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Mitral valve abnormalities and catecholamine activity in anxious patients
P.s.vchiurr_v
Rwurch.
20,
I 3-1X
13
Elsevier
Mitral Valve Abnormalities Anxious Patients Stephen David
R. Dager, L. Dunner
Received February
Arifulla
Khan,
and Catecholamine
Keith
A. Comess,
Vidmantys
Activity
in
Raisys,
and
18. 1986; revised version received June 4, 1986; accepted June 20. 1986.
Abstract. We studied 38 anxiety disorder patients, 19 of whom had evidence of mitral valve abnormalities by two-dimensional echocardiography. The presence or absence of mitral valve abnormalities was not related to 3-methoxy-4hydroxyphenylglycol/creatinine excretion, platelet and plasma monoamine oxidase-type activity, or autonomic arousal as measured by blood pressure and resting heart rate. These findings fail to support the hypothesis that mitral valve abnormalities identify a specific subpopulation of anxious patients with differences in catecholamine function. Words. Key catecholamines,
monoamine 3-Methoxy-rl-hydroxyphenylglycol, anxiety, panic disorder, mitral valve prolapse.
oxidase,
Mitral valve abnormalities have been associated with anxiety disorders and, more specifically, the phenomenon of panic attacks, although a mechanism for this relationship has not been established (Pariser et al., 1978; Dager et al., 1986). It has been postulated that increased catecholamine levels and/ or increased autonomic arousal may be the underlying disorder clinically manifested as both mitral valve abnormalities and anxiety symptoms in a subpopulation of anxious patients (Gorman et al., 1981~). We report our findings on catecholamine function as measured by 24-hour urinary 3-methoxy+hydroxyphenylglycol (MH PG), a major metabolite of catecholamines, and activity of platelet and plasma monoamine oxidase (MAO), an enzyme involved in the intracellular breakdown of catecholamines and indolamines, in relationship to mitral valve abnormalities. Autonomic arousal, as determined by systolic/diastolic blood pressure and heart rate in the resting state, was also studied.
Methods Subjects. Harborview
Thirty-eight outpatients entered into a psychopharmacology research program at Medical Center were studied. Subjects were evaluated by a faculty psychiatrist
Stephen R. Dager, M.D., and Arifulla Khan, M.B., B.S., are Assistant Professors; David L. Dunner, M.D., is Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine. Keith A. Comess, M.D., is Assistant Professor and Director of Adult Echocardiography, Department of Internal Medicine, Division of Cardiology, University of Arizona School of Medicine. Vidmantys Raisys, Ph.D.. is Associate Professor, Department of Laboratory Medicine, University of Washington School of Medicine. (Reprint requests to Dr. S.R. Dager, Harborview Medical Center, ZA-99, 325 9th Ave., Seattle, WA 98104, USA.) 0165.1781/X7/$03.50
Q 1987 Elsevier Science Publishers B.V.
14 and met DSM-//I criteria (American Psychiatric Association, 1980) for one of the following disorders: generalized anxiety disorder (n = 9): panic disorder (n = IS); agoraphobia with panic disorder (n = IO); and generalized anxiety disorder with panic attacks of insufficient frequency to diagnose panic disorder (n = 4). Subjects had not taken medicat.ions affecting the central nervous system for a minimum of 2 weeks before MHPG and MAO samples were obtained. Subjects were not on dietary restrictions before sample collection. All subjects had an interpretable echocardiographic evaluation of the mitral valve apparatus and a 24-hour urine collection of adequate volume (> 1,000 cc/24 hours), and 24-hour urine creatinine levels within normal range for our laboratory (men > I .O g/24 hours and women > 0.7 g/24 hours) (Veith et al., 1983). A subsample of 28 subjects also gave consent for measurement of platelet and plasma MAO activity. All subjects had a baseline blood pressure determination in the supine position and a resting heart rate taken on the day urine samples were returned and blood samples drawn. Cardiac Evaluation. The mitral valve apparatus was evaluated using two-dimensional echocardiography (2D-echo) with supplemental 2D-echo guided M-mode recordings. Diagnosis of mitral valve abnormalities was based on 2D-echo evidence of mitral leaflet flat closure or buckling below the level of the annular plane on one or more 2D-echo views (apical 4-chamber and parasternal long axis) with m-mode confirmation in questionable cases (Markiewicr et al., 1976) in conjunction with 2D-echo evidence of myxomatous degeneration elongation and thickening of the mitral leaflets (Dager et al., 1986). MHPG Determination. A 24-hour urine sample was collected following the first a.m. void on day I through the first a.m. void of the following day. Urine samples were kept refrigerated and brought by subjects to the clinic within 24 hours of collection, with samples being stored at -30°C. MHPG values were determined by high performance liquid chromatography with an electrochemical detection method using glusulase to hydrolyse sulphate and glucuronide for measurement of total MHPG (Moleman and Borstrok, 1982; Hammond and Johnston. 1984). The coefficient of variation for this assay in our laboratory was c).Xyo for repeat pooled sample measurements. MHPG activity was reported as a function of urinary creatinine excretion (M H PG pg/creatinine mg) to control for urine volume variability (Paterson, 1967). Platelet and Plasma MAO Activity Assay. Enzyme activity was determined using the technique developed by Murphy et al. (1976). The coefficient of variation for this assay in our laboratory was 5% for split sample and pooled sample measurements (Khan et al.. 1986). Statistical Tests. The data were subjected to analysis of variance (ANOVA). Biochemical indices and indices of autonomic arousal were further analyzed using Student’s t test for comparisons between MHPG levels, MHPG/creatinine ratio, platelet and plasma MAO activity, heart rate and blood pressure in relationship to cardiac and psychiatric diagnosis, and age and sex of the subjects. Cross-tabulations of age, sex, and cardiac and psychiatric diagnoses were performed usingx* test with Yates’correction where appropriate to determine significant interaction between variables.
Results Patients were differentiated by the presence or absence of mitral valve abnormalities. Because age and sex have been reported to affect prevalence rates of mitral valve abnormalities (Savage et al., 1983) these factors were analyzed in our sample with the finding of a higher prevalence of mitral valve abnormalities in females, although this did not reach statistical significance. When patients were diflerentiated by psychiatric diagnosis, no significant associations were found in comparisons ot generalized anxiety patients with panic disorder patients or all patients with panic attacks for biochemical indices of MHPG, M HPG/creatinine, platelet and plasma MAO activity, heart rate, and blood pressure using ANOVA. There was an increased
15 prevalence of mitral valve abnormalities in patients experiencing panic attacks as compared to anxious patients without panic attacks (x2 = 3.6, c$= I, p < 0.06). No statistically significant associations were found between the presence Or absence of mitral valve abnormalities and biochemical indices of MHPG, MHPG/creatinine, and platelet and plasma MAO activity. In addition, no statistically significant associations were found between systolic/diastolic blood pressure or heart rate and mitral valve abnormalities. (See Table 1.) These findings of a lack of relationship held true for both males and females when studied separately. Sex differences were noted for biochemical indices: mean M H PC ,ug/dl + SD was higher in males (males = 246.2 f I8 I .4 vs. females = 90.7 f 98.7, f = 3.42, &= 36, (, < 0.002) mean M H PG pg/creatinine mg I!I SD was higher in males (males = I .96 f I .20 vs. females = I. I2 f I. 16, t = 2.2, $136, p < 0.04). and mean platelet MAO-B activity (nmole/ 100 million platelets/ hour) was higher in females (males = 8.9k2.4~~. females= 13.4+3.8,f=3.5,~Q=26,p
Table 1. Mitral valve abnormalities in relationship urinary MHPGkreatinine, anxious oatients
and platelet Normal mitral valve
Mean age in years i Proportion
SD
females
S
to demographic features, and plasma MAO-B activity in
Abnormal mitral valve
Significance
36.6 f 10.8
32.4 + 7.6
t = 1.4, p = NS
1 Oil 9 (52.6%)
13119 (68.4%)
~2 = 0.44, df = 1, p = NS
12119 (63.2%)
17119 (89.5%)
x2 = 3.6, df = 1, p
171.9 + 165.7
132.5 f 146.2
t=oxi,df=36,p=NS
Proportion with history of panic attacks MHPG
(pg/dl) + SD
MHPG pgicreatinine
mg + SD
(n = 19)
(n = 19)
1.54 + 1.25
1.36 f 1.24
(n = 19)
(n = 19)
11.4 + 3.1
12.0 + 5.1
(n = 16)
(n = 12)
18.3 + 3.9
20.2 + 5.2
(n = 16)
(n = 12)
126.45 f 12.6
120.0 rF_16.6
(n = 19)
(n = 19)
80.7 f 9.1
77.2 t 11.5
(n = 19)
(n = 19)
78.3 f 14.3
76.2 f 14.6
(n = 19)
(n = 19)
= 0.06
t = 0.44, df = 36, p = NS
Platelet MAO-B activity (nmoleilO0 million platelets/hour
Z!ZSD)
t = 0.42, df = 26, /J = NS
Plasma MAO activity (nmole/ 100 million platelets/hour
f
SD)
t=l,ll,df=26,p=NS
Systolic blood pressure (MmHg
+ SD)
t = 0.49, df = 36, p = NS
Diastolic blood pressure (MmHg k SD) Resting heart rate
MHPG = 3-methoxy-4-hydroxyphenylglycol MAO ==monoamine oxidase.
t=l,O,df=36,p=NS t = 0.45, df = 36, p = NS
16 reported (Dager et al., 1986) ranging from definite prolapse (n = I I) to possible prolapse (n = 8) to no evidence of prolapse (n = 19). ANOVA showed no significant association between the degree of cardiac pathology and biochemical indices or autonomic arousal.
Discussion We found no relationship between mitral valve abnormalities and catecholamine activity as measured by urinary MHPG/creatinine and MAO-B activity, or physiological indicators of autonomic arousal as measured by blood pressure or resting heart rate, in a sample of patients with anxiety disorder. Moreover, these indices did not relate to severity of mitral valve pathology. Our finding of increased mitral valve abnormalities associated with the phenomena of panic attacks, as compared to generalized anxiety, has previously been reported (Dager et al., 1986). Increased platelet MAO activity found in females has been described (Khan et al., 1986). Findings of increased MHPG or MHPG/creatinine in males are’consistent with earlier reports and may reflect increased body mass or activity level (Veith et al., 1983). Considerable research has been focused on the relationship between anxiety and increased catecholamines. Stress has been demonstrated to raise norepinephrine and epinephrine levels (Dimsdale and Moss, 1980). Panic patients have been reported to have increased epinephrine and norepinephrine plasma levels (Nesse et al., 1984). Increased locus ceruleus activity has been shown to produce anxiety in animals (Redmond and Juang, 1979). In humans, administration of yohimbine (Holmberg and Gershon, 1961; Charney et al., 1984), isoproterenol (Rainey et al., 1984) epinephrine, and norepinephrine (Guttmacher et al., 1983) has been reported to provoke anxiety symptoms. Yohimbine-induced anxiety has been correlated to increases in plasma MHPG (Charney et al., 1984). These findings suggest a relationship between the clinical phenomenon of anxiety and increased catecholamines. Mitral valve abnormalities have also been associated with panic/anxiety, but mitral valve abnormalities do not appear to differentiate subgroups of anxious patients based on treatment outcome or sensitivity to lactate infusion (Gorman et al., 1981a, 19816). Our findings suggest that mitral valve abnormalities and increased catecholamines/autonomic arousal in anxious patients are unrelated. In contrast, a recent study has reported decreased urinary catecholamine activity in a subgroup of anxiety patients with mitral valve abnormalities (Nesse et al., 1985). A limitation of that conclusion was the small sample studied (n = 7). Further, that study was in disagreement with findings from larger samples of patients with mitral valve abnormalities studied by cardiologists. Several reports have suggested that a relationship exists between mitral valve abnormalities and increased catecholamine function (Gaffney et al., 1979; Boudoulas et al., 1980; Pasternac et al., 1982; Puddu et al., 1983). These studies have investigated symptomatic populations discovered to have mitral valve abnormalities in association with symptoms indistinguishable from pain/anxiety as compared to nonanxious controls. Gaffney et al. (1979) demonstrated that the presence of clinical symptoms (chest pain, palpitations. and dyspnea) best correlated with the degree of autonomic dysfunction in patients with mitral valve abnormalities. Recent work suggests that these presumed cardiac
17 symptoms are probably not manifestations of mitral valve abnormalities (Jeresaty, 1979; Levine and Weyman, 1984). There is no evidence that asymptomatic patients with mitral valve abnormalities have increased catecholamines/autonomic arousal. These factors suggest to us that reports of increased catecholamines/autonomic arousal are associated with the clinical state of anxiety, irrespective of findings of mitral valve abnormalities. The epidemiological association between anxiety disorders and mitral valve abnormalities may be secondary to precipitation of mitral valve prolapse by panic attacks (Klein and Gorman, 1984). There is evidence from multiple sources supporting this hypothesis. We have found a relationship between mitral valve abnormalities and the phenomenon of panic attacks as compared to generalized anxiety without panic attacks (Dager et al., 1986). There is evidence suggesting that mitral valve abnormalities may be related to collagen abnormalities of connective tissue (Read et al., 1965; Rosenberg et al., 1983). Additionally, it has been reported that acute reversible mitral valve prolapse can be provoked by the inhalation of amyl nitrite (Gavin et al., 1983). Thus, it is possible that recurrent panic attacks may result in hemodynamic changes which in susceptible individuals with collagen abnormalities may be manifested as echocardiographic evidence of mitral valve prolapse. This hypothesis, now under further investigation, is consistent with our findings that anxiety/panic patients differentiated by the presence or absence of mitral valve abnormalities do not differ in catecholamine activity, as indicated by urinary MHPG/creatinine or MAO-B activity, and autonomic arousal, as measured by blood pressure and resting heart rate. Acknowledgment. Marcy Hall.
We are
grateful for the secretarial assistance of Dorothy
Reedy and
References American .Psychiatric Association. DSM-III: Diagnostk and Statistical Manual of’ Mental Disorders. 3rd ed. APA, Washington, DC (1980). Boudoulas, H., Reynolds, J.C., Malzaferri, E., and Wooley, C.F. Metabolic studies in mitral valve prolapse syndrome. Circulation, 61, 1200 (1980). Charney, D.S., Heninger, G.R., and Breier, A. Noradrenergic function in panic anxiety. Archives of’ General Psychiatry, 91, 75 I ( 1984). Dager, S.R., Comess, K.A., and Dunner, D.L. Differentiation of anxious patients by ZD-echocardiographic evaluation of the mitral valve. American Journal of’ Psychiatry, 143, 533 ( 1986)‘. Dimsdale, J.E., and Moss, T. Plasma catecholamine in stress and exercise. Journal of the American Medical Association, 243, 340 ( 1980). Gaffney, F.A., Karlsson, E.S.. Campbell, W.G., Schutte, J.E., Nixon, J.V., Willerson, J.T., and Blomquist, C.G. Autonomic dysfunction in women with mitral valve prolapse syndrome. Circulation. 59, 894 ( 1979). Gavin, W.A., Pearlman, AS., and Saal, A.K. Abnormal mitral leaflet coaptation: A nonspecific 2-D echo finding. Circulation. 68, (Suppl. II), I I I (1983). Gorman, J., Fyer, A., Gliklich, J., King, D., and Klein, D.F. Mitral valve prolapse and panic disorders; Effect of imipramine. In: Klein, D.F., and Rabkin, J., eds. Anxiety: New Research and Changing Concepts. Raven Press, New York (198la). Gorman, J.M., Fyer, A.F., Gliklich, J., King, D., and Klein, D.F. Effects of sodium lactate on patients with panic disorder and mitral valve prolapse. American Journal oj’Ps_vchiatry. 138,247 (198lh).
18
Guttmacher,
L.B.,
Comprehensive
Murphy,
Psychiatry,
D.L.,
and
Insel,
T.R.
Pharmacologic
models
of anxiety.
24, 3 12 ( 1983).
Hammond, V.A., and Johnston, D.G. A semi-automated assay for plasma catecholamines using high-performance liquid chromatography with electrochemical detection. Clinka Chimica
Acta.
Holmberg,
137, 87
( 1984).
G.. and Gershon,
S. Autonomic
and psychic effects of yohimbine
hydrochloride.
Ps.c~c~hopharmac~ologia,2, 93 ( 196 I). Jeresaty, R. Mirral Valve Prolapse.
Raven Press, New York (1979). Khan, A., Lee, E., Dager, S., Hyde, T.. Raisys, V.. Avery, D., and Dunner, MAO activity in anxiety and depression. Biok~gicd Psychiarry. 21, 847 (1986). Klein, D.F., and Gorman, J.M. Panic disorder and mitral valve prolapse. Clinid
Psychiarry,
D. Platelet Journal
q/’
2, I4 ( 1984).
Levine, R., and Weyman, A. Mitral valve prolapse: A disease in search of or created by its definition. E~.hoc,ardiogruph.v. 1, 3 (1984). Markiewicz, W., Stone, J.. London, E., Hunt, S.A.. and Popp, R.L. Mitral valve prolapse in one hundred presumably healthy young females. Circ~ulution. 43,464 (1976). Moleman, P., and Borstrok, J.J.M. Analysis of urinary 3-methoxy4-hydroxyphenylglycol by high-performance liquid chromatography and electrochemical detection. Journal o/’ Chromatography, 227, 39 I ( 1982). Murphy, D.L., Wright, C., Buchsbaum, M.S., Nichols, A., Costa, J.L.. and Wyatt, R.J. Platelet and plasma amine oxidase activity in 680 normals: Sex and age differences and stability over time. Biochemird Medicine, 16, 254 ( 1976). Nesse, R.M., Cameron, O.G., Buda, A.J., McCann, D.S., Curtis, G.C., and Huber-Smith, M.J. Urinary catecholamines and mitral valve prolapse in panic-anxiety patients. P.~~,chiarrr~ Research, 14,67 ( 1985). Nesse, R.M., Cameron, O.G.. Curtis, G.C., McCann, D.S., and Huber-Smith, M.J. Adrenergic Innction in patients with panic anxiety. Archives of General Ps.vchiarry, 41, 771 (1984).
Pariser, S., Pinta, E., and Jones, B. Mitral valve prolapse syndrome and anxiety neurosis/ panic disorder. American Journal of’ Psychiatry, 135, 240 (1978). Pasternac, A., Tubau, J.F., Puddu, P.E., Krol, R.B., and \DeChamplain, J. Increased plasma catecholamine levels in patients with symptomatic mitral valve prolapse. American Journal of Medicine, 73, 783 ( 1982). Paterson, N. Relative constancy of 24-hour urine volume and 24-hour creatinine output. Clinica Chimica Acta, 18, 57 ( 1967). Puddu, P.E., Pasternac, A., Tubau, J.F., Krol, R., Farley, I,., and DeChamplain, J. QT interval prolongation and increased plasma catecholamine levels in patients with mitral valve prolapse. American Heart Journal, 105,442 ( 1983). Rainey, J.M., Jr., Pohl, R.B., Williams, M., Knitter, E., Freedman, R.R., and Ettedgui, E. A comparison of lactate and isoproterenol anxiety states. Psychopafho1og.v. 17 (Suppl. I), 74 ( 1984). Read, R.C., Thai, A.P., and Wendt, V.E. Symptomatic valvular myxomatous transformation (the floppy valve syndrome): A possible forme fruste of the Marfdn syndrome. Circulation.
32, 897 ( 1965).
Redmond, D.E., and Juang, Y.H. New Evidence for a locus coeruleus-norepinephrinc connection with anxiety. Lifl, Sciences, 25, 2 149 ( 1979). Rosenberg, C.A., Derman, G.H., Grabb, W.C., and Buda, A.J. Hypomastra and mitral valve prolapse. New England Journal of Medicine. 309, 1230 (1983). Savage, D.D., Garrison, R.J., Devereux, R.B., Castelli. W.. Anderson, S.. Levy, I).. McNamara, P., Stokes, J., Kannel, W., and Feinleib, M. Mitral valve prolapse in the general population: 1. Epidemiological features-The Framingham study. American Hrarr Journal. 106, 571 (1983).
Veith, R.C., Bielski, R.J., Bloom, V., Fawcett, J.A.. Narasimhachari, N.. and Friedel. R. Urinary MHPG excretion and treatment with desipramine or amitriptyline: Prediction of effect of treatment and methodological hazards. Jownul c!/’ Clinkal response, Ps.vc,hopharmac,olf)g.:v. 3, I8 ( 1983).
Rwurch.
20,
I 3-1X
13
Elsevier
Mitral Valve Abnormalities Anxious Patients Stephen David
R. Dager, L. Dunner
Received February
Arifulla
Khan,
and Catecholamine
Keith
A. Comess,
Vidmantys
Activity
in
Raisys,
and
18. 1986; revised version received June 4, 1986; accepted June 20. 1986.
Abstract. We studied 38 anxiety disorder patients, 19 of whom had evidence of mitral valve abnormalities by two-dimensional echocardiography. The presence or absence of mitral valve abnormalities was not related to 3-methoxy-4hydroxyphenylglycol/creatinine excretion, platelet and plasma monoamine oxidase-type activity, or autonomic arousal as measured by blood pressure and resting heart rate. These findings fail to support the hypothesis that mitral valve abnormalities identify a specific subpopulation of anxious patients with differences in catecholamine function. Words. Key catecholamines,
monoamine 3-Methoxy-rl-hydroxyphenylglycol, anxiety, panic disorder, mitral valve prolapse.
oxidase,
Mitral valve abnormalities have been associated with anxiety disorders and, more specifically, the phenomenon of panic attacks, although a mechanism for this relationship has not been established (Pariser et al., 1978; Dager et al., 1986). It has been postulated that increased catecholamine levels and/ or increased autonomic arousal may be the underlying disorder clinically manifested as both mitral valve abnormalities and anxiety symptoms in a subpopulation of anxious patients (Gorman et al., 1981~). We report our findings on catecholamine function as measured by 24-hour urinary 3-methoxy+hydroxyphenylglycol (MH PG), a major metabolite of catecholamines, and activity of platelet and plasma monoamine oxidase (MAO), an enzyme involved in the intracellular breakdown of catecholamines and indolamines, in relationship to mitral valve abnormalities. Autonomic arousal, as determined by systolic/diastolic blood pressure and heart rate in the resting state, was also studied.
Methods Subjects. Harborview
Thirty-eight outpatients entered into a psychopharmacology research program at Medical Center were studied. Subjects were evaluated by a faculty psychiatrist
Stephen R. Dager, M.D., and Arifulla Khan, M.B., B.S., are Assistant Professors; David L. Dunner, M.D., is Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine. Keith A. Comess, M.D., is Assistant Professor and Director of Adult Echocardiography, Department of Internal Medicine, Division of Cardiology, University of Arizona School of Medicine. Vidmantys Raisys, Ph.D.. is Associate Professor, Department of Laboratory Medicine, University of Washington School of Medicine. (Reprint requests to Dr. S.R. Dager, Harborview Medical Center, ZA-99, 325 9th Ave., Seattle, WA 98104, USA.) 0165.1781/X7/$03.50
Q 1987 Elsevier Science Publishers B.V.
14 and met DSM-//I criteria (American Psychiatric Association, 1980) for one of the following disorders: generalized anxiety disorder (n = 9): panic disorder (n = IS); agoraphobia with panic disorder (n = IO); and generalized anxiety disorder with panic attacks of insufficient frequency to diagnose panic disorder (n = 4). Subjects had not taken medicat.ions affecting the central nervous system for a minimum of 2 weeks before MHPG and MAO samples were obtained. Subjects were not on dietary restrictions before sample collection. All subjects had an interpretable echocardiographic evaluation of the mitral valve apparatus and a 24-hour urine collection of adequate volume (> 1,000 cc/24 hours), and 24-hour urine creatinine levels within normal range for our laboratory (men > I .O g/24 hours and women > 0.7 g/24 hours) (Veith et al., 1983). A subsample of 28 subjects also gave consent for measurement of platelet and plasma MAO activity. All subjects had a baseline blood pressure determination in the supine position and a resting heart rate taken on the day urine samples were returned and blood samples drawn. Cardiac Evaluation. The mitral valve apparatus was evaluated using two-dimensional echocardiography (2D-echo) with supplemental 2D-echo guided M-mode recordings. Diagnosis of mitral valve abnormalities was based on 2D-echo evidence of mitral leaflet flat closure or buckling below the level of the annular plane on one or more 2D-echo views (apical 4-chamber and parasternal long axis) with m-mode confirmation in questionable cases (Markiewicr et al., 1976) in conjunction with 2D-echo evidence of myxomatous degeneration elongation and thickening of the mitral leaflets (Dager et al., 1986). MHPG Determination. A 24-hour urine sample was collected following the first a.m. void on day I through the first a.m. void of the following day. Urine samples were kept refrigerated and brought by subjects to the clinic within 24 hours of collection, with samples being stored at -30°C. MHPG values were determined by high performance liquid chromatography with an electrochemical detection method using glusulase to hydrolyse sulphate and glucuronide for measurement of total MHPG (Moleman and Borstrok, 1982; Hammond and Johnston. 1984). The coefficient of variation for this assay in our laboratory was c).Xyo for repeat pooled sample measurements. MHPG activity was reported as a function of urinary creatinine excretion (M H PG pg/creatinine mg) to control for urine volume variability (Paterson, 1967). Platelet and Plasma MAO Activity Assay. Enzyme activity was determined using the technique developed by Murphy et al. (1976). The coefficient of variation for this assay in our laboratory was 5% for split sample and pooled sample measurements (Khan et al.. 1986). Statistical Tests. The data were subjected to analysis of variance (ANOVA). Biochemical indices and indices of autonomic arousal were further analyzed using Student’s t test for comparisons between MHPG levels, MHPG/creatinine ratio, platelet and plasma MAO activity, heart rate and blood pressure in relationship to cardiac and psychiatric diagnosis, and age and sex of the subjects. Cross-tabulations of age, sex, and cardiac and psychiatric diagnoses were performed usingx* test with Yates’correction where appropriate to determine significant interaction between variables.
Results Patients were differentiated by the presence or absence of mitral valve abnormalities. Because age and sex have been reported to affect prevalence rates of mitral valve abnormalities (Savage et al., 1983) these factors were analyzed in our sample with the finding of a higher prevalence of mitral valve abnormalities in females, although this did not reach statistical significance. When patients were diflerentiated by psychiatric diagnosis, no significant associations were found in comparisons ot generalized anxiety patients with panic disorder patients or all patients with panic attacks for biochemical indices of MHPG, M HPG/creatinine, platelet and plasma MAO activity, heart rate, and blood pressure using ANOVA. There was an increased
15 prevalence of mitral valve abnormalities in patients experiencing panic attacks as compared to anxious patients without panic attacks (x2 = 3.6, c$= I, p < 0.06). No statistically significant associations were found between the presence Or absence of mitral valve abnormalities and biochemical indices of MHPG, MHPG/creatinine, and platelet and plasma MAO activity. In addition, no statistically significant associations were found between systolic/diastolic blood pressure or heart rate and mitral valve abnormalities. (See Table 1.) These findings of a lack of relationship held true for both males and females when studied separately. Sex differences were noted for biochemical indices: mean M H PC ,ug/dl + SD was higher in males (males = 246.2 f I8 I .4 vs. females = 90.7 f 98.7, f = 3.42, &= 36, (, < 0.002) mean M H PG pg/creatinine mg I!I SD was higher in males (males = I .96 f I .20 vs. females = I. I2 f I. 16, t = 2.2, $136, p < 0.04). and mean platelet MAO-B activity (nmole/ 100 million platelets/ hour) was higher in females (males = 8.9k2.4~~. females= 13.4+3.8,f=3.5,~Q=26,p
Table 1. Mitral valve abnormalities in relationship urinary MHPGkreatinine, anxious oatients
and platelet Normal mitral valve
Mean age in years i Proportion
SD
females
S
to demographic features, and plasma MAO-B activity in
Abnormal mitral valve
Significance
36.6 f 10.8
32.4 + 7.6
t = 1.4, p = NS
1 Oil 9 (52.6%)
13119 (68.4%)
~2 = 0.44, df = 1, p = NS
12119 (63.2%)
17119 (89.5%)
x2 = 3.6, df = 1, p
171.9 + 165.7
132.5 f 146.2
t=oxi,df=36,p=NS
Proportion with history of panic attacks MHPG
(pg/dl) + SD
MHPG pgicreatinine
mg + SD
(n = 19)
(n = 19)
1.54 + 1.25
1.36 f 1.24
(n = 19)
(n = 19)
11.4 + 3.1
12.0 + 5.1
(n = 16)
(n = 12)
18.3 + 3.9
20.2 + 5.2
(n = 16)
(n = 12)
126.45 f 12.6
120.0 rF_16.6
(n = 19)
(n = 19)
80.7 f 9.1
77.2 t 11.5
(n = 19)
(n = 19)
78.3 f 14.3
76.2 f 14.6
(n = 19)
(n = 19)
= 0.06
t = 0.44, df = 36, p = NS
Platelet MAO-B activity (nmoleilO0 million platelets/hour
Z!ZSD)
t = 0.42, df = 26, /J = NS
Plasma MAO activity (nmole/ 100 million platelets/hour
f
SD)
t=l,ll,df=26,p=NS
Systolic blood pressure (MmHg
+ SD)
t = 0.49, df = 36, p = NS
Diastolic blood pressure (MmHg k SD) Resting heart rate
MHPG = 3-methoxy-4-hydroxyphenylglycol MAO ==monoamine oxidase.
t=l,O,df=36,p=NS t = 0.45, df = 36, p = NS
16 reported (Dager et al., 1986) ranging from definite prolapse (n = I I) to possible prolapse (n = 8) to no evidence of prolapse (n = 19). ANOVA showed no significant association between the degree of cardiac pathology and biochemical indices or autonomic arousal.
Discussion We found no relationship between mitral valve abnormalities and catecholamine activity as measured by urinary MHPG/creatinine and MAO-B activity, or physiological indicators of autonomic arousal as measured by blood pressure or resting heart rate, in a sample of patients with anxiety disorder. Moreover, these indices did not relate to severity of mitral valve pathology. Our finding of increased mitral valve abnormalities associated with the phenomena of panic attacks, as compared to generalized anxiety, has previously been reported (Dager et al., 1986). Increased platelet MAO activity found in females has been described (Khan et al., 1986). Findings of increased MHPG or MHPG/creatinine in males are’consistent with earlier reports and may reflect increased body mass or activity level (Veith et al., 1983). Considerable research has been focused on the relationship between anxiety and increased catecholamines. Stress has been demonstrated to raise norepinephrine and epinephrine levels (Dimsdale and Moss, 1980). Panic patients have been reported to have increased epinephrine and norepinephrine plasma levels (Nesse et al., 1984). Increased locus ceruleus activity has been shown to produce anxiety in animals (Redmond and Juang, 1979). In humans, administration of yohimbine (Holmberg and Gershon, 1961; Charney et al., 1984), isoproterenol (Rainey et al., 1984) epinephrine, and norepinephrine (Guttmacher et al., 1983) has been reported to provoke anxiety symptoms. Yohimbine-induced anxiety has been correlated to increases in plasma MHPG (Charney et al., 1984). These findings suggest a relationship between the clinical phenomenon of anxiety and increased catecholamines. Mitral valve abnormalities have also been associated with panic/anxiety, but mitral valve abnormalities do not appear to differentiate subgroups of anxious patients based on treatment outcome or sensitivity to lactate infusion (Gorman et al., 1981a, 19816). Our findings suggest that mitral valve abnormalities and increased catecholamines/autonomic arousal in anxious patients are unrelated. In contrast, a recent study has reported decreased urinary catecholamine activity in a subgroup of anxiety patients with mitral valve abnormalities (Nesse et al., 1985). A limitation of that conclusion was the small sample studied (n = 7). Further, that study was in disagreement with findings from larger samples of patients with mitral valve abnormalities studied by cardiologists. Several reports have suggested that a relationship exists between mitral valve abnormalities and increased catecholamine function (Gaffney et al., 1979; Boudoulas et al., 1980; Pasternac et al., 1982; Puddu et al., 1983). These studies have investigated symptomatic populations discovered to have mitral valve abnormalities in association with symptoms indistinguishable from pain/anxiety as compared to nonanxious controls. Gaffney et al. (1979) demonstrated that the presence of clinical symptoms (chest pain, palpitations. and dyspnea) best correlated with the degree of autonomic dysfunction in patients with mitral valve abnormalities. Recent work suggests that these presumed cardiac
17 symptoms are probably not manifestations of mitral valve abnormalities (Jeresaty, 1979; Levine and Weyman, 1984). There is no evidence that asymptomatic patients with mitral valve abnormalities have increased catecholamines/autonomic arousal. These factors suggest to us that reports of increased catecholamines/autonomic arousal are associated with the clinical state of anxiety, irrespective of findings of mitral valve abnormalities. The epidemiological association between anxiety disorders and mitral valve abnormalities may be secondary to precipitation of mitral valve prolapse by panic attacks (Klein and Gorman, 1984). There is evidence from multiple sources supporting this hypothesis. We have found a relationship between mitral valve abnormalities and the phenomenon of panic attacks as compared to generalized anxiety without panic attacks (Dager et al., 1986). There is evidence suggesting that mitral valve abnormalities may be related to collagen abnormalities of connective tissue (Read et al., 1965; Rosenberg et al., 1983). Additionally, it has been reported that acute reversible mitral valve prolapse can be provoked by the inhalation of amyl nitrite (Gavin et al., 1983). Thus, it is possible that recurrent panic attacks may result in hemodynamic changes which in susceptible individuals with collagen abnormalities may be manifested as echocardiographic evidence of mitral valve prolapse. This hypothesis, now under further investigation, is consistent with our findings that anxiety/panic patients differentiated by the presence or absence of mitral valve abnormalities do not differ in catecholamine activity, as indicated by urinary MHPG/creatinine or MAO-B activity, and autonomic arousal, as measured by blood pressure and resting heart rate. Acknowledgment. Marcy Hall.
We are
grateful for the secretarial assistance of Dorothy
Reedy and
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