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ORIGINAL ARTICLES |
From the Department of Psychiatry and Behavioral Neurosciences (V.K.Y., M.T.), Wayne State University School of Medicine, Detroit, Michigan; Institute of Cardiology (V.K.Y., R.K.), M.S. Ramaiah Institute of Cardiology, Bangalore, India; Department of Psychiatry (V.K.Y., P.C.), University of Alberta (V.K.Y., P.C.), Edmonton, Alberta, Canada; and Department of Psychiatry (K.J.B.), Friedrich Schiller University, Jena, Germany.
Address correspondence and reprint requests to V. K. Yeragani, #411, 11135-83 Avenue, Edmonton, Alberta, Canada T6G 2C6. E-mail: Vikramyershr{at}yahoo.com
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ABSTRACT |
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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.
Key Words: pulse wave velocity • autonomic function • atherosclerosis • arterial stiffness index • cardiovascular mortality • anxiety
Abbreviations: HR = heart rate; BP = blood pressure; PWV = pulse wave velocity; HF = high frequency (0.15–0.5 Hz); PTT = pulse transit time; HA = heart-ankle; BA = brachial-ankle; ECG = electrocardiogram; PCG = phonocardiogram; VP = vascular profiler; BMDP = biomedical data package; ANOVA = analysis of variance; MAP = mean arterial pressure; PEP = pre-ejection period; GAD = generalized anxiety disorder.
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INTRODUCTION |
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Some studies suggest a decrease in cardiac vagal function in conditions such as anxiety disorders, hypertension, and several cardiac diseases including coronary artery disease (7–12). This is important in light of the association between anxiety and an increase in cardiovascular mortality and sudden death (13–16). In a recent study, we found significant correlations between pulse wave velocity (PWV) and R-R interval (interbeat interval) high frequency (HF) (0.15–0.5 Hz) variability in patients with anxiety, which suggest decreased cardiac vagal function in these patients (17). PWV is an important noninvasive marker of atherosclerosis (18–21). PWV indicates the speed at which the pulse is transmitted from the heart to the end artery when blood is expelled during cardiac contraction. PWV is the most widely used measure of arterial stiffness in different clinical fields (22). The stiffer the arterial wall, the faster the arterial wave travels through the arterial wall. Carotid-femoral PWV reflects the stiffness of the large elastic arteries and is the most widely used measure of arterial stiffness. This is due to the fact that the atherosclerotic changes of the arterial wall begin at the aorta and stiffness of the aorta is related to cardiac afterload (23). Carotid-femoral PWV is useful in identifying patients with atherosclerosis as well as patients with a poor prognosis in cardiac disease (21,24–26). Brachial-ankle PWV (BAPWV), which is derived from the heart-brachial and heart-ankle PWV (HBPWV and HAPWV) is a measure of arterial stiffness (27) and its physiological characteristics are closer to carotid-femoral PWV than to femoral ankle PWV (28). The reproducibility of this measure is good (27) and recent data suggest that higher values of BAPWV are associated with more advanced changes of arterial atherosclerosis in clinical patients as well as in subclinical individuals who will develop cardiac disease (29,30). However, there is little information on the differences between left and right sides of the body in relation to pulse transit times (PTT) and PWV.
In this study, we examined if there is a significant difference in PWV between the right and the left sides of the body using HAPWV and BAPWV among controls, patients with panic disorder and patients with cardiovascular illness, as one investigator (V.K.Y.) observed a consistently exaggerated left-right difference of PWV in the above patient groups.
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METHODS |
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These studies received approval from the ethical committee at the MS Ramaiah Hospital, Bangalore, India. The studies were explained to the patients and informed consent was obtained before their participation in the studies. To alleviate any anxiety, especially with the patient group, we particularly stressed the noninvasive nature of the studies before the subjects' participation.
Data Acquisition
Vascular Profiler
Using the Vascular Profiler-1000 (Colin Medical Instruments, Japan), we could obtain BP in carotid artery and all four extremities, HAPWV, ankle-brachial pulse wave velocity, and pre-ejection period (PEP). The US Food and Drug Administration approved the COLIN VP-1000 (Model BP203RPE II, Form PWV/ABI, JAPAN). The device works on a WAVE technology (waveform analysis and vascular evaluation) that measures arterial compliance in central (large) arteries as well as the peripheral arteries that aid in early detection of vascular disease. This concept revolves around the Rotterdam Study that established the correlation between arterial stiffness and atherosclerosis and the clinical evidence of central (large) artery stiffness as an established independent marker of cardiovascular morbidity and mortality (21).
Measurement Principle for the BP
The machine detects the pulsation of the artery, caused by the contraction of the heart, as the pressure oscillation in the cuff. The relationship between the changes of cuff pressure and its oscillation is stored in memory and is used to determine BP. When the cuff pressure oscillation increases rapidly, this value is taken as systolic BP (SBP) and when the oscillation decreases rapidly, it is taken as diastolic BP (DBP). When the oscillation reaches a peak, cuff pressure is taken as mean arterial pressure (MAP). This is not affected by external noise or electrical signal units.
Carotid Arterial Pressure Tonometry
It uses the tonometric method for pulse wave detection. The pulse wave sensor pushes on the artery so that an area of the artery is flattened. When the wall of the blood vessel is flat, the inner pressure of the artery is communicated directly to the pressure sensor. Tonometry is much superior to the oscillometric method to obtain the pressure waveform. The percent MAP is calculated from the peak SBP, so it does not correspond to the averaged data.
All subjects were assessed in the same laboratory after they were acclimatized to the laboratory conditions for at least 10 to 15 minutes. They were all instructed not to smoke or consume caffeinated beverages at least for 3 hours before the tests. They were allowed to have a light breakfast or lunch. There was no significant difference in the time of the tests among the groups (controls: 11.5 ± 2; patients with GAD: 11.45 ± 2.8; patients with cardiac illness: 11.25 ± 3.8 AM).
The tests were performed as the subjects were in supine posture on the bed. We explained to the subjects that the test was completely noninvasive. Four oscillometric BP cuffs were applied to the four limbs. Lead I electrocardiogram (ECG) electrodes were applied and a phonocardiogram (PCG) sensor was placed on the V2 position on the chest. The test was then initiated to inflate and deflate all four cuffs together with lead I ECG and PCG monitoring. The carotid sensor was placed on the right carotid artery using a collar-shaped sensor. No subject complained of any discomfort during the procedure. After the technician made sure that all the signals were properly displayed, two sets of records were taken, each of 30-second duration. The machine has built-in software, which automatically calculates all the vascular indices. The sampling rate is 1024 Hz for the signals.
Measures Obtained From the Vascular Profiler: Vascular Indices
SBP, DBP, MAP, and pulse pressure (PP) (SBP – DBP) are the averages of 60 seconds of data. MAP was calculated as DBP + 1/3 of PP (SBP – DBP). PWV is the speed at which the pulse is transmitted from the heart to the end artery when blood is expelled during contraction. It is mainly used to evaluate the hardness of the arterial wall.
PWV = L (distance)/PTT. The PTT is calculated from the wave form taken from the carotid, brachial, and ankle arteries.
HAPWV indicates carotid to ankle PWV and BAPWV indicates brachial to ankle PWV. Distance is measured by VP-1000 and is automatically calculated by patient's height based on statistical studies. The path length between the arm and the ankle was determined using the subject's height and anthropomorphic data available.
BAPWV is calculated as follows: BAPWV = (Dhf + Dfa – Dhb)/Tba, where Dhf is the path length from suprasternal notch to femur; Dfa is the length from femur to ankle; Dhb is the length from suprasternal notch to brachial artery; and Tba is the time delay of the pulse wave between the brachial and posterior tibial arteries (28).
An increase in this measure indicates arterial stiffening. Arterial stiffness percentage is calculated according to the normal values of the population and also takes gender into account using the PWV measures. This measure is expressed using 0% as population normal value for that age group and gender. Thus, normal subjects have a value of 8 ± 12% in this study. This is expressed as a percentage. This percentage correlates significantly with the PWV on either side (r = .8; p < .00001).
PEP is the time between electrical agitation in the heart chamber and the opening of the aortic valve. Normal value is about 96 ± 10 ms (milliseconds).
R-R and QT Interval Variability
ECG was continuously acquired in lead II configuration in a noise-free environment after the data were obtained from the Vascular Profiler. The ECG signal was digitized at 1000 Hz and the data were saved on a PC for later analyses. The subjects rested quietly in the supine position for at least 5 minutes before the data for 320 seconds were acquired. We used 256 seconds of artifact-free data for analyses of heart rate variability (HRV).
We used a peak detection algorithm to identify the peaks of R waves and the beat-to-beat R-R intervals in ms were sampled at 4 Hz using linear interpolation. We used R-R time series free of ventricular premature beats and noise. The R-R interval data were then detrended by using the best-fit line before the computation of the spectral analyses. We used 256 seconds of data from subjects in the supine position for the analysis.
Spectral Analysis
R-R interval time series (256 seconds at 4 Hz = 1024 points) was subjected to spectral analysis and the power spectrum was computed using a rectangular window (7,9). The power was integrated in the HF (0.15–0.5 Hz) band, which reportedly reflects cardiac vagal function.
Statistical Analysis
We used BMDP statistical software to perform the statistical analyses. We performed two-way analysis of variance (ANOVA) with one grouping factor and right and left indices as the dependent measure. This was followed up with a one-way ANOVA to compare the left-right differences among the three groups, followed by Tukey studentized range post hoc tests to compare individual groups. We also compared SBP, DBP, MAP, and R-R interval HF power among the three groups on both the left and right sides. Paired t tests were used to compare the left-right differences for the vascular indices separately for each group. All tests were two-tailed and a probability value of <.05 was accepted as significant. We also compared normal controls and GAD patients with the cardiac patients with hypertension, who were not receiving any medication at the time of evaluation. Another comparison included cardiac patients who were on medications and those who were not.
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RESULTS |
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For all three measures—HAPWV, BAPWV, and arterial stiffness percentage—there were significant group, time, and group versus time interaction effects, suggesting that there was a differential effect among the groups for the left and right indices (Table 2). Paired t tests indicated that there was a highly significant difference between the right and left indices for the patient groups (p < .00001) although there were no such differences for the normal control group. PWV and arterial stiffness percentage were significantly higher in the patient groups compared with the normal controls, especially on the left side. Figure 1 shows the left-right differences among the groups. There was a significant difference for each of the measures only between the control and the patient groups. These values were significantly higher on the left side. There were no significant differences between patients with anxiety and patients with cardiac illness. For all comparisons, which included only untreated hypertensive patients, the results were essentially similar. We also used analysis of covariance to adjust for age, gender, mean R-R interval, and MAP. These results were also similar to the unadjusted comparisons. There were no significant differences between the left and right PWV measures between the medicated and unmedicated cardiac patients.
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There were no significant correlations between R-R HF power and PEP, and the left-right differences in PWV. However, there was a significant inverse relationship between PWV and R-R HF power in patients with GAD.
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DISCUSSION |
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Previous studies have mentioned a difference of up to 10 mm Hg between the cuff pressure of the right and the left upper limb as normal variation (32). When it exceeds this level, the interpretation is influenced by the overall clinical situation. In a case of supravalvular aortic stenosis, a larger difference has been attributed to the "Coanda effect" (33). However, this explanation does not hold true in the current patient population. In right-handed individuals, a marginally lower systolic pressure in the right upper limb can possibly be explained by the phenomenon of "functional sympatholysis," which was initially described in 1962 by Remensnyder and associates (34). This concept essentially centers around the blunted response of the vascular endothelium to vasoconstrictors like epinephrine secondary to the downregulation of the 
adrenoreceptors. This subtle difference in the autonomic tone between the two sides may not be obvious in the healthy subject.
Another interesting phenomenon is the concept of "cerebral handedness" of parasympathetic outflow. The right hemisphere exerts a greater parasympathetic control of the heart by virtue of its connection with the more influential right vagus nerve. This phenomenon has several interesting implications. First, the right hemisphere has been shown to have preferential access to a number of other autonomic functions, such as the galvanic skin response (35). Thus, it is possible that the right hemisphere has a greater involvement in the cerebral mediation of the autonomic nervous system in general. Furthermore, the right hemisphere is also believed to be more involved than the left hemisphere in cerebral contribution to emotion (36). This combination of both autonomic control and emotion-mediation systems in the same hemisphere may not be entirely coincidental. In the pioneering work of Lane et al. (37), patients with strokes in the right hemisphere were at a greater risk for cardiac arrhythmias. Naver et al. (38) found reduced respiratory heart rate variability in patients with right-sided strokes. Hachinski et al. (39) also found that experimentally induced right hemisphere strokes were associated with greater increases in sympathetic nerve discharge, plasma norepinephrine, and duration of the QT interval than were left hemisphere strokes. The right hemisphere is associated with the regulation of emotion and also parasympathetic function. In this context, it is important to note that autonomic dysfunction, especially diminished vagal function, has been described in patients with anxiety as well as cardiac disease (7–12). Heightened sympathetic nervous system activity and depressed activity of the parasympathetic nervous system have been described in patients with psychosocial stress and negative affect (40–43). Several studies showed an association between emotional arousal and anxiety and right hemispheric dysfunction (44–46).
This "parasympathetic withdrawal" coupled with the "functional sympatholysis" possibly exaggerates the difference in the vascular tone between the two sides, making the vessels in the left upper limb stiffer. PWV is directly related to vascular stiffness, and therefore, laterality may become more pronounced in patients with anxiety. It should be noted that patients with anxiety are at an increased risk for cardiac mortality compared with normal controls; this may explain the present findings of exaggerated left-right differences in PWV in these patients compared with normal controls. The same can be true for patients with hypertension and other cardiac illnesses. Our findings remained the same when we used unmedicated cardiac patients for comparison and also the left-right PWV difference was not significantly different between medicated and unmedicated cardiac patients. If patients with cardiovascular illness and those at risk for significant cardiac events have an enhanced process of vascular dysfunction such as atherosclerosis that is more pronounced on the left side, further studies are needed to examine this noninvasive "marker" in other groups of populations such as patients with subclinical hypothyroidism and several other medical conditions. However, we are not implying that the findings of this study are due to the dysfunction of right vagus nerve as this hypothesis would be too simplistic. We are rather implying a dysfunction of central autonomic control, which may result in the abnormalities observed in this study. It will also be important to study the effect of different medications on this left-right difference to determine if it normalizes after successful treatment of these conditions. However, this is a significant finding in view of the relationship between increased PWV and atherosclerosis and also the relationship between anxiety and cardiac mortality.
Limitations
It would have been more desirable to have a larger number of controls and patients with anxiety and also individual groups of patients with different cardiac illnesses with equal number of men and women. It is desirable to have a larger sample of patients with cardiac illness, who are unmedicated in different diagnostic categories but this is difficult in a real-life situation. It would also be important to use some measures of cerebral function to understand the laterality of autonomic function along with the indices used in this study. There was also no significant correlation of R-R HF power and the left-right differences in PWV, which suggests that it is too simplistic to assume that the findings are attributable solely to decreased vagal function. However, this is a preliminary attempt to examine these differences and future studies with a larger number of subjects in different disease conditions are under way in our laboratory.
The authors of this study did not receive any external funding.
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DOI:10.1097/PSY.0b013e3181574272
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