Panic Disorder and Chest Pain: A Study of Cardiac Stress Scintigraphy Patients Cameron Carter, MD, Richard Maddock, MD, Michael Zoglio, MD, Calvin Lutrin, MD, Susan Jella, PhD, and Ezra Amsterdam, MD

R ecurrent chest pain in the absence of coronary artery disease is a major public health problem. Despite

the reassurance provided by objective measures of coro- nary vessel patency and an excellent cardiac prognosis, many patients continue to experience symptoms, social and occupational disability, and to seek frequent med- ical therapy.14 Several studies have identified a high prevalence of panic disorder among patients with chest pain and normal coronary arteries.5-7 In populations undergoing coronary angiography or treadmill testing, 30% to 50% of patients with negative results meet cri- teria for panic disorder.5-7 The current study investigat- ed the prevalence of panic and other psychiatric disor- ders in the nuclear medicine department in patients with chest pain referred for noninvasive evaluation by myo- cardial stress perfusion scintigraphy. We also assessed 2 self-report measures, the Zung anxiety scale,* and the anxiety sensitivity index9 for their use as screens for pan- ic disorder.

Subjects were consecutive referrals with the com- plaint of chest pain to the Nuclear Medicine Department at the University of California, Davis Medical Center for stress (either treadmill or dipyridamole) myocardial scintigraphy. Only patients who were English speaking, willing to give written informed consent, and who had no prior confirmed history of coronary artery disease were included. A small minority of patients had previ- ous negative angiographic and scintigraphic studies. The myocardial perfusion status was unknown for the majority of patients. Psychiatric diagnoses were estab- lished before the cardiac testing procedure using the Structured Clinical Interview for the Diagnostic and Sta- tistical Manual (3rd edition, revised).lO This instrument has a high level of inter-rater reliability in patients with panic disorder presenting for cardiac evaluation. Diag- noses were made by consensus with the principal inves- tigator to control for rater drift. After the psychiatric interview, patients completed the Zung anxiety scale and the anxiety sensitivity index. The former is a 20-item self report measure that requires patients to rate the severi- ty of anxiety and associated somatic symptoms. The anx- iety sensitivity index is a 16-item self-report measure in which subjects rate the degree to which physiologic symptoms of arousal are‘ anxiety-producing. Chest pain quality was evaluated by retrospective chart review by an experienced cardiologist (EAA). Five dimensions of pain were rated as typical or atypical. These dimensions

From the Department of Psychiatry and the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California (Davis) Medi& Center, Sacramento, California. Dr. Carter’s address is: Western Psvchiatric Institute and Clinic, University of Pittsburgh, 38 11 O’Hara Skeet, Pittsburgh, Pennsylvania 15213. Manuscript received October 1, 1993; revised manuscript received and accepted December 22, 1993.

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were (1) onset with exertion (typical = yes); (2) relieved by nitroglycerin (typical = fully relieved); (3) duration (typical <5 minutes); (4) location (typical = retroster- nal, throat, jaw, left upper extremity); and (5) pain qual- ity (typical = pressure, squeezing, burning). A majority of items were available for most patients. Pain was scored as either typical angina, atypical angina, or nonanginal according to the following algorithm: typi- cal = 4 of 5 items typical or >l of available items atyp- ical and none nonanginal; atypical = no more than 2 items atypical or no more than half of items atypical; nonanginal = less than 3 of 5 typical or >50% of avail- able items atypical. Data were harvested from the chart by a research nurse and scored by the rater who remained unaware of the patient’s cardiac and psychi- atric status. Rest and stress scintigrams were obtained by myocardial imaging with either thallium-201 or tech- netium-99m sestamibi in conjunction with treadmill exercise or infusion of dipyridamole. Exercise was either symptom-limited or terminated because of electrocar- diographic ischemic ST-segment alteration. Images were analyzed by 2 nuclear medicine faculty physicians unaware of the patient’s psychiatric status. A positive scintigram was one with a defmitive regional perfusion defect on the stress image that was not present on the rest image. The absence of thisJinding dej?ned a nega- tive scan. No patient showed a fixed perfusion defect (present on both the rest and stress images) that was not considered to be an artifact (such as breast attenuation).

Fifty of 61 consecutive patients (82%) who met entry criteria participated. Six of the remaining 11 patients refused the psychiatric evaluation. Data were not obtained for 5 patients because of lack of clinician avail- ability at the time of stress testing. Seven of 50 patients (14%) had positive stress scintigrams. Twenty-eight (56%) met criteria for panic disorder. Only 1 patient with panic disorder had a positive scintigram, whereas 6 of the 22 patients without panic disorder had positive scintigrams (p ~0.05). Twenty-seven of the 43 patients (63%) with negative scintigrams had panic disorder. Demographic, psychiatric comorbidity, and question- naire data for patients with and without panic disorder are listed in Table I. The groups did not differ sign@- cantly in age, gender, or pain quality. Rates of psychi- atric comorbidity (agoraphobia, major depression, and generalized anxiety disorder) seen in the panic disorder group were similar to that usually seen in psychiatric samples, and comorbid diagnoses were significantly associated with this group. Although 16patients met cri- teria for generalized anxiety disorder, in all but 1 this was comorbid with panic disorder. The 1 patient who had generalized anxiety disorder alone also had a pos- itive stress scintigram. All 7 patients with major depres- sion had this diagnosis comorbid with panic disorder. Table II compares demographic and other variables in

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TABLE I Demographics and Clinical Comorbidities Associated with Panic Disorder

Panic Disorder

+ (n = 28) 0 (n = 22)

Age (years) 54 f 12 59+11 NS Sex (women:men) (no.) 19:9 1l:ll NS Dipyridamole*:treadmill (no.) 15:13 16:6 NS Chest pain (typical:atypical) (no.) 6:22 6:16 NS + Myocardial scintigraphy (no.) 1 6 p co.05 Zung anxiety scale (score) 41 f7 35 * 5 p co.01 Anxiety sensitivity index (score) 44 f 12 28 k 8 p eo.001 Agoraphobia (no.) 14 2 p <0.005 Major depression (no.) 7 0 p <0.03 Generalized anxiety disorder (no.) 15 1 p co.oo1

*Method of inducing stress during scintigraphy. + = positive; 0 = negative.

patients with and without a positive stress scintigram. Neither age, gender, nor chest pain quality was associ- ated with CAD. However, as previously noted, a diag- nosis ofpanic disorder was significantly associated with absence of evidence of coronary artery disease as indi- cated by negative scintigraphy. Thirty-seven patients completed the Zung scale and 35 completed the anxiety sensitivity index (all completers of the anxiety sensitivi- ty index were completers of the Zung scale). The usual reason for not completing ratings was a lack of time before scintigraphy to complete both the interview and the ratings, Having completed the stress’ procedure, patients were often unwilling to remain in the laborato- ry to complete ratings. There were no signi@cant differ- ences between completers and noncompleters on the prevalence of panic disorder for either measure. Scores on the Zung anxiety scale and the anxiety sensitivity index were significantly higher in patients with panic disorder (p ~0.01 and p <O.OOl, respectively). Table III presents an analysis of the potential usefulness of these measures as screening tests for panic disorder in this setting. Using a cutoff of 30, the anxiety sensitivity index had a sensitivity of 95% and a specificity of 75% for a total accuracy of 86%. This was associated with a pos- itive predictive value of 82% and a negative predictive value of 92%. Using a cutoff of 36, the Zung scale had a sensitivity of 90% and a specificity of 53% for a total accuracy of 73%. The positive predictive value was 69% and the negative predictive value 82%.

These results suggest that in this population of patients with chest pain, who had no previously docu- mented coronary artery disease and were referred for myocardial stress scintigraphy, panic disorder is very common. Whereas only 14% of this patient group had positive stress scintigrams, 56% had panic disorder. When we consider the group of patients for whom stress scintigraphy was negative, this proportion increases to 63%. In this study a negative stress scintigram was accepted as evidence of absence of significant coronary artery disease. Whereas the negative predictive accura- cy of any noninvasive test is imperfect, the false-nega- tive rate in our patients should be minimal since the group has characteristics consistent with a low preva- lence of coronary artery disease (atypical chest pain and a high proportion of women). It is unlikely that the

TABLE II Predictors of Positive Myocardial Stress Scintigraphy

Scintigraphy

f 0

Age (years) 62+12 56fll NS Sex (women:men) (no.) 3:4 27:16 NS Pain (typical:atypical) (no.) 1:6 11:32 NS Dipyridamole:treadmill (no.) 6:l 25:18 NS Panic disorder (no.) 1 27 p co.05

+ = positive; 0 = negative.

TABLE Ill Rating Scale Performance and Panic Disorder Diagnosis

Anxiety Zung Sensitivity Index >30 Anxiety Scale >36

Sensitivity 95% (18/l 9) 90% (18/20) Specificity 75% (12/16) 53% (9/l 7) + Predictive value 82% (18/22) 69% (18/26) - Predictive value 92% (1203) 82% (9/l 1)

reduced positive predictive value of the scintigram in this group would signilicantly alter our results. The num- ber of positives is small; therefore, even a relatively high- false positive rate would represent a small absolute num- ber. Chest pain quality did not predict the presence of either panic disorder or positive stress scintigram. We attribute this unexpected finding to the shortcomings of the retrospective approach used. The small number of patients (12 of 50) with typical pain may also have con- tributed to a lack of sensitivity of our measure.

The anxiety sensitivity index, at a cutoff level of 30, showed considerable promise as a screen for panic dis- order. This new finding requires conlirrnation. If the sen- sitivity, specilicity, and predictive value of this measure for the diagnosis of panic disorder is confirmed, it would be reasonable to use it routinely to screen for panic dis- order in patients such as those in the current study. Gen- eralized anxiety disorder and major depression did occur among the patients in this study but were uncommon in the absence of panic disorder. We made a similar obser- vation with regard to major depression in our study of patients with acute chest pain in the coronary care unit.7 Regardless of the presence of other anxiety or mood symptoms, it appears to be the occurrence of frequent panic attacks that results in patients seeking cardiac eval- uation for chest pain.

The results of this and earlier studies5-7 suggest that the salient question facing clinicians is not whether to evaluate patients with chest pain for panic disorder, but at what point in their evaluation this diagnosis should be considered. Because there is up to a 60% prevalence of panic disorder in patients who lack objective evidence of coronary artery disease, all patients with chest pain who have coronary disease excluded should be evaluat- ed for panic disorder. Since coronary artery disease is potentially fatal, should a diagnosis of panic disorder be considered only after this has been excluded by objec- tive testing, or at an earlier point in the diagnostic process? For a given patient, the answer must depend on many factors. This latter question, and the factors rele-

BRIEF REPORTS 297

RB. Unimoroved chest uain in uatients with minimal or no coronarv disease: a behavioralbhenomenon.‘Am He&J 1984; 108:67-72. 4. Isner JM, Salem DN, Banas JS, Levine HJ. Long-term clinical course of patients with normal coronary arteriogmphy: follow-up study of 128 patients with normal or nearly normal coronary arteriograms. Am HeertJ 1981;102:645-653. 5. Cormier LE, Katon W, Russo J, H&field M, Hall ML, Vitaliano P. Chest pain with negative cardiac diagnostic studies: relationship to psychiatric illness. J Nerv Merit Dis 1988; 176:351-358. 6. Beitman BD. Mukerii V. Lamb&i JW. Schmid L. Derosear L. Kushner M. Flak-

vant to its solution, should be the focus of future inves- tigations of panic disorder in patients complaining of chest pain.

Acknowledgment: We gratefully acknowledge the assistance of Joyce Groen, Sharon Wimburg, Trish Foley, and Karen Kirstch for their assistance with sub- ject recruitment and data management.

1. Levy EB, Winkle RA. Continuing disability of patients with chest pain and nor- mal coronary aneriograms. J Chron Dis 1979,32:191-196. 2 Bass C, Wade C, Hand D, Jackson G. Patients with angina with normal and near- normal coronary arteries: clinical and psychosocial state at 12 months after angiog- raphy. Br Med .I 1983;287:1505-1508. 3. Weilgosz AT, Fletcher RH, McCants CB, McKhmis RA, Haney TL, Williams

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er G, Basha I. Panic disorder in patients with chest pain and an&graphically nor- mal coronary arteries. Am J Cardiol 1989;63:1399-1403. 7. Carter CS, Maddock RJ, Amsterdam E, McCormick S, Waters C, Billet J. Pan- ic disorder and chest pain in the coronary care unit. Psychosomafics 199233: 302-309. 8. Zung WK. A rating instrument for anxiety disorders. Psychosomafics 1971;12: 371-379. 9. Reiss S. Peterson RA. Gurskv DM. Mcnallv RJ. Anxietv sensitivitv. anxietv fre- quency a&l the predicti& of fe&f&ess. B&v Res 77&1986;24:1>. . 10. Spitzer RL, Williams JBW. Structured Clinical Interview for DSMIII. 3rd revised ed. NY: New York State Psychiatric Institute, 1987.

Cardiac Autonomic Control and Hostility in Healthy Subjects Richard P. Sloan, PhD, Peter A. Shapiro, MD, J. Thomas Bigger Jr, MD, Emilia Bagiella, MS, Richard C Steinman, BA, and Jack M. Gorman, MD

D isordered autonomic regulation of the cardiovascu- lar system has been implicated in sudden cardiac

death and coronary artery disease in numerous studies. Bigger et al’ showed that survival after myocardial infarction was predicted by high-frequency (Ill?) power of the heart period power spectrum, a measure of vagal modulation of RR intervals,2 by power in other fre- quency bands, and by the low-frequency (LF) to I-IF power ratio, a measure that has been used to estimate sympathovagal balance. Increased heart rate, reflecting global cardiac autonomic control, is associated with development of atherosclerosis in animal models3 and age-adjusted levels of atherogenic lipoproteins in humans.4 Heart rate-lowering interventions such as sur- gical ablation of the sinoatrial node and j3-adrenergic antagonists have antiatherogenic effects.3

Cardiovascular regulation by the autonomic nervous system may link negative personality characteristics, e.g., hostility, with increased risk of coronary artery dis- ease, an association generally supported by available data.5Jj Two views about the nature of the link, the con- stitutional and the transactional theories, specify differ-

From the Behavioral Medicine Program, Columbia-Presbyterian Med- ical Center, New York, the Division of Consultation/Liaison Psychiatry and the Division of Clinical Psychobiology, Department of Psychiatry: the Division of Cardiology, the Department of Medicine, and the Divi- sion of Biostatistics, School of Public Health, Columbia University, New York; and the New York State Psychiatric Institute, New York, New York. This study was supported in part by Grant MH-43977, Research Scientist Develonment Award MN-00416 (Dr. Gorman), and Scientist Development Award MH-01035 (Dr. Sloan) from the National Institute of Mental Health. Rockville. Man/land: Grant MOlRROO645 from the General Clinical Research Centers Program of the National Institutes of Health, Bethesda, Maryland; an Irving Assistant Professorship (Dr. Shapiro); and the Nathaniel Wharton Fund. Dr. Sloan’s address is: Behavioral Medicine Program, Box 427, Columbia-Presbyterian Med- ical Center. 622 West 168th Street. New York, New York 10032. Manu- script received July 19, 1993; rev&d manuscript received and accept- ed December 22, 1993.

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ent mechanisms. The constitutional theory holds that the autonomic activity associated with risk of coronary artery disease is caused by a constitutional characteris- tic which also accounts for hostility.5 In this view, hos- tility is a marker of factors that influence brainstem car- dioregulatory centers. The transactional theory holds that hostile persons interact with their environment in a way that creates interpersonal conflict and reduces social sup- port5 Since in laboratory experiments, psychological stressors decrease HF power in the heart period power spectrum,7 the stressfuhress of the transactions that per- sons high in hostility have with their interpersonal envi- ronments suggests an inverse relation between hostility and HF power, which in turn may increase risk of coro- nary artery disease.

We examined the relation between cardiac autonom- ic control, as measured by 24-hour heart period vari- ability, and hostility in a group of healthy subjects. Our primary hypothesis was that hostility would be associ- ated with reduced levels of vagal modulation of RR inter- vals, i.e., HF power, and an increased LFIHF ratio, both adjusted for age. Because vagal modulation declines with age, we also tested the signtjicance of the age-hos- tility interaction. Moreover, because cardiac vagal mod- ulation is subject to diurnal variation, we conducted these analyses for the entire 24-hour period, for daytime (7:30 to 21:30), and nighttime (0O:OO to 5:OO). The night-day analysis also permitted us to evaluate the con- stitutional versus transactional hypotheses.

Thirty-eight healthy volunteers (33 men and 5 women, mean age [* SD] 36 f 12 years) participated. Subjects arrived at the laboratory at 8:00 A.M. and had a 24-hour ambulatory electrocardiographic recorder attached. They then completed the 50-item Cook-Med- ley hostility scale (range of scores 0 to 50).8 After par- ticipation in a psychophysiology study, they resumed normal daily activities. Three of the 38 Holter record- ings were not analyzable because of excessive noise. The remaining 35 subjects form the study sample.

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