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Inflammation, Depressive Symptomatology, and Coronary Artery Disease

From the Departments of Medical, Clinical, and Experimental Psychology (A.A., J.B.), Cardiology (F.W.B.), Microbiology (C.B.), and Neurology (M.D.), Maastricht University, Maastricht, The Netherlands.

Address reprints requests to: A. Appels, PhD, Department of Medical, Clinical, and Experimental Psychology, Maastricht University, Box 616, 6200 MD, Maastricht, The Netherlands. Email: ad.appels{at}mp.unimaas.nl

	ABSTRACT

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OBJECTIVE: Many patients feel exhausted or depressed before the onset of an acute coronary event, but little is known about the origin of these feelings. We tested the hypothesis that the depressive symptomatology is associated with a reactivation of latent viruses and inflammation of a coronary vessel.

METHODS: A blood sample was drawn and a biopsy sample was obtained from the coronary lesion of 15 exhausted and 15 nonexhausted patients treated with directional coronary angioplasty because of severe angina. Blood samples were analyzed to measure antibody titers against Chlamydia pneumoniae, cytomegalovirus, and the cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-. The biopsy sample was analyzed for the presence of IL-1ß and TNF-.

RESULTS: E-hausted/depressed patients had higher antibody titers against cytomegalovirus, higher levels of C. pneumoniae immunoglobulin G, and higher levels of IL-1ß and TNF-. No associations between the mental state of a patient and cytokine mRNA in the biopsy sample were found.

CONCLUSIONS: The findings indicate that the mental state of angioplasty patients is positively associated with serological markers of inflammation. It remains to be seen whether the inflammation causes feelings of exhaustion, whether exhaustion and depression set the stage for inflammation, or whether existing feelings of exhaustion are amplified by the inflammation.

Key Words: inflammation, • depression, • exhaustion, • cytokines, • cytomegalovirus, • Chlamydia pneumoniae.

Abbreviations: ACS = acute coronary syndrome;; CMV = cytomegalovirus;; DCA = directional coronary angioplasty;; DSM = Diagnostic and Statistical Manual of Mental Disorders;; ELISA = enzyme-linked immunosorbent assay;; Ig = immunoglobulin;; IL = interleukin;; MIVE = Maastricht Interview Vital Exhaustion;; PCR = polymerase chain reaction;; PDGF = platelet-derived growth factor;; SCID = Structural Clinical Interview for DSM-IV;; TNF = tumor necrosis factor.

	INTRODUCTION

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Depressive symptomatology, especially excess fatigue, feelings of general malaise, and increased irritability, have been found by many researchers to belong to the precursors of first and recurrent ACSs (1–6). The origin of these feelings is still poorly understood. Detailed investigations showed that the feelings of exhaustion and malaise are not or are only modestly associated with left ventricular ejection fraction and the amount of vessel disease (7, 8). Significant associations have been observed between this state and "prolonged overtime work," "financial problems," and other life stressors, suggesting that the depressive symptomatology may reflect a breakdown in adaptation to prolonged stress (9). However, this state has also been observed in otherwise healthy and happy subjects.

The mean duration of the feelings of exhaustion and malaise before an ACS is about 12 months with a standard deviation of about 15 months. The strength of the association between these feelings and the occurrence of an ACS seems to be inversely related to the duration of the symptoms (3, 10). This raises the question of whether the depressive symptomatology is associated with functional processes in a coronary artery leading to an acute occlusion, especially with inflammation.

Atherogenesis has been proposed to represent a sequence of events triggered by the response to vascular injury. The main forms of injury to the vessel wall are oxidized low-density lipoproteins, blood flow shear, oxygen-derived free radicals, vasoactive amines, and cigarette smoking. Recent investigations indicate that infections by CMV or Chlamydia pneumoniae also might belong to these factors (11–16). The presence of numerous macrophages and T-lymphocytes in the coronary lesion indicates that not only is there an inflammatory reaction secondary to tissue damage but also a true, primary immunological reaction. The activated macrophages play a role in the fibroproliferative process by their capacity to form PDGFs. They also secrete cytokines, including IL-1ß, IL-6, and TNF-. These cytokines can induce proliferation and migration of smooth muscle cells by stimulating other growth factors. When the response becomes excessive, high doses of IL-1 and TNF- can inhibit the proliferative effect of growth factors by downregulating PDGF receptors (17–19).

The cytokines are tailored to function as an "SOS signal" for tissue damage. This information is relayed to other parts of the body, including the brain, where they evoke feelings of lack of well-being, general malaise, sickness, and tiredness (20–22). Therefore, the feelings of exhaustion that occur before an acute coronary event may form part of the reaction to inflammation. This chain of events is still rather speculative. However, testable hypotheses may be derived from this model.

The purpose of this study was to test the hypotheses that angioplasty patients who feel exhausted have 1) higher blood levels of IL-1ß, IL-6, and TNF-; 2) higher antibody titers for CMV and C. pneumoniae; and 3) higher levels of IL-1ß and TNF- in biopsy samples of the coronary lesion than angioplasty patients who do not feel exhausted or depressed.

A state of exhaustion has some common variance with major depression. This raises the question of whether a state of exhaustion is associated with the inflammation indices or elevated antibody titers because some exhausted patients are depressed. To study this question, an assessment of major depression was included.

	METHODS

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Participants
Study subjects were 30 men, aged 40 to 73 years, who received DCA because of severe, stable angina pectoris. All patients had angiographic documentation of one or more de novo coronary lesions without recent or remote myocardial infarction. All patients came from the Maastricht, The Netherlands, area and were enrolled on a consecutive basis. Subjects who reported chronic infectious or inflammatory disease were excluded.

All patients were approached by the cardiologist, who performed the intervention, on the day before DCA was performed. Only patients who were good candidates for DCA were included. The cardiologist explained the aim of the study and asked for consent. Those who gave written consent were subsequently interviewed by the third author on the day before the intervention. All interviews were recorded on audiotape. Enrollment was discontinued when a group of 15 nonexhausted and a group of 15 exhausted patients agreed to participate and underwent successful DCA. About 45 patients were approached. The major reason for exclusion was a MIVE score >3 and <8.

Measures
Mental state was assessed by using the MIVE, a standardized interview designed to assess vital exhaustion (23). Vital exhaustion is a state characterized by unusual tiredness and lack of energy, increased irritability, and feelings of demoralization. This state has been found to precede the onset of fatal or nonfatal myocardial infarction in apparently healthy men and to increase the risk of a new coronary event in angioplasty patients (3, 6). The interview consists of 23 questions. Those who endorsed three or fewer complaints were classified as nonexhausted, whereas those who endorsed eight or more complaints were classified as exhausted. Because the validity of the MIVE has been established in men only, no women were included in this study. Major depression was assessed by using the SCID, a standardized interview designed to assess psychopathology according to DSM criteria. Elevated scores on this interview have been found to increase the risk of a recurrent myocardial infarction (8). Only the part assessing major depression was used to lower the burden of the study for the patients and because no other affective disorders are found to belong to the precursors of a coronary event. A time frame of 1 month (eg, how did you feel during last 4 weeks?) was used for both the MIVE and the SCID.

Cardiological and Immunological Techniques
A 9F guiding catheter was introduced into the diseased artery. A guidewire was then advanced, and the DCA system was placed in the coronary lesion. The biopsy samples obtained by this procedure were immediately frozen in liquid nitrogen.

The following blood samples were drawn 1 hour before the cardiac intervention: 10 ml of sodium citrate–buffered whole blood, 20 ml of whole blood anticoagulated with ethylenediaminetetraacetic acid, and 10 ml of serum. Plasma was divided into aliquots and stored at -70°C.

Levels of IL-1ß, IL-6, and TNF- in anticoagulated blood were measured using Pelikine Compact ELISA kits (Central Laboratory, Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands) according to the manufacturer’s instructions. For quantitative detection of anti–C. pneumoniae IgG and IgA in anticoagulated whole blood, the Bioclone Elegance Chlamydia IgG and IgA ELISA detection kit (Bioclone Australia Pty. Limited, Marrickville, NSW, Australia) was used.

Anti-CMV IgG and anti-CMV IgM antibodies were tested with a commercially available kit (Axsym, Abbott Laboratories, Chicago, IL). The kits were used and the results interpreted as suggested by the manufacturer. In addition, we used a sensitive ELISA using the highly immunogenic antigens ppUL32, which encodes the basic phosphoprotein of 150 kd, and ppUL80a, which encodes the assembly protein of 38 kd (24). For construction of these antigens, recombinant proteins (25) of human CMV Towne strain were used.

For quantification of cytokine mRNA, total RNA was extracted from the cells using the RNeasy method (Qiagen, Westburg, Leusden, The Netherlands). Subsequently, total RNA and/or standard RNA was reverse transcribed into first strand of cDNA using a reverse transcription system (Promega, Leiden, The Netherlands). The PCR standard RNA was obtained from the cloned synthetic DNA constructs pQA and pQB comprising the cytokine primer pairs (26). The cDNA was extracted, precipitated, and dissolved in 35 ml of water. One milliliter of cDNA was amplified by PCR as described (27). Biotin and tris(2,2'-bipyridine) ruthenium (TBR) labeled PCR amplification products were quantified using the QPCR System 50000 (Perkin Elmer, Nieuwekerk san de Yssel, The Netherlands) as described by Vandevyver et al. (27). Background levels were determined with an appropriate blank sample (QPCR assay buffer, Perkin Elmer), and an external standard curve was measured simultaneously with each sample to enable quantification of the samples.

Statistical Analysis
Because of the small number of subjects and the skewed distribution of some variables, data were analyzed by using the Mann-Whitney U test. A one-tailed test was used to test for statistical significance because our hypotheses were unidirectional a priori. Because of technical errors, data on serum IL-1ß and TNF- were not available for one subject, and data on IL-6 were missing for two subjects.

	RESULTS

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Mean age of the subject group was 56.7 years (SD = 8.9 years, range = 40–73 years). There was no statistical difference between groups in relation to age, number of diseased vessels, location of the coronary lesion, systolic blood pressure, diastolic blood pressure, and weight. None of the patients was currently being treated for a mental disorder or used psychotropic drugs. Agreement of the assessment of exhaustion between the third and first authors was almost perfect (Kendall’s = 0.97).

All subjects except one (97%) were seropositive for C. pneumoniae. Nineteen (63%) were seropositive for CMV. Serum TNF- levels were above the normal value of 10 pg/ml in all subjects, and the IL-1ß levels of all subjects except one were above the normal value of 5 pg/ml. IL-6 levels were above the normal value in 43% of subjects.

As predicted, mean values of IL-1ß and TNF- were significantly higher in the exhausted group than in the nonexhausted group. The difference in IL-6 was also in the same direction but just failed to reach statistical significance. These results indicate that the mental state in angioplasty patients is positively associated with the level of cytokines, especially IL-1 ( Table 1), confirming hypothesis 1.

View this table: [in this window] [in a new window]   Table 1. Differences in Serum Levels of IL-1ß, IL-6, and TNF- Between Exhausted and Nonexhausted Angioplasty Patients

No association was observed between vital exhaustion and C. pneumoniae IgA. The difference in C. pneumoniae IgG was in the predicted direction and approached statistical significance ( Table 2). These results confirm hypothesis 2 as far as CMV is concerned. No associations between exhaustion and IL-1 or TNF- in the biopsy sample was observed. Therefore, hypothesis 3 could not be confirmed.

To control for the possibility that exhaustion was associated with the inflammation indices or CMV/C. pneumonia because some of the exhausted subjects were depressed, analyses were repeated excluding the data of the three depressed subjects. Despite the loss of statistical power by the reduction of the number of patients, the mean values of IL-1ß remained significantly higher in the exhausted group (p = .01), as did mean values of CMV IgM pp38 (p = .07). Therefore, it is reasonable to conclude that the association between cytokines and activated CMV on one hand and exhaustion on the other is not due to the fact that some of the exhausted patients were depressed. In other words, immune changes are also present in nondepressed but exhausted patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
The purpose of this study was to test the hypothesis that depressive symptomatology in angioplasty patients is associated with inflammation as indicated by elevated cytokines and antibody titers for CMV and C. pneumoniae. The observations that IL-1ß, CMV IgM pp38, and CMV IgG pp150 were significantly elevated in the exhausted group and that the difference between both groups with regard to IL-6 and C. pneumoniae IgG nearly reached statistical significance supports to this hypothesis. Therefore, this study is the first to show an association between the mental state of coronary patients and inflammation.

In this study, depressive symptomatology was assessed in two ways, as a general measure of distress and as a psychiatric disorder. Both measures were found to be associated with cytokine levels (IL-1ß and IL-6) and antibody titers for CMV (IgG 150 and IgM 38). Detailed analyses showed that the immune changes were also present in nondepressed but exhausted patients. Clinical evidence suggested that the three depressed patients were particularly distressed because of their debilitating tiredness. In this respect, it is of interest to note that none of the patients suffered from feelings of excess fatigue or malaise for >18 months. Therefore, none met DSM criteria for dysthymic disorder.

No associations were observed between depressive symptomatology and IL-1 or TNF- in the biopsy sample. This might be due to the fact that the quantity and composition of the samples differed among patients. In some patients only calcified tissue was obtained, causing a sampling error. Therefore, the data do not allow a distinction between inflammation in an atheromatous plaque and the total inflammatory burden in a patient.

The strength of the association between the depressive symptomatology and the serological markers of inflammation might be underestimated in this study. For logistic reasons only patients suffering from stable angina were included. It is possible that the observed differences would have been larger if patients suffering from unstable angina had been included, because in this group the inflammation process is probably more recent and active.

The major question raised by the results is whether the inflammation causes depressive feelings or whether a depressive state sets the stage for activation of latent viruses and bacteria leading to inflammation. Because of the cross-sectional nature of this study, it is impossible to solve this "chicken before the egg" problem. The answer to this question has far-reaching consequences for understanding the pathogenesis of ACSs and for the treatment of coronary patients. Therefore, three alternative explanations merit discussion: depressive symptomatology is a marker of inflammation, depressive symptomatology fosters inflammation, and cytokines amplify existing depressive symptomatology.

Gurfinkel et al. (28) have provided evidence that treatment of coronary patients with antibiotics may reduce the incidence of new cardiac events in patients with acute myocardial infarction. This observation supports the hypothesis that C. pneumoniae is causally involved in the pathogenesis of acute myocardial infarction. No assessment of the mental state of the patients was made in the study. If future studies showed that treatment with antibiotics also resulted in significant improvement of the mental state of coronary patients, the interpretation of depression as a marker of inflammation would receive support.

Prolonged stress may result in activation of the hypothalamic-pituitary-adrenal axis, leading to decreased immunocompetence. If the exposure to stress is long-lasting, the activity of the hypothalamic-pituitary-adrenal axis may decrease, leading to fatigue and increased activation of immune-mediated inflammation (29–31). If future studies show that a behavioral intervention has a beneficial effect on immunological and microbiological parameters, the interpretation of depressive symptomatology fostering inflammation would be supported.

One major unresolved question regarding the infection hypothesis is what caused the reactivation of C. pneumoniae, CMV, or other possibly involved antigens. It is at least conceivable that a circular process occurs during the year before an acute coronary event: Prolonged stress results in reactivation of latent viruses or bacteria, which amplifies the feelings of distress through the release of cytokines. Testing this circular model requires a prospective study with repeated measurements of all relevant variables and precise definition of the time window of the exposure-disease association.

	ACKNOWLEDGMENTS

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This study was supported by a grant from the Dutch Heart Foundation.

We want to express our appreciation to A. VanderBorght and P. Stinissen, Dr Willems Institute, University of Limburg, Diepenbeek, Belgium, for the assessment of cytokine mRNA.

Received for publication August 24, 1999.

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