right differences in pulse wave velocity (PWV) measures in normal controls and patients with anxiety disorders and cardiac disease. Pulses from the right and left sides of normal subjects are highly correlated at each segmental level. However, some evidence suggests that the right hemisphere has a greater effect on parasympathetic activity, as there may be a right hemisphere disadvantage in patients with low cardiac vagal function. Decreased vagal function is associated with vascular dysfunction and hypertension. METHODS: We compared normal controls (n = 22), patients with anxiety (n = 26), and patients with cardiovascular disease (n = 72) using the Vascular Profiler (VP-1000), which enables the measurement of ankle and brachial blood pressure (BP) in both arms (brachial), both legs (ankle) and carotid artery, and lead I electrocardiogram and phonocardiogram. Using these signals, PWV, and arterial stiffness index % were calculated for the comparison of these measures on the right and left sides of the body. RESULTS: Patients with anxiety and cardiovascular disease had significantly higher left-right differences in heart-ankle pulse wave velocity, brachial-ankle pulse wave velocity, and arterial stiffness index percentage compared with that of normal controls. Our data also showed significant differences between left-right vascular indices in patients with anxiety and cardiovascular disease (p < .00001); there was no such significant difference in normal controls. CONCLUSIONS: These results may implicate an exaggerated vagal withdrawal in the left extremities resulting in higher PWV in patients with anxiety and cardiovascular illness.

Relationship between beat-to-beat variability of RT-peak and RT-end intervals in normal controls, patients with anxiety, and patients with cardiovascular disease.

BACKGROUND: Some studies suggest that it is important to take the end of "T" wave to quantify QT-interval variability, which signifies cardiac repolarization lability, as there is substantial and important information beyond the peak of the T wave on the surface electrocardiogram. METHODS: In this study, we examined the relationship between the variability of beat-to-beat RTe (beginning of R-peak to T-end) and the variability of RTp (R-peak to T-peak) in the following groups: normal controls (n = 26), patients with anxiety (n = 26), and patients with cardiovascular disease with or without diabetes (n = 63). We obtained ECG sampled at 1024 Hz in lead II configuration in supine posture to obtain beat-to-beat interbeat interval (R-R) and RT-interval variability for 256 seconds. RESULTS: We found significant positive correlations (r = 0.8; P < 0.00001) in normal controls and patients with anxiety between the variability of RTeVI and RTpVI (RTe and RTp variability indices, respectively, corrected for the mean of RTe and RTp and the mean and the variance of R-R). These correlations were also statistically significant in the medically ill group but the r values were much smaller (r = 0.45 in various groups). The slopes were also significantly different between the two groups (P < 0.001). Bland-Altman plots also showed better agreement between the two measures in the controls and patients with anxiety compared to the group with cardiovascular disease. CONCLUSIONS: These findings have methodological implications for studies comparing people with and without overt cardiovascular illness. While RTe or RTp variability index may be used interchangeably in normal controls and some patients with no overt cardiovascular problems, it may be more prudent to use both RTe and RTp variability indices in patients with cardiovascular illness. These indices, especially RTeVI, may provide different information about cardiac repolarization lability. Future studies should address the importance of the relative usefulness of these two measures especially in cardiac patients before and after successful treatment.

Increased pulse-wave velocity in patients with anxiety: implications for autonomic dysfunction.

Decreased vagal function is associated with vascular dysfunction. In this study, we compared vascular indices and correlated heart rate and QT variability measures with vascular indices in patients with anxiety disorders and normal controls. We compared age- and sex-matched controls (n=23) and patients with anxiety (n=25) using the Vascular Profiler (VP-1000; Colin Medical Instruments, Japan), approved by the US Food and Drug Administration. Using this machine, we obtained ankle and brachial blood pressure (BP) in both arms (brachial), both legs (ankle), and carotid artery, and lead I electrocardiogram (ECG) and phonocardiogram. Using these signals, pulse-wave velocity (PWV), and arterial stiffness index % and preejection period can be calculated. We also obtained ECG sampled at 1000 Hz in lead II configuration in supine posture to obtain beat-to-beat interbeat interval (R-R) and QT interval variability for 256 s. Patients with anxiety had significantly higher carotid mean arterial pressure (MAP) %, brachial-ankle PWV (BAPWV), arterial stiffness index %, MAP, and diastolic BP of the extremities compared to controls. We found significant negative correlations (r values from .4 to .65; P<.05 to .007) between R-R interval high-frequency (0.15-0.5 Hz) power (which is an indicator of cardiac vagal function), and increased BAPWV and systolic BP of the extremities only in patients. We were unable to find such correlations in controls. We also found significant positive correlations between QT variability index (a probable indicator of cardiac sympathetic function) and MAP of the extremities and BAPWV only in the patient group. These findings suggest an important association between decreased vagal and increased sympathetic function, and decreased arterial compliance and possible atherosclerotic changes and increased BP in patients with anxiety.

Decreased coherence in higher frequency ranges (beta and gamma) between central and frontal EEG in patients with schizophrenia: A preliminary report.

Schizophrenia is associated with a dysfunction of cognitive integration that may be due to abnormalities in inhibitory neural circuitry. A previous study found a failure of gamma band (25-45 Hz) synchronization in patients with schizophrenia compared to controls. Another recent study also stressed the importance of investigating high frequencies in the scalp-recorded sleep electroencephalogram (EEG). In this study, we compared coherence between first episode drug-naïve patients with schizophrenia (n=8) and age- and sex-matched normal controls (n=8) using two 32-s epochs of C4 and F4 EEG. The coherence was obtained using 4096 data points (128 Hz signal) using cross-spectral analysis with Blackman-Tukey window in beta (15.25-24.75 Hz) and gamma (25-44.75 Hz) frequency bands. We used wake, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep periods for the analyses. Our results show a significant decrease in coherence in both beta and gamma frequency bands in patients. Post-hoc 't' tests revealed a significantly lower coherence only during the wake stage in patients with schizophrenia in beta as well as gamma frequency bands. These results further support the importance of the analyses of high-frequency bands in the EEG and support previous findings of abnormal neural synchrony in patients with schizophrenia. These results have been discussed further in relation to wake and sleep stages.

Effect of mechanical coronary reperfusion on QT dispersion in acute coronary syndrome.

BACKGROUND: The time for cardiac repolarization and homogeneity of repolarization on surface electrocardiogram is denoted by QT interval and QT dispersion, respectively. Numerous studies suggest an association between an increased dispersion of the QT interval obtained from the 12-lead electrocardiogram and increased risk for serious cardiac events. METHODS AND RESULTS: We evaluated the effect of thrombolysis and percutaneous transluminal coronary angioplasty on QT dispersion in acute coronary syndrome in 45 patients (age: 55 +/- 6 years). QT dispersion was calculated on admission and immediately after the procedure (thrombolysis and percutaneous transluminal coronary angioplasty). There was a significant decrease in QT dispersion after percutaneous transluminal coronary angioplasty (75 +/- 21 ms to 38 +/- 20 ms, p < 0.0001). In a subset of these patients with acute myocardial infarction (n = 29) who underwent thrombolysis, QT dispersion decreased only marginally (78 +/- 19 ms to 67 +/- 22 ms, p < 0.05). Even in this subgroup, there was a significant decrease in QT dispersion after percutaneous transluminal coronary angioplasty (to 37 +/- 22 ms, p < 0.0001). In patients with unstable angina (n = 16), there were similar significant changes after percutaneous transluminal coronary angioplasty (p < 0.0001). CONCLUSIONS: These results suggest a highly significant decrease in QT dispersion after percutaneous transluminal coronary angioplasty compared to a less significant decrease after thrombolysis, which may have clinical implications.

Circadian changes in the QT variability index in the beagle dog.

1. QT variability is a non-invasive marker of cardiac repolarization lability and a higher QT variability is associated with sudden death. No data exist as to the circadian fluctuations in QT variability and the QT variability index (QTvi) in the canine. The purpose of the present investigation was to explore QT interval variability over 24 h in the healthy dog. 2. Continuous lead II electrocardiogram and blood pressure data were collected for 24 h from three beagles instrumented with radiotelemetry devices. The mean heart rate (HR), detrended HR variance, mean QT interval and detrended QT variance were calculated from the instantaneous HR and QT time series of 1024 points (256 s), as described previously, and a normalized QTvi was derived. 3. The dog has a diurnal pattern of QTvi similar to healthy humans. Both dogs and humans exhibit a significantly higher QTvi during active waking hours, with more negative values during deep sleep. 4. These findings suggest QTvi may serve as an additional non-invasive tool to assess ventricular repolarization lability in dogs in relation to any conditions or drugs that are known to be associated with increased cardiac mortality.

Decreased nonlinear complexity and chaos during sleep in first episode schizophrenia: a preliminary report.

Schizophrenia is characterized by disturbed sleep architecture. It has been thought that sleep abnormalities may underlie information processing deficits associated with this disorder. Nonlinear analyses of sleep data can provide valuable information on sleep characteristics that may be relevant to the functions of sleep. This study examined the predictability and nonlinear complexity of sleep EEG time series in two EEG channels (C4 and F4) using measures of nonlinearity, such as symbolic dynamics and the largest Lyapunov exponent (LLE) in schizophrenia. A series of antipsychotic naive patients with first episode of schizophrenia or schizoaffective disorder and age-matched healthy controls were studied during awake period, stage 1/2, slow wave sleep (stage 3/4) and rapid eye movement (REM) sleep. Nonlinearity scores were significantly lower during awake stage in patients compared to controls suggesting that there may be a diminished interplay between various parameters for the genesis of waking EEG. Symbolic dynamics and LLE were significantly lower in patients during REM compared to healthy controls, suggesting decreased nonlinear complexity of the EEG time series and diminished chaos in schizophrenia. Decreased nonlinear complexity was also correlated with neurocognitive deficits as assessed by the Wisconsin card sorting test. Diminished complexity of EEG time series during awake and REM sleep in patients with schizophrenia may underlie the impaired ability to process information in psychotic disorders such as schizophrenia.

Paroxetine decreases respiratory irregularity of linear and nonlinear measures of respiration in patients with panic disorder. A preliminary report.

Previous studies indicate that serotonin reuptake inhibitors do not appear to have serious cardiac side effects. However, the effects of these agents on respiratory measures have not been studied in detail. Several studies indicate that patients with anxiety exhibit irregular breathing patterns as measured by tidal volume and respiratory rate. In this study, we evaluated the effects of a serotonin reuptake inhibitor, paroxetine, on respiratory variability in patients with panic disorder (n = 13), using linear and nonlinear measures of regularity, approximate entropy (APEN) and a measure of chaos, the largest Lyapunov exponent (LLE), with pre- and posttreatment lung volume time series (256 s long sampled at 4 Hz). Our results show that paroxetine significantly decreases some of the linear measures of variability and supine APEN and standing LLE of lung volume series after successful treatment. The implications of these findings on respiratory and cardiovascular function have been discussed.

Effect of nortriptyline and paroxetine on measures of chaos of heart rate time series in patients with panic disorder.

Tricyclic antidepressants have notable cardiac side effects, and this issue has become important due to the recent reports of increased cardiovascular mortality in patients with depression and anxiety. Several previous studies indicate that serotonin reuptake inhibitors (SRIs) do not appear to have such adverse effects. Apart from the effects of these drugs on routine 12-lead ECG, the effects on beat-to-beat heart rate (HR) and QT interval time series provide more information on the side effects related to cardiac autonomic function. In this study, we evaluated the effects of two antidepressants, nortriptyline (n=13), a tricyclic, and paroxetine (n=16), an SRI inhibitor, on HR variability in patients with panic disorder, using a measure of chaos, the largest Lyapunov exponent (LLE) using pre- and posttreatment HR time series. Our results show that nortriptyline is associated with a decrease in LLE of high frequency (HF: 0.15-0.5 Hz) filtered series, which is most likely due to its anticholinergic effect, while paroxetine had no such effect. Paroxetine significantly decreased sympathovagal ratios as measured by a decrease in LLE of LF/HF. These results suggest that paroxetine appears to be safer in regards to cardiovascular effects compared to nortriptyline in this group of patients.

Heart rate and QT interval variability: abnormal alpha-2 adrenergic function in patients with panic disorder.

Anxiety disorders are associated with an increase in cardiovascular mortality. Studies using heart rate (HR) and QT interval variability measures suggest a decreased cardiac vagal function and a relatively increased sympathetic function in anxiety. This is important, as increased sympathovagal balance is associated with life-threatening arrhythmias. Several studies have shown that panic disorder is associated with an increased sensitivity to yohimbine and a blunted growth hormone response to clonidine, which are alpha-2 adrenoceptor antagonist and agonist, respectively. This study investigated the changes in QTvi (QT variance corrected for mean QT interval squared/HR variance corrected for mean HR squared) during placebo, oral clonidine (150 mg) and oral yohimbine (20 mg) in a double-blind design in 12 normal controls and 19 patients with panic disorder. HR and QT variability measures, especially QTvi, were obtained before and after the administration of these drugs to patients in supine and standing postures. As expected, patients with panic disorder became more anxious after yohimbine. In addition, the patients had a significant increase in QTvi after yohimbine and a significant decrease in QTvi after clonidine, which was not seen in the control group. The decreased anxiety after placebo was associated with decreased QTvi in patients. This study supports the previous reports of an abnormal sensitivity of alpha-2 adrenergic receptors in patients with panic disorder compared to controls and partly explains the association of increased cardiovascular mortality with conditions of anxiety. QTvi, a non-invasive indicator of cardiac repolarization lability, appears to be a useful tool to study cardiac sympathetic function.

Nonlinear measures of QT interval series: novel indices of cardiac repolarization lability: MEDqthr and LLEqthr.

In this study, we investigated nonlinear measures of chaos of QT interval time series in 28 normal control subjects, 36 patients with panic disorder and 18 patients with major depression in supine and standing postures. We obtained the minimum embedding dimension (MED) and the largest Lyapunov exponent (LLE) of instantaneous heart rate (HR) and QT interval series. MED quantifies the system's complexity and LLE predictability. There was a significantly lower MED and a significantly increased LLE of QT interval time series in patients. Most importantly, nonlinear indices of QT/HR time series, MEDqthr (MED of QT/HR) and LLEqthr (LLE of QT/HR), were highly significantly different between controls and both patient groups in either posture. Results remained the same even after adjusting for age. The increased LLE of QT interval time series in patients with anxiety and depression is in line with our previous findings of higher QTvi (QT variability index, a log ratio of QT variability corrected for mean QT squared divided by heart rate variability corrected for mean heart rate squared) in these patients, using linear techniques. Increased LLEqthr (LLE of QT/HR) may be a more sensitive tool to study cardiac repolarization and a valuable addition to the time domain measures such as QTvi. This is especially important in light of the finding that LLEqthr correlated poorly and nonsignificantly with QTvi. These findings suggest an increase in relative cardiac sympathetic activity and a decrease in certain aspects of cardiac vagal function in patients with anxiety as well as depression. The lack of correlation between QTvi and LLEqthr suggests that this nonlinear index is a valuable addition to the linear measures. These findings may also help to explain the higher incidence of cardiovascular mortality in patients with anxiety and depressive disorders.

Nonlinear measures of respiration: respiratory irregularity and increased chaos of respiration in patients with panic disorder.

BACKGROUND: Respiratory irregularity has been previously reported in patients with panic disorder using time domain measures. However, the respiratory signal is not entirely linear and a few previous studies used approximate entropy (APEN), a measure of regularity of time series. We have been studying APEN and other nonlinear measures including a measure of chaos, the largest Lyapunov exponent (LLE) of heart rate time series, in some detail. In this study, we used these measures of respiration to compare normal controls (n = 18) and patients with panic disorder (n = 22) in addition to the traditional time domain measures of respiratory rate and tidal volume. METHODS: Respiratory signal was obtained by the Respitrace system using a thoracic and an abdominal belt, which was digitized at 500 Hz. Later, the time series were constructed at 4 Hz, as the highest frequency in this signal is limited to 0.5 Hz. We used 256 s of data (1024 points) during supine and standing postures under normal breathing and controlled breathing at 12 breaths/min. RESULTS: APEN was significantly higher in patients in standing posture during normal as well as controlled breathing (p = 0.002 and 0.02, respectively). LLE was also significantly higher in standing posture during normal breathing (p = 0.009). Similarly, the time domain measures of standard deviations and the coefficient of variation (COV) of tidal volume (TV) were significantly higher in the patient group (p = 0.02 and 0.004, respectively). The frequency of sighs was also higher in the patient group in standing posture (p = 0.02). In standing posture, LLE (p < 0.05) as well as APEN (p < 0.01) contributed significantly toward the separation of the two groups over and beyond the linear measure, i.e. the COV of TV. CONCLUSION: These findings support the previously described respiratory irregularity in patients with panic disorder and also illustrate the utility of nonlinear measures such as APEN and LLE as additional measures toward a better understanding of the abnormalities of respiratory physiology in similar patient populations as the correlation between LLE, APEN and some of the time domain measures only explained up to 50-60% of the variation.

Significant difference in beat-to-beat QT interval variability among different leads.

QT interval on the surface electrocardiogram (ECG) reflects the time for repolarization of myocardium, and QTc prolongation is strongly associated with sudden cardiac death. Findings of studies that have examined the dispersion of QT interval in 12-lead ECGs strongly suggest that an increased QT dispersion between different leads is associated with an increased risk of cardiac mortality. Recent studies using novel techniques on beat-to-beat QT interval variability have also shown that the interval is both influenced by the autonomic nervous system and a predictor of sudden cardiac death. However, in these studies the variability of QT was quantified in a single lead, and thus is different from QT dispersion. The present study examined whether there was a significant difference between QT variability (detrended QT variance [QTv]) and Qtvi (index of QT interval variability corrected for mean QT squared divided by heart rate variability corrected for mean heart rate squared) in 17 data sets of continuous ECGs recorded in three channels (leads V(5), V(1), and V(3)) during ambulatory monitoring of ECG digitized at 1,000 Hz. The results showed a highly significant difference between QT variability measures (QTv and QTvi) (P < 0.0001) in two of three lead configurations that were used (V(5) and V(1) versus V(3)). This finding underscores the importance of using the same lead while recording ECG for the calculation of QT variability, though further investigations are clearly warranted before any definitive conclusion can be made. These findings should be evaluated in relation to the issue of local versus global cardiac repolarization of ventricular myocardium.

Twenty-four-hour QT interval variability: increased QT variability during sleep in patients with panic disorder.

Recent studies on beat-to-beat QT interval variability (QTV) have shown that it can be used as a noninvasive measure of cardiac repolarization lability. It is also a predictor of sudden cardiac death and is higher in patients with anxiety and depression. This study examined the diurnal measures in QTV in 32 normal adults and 22 patients using 24-hour electrocardiogram records. We obtained 8 5-min segments of ECG sampled at 1,000 Hz from the 24-hour records. Our results show that QTV measures at nighttime are significantly higher in patients with panic disorder compared with controls. These findings demonstrate blunted diurnal changes in ventricular repolarization lability in patients resulting in a higher QT variability index during sleep. We speculate that these effects may relate to a relative increase in cardiac sympathetic activity in patients with panic disorder, and may contribute to the increased risk for cardiac mortality in patients with anxiety.

Diminished chaos of heart rate time series in patients with major depression.

BACKGROUND: Depression and anxiety have been linked to serious cardiovascular events in patients with preexisting cardiac illness. A decrease in cardiac vagal function as suggested by a decrease in heart rate (HR) variability has been linked to sudden death. METHODS: We compared LLE and nonlinearity scores of the unfiltered (UF) and filtered time series (very low, low, and high frequency; VLF, LF and HF) of HR between patients with depression (n = 14) and healthy control subjects (n = 18). RESULTS: We found significantly lower LLE of the unfiltered series in either posture, and HF series in patients with major depression in supine posture (p <.002). LLE (LF/UF), which may indicate relative sympathetic activity was also significantly higher in supine and standing postures in patients (p <.05); LF/HF (LLE) was also higher in patients (p <.05) in either posture. CONCLUSIONS: These findings suggest that major depression is associated with decreased cardiac vagal function and a relative increase in sympathetic function, which may be related to the higher risk of cardiovascular mortality in this group and illustrates the usefulness of nonlinear measures of chaos such as LLE in addition to the commonly used spectral measures.

Heart rate time series: decreased chaos after intravenous lactate and increased non-linearity after isoproterenol in normal subjects.

In this study, we reanalyzed our previous heart rate time series data on the effects of intravenous sodium lactate (n=9) and intravenous isoproterenol (n=11) using non-linear techniques. Our prior findings of significantly higher baseline non-linear scores (NL: S(netGS)) and significantly lower largest Lyapunov exponents in supine posture in patients with panic disorder compared to control subjects prompted this study. We obtained the largest Lyapunov exponent (LLE), and a measure of non-linearity (NL: S(netGS)) of heart rate time series. LLE quantifies predictability and NL quantifies the deviation from linear processes. There was a significant increase in NL score, (S(netGS)) after isoproterenol infusions and a significant decrease in LLE (an increase in predictability indicating decreased chaos), after intravenous lactate in supine posture in normal control subjects. Increased NL scores in supine posture after intravenous isoproterenol may be due to a relative increase in cardiac sympathetic activity or a decrease in vagal activity at least in certain circumstances, and an overall decrease in LLE may indicate an impaired cardiac autonomic flexibility after intravenous sodium lactate, as LLE is diminished by autonomic blockade by atropine. Band analysis of LLE (LF/HF) (LF: 0.04-0.15 Hz and HF: 0.15-0.5 Hz) showed an increase of these ratios during either condition with a higher sympathovagal interaction after the drug administration. These findings may throw new light on the association of anxiety and significant cardiovascular events.