Effects of isoproterenol infusions on heart rate variability in patients with panic disorder

PSYCHIATRY RESEARCH ELSEVlER

Psychiatry Research 56 (1995) 289-293

Effects of isoproterenol infusions on heart rate variability in patients with panic disorder Vikram K. Yt%agani*a9b,Robert PohlC, K. SrinivasanC, Richard Balon”, C. RameshC, Richard Berchouc ‘Psychiatry Service, Department of Veterans Affairs Mediral Center (116A), 4100 West Third Street, Dayton, OH 45428, USA bDepartment of Psychiatry, Wright State University School of Medicine, Dayton, OH 45401-8325, USA =Department of Psychiatry, Wayne State University School of Medicine, University Psychiatric Center, 2751 East Jefferson Avenue, Detroit, MI 48207, USA Received 25 February 1994; revision received 6 July 1994; accepted 25 October 1994

Abstract

Some evidence suggests that patients with panic disorder have a decreased cardiac vagal and a relatively higher sympathetic activity. In this study, spectral analysis of the time series of heart rate before and after isoproterenol infusions was used to study heart rate variability in six panic disorder patients and 11 normal control subjects. These preliminary

data reveal a significant increase of sympathovagal ratios only in the patient group after isoproterenol administration. The findings suggest a relative increase in cardiac sympathetic and a relative decrease in cardiac vagal function in patients with panic disorder during isoproterenol infusions.

Cardiovascular function; Sympathovagal ratio; Spectral analysis; Anxiety disorder; Adrenergic receptors; Panic attacks

Keywords:

1. Introduction

Panic disorder patients experience panic attacks, which are characterized by chest pain, heart pounding, tachycardia, dizziness, and shortness of breath - symptoms suggestive of autonomic dysfunction (American Psychiatric Association, 1987). We previously reported a decreased cardiac cholinergic function and a relative increase in syml Corresponding author, Tel: +I 513 268-651I extn. 1260; Fax: +I 513 267-3924.

pathetic function in patients with panic disorder, as well as an exaggerated response to pharmacological challenge with yohimbine, compared with findings in normal control subjects (Yeragani et al., 1992, 1993a). We have also found that sodium lactate produces a significant decrease in cardiac cholinergic function and an alteration of sympathovagal ratios in normal control subjects (Yeragani et al., 1994b), findings in agreement with the report of George et al. (1989). In another recent study, we reported that the vagal withdrawal and the increase in sympathovagal ratios

0165-1781/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-1781(95)02608-Y

290

V.K. Yeragani et al. / Psychiairy Research 56 (1995) 289-293

associated with sodium lactate infusions are significantly higher in patients with panic disorder than in normal control subjects (Yeragani et al., 1994a). Several recent studies in cardiology suggest that a decrease in cardiac choline@ activity or an increase in cardiac sympathetic activity is associated with an increase in cardiovascular morbidity (Kleiger et al., 1987; Malik and Camm, 1990; Malliani et al., 1991; Bigger et al., 1992). This may be especially important in psychiatric research because some studies suggest an increased risk for cardiovascular illness in panic disorder patients (Coryell et al., 1986; Weissman et al., 1990). In a recent prospective study, Kawachi et al. (1994) reported on a 2-year follow-up of 33,999 male health professionals aged 42-77 years. Levels of phobic anxiety were correlated with fatal and nonfatal coronary heart disease, and the findings indicated a strong causal association between phobic anxiety and fatal cardiac disease. Thus, it is important to study cardiac autonomic function in this group of patients. Spectral analysis of heart rate (HR) time series has been extensively used to study cardiac autonomic function (Sayers, 1973; Malliani et al., 1991). Fourier Transformation of HR time series reveals a peak at 0.01-0.05 Hz (low frequency, LF), which may relate to thermoregulatory mechanisms and peripheral vascular tone; a peak at 0.07-o. 15 Hz (mid-frequency, MF), which is related to baroreceptor control; and a third peak at 0.15-0.5 Hz (high frequency, HF), which is related to respiratory sinus arrhythmia. The HF power appears to be modulated exclusively by cholinergic activity in both sitting and standing postures, and the MF power, dually by cholinergic and adrenergic systems (Akselrod et al., 1981, 1985; Pomeranz et al., 1985; Pagani et al., 1986; Weise et al., 1987; Yeragani et al., 1992). A change from supine to standing posture results in vagal withdrawal and an increase in sympathetic activity associated with a decrease in HF power and an increase in MF power. The ratio of MF/HF power, especially during standing posture, has been used as a measure of sympathovagal interaction (Pagani et al., 1984, 1986; Bigger et al., 1992; Yeragani et al., 1993b). Isoproterenol infusions induce panic attacks more

frequently in patients with panic disorder than in normal control subjects (Pohl et al., 1988). In this pilot study, we hypothesized that patients with panic disorder would have higher sympathovagal ratios during isoproterenol infusions compared with those of normal control subjects. 2. Methods Eleven normal subjects (5 men, 6 women; mean age = 25.1 years, SD = 1.3) and six panic disorder patients (2 men, 4 women; mean age = 27.5 years, SD = 4.8) participated in this study. The subjects were all physically healthy. This study was approved by the Institutional Review Board at Lafayette Clinic, Detroit, Mich., USA, and a signed informed consent was obtained from participants. Isoproterenol was administered intravenously at a dose of 15 ng/kg/min over a 10-min period with the subject in a supine posture. The electrocardigram (ECG) was recorded with limb leads by a Hewlett Packard 78352 A Patient Monitor and a 78173 A ECG Monitor (Palo Alto, Calif., USA). Anxiety was assessed with the Panic Description Scale (PDS; Rainey et al., 1984; Yeragani et al., 1989), a subjective rating of panic attack severity (l-5) and generalized nervousness (l-5). The ECG and blood pressure were recorded for 10 min with the subject in a supine posture before the infusions and for 10 min during the infusions. However, we used only 256 s of real-time data before and after the infusion for spectral analysis. The reason for this limitation is that HR time series tend not to be stationary during the first 2-3 min of the infusion. The post-isoproterenol segments of data were taken about 5 min after the beginning of the infusion after visual inspection of the data for lack of significant nonstationarities. Spectral analysis of HR was performed as described in previous reports (Berger et al., 1986; Yeragani et al., 1992,1993a). The ECG was sampled at 500 Hz and recorded onto a personal computer using an A/D board with 1Zbit precision. RR intervals were found by taking the time difference between points of maximum derivative between successive QRS complexes. All analyses were performed after the data had been played back to permit visual inspection for the elimina-

291

V. K. Yeragani et al. /Psychiatry Research 56 (19951 289-293

Table 1 Heart rate variability measures before and during isoproterenol infusions in patients with panic disorder and normal control subjects Variable

Control subjects (n = I I)

Patients (n = 6)

Heart rate (beats/mm) Heart rate variance (beats/mm*) Low frequency power (beats/mm*) Mid-frequency (MF) power (beats/mm*) High frequency (HF) power (beats/min*) MF/HF ratio

Pre-isoproterenol

Post-isoproterenol

Pre-isoproterenol

Post-isoproterenol

70.9 f 14.6 6.0 f I.8

96.9 l 19.3 8.6 f 5.8

65.1 zt 10.2 6.2 zt 2.2

86.5 f 12.2 5.6 f 1.6

22.0 f 8.1

47.5 zt 36.3

32.7 f 33.4

25.9 f 15.6

20.1 f 20.4

25.3 ziz16.5

17.7 zt 16.1

15.9 f 12.6

14.8 f II.7

16.2 zt 25.6

8.5 zt 5.4

11.3 f 9.6

1.7 * 1.4

4.9 f 3.7

2.4 f 1.5

2.2 f I,9

tion of artifacts. The method of Berger et al. (1986) was used to obtain a smoothed instantaneous HR series sampled at 4 Hz. The power spectrum was obtained as the magnitude squared of the Fast Fourier Transform using a rectangular data window. The power spectra were then integrated over LF (0.01-0.05 Hz), MF (0.07-o. 15 Hz), and HF (0.2-0.5 Hz) bands. The direct current component was removed during the computation of the power spectrum. The ratio of MF/I-IF power, which reflects the sympathovagal interaction, was also calculated. It is ideal to obtain the MF/HF ratio with the subject in a standing posture, but due to the lack of standing data, supine ratios were used. However, data from our other studies in children and adults suggest a significant correlation between supine and standing MF/HF ratios.

BMDP software was used to perform statistical analyses. Two-way analyses of variance were carried out with one grouping factor (patients vs. control subjects) and one repeated measures factor (pre- and post-MF/HF ratio, HR, HR variance, and LF, MF, and HF powers). GreenhouseGeisser corrections were applied when appropriate. All probability levels reported are two-tailed, and significance is defined as P s 0.05. 3. Results Tables 1 and 2 show HR variability and anxiety measures, respectively, before and after the infusion. According to the patients’ subjective evaluation, three had panic attacks, which also were accompanied by substantial increases in the PDS

Table 2 Anxiety measures and MF/HF ratios in patients with panic disorder

Patient Patient Patient Patient Patient Patient

I 2 3 4 5 6

MF/HF I

MFlHF II

PDS I

PDS II

PA I

PA II

GN I

GN II

3.26 1.86 0.49 0.41 3.39 0.81

6.9 9.4 0.71 0.42 4.23 7.62

2 3 I3 2 0 0

34 31 44 6 5 7

0 0 1 0 0 0

1 3 4 0 0 0

2 2 3 1 0 2

3 3 3 1 0 2

Note. PDS, Panic Description Scale; PA, panic attack; GN, generalized nervousness. I and II refer to the pre- and postisoproterenol conditions. MF/HF (mid-frequency/high frequency) ratios indicate the sympathovagal interaction.

292

V. K. Yeragani et al. /Psychiatry

scores. There was no significant difference in age between the two groups. Isoproterenol produced an increase in HR both in control subjects and patients (F= 137; df = 1, 15; P = 0.00001). The PDS scores were significantly higher in patients both before and after the infusion (F= 15.3; df = 1, 15; P < 0.002). There was also a greater increase in PDS scores in patients compared with control subjects (interaction effect: F = 19.2; df = 1, 15; P < 0.0005). There were no significant group or interaction effects for the comparisons of HR variance or LF, MF, and HF powers. There was a significant time effect (F = 5.9; df = 1, 15; P < 0.03) and an interaction effect (F = 7; df = 1, 15; P < 0.02) for the comparison of MF/HF ratios between patients and control subjects, which showed a significant increase in the ratios only in patients. 4. Discussion Although there was a significant isoproterenolinduced increase in sympathovagal ratios in patients with panic disorder, there was no corresponding change in control subjects. These findings suggest a sympathetic predominance during isoproterenol infusions in patients with panic disorder compared with normal control subjects. The patients experienced significantly greater anxiety, as assessed by the PDS, than did the control subjects, a finding that is in agreement with our previous study (Pohl et al., 1988). The increase in sympathovagal ratios in patients may have resulted either from the anxiety the patients experienced or an increased sensitivity to the adrenergic effects of isoproterenol infusions. These findings are also in agreement with our previous findings of an exaggerated cardiac vagal withdrawal and a higher increase of sympathovagal ratios in patients with panic disorder during lactate infusions compared with normal control subjects (Yeragani et al., 1994a). In this study, three patients who had panic attacks had a significant increase of the MF/HF ratios (Table 2). There was, however, a significant increase of the MFEIF ratio in one patient who had a relatively low PDS score and who did not have a panic attack. Due to the small number of patients in this study, we cannot

Research 56 (1995) 289-293

reach any definite conclusions as to whether the ratios increase more significantly in panickers than in nonpanickers. If these ratios were higher in the patients in general after isoproterenol, this would suggest that their responses to isoproterenol differed from those of control subjects. We should point out that MF/HF ratios obtained with subjects in standing postures may offer a more specific measure of the sympathovagal interaction. However, Pagani et al. (1991) have shown that psychological stress can produce significant increases in sympathovagal ratios, causing sympathetic predominance. It is also important to note that, in one of the recent studies, isoproterenol infusions did result in significant increases in LF/HF ratios in normal controls, when the drug was given at a higher dose (about 3 mcg per minute) (Ahmed et al., 1994). In our previous report on the effects of yohimbine in patients with panic disorder and normal control subjects, we found that patients had a significantly higher increase in the standing MF power, a finding that suggested a higher sympathetic responsiveness. However, yohimbine also caused a significant increase in HF power, so that we were unable to find any differences in the MF/HF ratio after yohimbine challenge (Yeragani et al., 1992). These findings are of interest due to the fact that sympathetic predominance or a decrease in cardiac vagal function is associated with an increased risk for cardiovascular morbidity in patients with heart disease (Malik and Camm, 1990; Malliani et al., 1991; Bigger et al., 1992). However, our findings are preliminary and need to be replicated in a larger group of patients and control subjects. We also do not have respiratory data in this study and thus cannot comment on the possible changes in HF power due to changes in respiratory rate or tidal volume. References Ahmed, M.W., Kadish, A.H., Parker, M.A. and Goldberger, J.J. (1994) Effects of physiologic adrenergic stimulation on heart rate variability. J Am Coil Cardiol24, 1082-1090. Aksclrod, S., Gordon, D., Madwed, J.B., Snidman, N.C., Shannon, DC. and Cohen, R.J. (1985) Hemodynamic regulation: investigation by spectral analysis. Am J Physiol249, H867-H875.

V.K. Yeragani et al. /Psychiatry Research S6 (1995) 289-293

Akselrod, S., Gordon, D., Ubel, F.A., Shannon, D.C., Barger, AC. and Cohen, R.J. (1981) Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 213, 220-222. American Psychiatric Association. (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC, pp. 235-241. Berger, R.D., Akselrod, S., Gordon, D. and Cohen, R. (I 986) An efficient algorithm for spectral analysis of heart rate variability. IEEE Trans Biomed Eng 33, 900-904. Bigger, J.T., Fleiss, J.L., Steinman, R., Rolnitzky, L.M., Kleiger, R.E. and Rottman, J.N. (1992) Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 85, I64- I7 1. Coryell, W., Noyes, R. and House, J.D. (1986) Mortality among outpatients with anxiety disorders. Am J Psychiatry 143, 508-510.

George, D.T., Nutt, D.J., Walker, W.V., Porges, SW., Adinoff, B. and Linnoila, M. (1989) Lactate and hyperventilation substantially attenuate vagal tone in normal volunteers. Arch Gen Psychiatry 46, 153- 156. Kawachi, I., Colditz, G.A., Ascherio, A., Rimm, E.B., Giovannucci, E., Stampfer, M.J. and Willett, W.C. (1994) Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 89, 1992-1997. Kleiger, R.E., Miller, J.P., Bigger, J.T. and Moss, A.J. (1987) Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol59, 256-262.

Malik, M. and Camm, A.J. (1990) Heart rate variability. C/in Cardiol 13, 570-576.

Malliani, A., Pagani, M., Lombardi, F. and Cerutti, S. (1991) Cardiovascular neural regulation explored in the frequency domain. Circulation 84, 482-492. Pagani, M., Lombardi, F., Guzzetti, S., Rimoldi, O., FurIan, R., Pizzinelli, P., Sandrone, G., Malfatto, G., Dell’Orto, S., Piccaluga, E., Turiel, M., Baselli, G., Cerutti, S. and Malliani, A. (1986) Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympathovagal interaction in man and conscious dog. Circ Res 59, 178-193. Pagani, M., Lombardi, F, Guzzetti, S., Sandrone, G., Rimoldi, O., Malfatto, G., Cerutti, S. and Malliani, A. (1984) Power spectral density of heart rate variability as an index of sympatho-vagal interaction in normal and hypertensive subjects. J Hypertension 2(Suppl. 3), 383-385. Pagani, M., Mazzuero, G., Ferrari, A., Liberati, D., Cerutti, S., Vaitl, D., Tavazzi, L. and Malliani, A. (1991) Sympathovagal interaction during mental stress. Circulation 83 (Suppl. II), 11-43-11-51.

293

Pohl, R., Yeragani, V.K., Balon, R., Rainey, J.M., Lycaki, H., Ortiz, A., Berchou, R. and Weinberg, P. (1988) Isoproterenol-induced panic attacks. Biol Psychiatry 24, 891-902. Pomeranz, B., Macaulay, R.J.B., Caudill, M.A., Kutz, 1.. Adam, D., Gordon, D., Kilborn, K.M., Barger, A.C., Shannon, DC., Cohen, R.J. and Benson, H. (1985) Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 248, Hl51-H153. Rainey, J., Pohl, R., Williams, M., Knitter, E., Freedman, R.R. and Ettedgui, E. (1984) A comparison of lactate and isoproterenol anxiety states. Psychopathology 17 (Suppl. I), 74-82. Sayers, B.Mc.A. (1973) Analysis of heart rate variability. Ergonomics 16, 17-32.14.

Weise, F., Heydenreich, F. and Runge, U. (1987) Contributions of sympathetic and vagal mechanisms to the genesis of heart rate fluctuations during orthostatic load: a spectral analysis. J Auton Nerv Syst 21, 127-134.

Weissman, M.W., Markowitz, J.S., Ouelette, R., Greenwald, S. and Kahn, J.P. (1990) Panic disorder and cardiovascularicerebrovascular problems. Am J Psychiatry 147, 1504-1507.

Yeragani, V.K., Balon, R. and Pohl, R. (1989) Lactate infusions in panic disorder patients and normal controls: autonomic measures and subjective anxiety. Acra Psychiatr Stand 79, 32-40.

Yeragani, V.K., Berger, R., Pohl, R., Srinivasan, K., Balon, R., Ramesh, C. and Weinberg, P. and Berchou, R. (1992) Effects of yohimbine on heart rate variability in panic disorder patients and normal controls: a study of power spectral analysis of heart rate. J Cardiovasc Pharmaeo/20,609-618. Yeragani, V.K., Pohl, R., Berger, R., Balon, R., Ramesh, C., Glitz, D., Srinivasan, K. and Weinberg, P. (1993a) Decreased heart rate variability in panic disorder patients: a study of power spectral analysis of heart rate. Psychiatry Res 46, 89-103.

Yeragani, V.K., Srinivasan, K., Balon, R., Ramesh, C. and Berchou, R. (1994a) Lactate sensitivity and cardiac cholinergic function in panic disorder. Am J Psychiatry 151, 1226- 1228. Yeragani, V.K., Srinivasan, K., Pohl, R., Berger, R., Balon, R. and Berchou, R. (1994b) Sodium lactate increases sympathovagal ratios in normal controls: a study of spectral analysis of heart rate, blood pressure and respiration. Psychiatry Res 54, 97-114.

Yeragani, V.K., Srinivasan, K., Vempati, S., Pohl, R. and Balon, R. (1993b) Fractal dimension of heart rate time series: an effective measure of autonomic function. J Appl Physiol75, 2429-2438.