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Association Between Anxiety and C-Reactive Protein Levels in Stable Coronary Heart Disease Patients
Association Between Anxiety and C-Reactive Protein Levels in Stable Coronary Heart Disease Patients Bettina Bankier, M.D., Sc.M., Justine Barajas Abelardo Martinez-Rumayor, M.D., James L. Januzzi, M.D.
Background: Anxiety is highly prevalent among patients with stable coronary heart disease (CHD). However, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. Objective: This study aimed for a comprehensive evaluation of anxiety in stable CHD patients, in addition to cardiac biomarkers such as C-reactive protein (CRP), troponin T, and amino-terminal pro-B-type brain natriuretic peptide. Method: The study included 43 CHD patients with anxiety disorder and 42 CHD patients without psychiatric disorder given the Structured Clinical Interview for DSM–IV. Results: Regression analyses showed an association between anxiety (anxiety disorder, not otherwise specified) and CRP levels, despite model adjustment for various related demographic and clinical variables. Anxiety was associated with CRP levels. Conclusion: There are significant associations between anxiety and CHD risk, with a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely CRP. It is not clear whether this association is directly causal or relates to other medical processes among patients with heightened anxiety. The findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well. (Psychosomatics 2009; 50:347–353)
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everal studies shed light on the impact of heightened anxiety and specific anxiety disorders on cardiovascular complications, including incident coronary heart disease (CHD) and recurrence of CHD.1–7 Anxiety is highly prevalent among patients with stable CHD.8 However, despite the apparent relationships between anxiety and CHD morbidity and mortality, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. In an effort to explain the links between psychiatric symptoms and disorders and CHD, specific biomarkers have been added to research analyses. For example, Empana et al.9 suggested an association of depressive mood with inflammatory markers and suggested that depressive mood is related to CHD even after adjustment for these inflammatory markers. Furthermore, Frasure-Smith et al.10 demonstrated that depression and C-reactive protein Psychosomatics 50:4, July-August 2009
(CRP) levels represented overlapping prognostic risks over 2 years in men assessed 2 months after acute coronary syndrome. However, previous research seemed to mainly focus on the association of depressive disorders with specific biomarkers in CHD patients, without consideration of anxiety and specific anxiety disorders. In this study, we aimed for a comprehensive evaluation of anxiety disorders in stable CHD patients, including meticulous psychiatric assessment, as well as assessment Received December 15, 2007; revised April 9, 2008; accepted April 9, 2008. From the Department of Psychiatry, and Division of Cardiology, Massachusetts General Hospital; and the Department of Psychiatry and Psychotherapy, Medical University Vienna, Austria. Send correspondence and reprint requests to Bettina Bankier, M.D., Sc.M., Department of Psychiatry and Psychotherapy, Medical University Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090, Vienna, Austria. e-mail: bettina.bankier@ meduniwien.ac.at © 2009 The Academy of Psychosomatic Medicine
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Anxiety and C-Reactive Protein of biomarkers such as CRP, a marker for inflammation; troponin T (TnT), a marker for necrosis; and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP), a marker for left-ventricular dysfunction and congestive heart failure. We hypothesized that significant associations would exist between anxiety disorders and these specific biomarkers. METHOD Design and Setting We performed a cross-sectional study of 85 stable CHD outpatients (N⫽43 with anxiety disorder; N⫽42 with no psychiatric disorder) between July 2005 and June 2006 in the Outpatient Cardiology Clinic at the Massachusetts General Hospital (MGH). Stable CHD outpatients of one cardiologist (JLJ) were included in the study. Stable CHD patients with anxiety disorder in conjunction with depressive disorder or with another psychiatric disorder, for example, substance abuse or dependency, were not included in this analysis, to allow for the assessment of anxiety unconfounded by other comorbid psychiatric conditions. The research protocol was approved by the Institutional Review Board of the MGH. Psychiatric consultation and treatment referral were offered in accordance with psychiatric diagnoses determined by the interview. Recruitment Procedure The study recruitment overture was made at the front desk at the Outpatient Cardiology Clinic in the form of a questionnaire, which asked outpatients in an anonymous fashion whether they would be interested in being enrolled in the study. The study was presented as a research study including an interview about anxiety, mood, and psychosocial aspects of patients with diagnosed CHD. If patients agreed to participate and met study criteria, the cardiologist requested their inclusion before the cardiac outpatient visit. The interviews were conducted immediately before or immediately after the outpatient visit. The first author (BB) was continuously present at the cardiac outpatient unit during the days the CHD patients were scheduled. Patients who were included in the study signed a detailed written informed consent. No incentives or reimbursements were given to the patients. Medical Inclusion and Exclusion Criteria There was no restriction regarding the age of participants in the study. The medical inclusion criteria for 348
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stable CHD outpatients were 1) CHD diagnosed via a positive stress test (included treadmill stress test, infusion stress test, stress echo as well as thallium or nuclear imaging testing); or 2) history of documented myocardial infarction (MI) by ECG and creatine phosphokinase isoenzymes/troponins; or 3) coronary atherosclerosis (documented by coronary angiography), with or without revascularization procedures including percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). The medical exclusion criteria were 1) active, unstable angina; 2) active congestive heart failure (CHF) with Class IV symptoms by New York Heart Association Symptom Severity estimates; 3) severe comorbid cardiac disease, for example, advanced valvular heart disease; and 4) previous valve-replacement therapy. We also excluded subjects with unstable medical disorders (unstable neurological, endocrine, pulmonary, gastrointestinal, hepatic, renal, immunological or hematological disease, organic brain disease, or cancer) as determined by history, physical, ECG, and laboratory examination. Cardiac Biomarker Assessment At the time of enrollment, we obtained a sample of blood, which was tested for CRP with a high-sensitivity assay (Dade-Behring, Inc.; Newark, DE, U.S.). This assay is a turbidometric immunoassay with a dynamic range of 0.05 mg/L to 25.0 mg/L. Generally speaking, ⬍1 mg/L is considered as “low risk” for acute myocardial infarction, whereas ⬎3 mg/L is considered “high risk.”11–14 Also, we determined concentrations of TnT by use of a standard immunoassay (Roche Diagnostics, Inc.; Indianapolis, IN). In healthy reference populations, the 99th percentile for this assay is considered to be ⬍0.01 ng/mL;15 the cutpoint yielding acceptable analytic precision is 0.03 ng/mL. Last, NT-proBNP concentrations were determined by using standard immunochemical methods (Roche Diagnostics, Inc.; Indianapolis, IN). The lower detectable limit with this assay is ⬎5 ng/L. Normal outpatient reference ranges for NT-proBNP are ⬍125 ng/L for patients ⬍75 years old and ⬍450 ng/L for patients age 75⫹ years. Psychiatric Assessment Psychiatric diagnoses were established by using the Structured Clinical Interview for DSM–IV (SCID; Diagnostic and Statistical Manual of Mental Disorders, 4th Edition).16 Psychiatric assessment was performed on Axis Psychosomatics 50:4, July-August 2009
Bankier et al. I (Clinical Disorders), Axis III (General Medical Conditions), Axis IV (Psychosocial and Environmental Problems), and Axis V (Global Assessment of Functioning). The first author (BB) conducted all structured clinical interviews and was blinded to all psychiatric information about the cardiac patients before the study interview. Psychiatric exclusion criteria were significant risk of suicide or homicide or the presence of any one of the following DSM–IV diagnoses: 1) substance use disorders, including alcohol, active within the last 3 months; 2) schizophrenia; 3) delusional disorder; 4) psychotic disorders not elsewhere classified; 5) bipolar disorder; 6) delirium; and 7) dementia. In particular, actively suicidal and psychotic patients were not included in the study, since the Institutional Review Board of the MGH discourages recruitment of subjects who are clinically unstable; that is, actively suicidal or psychotic, in studies that offer no direct treatment benefit.
Data Analyses Concentrations of biomarkers of the anxiety-disorders group and the group with no psychiatric disorder were generated with mean plus standard deviation (SD), and comparisons between groups were performed by with analysis of variance (ANOVA). Stepwise multiple-regression analyses were performed to assess the relationships TABLE 1.
between the biomarkers CRP, TnT, and NT-proBNP (dependent variables) and specific anxiety disorders in stable CHD patients. Also, independent variables included psychiatric disorder status, age, gender, marital status, educational attainment, family history of CHD, past and current overweight or obesity, past and current smoking status, type II diabetes mellitus, hypertension, hyperlipidemia, current benzodiazepine treatment, and current antidepressant treatment. Data collection and calculations were performed with SPSS 15.0 for Windows software.17
Demographic Characteristics In the group of stable CHD patients with anxiety disorders (N⫽43), the mean age was 70 years (SD: 10), and 72% (N⫽31) of the patients were men. Considering the group of stable CHD patients with no psychiatric disorder (N⫽42), the mean age was 68 (SD: 13), and 76% (N⫽32) of the patients were men. Table 1 summarizes demographic characteristics of the study participants in both groups, including age, gender, marital status, children, educational attainment, and ethnicity. Also, Table 1 presents medical background, including family history of CHD, past and current overweight or obesity, past and current smoking status, type II diabetes mellitus, hypertension, and hyperlipidemia.
Demographic Characteristics and Medical Backgrounds of Stable Coronary Heart Disease (CHD) Outpatients With Anxiety Disorder (Nⴝ43), and With No Psychiatric Disorder (Nⴝ42)
Stable CHD Patients (Nⴝ85) Age, years, mean (SD) Gender Marital status Children, N, mean (SD) Race, white Education Completed high school Completed 4 years of college Family history of CHD History of overweight or obesity Current overweight or obesity Smoking history Current smoking Type II diabetes mellitus Hypertension Hyperlipidemia
Stable CHD Outpatients With One or More Anxiety Disorders (Nⴝ43)
Stable CHD Outpatients With No Psychiatric Disorder (Nⴝ42)
70 (10) 72% men (N⫽31) 70% married (N⫽30) 2.9 (2.8) 95% (N⫽41)
68 (13) 76% men (N⫽32) 81% married (N⫽34) 2.6 (1.6) 98% (N⫽41)
40% (N⫽17) 33% (N⫽14) 42% (N⫽18) 28% (N⫽12) 28% (N⫽12) 67% (N⫽29) 2% (N⫽1) 30% (N⫽13) 81% (N⫽35) 84% (N⫽36)
24% (N⫽10) 12% (N⫽5) 36% (N⫽15) 24% (N⫽10) 19% (N⫽8) 57% (N⫽24) 7% (N⫽3) 24% (N⫽10) 81% (N⫽34) 86% (N⫽36)
SD: standard deviation.
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Anxiety and C-Reactive Protein RESULTS Anxiety Disorders and Psychopharmacological Treatment Of 43 stable CHD outpatients with anxiety disorder, 5 fulfilled clinical criteria for generalized anxiety disorder (GAD; overlap with specific phobia: N⫽1), 1 had posttraumatic stress disorder (PTSD), 8 had social phobia, 13 had specific phobia (overlap with social phobia: N⫽1), 1 patient had panic disorder with agoraphobia, 3 patients had agoraphobia alone, and 14 stable CHD patients had anxiety disorder not otherwise specified; in all cases, heightened generalized anxiety did not meet all clinical criteria for GAD. If a patient fulfilled clinical criteria for more than one specific anxiety disorder, then both specific anxiety disorders were recorded. In considering past and current psychopharmacological treatment of stable CHD patients with anxiety disorder, 11 patients reported past use of benzodiazepines as treatment against heightened anxiety, whereas 8 patients mentioned current use of benzodiazepines. Eleven patients had been diagnosed with anxiety disorder in the past. Five patients reported past use of antidepressants, and three patients reported current use of antidepressant medication as treatment against anxiety; two of these patients reported current use of an SSRI (serotonin reuptake inhibitor) medication. Again, patients who fulfilled clinical criteria for a specific anxiety disorder in conjunction with depressive TABLE 2.
disorder or another psychiatric disorder according to the DSM–IV were not included in this study. With regard to psychosocial and environmental problems (Axis IV of the DSM–IV), 26% of patients (N⫽11) with anxiety disorder reported problems with their primary social support group, and 21% (N⫽9) mentioned occupational problems. In the group of stable CHD outpatients with no psychiatric disorder, 17% (N⫽7) reported problems with their primary social support group, whereas 14% (N⫽6) mentioned occupational problems. Stable CHD patients with anxiety disorder had a mean of 64 (SD: 5) on the Global Assessment of Functioning Scale (GAS; 1–100; Axis V of the DSM–IV), versus a mean of 72 (SD: 8) in patients with no psychiatric disorder. Associations Among Anxiety Disorders and Levels of CRP, TnT, and NT-proBNP Table 2 presents concentrations (mean and SD) of CRP, TnT, and NT-proBNP in stable CHD patients with anxiety disorder and in patients with no psychiatric disorder. In particular, stable CHD patients with heightened anxiety in the group with Anxiety Disorder Not Otherwise Specified had a higher mean level of CRP (mean: 8.6 mg/L,) than CHD patients with no psychiatric disorder (mean: 4.04 mg/L; SD: 4.1; p⫽0.04). Also, agoraphobia patients showed a higher mean level of CRP (14.5 mg/L; p⫽0.02). Accordingly, stepwise multiple-regression anal-
Means and Standard Deviations (SD) of C-Reactive Protein (CRP; mg/L), TnT (ng/mL), and NT-proBNP (ng/L) in stable Coronary Heart Disease (CHD) Outpatients With Anxiety Disorder (Nⴝ43) and in CHD Patients With No Psychiatric Disorder (Nⴝ42) Stable CHD Patients (Nⴝ85)
Anxiety disorder (N⫽43) No psychiatric disorder (N⫽42) Generalized anxiety disorder (GAD; N⫽5) Specific phobia (N⫽13) Social phobia (N⫽8) Agoraphobia (N⫽3) Anxiety disorder, not otherwise specified (N⫽14)
CRP Mean (SD) mg/L 6.1 (SD: 8.8) NS 4.04 (SD: 4.1) NS 2.4 (SD: 2.4) NS 3.5 (SD: 3.6) NS 5.1 (SD: 8.8) NS 14.5 (SD: 2.7) p⫽0.02 8.6 (SD: 12.5) p⫽0.04
TnT Mean (SD) ng/mL 0.003 (SD: 0.009) NS 0.005 (SD: 0.015) NS ⬍0.001 NS 0.002 (SD: 0.008) NS ⬍0.001 NS ⬍0.001 NS 0.008 (SD: 0.014) NS
NT-proBNP Mean (SD) ng/L 498 (SD: 977) NS 581 (SD: 1,007) NS 241 (SD: 235) NS 191 (SD: 159) NS 238 (SD: 233) NS 406 (SD: 526) NS 1,028 (SD: 1,584) p⫽0.04
Reference levels: CRP ⬎3mg/L; TnT ⬎0.01 ng/mL; for NT-proBNP: ⬎125 ng/L for age ⬍75, and ⬎450 ng/L for age 75⫹ years; NS: not significant.
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Bankier et al. yses showed significant relationships between heightened anxiety and CRP levels (⫽0.265; p⫽0.01), and between agoraphobia and CRP (⫽0.251; p⫽0.02). In our sample, no anxiety disorder showed a significant association with TnT or NT-proBNP levels. In considering independent variables other than specific anxiety disorders, age showed a significant relationship with TnT levels (⫽0.305; p⫽0.007) and NT-proBNP levels (⫽0.417; p ⬍0.001). A history of overweight or obesity showed a significant association with TnT (⫽0.234; p⫽0.03), and type II diabetes was significantly related to CRP (⫽0.210; p⫽0.04). Furthermore, our findings suggest an association between current antidepressant treatment and NT-proBNP levels (⫽0.284; p⫽0.004). The results of the stepwise multiple-regression analyses are presented in Table 3. DISCUSSION Our findings describe an association between heightened generalized anxiety and CRP levels in stable CHD patients, despite adjusting the models for several variables known to influence CRP levels, such as various demographic and clinical variables. Among stable CHD patients with anxiety detected using formal methods, concentrations of CRP were significantly higher than among nonanxious patients, and these concentrations of CRP were considerably higher than the cut-point identifying high risk for future CHD events. Accordingly, our hypotheses suggested significant associations between anxiety and one or more cardiac biomarkers predicting CHD risk. Surprisingly, the results of this study do not show an association between generalized anxiety disorder itself and other cardiac biomarker levels. However, it may be that heightened anxiety exerts its detrimental effect on cardiac hemostasis first of all by its chronicity, and not by its level of TABLE 3.
severity. This approach might be in line with previous epidemiological research underlining the impact of heightened anxiety, mostly untreated for many years, on CHD morbidity and mortality.2 Accordingly, von Ka¨nel et al.18 described a low-grade systemic proinflammatory state in PTSD patients that was related to PTSD symptom levels, suggesting one mechanism by which this anxiety disorder could contribute to atherosclerotic disease. The biomarkers studied, CRP, TnT, and NT-proBNP, have each been shown to be of use for stratifying risk for future cardiac events among ambulatory patients such as the ones enrolled to this study.19 –22 In particular, CRP is held to predict risk largely by identifying inflammation in underlying coronary plaques, whereas TnT and NTproBNP are expected to be more elevated in those with more complex underlying CHD. Ridker et al.19 underlined the use of CRP levels for monitoring cardiovascular risk, showing that CHD patients with low CRP levels after statin therapy had better clinical outcome than those with higher CRP levels. With respect to TnT, in a large population study, detectable levels were correlated with clinical variables or structural abnormalities on cardiac imaging.15 Last, NT-proBNP concentrations have been found to be powerfully prognostic for CHD events among subjects with stable CHD, independent of left-ventricular dysfunction.21–22 However, in the present study, neither TnT nor NT-proBNP levels showed a significant association between anxiety or specific anxiety disorders. These findings might be related to the relatively uncomplicated underlying stable CHD of patients included in this study. To our knowledge, to date, our study is the most comprehensive evaluation of associations between anxiety disorders (as determined by the use of the DSM–IV clinical nomenclature and not a questionnaire cut-off or a construct such as, for example, psychological distress, that is not easily translated into the DSM code) and cardiac
Associations Among Demographic, Medical, and Comorbid Psychiatric Variables and Levels of C-Reactive Protein (CRP), Troponin T (TnT), and Amino-Terminal Pro-B-Type Brain Natriuretic Peptide (NT-proBNP) in Stable Coronary Heart Disease (CHD) Outpatients, by Stepwise Multiple-Regression Analyses
Stable CHD Patients (Nⴝ85)
CRP  Coefficient (p)
TnT  Coefficient (p)
NT-proBNP  Coefficient (p)
Age History of overweight or obesity Type II diabetes mellitus Current antidepressant medication Agoraphobia Anxiety disorder, not otherwise specified
–0.028 (NS) 0.060 (NS) 0.210 (p⫽0.04) –0.012 (NS) 0.251 (p⫽0.02) 0.265 (p⫽0.01)
0.305 (p⫽0.007) 0.234 (p⫽0.03) 0.133 (NS) 0.176 (p⫽0.09) –0.151 (NS) 0.095 (NS)
0.417 (p⬍0.001) 0.112 (NS) 0.095 (NS) 0.284 (p⫽0.004) –0.004 (NS) 0.061 (NS)
Beta coefficients. NS: not significant.
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Anxiety and C-Reactive Protein biomarkers in ambulatory CHD patients. Also, the results of this study suggest that the current main focus on depressive disorders and cardiac biomarkers in CHD patients should be widened to include anxiety disorders. Furthermore, a significant association between anxiety and CRP levels enhances the approach of comprehensive, multidisciplinary care of CHD patients, including screening and treatment of heightened anxiety or specific anxiety disorders in concert with thorough and contemporary risk-stratification, using biomarkers predictive of future CHD events. There is no question that quality of life may be improved with vigorous treatment intervention for anxiety in CHD patients, and many expect that cardiovascular morbidity and mortality would be improved as well in this context.23–25 In a similar fashion, data are emerging about the use of biomarkers to track or monitor stability of patients with CHD, and the potential for ascertaining actionable information from biomarkers in this setting is very real.19 –22,26 Methodological Limitations First, stable CHD outpatients of one cardiologist of the MGH Cardiology Divsion’s outpatient clinic represent a possible selection bias, although homogeneity in treatment from a single practitioner would be expected to reduce the confounding effects of variable treatment patterns. Second, CHD patients with psychiatric disorders are higher utilizers of clinics, and hence they are more likely to be represented in this study. Third, since 95% of stable CHD patients with anxiety disorder and 98% of patients with no psychiatric disorder were white, the findings cannot be necessarily generalized for other ethnicities. Fourth, we aimed to present gender-comparable groups with anxiety disorder and no psychiatric disorder (28% women in the anxiety group, 24% women with no psychiatric disorder). However, to allow for a gender-specific analysis,
future research needs to include male and female CHD patients in distinct groups. Fifth, since the mean age of study participants in both groups was 70 years (anxiety disorder group), and 68 years (no psychiatric disorder), we cannot exclude a potential impact of unmeasured generalmedical conditions on the biomarker levels. However, we did not include CHD patients with unstable general-medical conditions in this study. Sixth, we did not include a continuous measure of anxiety severity in this study. Accordingly, there may be a relationship between anxiety and CRP levels that is only partly revealed by categorical measures such as diagnosis. Also, our findings are limited by the small sample size of both groups, and the results of this study need to be replicated in larger studies. Finally, the value of the results is limited by the fact that study participants were stable CHD outpatients, and, therefore, the results cannot be generalized to all CHD patients. CONCLUSIONS Our results are in line with previous research demonstrating significant associations between anxiety and CHD risk, but extend this finding by identifying a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely, CRP. Whether this association is directly causal or reflects more insidious medical processes among patients with heightened anxiety deserves further study. In context, our findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well. This work was fully supported by a NARSAD Young Investigator Award 2005, Mental Health Research Association, Great Neck, NY (NARSAD Fund No. 760-2339-5, Grant 218960 to B.B).
References 1. Barger SD, Sydeman SJ: Does generalized anxiety disorder predict coronary heart disease risk factors independently of major depressive disorder? J Affect Disord 2005; 88:87–91 2. Kubzansky LD, Cole SR, Kawachi I, et al: Shared and unique contributions of anger, anxiety, and depression to coronary heart disease: a prospective study in The Normative Aging Study. Ann Behav Med 2006; 31:21–29 3. Kubzansky LD, Koenen KC, Spiro A III, et al: Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study. Arch Gen Psychiatry 2007; 64:109 –116
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4. Kawachi I, Colditz GA, Ascherio A, et al: Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 1994; 89:1992–1997 5. Kawachi I, Sparrow D, Vokonas PS, et al: Symptoms of anxiety and risk of coronary heart disease: The Normative Aging Study. Circulation 1994; 90:2225–2229 6. Watkins LL, Blumenthal JA, Davidson JR, et al: Phobic anxiety, depression, and risk of ventricular arrhythmias in patients with coronary heart disease. Psychosom Med 2006; 68:651– 656 7. Grace SL, Abbey SE, Irvine J, et al: Prospective examination of anxiety persistence and its relationship to cardiac symptoms and
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Bankier et al. recurrent cardiac events. Psychother Psychosom 2004; 73:344 – 352 8. Bankier B, Januzzi JL, Littman AB: The high prevalence of multiple psychiatric disorders in stable outpatients with coronary heart disease. Psychosom Med 2004; 66:645– 650 9. Empana JP, Sykes DH, Luc G, et al: Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2005; 111:2299 –2305 10. Frasure-Smith N, Lesperance F, Irwin MR, et al: Depression, C-reactive protein, and two-year major adverse cardiac events in men after acute coronary syndrome. Biol Psychiatry 2007; 62: 302–308 11. Ridker PM: High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation 2001; 103:1813–1818 12. Ridker PM, Wilson PW, Grundy SM: Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 2004; 109:2818 –2825 13. Ridker PM: Inflammatory biomarkers and risks of myocardial infarction, stroke, diabetes, and total mortality: implications for longevity. Nutr Rev 2007; 65:253–259 14. Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49:2129 –2138 15. Wallace TW, Abdullah SM, Drazner MH, et al: Prevalence and determinants of troponin-T elevation in the general population. Circulation 2006; 113:1958 –1965 16. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000
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17. SPSS 15.0 for Windows, Chicago, IL, User’s Guide, 2006 18. von Ka¨nel R, Hepp U, Kraemer B, et al: Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. J Psychiatr Res 2007; 41:744 –752 19. Ridker PM, Cannon CP, Morrow D, et al: C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352:20 –28 20. Ray KK, Cannon CP, Cairns R, et al: Relationship between uncontrolled risk factors and C-reactive protein levels in patients receiving standard or intensive statin therapy for acute coronary syndromes in the Prove IT-TIMI-22 Trial. J Am Coll Cardiol 2005; 46:1417–1424 21. Kragelund C, Gronning B, Omland T, et al: Is N-terminal proB-type natriuretic peptide (NT-proBNP) a useful screening test for angiographic findings in patients with stable coronary disease? Am Heart J 2006; 151:712.e1–712.e7 22. Bibbings-Domingo K, Gupta R, Na B, et al: N-terminal fragment of the pro-hormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary disease. JAMA 2007; 297:169 –176 23. Januzzi JL Jr, Stern TA, Pasternak RC, et al: The influence of anxiety and depression on outcomes of patients with coronary artery disease. Arch Intern Med 2000; 160:1913–1921 24. Todaro JF, Shen BJ, Niaura R, et al: Effect of negative emotions on frequency of coronary heart disease (The Normative Aging Study). Am J Cardiol 2003; 92:901–906 25. Nicholson A, Fuhrer R, Marmot M: Psychological distress as a predictor of CHD events in men: the effect of persistence and components of risk. Psychosom Med 2005; 67:522–530 26. Troughton RW, Frampton CM, Yandle TG, et al: Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000; 355:1126 –1130
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Background: Anxiety is highly prevalent among patients with stable coronary heart disease (CHD). However, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. Objective: This study aimed for a comprehensive evaluation of anxiety in stable CHD patients, in addition to cardiac biomarkers such as C-reactive protein (CRP), troponin T, and amino-terminal pro-B-type brain natriuretic peptide. Method: The study included 43 CHD patients with anxiety disorder and 42 CHD patients without psychiatric disorder given the Structured Clinical Interview for DSM–IV. Results: Regression analyses showed an association between anxiety (anxiety disorder, not otherwise specified) and CRP levels, despite model adjustment for various related demographic and clinical variables. Anxiety was associated with CRP levels. Conclusion: There are significant associations between anxiety and CHD risk, with a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely CRP. It is not clear whether this association is directly causal or relates to other medical processes among patients with heightened anxiety. The findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well. (Psychosomatics 2009; 50:347–353)
S
everal studies shed light on the impact of heightened anxiety and specific anxiety disorders on cardiovascular complications, including incident coronary heart disease (CHD) and recurrence of CHD.1–7 Anxiety is highly prevalent among patients with stable CHD.8 However, despite the apparent relationships between anxiety and CHD morbidity and mortality, the biologic effects that may connect these two seemingly unrelated disorders is not well understood. In an effort to explain the links between psychiatric symptoms and disorders and CHD, specific biomarkers have been added to research analyses. For example, Empana et al.9 suggested an association of depressive mood with inflammatory markers and suggested that depressive mood is related to CHD even after adjustment for these inflammatory markers. Furthermore, Frasure-Smith et al.10 demonstrated that depression and C-reactive protein Psychosomatics 50:4, July-August 2009
(CRP) levels represented overlapping prognostic risks over 2 years in men assessed 2 months after acute coronary syndrome. However, previous research seemed to mainly focus on the association of depressive disorders with specific biomarkers in CHD patients, without consideration of anxiety and specific anxiety disorders. In this study, we aimed for a comprehensive evaluation of anxiety disorders in stable CHD patients, including meticulous psychiatric assessment, as well as assessment Received December 15, 2007; revised April 9, 2008; accepted April 9, 2008. From the Department of Psychiatry, and Division of Cardiology, Massachusetts General Hospital; and the Department of Psychiatry and Psychotherapy, Medical University Vienna, Austria. Send correspondence and reprint requests to Bettina Bankier, M.D., Sc.M., Department of Psychiatry and Psychotherapy, Medical University Vienna, Wa¨hringer Gu¨rtel 18-20, A-1090, Vienna, Austria. e-mail: bettina.bankier@ meduniwien.ac.at © 2009 The Academy of Psychosomatic Medicine
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Anxiety and C-Reactive Protein of biomarkers such as CRP, a marker for inflammation; troponin T (TnT), a marker for necrosis; and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP), a marker for left-ventricular dysfunction and congestive heart failure. We hypothesized that significant associations would exist between anxiety disorders and these specific biomarkers. METHOD Design and Setting We performed a cross-sectional study of 85 stable CHD outpatients (N⫽43 with anxiety disorder; N⫽42 with no psychiatric disorder) between July 2005 and June 2006 in the Outpatient Cardiology Clinic at the Massachusetts General Hospital (MGH). Stable CHD outpatients of one cardiologist (JLJ) were included in the study. Stable CHD patients with anxiety disorder in conjunction with depressive disorder or with another psychiatric disorder, for example, substance abuse or dependency, were not included in this analysis, to allow for the assessment of anxiety unconfounded by other comorbid psychiatric conditions. The research protocol was approved by the Institutional Review Board of the MGH. Psychiatric consultation and treatment referral were offered in accordance with psychiatric diagnoses determined by the interview. Recruitment Procedure The study recruitment overture was made at the front desk at the Outpatient Cardiology Clinic in the form of a questionnaire, which asked outpatients in an anonymous fashion whether they would be interested in being enrolled in the study. The study was presented as a research study including an interview about anxiety, mood, and psychosocial aspects of patients with diagnosed CHD. If patients agreed to participate and met study criteria, the cardiologist requested their inclusion before the cardiac outpatient visit. The interviews were conducted immediately before or immediately after the outpatient visit. The first author (BB) was continuously present at the cardiac outpatient unit during the days the CHD patients were scheduled. Patients who were included in the study signed a detailed written informed consent. No incentives or reimbursements were given to the patients. Medical Inclusion and Exclusion Criteria There was no restriction regarding the age of participants in the study. The medical inclusion criteria for 348
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stable CHD outpatients were 1) CHD diagnosed via a positive stress test (included treadmill stress test, infusion stress test, stress echo as well as thallium or nuclear imaging testing); or 2) history of documented myocardial infarction (MI) by ECG and creatine phosphokinase isoenzymes/troponins; or 3) coronary atherosclerosis (documented by coronary angiography), with or without revascularization procedures including percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). The medical exclusion criteria were 1) active, unstable angina; 2) active congestive heart failure (CHF) with Class IV symptoms by New York Heart Association Symptom Severity estimates; 3) severe comorbid cardiac disease, for example, advanced valvular heart disease; and 4) previous valve-replacement therapy. We also excluded subjects with unstable medical disorders (unstable neurological, endocrine, pulmonary, gastrointestinal, hepatic, renal, immunological or hematological disease, organic brain disease, or cancer) as determined by history, physical, ECG, and laboratory examination. Cardiac Biomarker Assessment At the time of enrollment, we obtained a sample of blood, which was tested for CRP with a high-sensitivity assay (Dade-Behring, Inc.; Newark, DE, U.S.). This assay is a turbidometric immunoassay with a dynamic range of 0.05 mg/L to 25.0 mg/L. Generally speaking, ⬍1 mg/L is considered as “low risk” for acute myocardial infarction, whereas ⬎3 mg/L is considered “high risk.”11–14 Also, we determined concentrations of TnT by use of a standard immunoassay (Roche Diagnostics, Inc.; Indianapolis, IN). In healthy reference populations, the 99th percentile for this assay is considered to be ⬍0.01 ng/mL;15 the cutpoint yielding acceptable analytic precision is 0.03 ng/mL. Last, NT-proBNP concentrations were determined by using standard immunochemical methods (Roche Diagnostics, Inc.; Indianapolis, IN). The lower detectable limit with this assay is ⬎5 ng/L. Normal outpatient reference ranges for NT-proBNP are ⬍125 ng/L for patients ⬍75 years old and ⬍450 ng/L for patients age 75⫹ years. Psychiatric Assessment Psychiatric diagnoses were established by using the Structured Clinical Interview for DSM–IV (SCID; Diagnostic and Statistical Manual of Mental Disorders, 4th Edition).16 Psychiatric assessment was performed on Axis Psychosomatics 50:4, July-August 2009
Bankier et al. I (Clinical Disorders), Axis III (General Medical Conditions), Axis IV (Psychosocial and Environmental Problems), and Axis V (Global Assessment of Functioning). The first author (BB) conducted all structured clinical interviews and was blinded to all psychiatric information about the cardiac patients before the study interview. Psychiatric exclusion criteria were significant risk of suicide or homicide or the presence of any one of the following DSM–IV diagnoses: 1) substance use disorders, including alcohol, active within the last 3 months; 2) schizophrenia; 3) delusional disorder; 4) psychotic disorders not elsewhere classified; 5) bipolar disorder; 6) delirium; and 7) dementia. In particular, actively suicidal and psychotic patients were not included in the study, since the Institutional Review Board of the MGH discourages recruitment of subjects who are clinically unstable; that is, actively suicidal or psychotic, in studies that offer no direct treatment benefit.
Data Analyses Concentrations of biomarkers of the anxiety-disorders group and the group with no psychiatric disorder were generated with mean plus standard deviation (SD), and comparisons between groups were performed by with analysis of variance (ANOVA). Stepwise multiple-regression analyses were performed to assess the relationships TABLE 1.
between the biomarkers CRP, TnT, and NT-proBNP (dependent variables) and specific anxiety disorders in stable CHD patients. Also, independent variables included psychiatric disorder status, age, gender, marital status, educational attainment, family history of CHD, past and current overweight or obesity, past and current smoking status, type II diabetes mellitus, hypertension, hyperlipidemia, current benzodiazepine treatment, and current antidepressant treatment. Data collection and calculations were performed with SPSS 15.0 for Windows software.17
Demographic Characteristics In the group of stable CHD patients with anxiety disorders (N⫽43), the mean age was 70 years (SD: 10), and 72% (N⫽31) of the patients were men. Considering the group of stable CHD patients with no psychiatric disorder (N⫽42), the mean age was 68 (SD: 13), and 76% (N⫽32) of the patients were men. Table 1 summarizes demographic characteristics of the study participants in both groups, including age, gender, marital status, children, educational attainment, and ethnicity. Also, Table 1 presents medical background, including family history of CHD, past and current overweight or obesity, past and current smoking status, type II diabetes mellitus, hypertension, and hyperlipidemia.
Demographic Characteristics and Medical Backgrounds of Stable Coronary Heart Disease (CHD) Outpatients With Anxiety Disorder (Nⴝ43), and With No Psychiatric Disorder (Nⴝ42)
Stable CHD Patients (Nⴝ85) Age, years, mean (SD) Gender Marital status Children, N, mean (SD) Race, white Education Completed high school Completed 4 years of college Family history of CHD History of overweight or obesity Current overweight or obesity Smoking history Current smoking Type II diabetes mellitus Hypertension Hyperlipidemia
Stable CHD Outpatients With One or More Anxiety Disorders (Nⴝ43)
Stable CHD Outpatients With No Psychiatric Disorder (Nⴝ42)
70 (10) 72% men (N⫽31) 70% married (N⫽30) 2.9 (2.8) 95% (N⫽41)
68 (13) 76% men (N⫽32) 81% married (N⫽34) 2.6 (1.6) 98% (N⫽41)
40% (N⫽17) 33% (N⫽14) 42% (N⫽18) 28% (N⫽12) 28% (N⫽12) 67% (N⫽29) 2% (N⫽1) 30% (N⫽13) 81% (N⫽35) 84% (N⫽36)
24% (N⫽10) 12% (N⫽5) 36% (N⫽15) 24% (N⫽10) 19% (N⫽8) 57% (N⫽24) 7% (N⫽3) 24% (N⫽10) 81% (N⫽34) 86% (N⫽36)
SD: standard deviation.
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Anxiety and C-Reactive Protein RESULTS Anxiety Disorders and Psychopharmacological Treatment Of 43 stable CHD outpatients with anxiety disorder, 5 fulfilled clinical criteria for generalized anxiety disorder (GAD; overlap with specific phobia: N⫽1), 1 had posttraumatic stress disorder (PTSD), 8 had social phobia, 13 had specific phobia (overlap with social phobia: N⫽1), 1 patient had panic disorder with agoraphobia, 3 patients had agoraphobia alone, and 14 stable CHD patients had anxiety disorder not otherwise specified; in all cases, heightened generalized anxiety did not meet all clinical criteria for GAD. If a patient fulfilled clinical criteria for more than one specific anxiety disorder, then both specific anxiety disorders were recorded. In considering past and current psychopharmacological treatment of stable CHD patients with anxiety disorder, 11 patients reported past use of benzodiazepines as treatment against heightened anxiety, whereas 8 patients mentioned current use of benzodiazepines. Eleven patients had been diagnosed with anxiety disorder in the past. Five patients reported past use of antidepressants, and three patients reported current use of antidepressant medication as treatment against anxiety; two of these patients reported current use of an SSRI (serotonin reuptake inhibitor) medication. Again, patients who fulfilled clinical criteria for a specific anxiety disorder in conjunction with depressive TABLE 2.
disorder or another psychiatric disorder according to the DSM–IV were not included in this study. With regard to psychosocial and environmental problems (Axis IV of the DSM–IV), 26% of patients (N⫽11) with anxiety disorder reported problems with their primary social support group, and 21% (N⫽9) mentioned occupational problems. In the group of stable CHD outpatients with no psychiatric disorder, 17% (N⫽7) reported problems with their primary social support group, whereas 14% (N⫽6) mentioned occupational problems. Stable CHD patients with anxiety disorder had a mean of 64 (SD: 5) on the Global Assessment of Functioning Scale (GAS; 1–100; Axis V of the DSM–IV), versus a mean of 72 (SD: 8) in patients with no psychiatric disorder. Associations Among Anxiety Disorders and Levels of CRP, TnT, and NT-proBNP Table 2 presents concentrations (mean and SD) of CRP, TnT, and NT-proBNP in stable CHD patients with anxiety disorder and in patients with no psychiatric disorder. In particular, stable CHD patients with heightened anxiety in the group with Anxiety Disorder Not Otherwise Specified had a higher mean level of CRP (mean: 8.6 mg/L,) than CHD patients with no psychiatric disorder (mean: 4.04 mg/L; SD: 4.1; p⫽0.04). Also, agoraphobia patients showed a higher mean level of CRP (14.5 mg/L; p⫽0.02). Accordingly, stepwise multiple-regression anal-
Means and Standard Deviations (SD) of C-Reactive Protein (CRP; mg/L), TnT (ng/mL), and NT-proBNP (ng/L) in stable Coronary Heart Disease (CHD) Outpatients With Anxiety Disorder (Nⴝ43) and in CHD Patients With No Psychiatric Disorder (Nⴝ42) Stable CHD Patients (Nⴝ85)
Anxiety disorder (N⫽43) No psychiatric disorder (N⫽42) Generalized anxiety disorder (GAD; N⫽5) Specific phobia (N⫽13) Social phobia (N⫽8) Agoraphobia (N⫽3) Anxiety disorder, not otherwise specified (N⫽14)
CRP Mean (SD) mg/L 6.1 (SD: 8.8) NS 4.04 (SD: 4.1) NS 2.4 (SD: 2.4) NS 3.5 (SD: 3.6) NS 5.1 (SD: 8.8) NS 14.5 (SD: 2.7) p⫽0.02 8.6 (SD: 12.5) p⫽0.04
TnT Mean (SD) ng/mL 0.003 (SD: 0.009) NS 0.005 (SD: 0.015) NS ⬍0.001 NS 0.002 (SD: 0.008) NS ⬍0.001 NS ⬍0.001 NS 0.008 (SD: 0.014) NS
NT-proBNP Mean (SD) ng/L 498 (SD: 977) NS 581 (SD: 1,007) NS 241 (SD: 235) NS 191 (SD: 159) NS 238 (SD: 233) NS 406 (SD: 526) NS 1,028 (SD: 1,584) p⫽0.04
Reference levels: CRP ⬎3mg/L; TnT ⬎0.01 ng/mL; for NT-proBNP: ⬎125 ng/L for age ⬍75, and ⬎450 ng/L for age 75⫹ years; NS: not significant.
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Bankier et al. yses showed significant relationships between heightened anxiety and CRP levels (⫽0.265; p⫽0.01), and between agoraphobia and CRP (⫽0.251; p⫽0.02). In our sample, no anxiety disorder showed a significant association with TnT or NT-proBNP levels. In considering independent variables other than specific anxiety disorders, age showed a significant relationship with TnT levels (⫽0.305; p⫽0.007) and NT-proBNP levels (⫽0.417; p ⬍0.001). A history of overweight or obesity showed a significant association with TnT (⫽0.234; p⫽0.03), and type II diabetes was significantly related to CRP (⫽0.210; p⫽0.04). Furthermore, our findings suggest an association between current antidepressant treatment and NT-proBNP levels (⫽0.284; p⫽0.004). The results of the stepwise multiple-regression analyses are presented in Table 3. DISCUSSION Our findings describe an association between heightened generalized anxiety and CRP levels in stable CHD patients, despite adjusting the models for several variables known to influence CRP levels, such as various demographic and clinical variables. Among stable CHD patients with anxiety detected using formal methods, concentrations of CRP were significantly higher than among nonanxious patients, and these concentrations of CRP were considerably higher than the cut-point identifying high risk for future CHD events. Accordingly, our hypotheses suggested significant associations between anxiety and one or more cardiac biomarkers predicting CHD risk. Surprisingly, the results of this study do not show an association between generalized anxiety disorder itself and other cardiac biomarker levels. However, it may be that heightened anxiety exerts its detrimental effect on cardiac hemostasis first of all by its chronicity, and not by its level of TABLE 3.
severity. This approach might be in line with previous epidemiological research underlining the impact of heightened anxiety, mostly untreated for many years, on CHD morbidity and mortality.2 Accordingly, von Ka¨nel et al.18 described a low-grade systemic proinflammatory state in PTSD patients that was related to PTSD symptom levels, suggesting one mechanism by which this anxiety disorder could contribute to atherosclerotic disease. The biomarkers studied, CRP, TnT, and NT-proBNP, have each been shown to be of use for stratifying risk for future cardiac events among ambulatory patients such as the ones enrolled to this study.19 –22 In particular, CRP is held to predict risk largely by identifying inflammation in underlying coronary plaques, whereas TnT and NTproBNP are expected to be more elevated in those with more complex underlying CHD. Ridker et al.19 underlined the use of CRP levels for monitoring cardiovascular risk, showing that CHD patients with low CRP levels after statin therapy had better clinical outcome than those with higher CRP levels. With respect to TnT, in a large population study, detectable levels were correlated with clinical variables or structural abnormalities on cardiac imaging.15 Last, NT-proBNP concentrations have been found to be powerfully prognostic for CHD events among subjects with stable CHD, independent of left-ventricular dysfunction.21–22 However, in the present study, neither TnT nor NT-proBNP levels showed a significant association between anxiety or specific anxiety disorders. These findings might be related to the relatively uncomplicated underlying stable CHD of patients included in this study. To our knowledge, to date, our study is the most comprehensive evaluation of associations between anxiety disorders (as determined by the use of the DSM–IV clinical nomenclature and not a questionnaire cut-off or a construct such as, for example, psychological distress, that is not easily translated into the DSM code) and cardiac
Associations Among Demographic, Medical, and Comorbid Psychiatric Variables and Levels of C-Reactive Protein (CRP), Troponin T (TnT), and Amino-Terminal Pro-B-Type Brain Natriuretic Peptide (NT-proBNP) in Stable Coronary Heart Disease (CHD) Outpatients, by Stepwise Multiple-Regression Analyses
Stable CHD Patients (Nⴝ85)
CRP  Coefficient (p)
TnT  Coefficient (p)
NT-proBNP  Coefficient (p)
Age History of overweight or obesity Type II diabetes mellitus Current antidepressant medication Agoraphobia Anxiety disorder, not otherwise specified
–0.028 (NS) 0.060 (NS) 0.210 (p⫽0.04) –0.012 (NS) 0.251 (p⫽0.02) 0.265 (p⫽0.01)
0.305 (p⫽0.007) 0.234 (p⫽0.03) 0.133 (NS) 0.176 (p⫽0.09) –0.151 (NS) 0.095 (NS)
0.417 (p⬍0.001) 0.112 (NS) 0.095 (NS) 0.284 (p⫽0.004) –0.004 (NS) 0.061 (NS)
Beta coefficients. NS: not significant.
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Anxiety and C-Reactive Protein biomarkers in ambulatory CHD patients. Also, the results of this study suggest that the current main focus on depressive disorders and cardiac biomarkers in CHD patients should be widened to include anxiety disorders. Furthermore, a significant association between anxiety and CRP levels enhances the approach of comprehensive, multidisciplinary care of CHD patients, including screening and treatment of heightened anxiety or specific anxiety disorders in concert with thorough and contemporary risk-stratification, using biomarkers predictive of future CHD events. There is no question that quality of life may be improved with vigorous treatment intervention for anxiety in CHD patients, and many expect that cardiovascular morbidity and mortality would be improved as well in this context.23–25 In a similar fashion, data are emerging about the use of biomarkers to track or monitor stability of patients with CHD, and the potential for ascertaining actionable information from biomarkers in this setting is very real.19 –22,26 Methodological Limitations First, stable CHD outpatients of one cardiologist of the MGH Cardiology Divsion’s outpatient clinic represent a possible selection bias, although homogeneity in treatment from a single practitioner would be expected to reduce the confounding effects of variable treatment patterns. Second, CHD patients with psychiatric disorders are higher utilizers of clinics, and hence they are more likely to be represented in this study. Third, since 95% of stable CHD patients with anxiety disorder and 98% of patients with no psychiatric disorder were white, the findings cannot be necessarily generalized for other ethnicities. Fourth, we aimed to present gender-comparable groups with anxiety disorder and no psychiatric disorder (28% women in the anxiety group, 24% women with no psychiatric disorder). However, to allow for a gender-specific analysis,
future research needs to include male and female CHD patients in distinct groups. Fifth, since the mean age of study participants in both groups was 70 years (anxiety disorder group), and 68 years (no psychiatric disorder), we cannot exclude a potential impact of unmeasured generalmedical conditions on the biomarker levels. However, we did not include CHD patients with unstable general-medical conditions in this study. Sixth, we did not include a continuous measure of anxiety severity in this study. Accordingly, there may be a relationship between anxiety and CRP levels that is only partly revealed by categorical measures such as diagnosis. Also, our findings are limited by the small sample size of both groups, and the results of this study need to be replicated in larger studies. Finally, the value of the results is limited by the fact that study participants were stable CHD outpatients, and, therefore, the results cannot be generalized to all CHD patients. CONCLUSIONS Our results are in line with previous research demonstrating significant associations between anxiety and CHD risk, but extend this finding by identifying a potential biologic link between anxiety and elevations in a biomarker with powerful prognostic risk, namely, CRP. Whether this association is directly causal or reflects more insidious medical processes among patients with heightened anxiety deserves further study. In context, our findings suggest that the current focus on depressive disorders with respect to biomarkers and CHD outcomes should be broadened to include anxiety disorders, as well. This work was fully supported by a NARSAD Young Investigator Award 2005, Mental Health Research Association, Great Neck, NY (NARSAD Fund No. 760-2339-5, Grant 218960 to B.B).
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