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Anxiety Reduces Baroreflex Cardiac Control in Older Adults With Major Depression

From the Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, Durham, North Carolina (L.L.W., R.K., J.A.B.); and Hebrew Rehabilitative Center for the Aged, Boston, Massachusetts (P.G.).

Address reprint requests to: Dr. Lana Watkins, Department of Psychiatry and Behavioral Sciences, Box 3119, Duke Medical Center, Durham, NC 27710. Email: watkins1{at}mail-wa.acpub.duke.edu

	ABSTRACT

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OBJECTIVE: Although depression and anxiety predict risk of cardiac mortality, the contributions of depression and anxiety to vagal cardiac control have not been systematically evaluated. The goal of this study was to examine the relationship between state anxiety and vagal control of heart rate in older adults with major depressive disorder (MDD). Older adults (50–70 years old) were selected for this study because of the greater cardiac risk associated with low vagal cardiac control across this age range.

METHODS: Fifty-six men and women with MDD were evaluated. MDD was diagnosed using the Diagnostic Interview Schedule, and severity of depression was measured using the Beck Depression Inventory and the Hamilton Rating Scale for depression. State anxiety was measured using the Spielberger State Anxiety Inventory. Power spectral analysis was used to measure two indices of vagal control: baroreflex control of heart rate (BRC_SPEC) and respiratory sinus arrhythmia (RSA).

RESULTS: State anxiety was negatively correlated with levels of BRC_SPEC (r = -0.32, p < .05), whereas depression severity was not related to either RSA or BRC_SPEC. Furthermore, BRC_SPEC was reduced by approximately 33% in MDD patients with state anxiety scores (ST-ANX) in the highest quartile (ST-ANX > 41, N = 13), compared with patients with ST-ANX scores in the lowest quartile (ST-ANX < 25, N = 14; p < .05).

CONCLUSIONS: Anxiety, but not depression severity, is associated with reduced BRC_SPEC in older men and women. Future studies are needed to determine whether comorbid anxiety contributes to the increased cardiovascular risk associated with MDD.

Key Words: baroreflex control of heart rate • respiratory sinus arrhythmia • spectral analysis • Spielberger State Anxiety Inventory • Beck DepressionInventory • Hamilton Rating Scale for Depression

Abbreviations: HR = heart rate; HRV = heart rate variability; CAD =coronary artery disease; MDD = major depressive disorder; RSA= respiratory sinus arrhythmia; BRC_SPEC = baroreflexcontrol of heart rate; BDI = Beck Depression Inventory; HRSD= Hamilton Rating Scale for Depression; ST-ANX = state anxietyscore; SBP = systolic blood pressure; DBP = diastolic bloodpressure; BMI = body mass index; bpm = beats per minute; BRC_PHEN = baroreflex sensitivity assessed withphenylephrine injection.

	INTRODUCTION

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It is well established that impaired autonomic nervous system control of HR, defined by low HRV, predicts cardiac mortality (1–4). Although the role of sympathetic hyperactivity in the genesis of malignant arrhythmias is well documented (5, 6), recent studies have demonstrated that low levels of protective vagal reflexes are a powerful marker of risk of arrhythmias (7–9). In particular, reduced baroreceptor-mediated vagal reflex control of HR has been associated with life-threatening arrhythmias (10, 11) and fatal cardiac events in patients (12–14) and in experimental animal models of myocardial ischemia (7, 8, 15). Loss of the protective effects of vagal activation has been postulated to increase the vulnerability to sympathetically driven ischemia and malignant arrhythmias.

Recently, it was demonstrated that patients with CAD who have MDD have reduced HRV compared with nondepressed CAD patients (16, 17). These findings have been interpreted to suggest that impaired vagal cardiac control may contribute to the excess cardiac mortality associated with depression (18–20). However, in healthy volunteers, the presence of depression has not been found to be related to reduced HRV (21–23).

One possible explanation for the inconsistent effects of depression on cardiac autonomic control is that the presence of anxiety confounds the relationship between depression and HRV. High levels of anxiety are common in patients with depression (24), with estimates of comorbid anxiety as high as 67% in patients with depressive disorder (25). In addition, several studies have demonstrated a relationship between symptoms of anxiety and reduced HRV. For example, anxiety symptoms are associated with lower HRV measured by the standard deviation of resting HR (26–28), as well as that measured by more selective measures of vagal cardiac control (28–32). Interestingly, abnormally low vagal control was observed recently in depressed patients with high anxiety but not in depressed patients with low anxiety (22), suggesting that anxiety may moderate the relationship between depression and reduced HRV. The lack of consistent effects of depression on HRV may also be related to the failure to consider the severity of depression when evaluating its effects on HRV. It is possible that individuals with mild depression may not show significant reductions in HRV. The effects of depression severity on vagal control of HR have not been evaluated.

The present study examined whether depression severity is associated with decreased vagal cardiac control and whether the presence of high anxiety mediates this relationship. In addition, two measures of vagal cardiac control derived using power spectral analysis are compared, RSA and BRC_SPEC. Because BRC_SPEC has been found to be more strongly related to anxiety than RSA in young healthy volunteers (31), it was hypothesized that a similar relationship may be observed in older volunteers with MDD.

	METHODS

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Subjects
The sample consisted of 56 men and women (17 men and 39 women) who met DSM-IV (33) criteria for MDD (Table 1 ). Volunteers were 50 to 69 years of age and were primarily Caucasian (82% Caucasian, 15% African American, and 3% Hispanic). All volunteers were recruited by posted fliers, newspaper advertisements, and letters to local physicians as part of a larger study designed to compare the efficacy of different types of antidepressant therapy. Each volunteer received a medical examination, which included a detailed medical history, blood pressure screening, and resting electrocardiogram. Volunteers also received a submaximal treadmill test to rule out silent myocardial ischemia. Exclusion criteria included recent (6 months) myocardial infarction, abnormal results on the resting electrocardiogram (>2 mm ST segment depression), abnormal blood pressure response to exercise, autonomic neuropathy, and dementia. No volunteers were taking medications with sedative, antidepressant, or anxiolytic effects; however, approximately 25% of the sample were taking antihypertensive medications. The most common class of antihypertensive medication was diuretics (N = 7), followed by angiotensin-converting enzyme inhibitors (N = 4), ß-blockers (N = 3), and calcium channel blockers. In addition, one volunteer was receiving anticoagulant therapy with Coumadin for deep-vein thrombosis, seven subjects were taking thyroid medication, six were taking medications to reduce stomach acid, five were taking drugs for allergies (antihistamines, ß-agonists, or steroid inhalers), and two were taking antibiotics. All subjects read and signed a consent form approved by the Duke University Medical Center Institutional Review Board.

Beat-by-beat blood pressure and HR data were collected with subjects in a supine position, after at least 5 minutes of rest. Blood pressure was measured continuously using the Finapres noninvasive blood pressure monitor, with the appropriate size cuff applied to the middle finger of the left hand. This instrument, which uses the vascular unloading technique to measure SBP, DBP, and mean blood pressure on a beat-by-beat basis, has been validated against intraarterial measures under various conditions (38, 39). The Finapres-derived beat-by-beat HR values are highly correlated (r2 = 0.998), with beat-by-beat HR estimated by electrocardiographic recordings (40). After 5 minutes of calibration, two consecutive 5-minute files of continuous blood pressure and HR measurements were recorded for assessment of BRC_SPEC and RSA. During the first file, blood pressure and HR data were collected while patients breathed at a fixed rate of one breath every 5 seconds. During the second 5-minute period, patients were allowed to breathe at their regular relaxed rate of breathing. The automatic servo-adjustment option of the Finapres was disabled for each 5-minute recording period.

The beat-by-beat SBP and HR data were edited for artifacts, linearly interpolated, and resampled at a frequency of 4 Hz to generate an equally spaced time series for the variables. A fast Fourier transform was then applied to the interpolated data after detrending and application of a Hanning filtering window. Power spectra were derived for each 300-second file using the Welch algorithm, which ensembles averages successive periodograms (41). The averaged spectrum was derived from the power spectra estimated from nine 60-second data segments, overlapping by half. For each 60-second segment, 256 points were analyzed, which included 240 sampled points with zero padding.

RSA was estimated from the R-R interval power summed across the high-frequency band, which is associated with respiration (0.13–0.5 Hz). Raw power was log-transformed before analysis to normalize the values. Respiration rate was estimated from the frequency at which peak RSA was detected. These values correspond closely to respiration rate measured directly with strain gauge (29). Previous research has determined that RSA estimated across the respiratory frequency band is vagally mediated (42).

BRC_SPEC was estimated from the magnitude of the transfer function relating R-R interval oscillations to SBP oscillations across the 0.07- to 0.1299-Hz band. Coherence between SBP and R-R interval oscillations was required to be at least 0.5 to be accepted as estimates of baroreflex control. Spectral analysis–derived estimates of baroreceptor-mediated control of HR are significantly correlated with baroreflex control estimated using phenylephrine to stimulate baroreceptor pathways (43, 44) and are reduced after sinoaortic denervation (45, 46). Under supine conditions, the R-R interval oscillations at the baroreflex frequency are mediated by vagal control mechanisms (47).

Statistical Analyses
Normal gaussian distribution of the data was verified by the Kolmogorov-Smirnov goodness-of-fit test. If the data were not normally distributed, a logarithmic transformation was performed before the statistical analyses. Pearson correlations were used to examine univariate associations between continuous variables. 2 tests were used to compare categorical variables, and analysis of variance was used to compare vagal control measures between groups. Analysis of covariance was used to adjust for the confounding effects of blood pressure and age.

Multiple-regression analyses were used to examine whether vagal control of HR (BRC_SPEC or RSA) was related to severity of depression (BDI or HRSD score) or severity of anxiety symptoms (Spielberger state anxiety score) independent of blood pressure and age. To separate the effects of depression from the effects of anxiety, multiple-regression analyses were then repeated, including both depression score and anxiety score in the model.

	RESULTS

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Predictors of Vagal Control
As Table 2 shows, blood pressure was significantly related to both BRC_SPEC and RSA. Neither age nor BMI was related to the vagal control measures.

Association of Anxiety With Vagal Control Measures
State anxiety was negatively correlated with BRC_SPEC (r = -0.32, p < .05; see Figure 1 ) but not with RSA (r = -0.17, p = NS). State anxiety was also positively correlated with resting HR (r = 0.34, p < .01). Including ST-ANX scores in the multiple-regression model relating BRC_SPEC to blood pressure significantly improved the model (see Table 3 ). In contrast, the model relating RSA to blood pressure was not substantially improved after addition of anxiety to the blood pressure variable. To verify that the relationship between anxiety and vagal control was independent of comorbid depression, depression (BDI or HRSD score) was added to the explanatory terms in the model. Adding the depression term did not alter the relationship between anxiety and the vagal control measures.

View larger version (17K): [in this window] [in a new window]   Fig. 1. Correlation between baroreflex control of HR and state anxiety scores in subjects with MDD (N = 56; BRCSPEC = 10.8 - 0.1 x ST-ANX).

View larger version (15K): [in this window] [in a new window]   Fig. 2. Baroreflex control of HR in volunteers separated by quartile of ST-ANX score. Baroreflex control was estimated as the magnitude of the transfer function relating R-R interval oscillations to SBP oscillations across the low-frequency band (0.07–0.129 Hz). Points shown represent mean ± SEM.

	DISCUSSION

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The present finding that anxiety is related to reduced BRC_SPEC is consistent with previous reports of reduced HRV in volunteers with high anxiety (26–31) and extends these earlier findings by demonstrating that anxiety is associated with reduced BRC_SPEC in patients with MDD. BRC_SPEC was reduced by approximately 33% in subjects with the highest levels of anxiety and was not due to differences in age or hypertension.

Loss of the stabilizing influence of vagal control increases the susceptibility to sympathetic influences, creating an increased vulnerability to malignant arrhythmias under conditions of myocardial ischemia (6, 7). In particular, attenuated baroreceptor-mediated HR changes associated with pharmacologically induced blood pressure increases (ie, via phenylephrine) predict risk of life-threatening arrhythmias (10, 11) and cardiac mortality in postmyocardial infarction patients (12–14) and sudden cardiac death in experimental animal models (8, 15). The present findings of reduced BRC_SPEC in volunteers with high anxiety are consistent with a role for reduced vagally mediated baroreflex control in the increased risk of cardiac events associated with anxiety (48–50); however, the present findings are limited because they are based on noninvasive estimation of baroreflex control derived using spectral analysis. Although BRC_SPEC detects the same magnitude of reduction with cardiovascular disease as BRC_PHEN (43, 51), and baroreflex control of HR derived from spontaneous blood pressure and HR variations is significantly correlated (r = 0.5–0.9) with baroreflex sensitivity assessed using phenylephrine injection (BRC_PHEN), the unexplained variance suggests that BRC_SPEC may measure a different aspect of baroreceptor functioning than the pharmacological method of assessing baroreflex control.

Despite the reduced level of BRC_SPEC and elevated HR observed with heightened anxiety, vagal cardiac control estimated from RSA was not significantly related to anxiety in the present study. Although these findings are consistent with those of an earlier study that reported that patients with panic disorder did not show significant reductions in resting RSA, despite showing a reduced standard deviation of R-R intervals (27), they are in contrast to previous findings of lower levels of RSA in patient groups with clinical anxiety disorders, including patients with phobic anxiety (28), generalized anxiety disorder (29), and posttraumatic stress disorder (30). One factor that may have contributed to the lack of a relationship between anxiety and RSA in the present study is the older age of the patients. Previous studies that have compared the risk stratification potential of BRC_SPEC vs. RSA have reported that RSA does not consistently stratify cardiac risk in older adults (10, 11). Together, these studies suggest that the sensitivity of RSA may be influenced by a floor effect, secondary to age-related reductions in RSA (52). Although BRC_SPEC also decreases with age (53–55), this measure maintains the ability to discriminate between groups at different levels of risk.

A second possibility is that RSA is less discriminative because of interindividual differences in respiratory parameters, given that both rate and depth of respiration influence the magnitude of RSA (56, 57). However, it is unlikely that interindividual differences in respiration influenced estimates of RSA in the current study, because RSA was estimated during periods of paced breathing as well as under the normal conditions of spontaneous breathing.

Certain limitations of the present findings should be noted. First, because the study tested whether vagal control was related to anxiety level experienced during the blood pressure/HR determination, the findings are limited to state, rather than trait, anxiety. Although state and trait anxiety are generally highly correlated under neutral, nonstressful, conditions (37), differences would be expected (higher state than trait) when the condition is perceived as stressful.

A second potential limitation is that the antihypertensive medications taken by a subset of the sample may have influenced the results of this study. Previous studies have shown that ß-receptor blockade increases the magnitude of Holter monitor–derived high-frequency variations in HR (58, 59) and may also increase high-frequency variations in HR under resting conditions (60, 61), although this has not been universally found (47, 62, 63). However, state anxiety was not significantly related to RSA in either the full cohort or the subset not taking antihypertensive medications, suggesting that the presence of these medications did not obscure the relationship between anxiety and RSA. Similarly, the relationship between anxiety and BRC_SPEC was maintained in the subset of patients not taking antihypertensive drugs, further demonstrating the lack of dependence on medication status.

The present study found no evidence of a relationship between depression severity and reduced vagal control of HR. These findings are consistent with the findings of previous studies comparing HRV between subjects with MDD and nondepressed control subjects under quiet, resting conditions (21–23). However, other studies measuring ambulatory HRV from Holter monitor–derived HR recordings have reported significant differences in 24-hour HRV between depressed and nondepressed patients with CAD(16, 17). It seems unlikely that the presence of coronary disease, which is known to reduce HRV (64), would facilitate observing a further reduction in HRV with depression. Differences in the measurement conditions (short-term resting vs. 24-hour ambulatory), however, could explain the different effects of depression found in these studies. For example, depression may influence the Holter monitor–derived indices of HRV assessed in the patients with CAD through depression-related physical inactivity. Given that physical activity is the primary determinant of ambulatory HRV (65, 66), along with the fact that depressive symptoms have been linked to reduced physical activity (67–69), it is possible that sedentary behavior contributes to the lower 24-hour HRV reported in depressed CAD patients. Depressed CAD patients often have greater overall impairment in multiple physiological systems (70), which would also lead to reduced physical activity. These effects of activity clearly would not be observed in the studies that assessed HRV under quiet resting conditions and failed to find any effect of depression (21–23).

A second possibility is that comorbid anxiety contributed to the low HRV found with depression. This interpretation is supported by the current findings as well as by the prevalence of high anxiety in MDD (24, 25). Interestingly, reduced HRV was not found with depression in the studies that specifically excluded patients with anxiety disorders (21) but was found in depressed patients with high anxiety (22).

In summary, the present study finds that state anxiety, but not depression severity, is associated with increased HR and reduced BRC_SPEC in older adults with MDD. The clinical significance of impaired vagal control in depressed patients with high levels of anxiety is not known. Additional studies are needed to determine whether anxiety mediates the relationship between depression and increased cardiac mortality.

	ACKNOWLEDGMENTS

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This study was supported by funds from the National Institutes of Health (Grants MH-49679, 5T32-AG-00029, and HL58946-01). The authors gratefully acknowledge the assistance of Dr. Norman Anderson for making this study possible by providing the Finapres equipment.

Received for publication June 12, 1998.

Revision received December 29, 1998.

	REFERENCES

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1. Molgaard H, Sorensen KE, Bjerregaard P. Attenuated 24-h heart rate variability in apparently healthy subjects, subsequently suffering sudden cardiac death. Clin Auton Res 1991; 1: 233–7.[Medline]
2. Kleiger RE, Miller JP, Bigger JT Multicenter Post-Infarct Research Group. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987; 59: 256–62.[Medline]
3. Odemuyiwa PO, Malik M, Farrell TG, Bashir Y, Poloniecki J, Camm JA. Comparison of the predictive characteristics of heart rate variability index and left ventricular ejection fraction for all-cause mortality, arrhythmic events and sudden death after acute myocardial infarction. Am J Cardiol 1991; 658: 434–9.
4. Bigger JT, Fleiss JL, Rolnitzky LM, Steinman RC. The ability of several short-term measures of RR variability to predict mortality after myocardial infarction. Circulation 1993; 88: 927–34.[Abstract/Free Full Text]
5. Lown B, Verrier RL, Corbalan R. Psychologic stress and threshold for repetitive ventricular response. Science 1973; 182: 834–6.[Abstract/Free Full Text]
6. Verrier RL, Lown B. Experimental studies of psychophysiological factors in sudden cardiac death. Acta Med Scand Suppl 1982; 660: 57–68.[Medline]
7. Schwartz P, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation 1992; 85: I-77–91.
8. Schwartz P, Billman GE, Stone HL. Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction an experimental model for sudden cardiac death. Circulation 1984; 69: 790–800.[Abstract/Free Full Text]
9. Landolina M, Mantica M, Pessano P, Manfredini R, Foresti A, Schwartz PJ, De Ferrari GM. Impaired baroreflex sensitivity is correlated with hemodynamic deterioration of sustained ventricular tachycardia. J Am Coll Cardiol 1997; 29: 568–75.[Abstract]
10. Hohnloser SH, Klingenheben T, van de Loo A, Hablawetz E, Just H, Schwartz PJ. Reflex versus tonic vagal activity as a prognostic parameter in patients with sustained ventricular tachycardia or ventricular fibrillation. Circulation 1994; 89: 1068–73.[Abstract/Free Full Text]
11. De Ferrari GM, Landolina M, Mantica M, Manfredini R, Schwartz PJ, Lotto A. Baroreflex sensitivity, but not heart rate variability, is reduced in patients with life-threatening ventricular arrhythmias long after myocardial infarction. Am Heart J 1995; 130: 473–80.[Medline]
12. Farrell TG, Paul V, Cripps TR, Malik M, Bennett ED, Ward D, Camm AJ. Baroreflex sensitivity and electrophysiological correlates in patients after acute myocardial infarction. Circulation 1991; 83: 945–52.[Abstract/Free Full Text]
13. Osterziel KJ, Hanlein D, Willenbrock R, Eichhorn C, Luft F, Dietz R. Baroreflex sensitivity and cardiovascular mortality in patients with mild to moderate heart failure. Br Heart J 1995; 73: 517–22.[Abstract/Free Full Text]
14. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478–84.[Medline]
15. Billman GE, Schwartz P, Stone HL. Baroreceptor reflex control of heart rate a predictor of sudden cardiac death. Circulation 1982; 66: 874–80.[Free Full Text]
16. Carney RM, Saunders RD, Freedland KE, Stein PK, Rich MW, Jaffe AS. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995; 76: 562–4.[Medline]
17. Krittayaphong R, Cascio WE, Light KC, Sheffield D, Golden RN, Finkel JB, Glekas G, Koch GG, Sheps DS. Heart rate variability in patients with coronary artery disease differences in patients with higher and lower depression scores. Psychosom Med 1997; 59: 231–5.[Abstract/Free Full Text]
18. Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995; 91: 999–1005.[Abstract/Free Full Text]
19. Ahern DK, Gorkin L, Anderson JL, Tierney C, Hallstrom A, Ewart C, Capone RJ, Schron E, Kornfeld D, Herd JA, Richardson DW, Follick MJ. Biobehavioral variables and mortality or cardiac arrest in the cardiac arrhythmia pilot study (CAPS). Am J Cardiol 1990; 66: 59–62.[Medline]
20. Barefoot JC, Helms MJ, Mark DB, Blumenthal JA, Califf RM, Haney TL, O’Connor CM, Siegler IC, Williams RB. Depression and long-term mortality risk in patients with coronary artery disease. Am J Cardiol 1996; 78: 613–7.[Medline]
21. Yeragani VK, Pohl R, Balon R, Ramesh C, Glitz D, Jung I, Sherwood P. Heart rate variability in patients with major depression. Psychiatr Res 1991; 37: 35–46.[Medline]
22. Tulen JHM, Bruijn JA, de Man KJ, van der Velden E, Pepplinkhuizen L, Man in’t Veld AJ. Anxiety and autonomic regulation in major depressive disorder an exploratory study. J Affect Disord 1996; 40: 61–71.[Medline]
23. Lehofer M, Moser M, Hoehnsaric R, Mcleod D, Liebmann P, Drnovsek B, Egner S, Hildebrandt G, Zapotoczky HG. Major depression and cardiac autonomic control. Biol Psychiatry 1997; 42: 914–9.[Medline]
24. Fawcett J, Kravitz HM. Anxiety syndromes and their relationship to depressive illness. J Clin Psychiatry 1983; 44: 8–11.[Medline]
25. Zung WWK, Magruder-Habib K, Velez R, Alling W. The comorbidity of anxiety and depression in general medical patients a longitudinal study. J Clin Psychiatry 1990; 51: 77–80.
26. Yeragani VK, Balon R, Pohl R, Ramesh C, Glitz D, Weinberg P, Merlos B. Decreased R-R variance in panic disorder patients. Acta Psychiatr Scand 1990; 81: 554–9.[Medline]
27. Yeragani VK, Pohl R, Berger R, Balon R, Ramesh C, Glitz D, Srinivasan K, Weinberg P. Decreased heart rate variability in panic disorder patients a study of power-spectral analysis of heart rate. Psychiatry Res 1993; 46: 89–103.[Medline]
28. Kawachi I, Sparrow D, Vokonas PS, Weiss ST. Decreased heart rate variability in men with phobic anxiety (data from the normative aging study). Am J Cardiol 1995; 75: 882–5.[Medline]
29. Thayer JF, Friedman BH, Borkovec TD. Autonomic characteristics of generalized anxiety disorder and worry. Biol Psychiatry 1996; 39: 255–66.[Medline]
30. Cohen H, Kotler M, Matar MA, Kaplan Z, Miodownik H, Cassuto Y. Power spectral analysis of heart rate variability in posttraumatic stress disorder patients. Biol Psychiatry 1997; 41: 627–9.[Medline]
31. Watkins LL, Grossman P, Krishnan R, Sherwood A. Anxiety and vagal control of heart rate. Psychosom Med 1998; 60: 498–502.[Abstract/Free Full Text]
32. Friedman BH, Thayer JF. Autonomic balance revisited panic anxiety and heart rate variability. J Psychosom Res 1998; 44: 133–51.[Medline]
33. DSM-IV. Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Association; 1994.
34. Robins LN, Helzer JE, Croughan J, Williams JBW, Spitzer RL, eds. The NIMH diagnostic interview schedule: version III. Washington DC: US Public Health Service; 1981, publication no. (HHS) AOM-T-42-3.
35. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatr 1961; 4: 561–71.
36. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278–96.[Medline]
37. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. Manual for the State-Trait Anxiety Inventory. Palo Alto (CA): Consulting Psychologists Press; 1983.
38. Parati G, Casadei R, Gropelli A, DiRienzo M. Comparison of finger and intra-arterial blood pressure monitoring at rest and during laboratory testing. Hypertension 1989; 13: 647–55.[Abstract/Free Full Text]
39. Hartikainen JEK, Tahvanainen KUO, Mantysaari MJ, Tikkanen OE, Lansimies EA, Airaksinen KEJ. Simultaneous invasive and noninvasive evaluations of baroreflex sensitivity with bolus phenylephrine technique. Am Heart J 1995; 130: 296–301.[Medline]
40. Low PA, Opfer-Gehrking TL, Zimmerman IR, O’Brien PC. Evaluation of heart rate changes electrocardiographic versus photoplethysmographic methods. Clin Auton Res 1997; 7: 65–8.[Medline]
41. Welch PD. The use of fast Fourier transform for the estimation of power spectra a method based on time averaging over short modified periodograms. IEEE Trans Audio Electroacoust 1967; 15: 70–3.
42. Grossman P, Kollai M. Respiratory sinus arrhythmia, cardiac vagal tone, and respiration within- and between-subject relations. Psychophysiology 1993; 30: 495.
43. Watkins LL, Grossman P, Sherwood A. Noninvasive assessment of baroreflex control in borderline hypertension comparison with the phenylephrine method. Hypertension 1996; 28: 238–43.[Abstract/Free Full Text]
44. Robbe HWJ, Mulder LJM, Ruddel H, Langewitz WA, Veldman JBP, Mulder G. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 1987; 10: 538–43.[Abstract/Free Full Text]
45. DiRienzo M, Parati G, Castiglioni P, Omboni S, Ferrari AU, Ramirez AJ, Pedotti A, Mancia G. Role of sinoaortic afferents in modulating blood pressure and pulse interval spectral characteristics in unanesthetized cats. Am J Physiol 1991; 261: H1811–8.[Abstract/Free Full Text]
46. Cerutti S, Barnes C, Paultre C. Baroreflex modulation of blood pressure and heart rate variabilities in rats assessment by spectral analysis. Am J Physiol 1994; 266: H1993–2000.[Abstract/Free Full Text]
47. Pomeranz B, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, Kilborn KM, Barger AC, Shannon DC, Cohen RJ, Benson H. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985; 248: H151–3.[Abstract/Free Full Text]
48. Kawachi I, Sparrow D, Vokonas PS, Weiss ST. Symptoms of anxiety and risk of coronary heart disease the normative aging study. Circulation 1994; 90: 2225–9.[Abstract/Free Full Text]
49. Kawachi I, Colditz GA, Ascherio A, Rimm EB, Giovannucci E, Stampfer MJ, Willett WC. Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 1994; 89: 1992–7.[Abstract/Free Full Text]
50. Haines AP, Imeson JD, Meade TW. Phobic anxiety and ischaemic heart disease. BMJ 1987; 295: 297–9.
51. Katsube Y, Sato H, Naka M, Ha Kim B, Kinoshita N, Koretsune Y, Hori M. Decreased baroreflex sensitivity in patients with stable coronary artery disease is correlated with the severity of coronary narrowing. Am J Cardiol 1996; 78: 1007–10.[Medline]
52. Pfeifer MA, Weinberg CR, Cook D. Differential changes of autonomic nervous system function with age in man. Am J Med 1983; 75: 249–58.[Medline]
53. Gribbin B, Pickering TG, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 1971; 29: 424–31.[Abstract/Free Full Text]
54. Simpson DM, Wicks R. Spectral analysis of heart rate indicates reduced baroreceptor-related heart rate variability in elderly persons. J Gerontol 1988; 43: M21–4.[Medline]
55. Parati G, Frattola A, DiRienzo M, Castiglioni P, Pedotti A, Mancia G. Effects of aging on 24-h dynamic baroreceptor control of heart rate in ambulant subjects. Am J Physiol 1995; 268: H1606–12.[Abstract/Free Full Text]
56. Eckberg DL, Kifle YT, Roberts VL. Human sinus arrhythmia as an index of vagal cardiac outflow. J Appl Physiol 1983; 54: 961–6.[Abstract/Free Full Text]
57. Grossman P, Karemaker J, Wieling W. Prediction of tonic parasympathetic cardiac control using respiratory sinus arrhythmia the need for respiratory control. Psychophysiology 1991; 28: 201–16.[Medline]
58. Goldsmith RL, Bigger JT, Bloomfield DM, Krum H, Steinman RC, Sacknerbernstien J, Packer M. Long-term carvedilol therapy increases parasympathetic nervous system activity in chronic congestive heart failure. Am J Cardiol 1997; 80: 1101–5.[Medline]
59. Sandrone G, Mortara A, Torzillo D, La Rovere MT, Malliani A, Lombardi F. Effects of beta blockers (atenolol or metoprolol) on heart rate variability after acute myocardial infarction. Am J Cardiol 1994; 74: 340–5.[Medline]
60. Bittiner SB, Smith SE. Beta-adrenoceptor antagonists increase sinus arrhythmia, a vagotonic effect. Br J Clin Pharmacol 1986; 22: 691–5.[Medline]
61. Coker R, Koziell A, Oliver C, Smith SE. Does the sympathetic nervous system influence sinus arrhythmia in man? Evidence from combined autonomic blockade. J Physiol 1984; 356: 459–64.[Abstract/Free Full Text]
62. Akselrod S, Gordon D, Madwed JB, Snidman NC, Shannon DC, Cohen RJ. Hemodynamic regulation investigation by spectral analysis. Am J Physiol 1985; 249: H867–75.[Abstract/Free Full Text]
63. Grossman P, Stemmler G, Meinhardt E. Paced respiratory sinus arrhythmia as an index of cardiac parasympathetic tone during varying behavioral tasks. Psychophysiology 1990; 27: 404–16.[Medline]
64. Bigger JT, Fleiss JL, Steinman RC, Rolnitzky LM, Schneider WJ, Stein PK. RR variability in healthy, middle-aged persons compared with patients with chronic coronary heart disease or recent acute myocardial infarction. Circulation 1995; 91: 1936–43.[Abstract/Free Full Text]
65. Osterhues HH, Hanzel SR, Kochs M, Hombach V. Influence of physical activity on 24-hour measurements of heart rate variability in patients with coronary artery disease. Am J Cardiol 1997; 80: 1434–7.[Medline]
66. Bernardi L, Valle F, Coco M, Calciati A, Sleight P. Physical activity influences heart rate variability and very-low-frequency components in Holter electrocardiograms. Cardiovasc Res 1996; 32: 234–7.[Abstract/Free Full Text]
67. Ruuskanen JM, Ruoppila I. Physical activity and psychological well-being among people aged 65 to 84 years. Age Ageing 1995; 24: 292–6.[Abstract/Free Full Text]
68. Foreyt JP, Brunner RL, Goodrick GK, St Jeor ST, Miller GD. Psychological correlates of reported physical activity in normal-weight and obese adults. Int J Obes Relat Metab Disord 1995; 19: S69–72.
69. Brown DR, Croft JB, Anda RF, Barrett DH, Escobedo LG. Evaluation of smoking on the physical activity and depressive symptoms relationship. Med Sci Sports Exerc 1996; 28: 233–40.[Medline]
70. Gonzalez MB, Snyderman TB, Colket JT, Arias RM, Jiang JW, O’Connor CM, Krishnan KR. Depression in patients with coronary artery disease. Depression 1996; 4: 57–62.[Medline]

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