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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2843-2847.)
© 1997 American Heart Association, Inc.

Articles

Elevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm

Jukka Juvonen; Heljä-Marja Surcel; Jari Satta; Anna-Maija Teppo; Aini Bloigu; Hannu Syrjälä; Juhani Airaksinen; Maija Leinonen; Pekka Saikku; ; Tatu Juvonen

From the National Public Health Institute, Oulu (J.J., H-M.S, A.B., M.L., P.S.); the Department of Surgery, Oulu University Hospital and University of Oulu (J.S., T.J.); the Department of Internal Medicine, University of Helsinki, Helsinki (A-M.T.); Hospital Infection Control, Oulu University Hospital (H.S.); the Department of Internal Medicine, Division of Cardiology, Oulu University Hospital and University of Oulu (J.A.); and the Department of Internal Medicine, Central Hospital of Kainuu, Kajaani, Finland (J.J.).

Correspondence to Tatu Juvonen, MD, PhD, Research Asst Professor, Department of Cardiothoracic Surgery, The Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1028, New York, NY 10029.

	Abstract

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Abstract The basic feature in the pathogenesis of abdominal aortic aneurysm (AAA) is the degradation of extracellular matrix components. This process is induced partly by cytokines secreted from inflammatory and mesenchymal cells. Circulating levels of inflammatory cytokines were studied in AAA patients and compared with subjects suffering from atherosclerotic disease only. Furthermore, the predictive value of cytokine concentrations was evaluated for aneurysm expansion rate. Circulating levels of interleukin 1ß (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor- (TNF-), and interferon- (IFN-) were measured in 50 AAA patients (40 men, 10 women), 42 patients with coronary heart disease (CHD) (23 men, 19 women), and 38 controls whose angiogram was normal (17 men, 21 women). No differences in cytokine concentrations were found between the CHD patients and the controls. AAA disease was found to be associated with significantly higher IL- 1ß and IL-6 concentrations in both male patients (median concentrations of 19.40 pmol/L and 6.45 pmol/L, respectively) and female patients (19.26 pmol/L and 7.99 pmol/L) than in either the CHD patients or the controls (P<.005). TNF- levels were slightly higher in the AAA patients (1.64 pmol/L in the males and 1.59 pmol/L in the females) than in the other groups (P <.05). IFN- levels were elevated significantly in the female AAA patients (3.75 pmol/L) compared with levels found in the other female (P<.05) or male (P<.01) patient groups. The measured cytokine concentrations were not related to the size of the aneurysm or the maximal thickness of the thrombus within the aneurysm. IFN- concentration showed a significant positive correlation to the aneurysm expansion (R=.37, P<.02) and negative correlation to the concentration of aminoterminal propeptide of type III procollagen during 6-month follow up (R=-.42, P<.005). The results show that circulating levels of inflammatory cytokines are elevated in patients with AAA disease, suggesting that the production of these cytokines is increased in these patients compared with CHD patients and controls. Elevated INF- concentrations seem to predict an increased rate of expansion in AAA.

Key Words: cytokines • abdominal aortic aneurysm • inflammation

	Introduction

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Increased circulating levels of cytokines, which are essential mediators of normal and pathologic immune responses, have been noted in a variety of diseases.^{1 2 3 4 5 6} Among the cardiovascular diseases, elevated circulating cytokine levels have been found in patients with various cardiomyopathies and myocarditis,⁴ acute myocardial infarction,⁵ and congestive heart failure,⁶ but not in those with stable coronary heart disease (CHD).⁴ Nevertheless, local expression of a number of inflammatory and chemotactic cytokines has been demonstrated in atherosclerotic plaques.^{7 8}

Abdominal aortic aneurysms (AAA) are often associated with atherosclerosis. There are, however, certain pathogenetic, epidemiological, and genetic differences between the two diseases.^{9 10} The basic phenomena in the pathogenesis of AAA are degradation of the extracellular matrix components (elastin and collagens) and loss of the structural integrity of the aortic wall.^{9 10} The AAA disease typically involves tissue inflammation as seen by the presence of inflammatory leukocytes and various cytokines, which are considered to participate in immunopathogenesis of AAA leading to the destruction of aortic matrix.^{9 10 11 12 13 14 15 16} Because of the potentially acute and lethal course of the disease, it would be a significant benefit to be able to screen unsuspected AAA and certain patients with known AAA for whom elective surgery is most appropriate.¹⁰ In certain diseases, circulating levels of individual cytokines have been found to correlate with the presence or severity of clinical symptoms,^{1 2 17 18} but these kinds of associations have not been studied in AAA disease.

The aim of the present study was to measure circulating levels of inflammatory cytokines (IL-1ß, TNF-, IL-6, and IFN-) in AAA patients to asses if the levels of circulating cytokines show any relationship with clinical parameters or with collagen metabolism.¹⁹ AAA has a strong male preponderance relative to atherosclerosis, but the reasons for this are unknown, and, consequently, we analyzed the cytokine findings separately in male and female patients in order to evaluate the potential immunologic basis for this difference.

	Methods

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Patients
The present study includes three different cohorts of patients as follows: 50 AAA patients, 42 CHD patients, and 38 controls. The demographic data of these groups are presented in Table 1. The AAA patients (40 men and 10 women) were a consecutive series of patients admitted to Oulu University Hospital between January and October 1993 for consideration of elective surgery and were included in a longitudinal clinical follow-up study. None of these aneurysm patients had symptoms related to their aneurysms; all were sent for vascular surgical consideration after an incidental finding of AAA by a general physician. The abdominal aorta was visualized by B-mode ultrasonography, and the dimensions of the aneurysm and thrombotic mass were determined. The ultrasonography was repeated after 6, 12, and 24 months.

View this table: [in this window] [in a new window]   Table 1. Demographic Data of Patients With Abdominal Aortic Aneurysm (AAA), Angiographically Diagnosed Coronary Heart Disease Patients (CHD), and Their Controls

The CHD patients and controls had been referred to the Cardiovascular Laboratory at Oulu University Hospital for coronary angiography during the same period of time because of chest pain. All of these patients underwent left-sided cardiac catheterization, including selective coronary arteriography in multiple views performed by Judkin's technique. The angiographic findings were interpreted by two independent cardiologists. A stenosis causing a >50% reduction in the luminar diameter was regarded as significant. The CHD group consisted of a consecutive cohort of 42 patients, 19 females and 23 males, with significant coronary artery disease. Their median symptoms were calculated to be NYHA (New York Heart Association) class III. Seventeen of them had three vessel disease, 10 two vessel disease, and 15 one vessel disease. The 38 randomly selected patients (21 females and 17 males) who comprised the control group had no significant coronary artery stenosis or atherosclerotic lesions in coronary angiography and were comparable with the AAA patients in terms of sex and age distribution. Patients with recent myocardial infarction, cardiomyopathy, congestive heart failure, or any infectious, inflammatory, or neoplastic disease were excluded. The protocol was approved by the Ethical Committee of the Faculty of Medicine at the University of Oulu.

Measurement of Cytokines
The sera for the cytokine assays were frozen and stored at -20°C until tested. Serum TNF- concentrations were measured with a solid phase radioimmunoassay (RIA),²⁰ the detection limit of which was 0.41 pmol/L. Serum IL-1ß was measured by a RIA modified from that of Cannon et al,²¹ in which values <1.18 pmol/L were considered normal, and serum IL-6 was also determined by RIA,²² the detection limit for which was 0.58 pmol/L. Serum IFN- was measured by EIA (Bender Medsystems, Vienna, Austria); the detection limit of the test, as indicated by the manufacturer, was 0.06 pmol/L.

Analysis of Collagen Metabolism
Collagen biosynthesis was analyzed by measuring a collagen turnover, the aminoterminal propeptide of type III procollagen (PIIINP), with an equilibrium-type RIA based on human antigen (Orion Diagnostica, Oulunsalo, Finland) with use of duplicate 200 µL aliquots of serum as previously described by Satta et al.¹⁹ Concentration of PIIINP is expressed as µg/L because its molecular weight slightly varies.

Statistical Methods
The statistical analyses were performed with SPSS statistical software (Windows 6.0), with comparisons among the three groups made by Kruskal-Wallis analysis of variance and differences between two groups analyzed with the Mann-Whitney U-test. Pearson correlation coefficients were used to test associations between continuous variables. Categorical variables were compared by ² test.

	Results

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Demographic data and distribution of the 130 patients by age and sex are shown in Table 1. Male and female patients are listed separately throughout because of the unequal distribution of these patient groups. The CHD patients were significantly younger than the AAA patients or the control subjects (P<.001), and the male CHD patients were younger than the female patients (P<.01). Smoking and hypertension were significantly more common in AAA patients than in controls (P<.001 and P<.05). When comparing CHD patients with controls, smoking was significantly more common in female (P<.01) but not in male patients (P>.05). Chronic obstructive pulmonary disease (COPD) was detected in nine (22.5%) of 40 male and two (20%) of 10 female AAA patients.

As shown in Fig 1, cytokine concentrations were comparable between the CHD patients and the controls, but IL-1ß, IL-6, and TNF- concentrations were significantly higher in the sera of male AAA patients (median concentrations 19.40, 6.45, and 1.64 pmol/L respectively) than in controls (2.06, 0.39 and 1.35 pmol/L) or in males with CHD (2.23, 2.31, and 1.35 pmol/L). No difference in IFN- concentrations was found between the male patient groups. Serum concentrations of IL-1ß, IL-6, and TNF- were also significantly higher in the female AAA patients (19.26, 7.99 and 1.59 pmol/L, respectively) than in either the control (2.06, 1.54, and 1.29 pmol/L) or the CHD female patients (2.21, 1.73, and 1.35 pmol/L). IFN- levels were significantly higher in the AAA females (median 3.75 pmol/L) than in the other female groups (1.89 pmol/L in the controls and 2.61 pmol/L in CHD, P<.05) or in the male patient groups (P<.05). No correlation was found between the serum levels of any cytokine and either age, diameter of aneurysm, or thickness of thrombus. Cytokine levels in either the 14 patients with a small AAA (maximal diameter <45 mm) or the seven patients with no ultrasonographically detectable thrombus were not significantly different from cytokine levels for the rest of the patients (P>.1).

View larger version (15K): [in this window] [in a new window]   Figure 1. Cytokine concentrations (pmol/L) in the serum of male and female abdominal aortic aneurysm (AAA), coronary heart disease (CHD), and control (C) patients. The distributions of circulating cytokine concentrations in the AAA patients and the controls were compared using the Mann-Whitney U test. ***P<.001, **P<.005, and *P<.05.

At the time of diagnosis, median maximal diameter of aneurysms in the AAA male and female patients was 48 mm (range 33 to 66 mm; SD 0.78, which showed a significant correlation to the median thickness of the thrombus 10.0 mm (range 0 to 35.0 mm; SD 9.69; R=.45, P<.001). Median PIIINP concentration (3.15 µg/L, range 1.80-5.30, SD 0.78), presence of hypertension, and COPD had no significant correlation to the aneurysm size. The thickness of thrombus correlated to PIIINP concentration (R=.73, P<.001).

As shown in Table 2, the average rate of aneurysm expansion was 4 to 5 mm within the first 12 months of follow-up. The aneurysm growth was not found to be influenced by hypertension, COPD, or smoking. The aneurysm expansion in 6 months follow-up showed a positive correlation to the IFN- concentration measured at the time of AAA diagnosis (R=.35, P<.02) and to low PIIINP concentration (R=.49, P<.0001). A correlation coefficient between IFN- and PIIINP concentrations was -.42 (P<.005). No correlation was found with the aneurysm expansion and IL-1ß, IL-6, or TNF- (P>.1).

View this table: [in this window] [in a new window]   Table 2. Mean Size of Aneurysm at 0, 6, 12, and 24 Months After Diagnosis

	Discussion

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Circulating inflammatory cytokines have been found to be elevated in patients with a variety of inflammatory diseases,^{1 2 3 4 5 6} and several inflammatory cytokines, including IL-1ß, IL-6, and TNF-, have been detected locally in atherosclerotic and AAA tissues.^{13 14 15 16} In this study we were able to demonstrate significantly higher levels of circulating IL-1ß, IL-6, and TNF- in the serum of AAA patients than in either CHD patients or angiographically normal controls. IL-1ß levels were especially high and provided a good demarcation between AAA patients and the other patient groups. The measured cytokine levels were the same in the AAA patients with small and large aneurysms (maximal diameter > or <45 mm) and in patients with or without detectable thrombus, suggesting that the cytokine-mediated inflammatory process is present as early as it is possible to diagnose the AAA disease and is not restricted to an advanced or "end stage" of the disease.

The presence of elevated cytokines (IL-1ß, IL-6, and TNF-) was associated with AAA disease but not with atherosclerosis because CHD patients had cytokine levels that did not differ from those of the controls with no angiographically verified lesions. However, AAA patients often have advanced atherosclerosis, and, therefore, we cannot exclude the possibility that the extent of atherosclerosis in the AAA patients was greater than that present in those with CHD. If this were true, it would be at least partly responsible for our results. Recently, Uno et al²³ published data supporting this possibility, demonstrating elevated levels of circulating cytokines in patients suffering from end stage occlusive arteriosclerosis, with signs of poor peripheral circulation such as cold, colored, or ulcerated extremities. We must also consider that in the general population, the incidence of unsuspected AAA has been estimated to be 1 to 2% and in screening studies of patients more than 50 years of age, 1 to 8%.^{10 24} Our CHD and control groups were not screened in this sense, and some cases with unsuspected AAA in these groups could possibly have affected on our results. However, because the control patients were quite young, the risk for unsuspected AAA is low.

Although circulating immunoreactive cytokines reflect production of these cytokines at sites of inflammation, they are not necessarily biologically active because immunoassays measure cytokine immunoreactivity regardless of its inactivation in specific circulating soluble receptors, beta-2-microglobulin, or other serum proteins.^{17 18} Matrix metalloproteinases (MMPs) have been suggested as mediators of the degradation of the structural proteins in the aneurysmal aortic wall,^{25 26 27 28 29} although this hypothesis has been questioned quite recently.³⁰ It must be emphasized that aneurysmal degeneration has been shown to involve additional proteinases, such as plasminogen activators.^{31 32} Based on previous publications, IL-1ß and TNF- are linked to AAA pathogenesis by inducing MMP expression and reducing the expression of tissue inhibitors of proteinases (TIMP).^{13 14 15 16} Together with IL-6, TNF- plays a role in neovascularization, and IL-6 seems to be at least partly responsible for the accumulation of immunoglobulins in the aneurysmal wall.^{33 34 35 36 37 38 39} Therefore, high concentrations of inflammatory cytokines in the AAA tissue may lead to increased degradation of the extracellular matrix, weakening of the vessel wall, and eventual dilatation of the aorta. Interestingly, it has been discovered recently that a metalloproteinase-like enzyme also mediates the posttranslational processing step required for conversion of membrane-bound pro TNF- (26kDa) to its 17 kDa soluble secreted form and that TNF- release is suppressed by MMP inhibitors.^{40 41 42} Inflammatory cytokines are also known to participate in the progression of atherosclerosis in several ways,^{7 8 17 39} and IL-1ß treatment has been shown to induce coronary intimal lesions in pigs in vivo.⁴³ On this basis, it is tempting to speculate that atherosclerosis may not be merely associated with AAA but that the inflammatory cytokines produced by AAA tissue can accelerate its progression in AAA patients.

According to our results, the expansion rate of the aneurysm could not be predicted by elevated concentrations of the proinflammatory cytokines (IL-1ß, IL-6, or TNF-). Instead, elevated IFN- levels seemed to predict aneurysm enlargement during the first 6 months follow-up correlating to low PIIINP concentration. IFN-, which is mostly produced by T cells, activates macrophages, stimulates the production of TNF- and IL-1ß, and has a specific effect on collagen metabolism by inhibiting the synthesis of type I and type III collagen alone or synergistically with TNF-.^{17 44 45} Increased IFN- production and positive correlation with both IFN- mRNA expressions and degree of adventitial inflammation have been demonstrated in AAA tissue.^{16 46} In accordance with our results, an inverse correlation between IFN- and PIIINP has been reported in patients with pulmonary fibrosis.⁴⁷ Our previous study provided evidence that collagen turnover is increased in AAA patients.¹⁹ However, the actual concentration of collagen in relation to aneurysm dilatation and rupture risk is debated continually.¹⁰ Most theories of aneurysm rupture have suggested inadequate collagen synthesis as the primary pathologic factor.⁴⁸ In the present study, the enhanced aneurysm expansion was associated with lowered PIIINP concentrations, indicating that collagen metabolism can be depressed in some stage of weakening of the aortic wall because of AAA disease. A positive correlation between IFN- concentration and aneurysm expansion suggests that collagen synthesis and repair processes are interrupted in the AAA wall. According to this study, the INF- levels were higher in female AAA patients than in other patient groups. Whether this is actually related to gender differences in AAA pathogenesis requires further study with larger patient groups.

Actively secreted cytokines associated with AAA^{13 14 15 16} are indicative of chronic inflammation in the AAA patients, and secreted IFN- suggests involvement of activated T cells. The primary reason for the inflammation remains obscure, but our recent demonstration of Chlamydia pneumoniae in AAA tissue⁴⁹ suggests that C. pneumoniae infection could be a causative agent. The fact that chlamydia can cause persistent infection, accelerate the production of inflammatory cytokines,⁵⁰ produce protease in HL cells,⁵¹ and provoke aneurysm formation in acute vascular infections⁵² makes C. pneumoniae a candidate for triggering AAA formation.

In conclusion, several cytokines are implicated in AAA and atherosclerosis processes, having multiple and complex effects on the pathogenic mechanisms involved in these diseases. An understanding of these mechanisms may thus help us to approach the problem of developing new treatments. In fact, many potential pharmacological strategies for the management of small AAAs have been presented.¹⁰ Future research will show whether the circulating concentrations of cytokines can be used to monitor the effect of these therapies.

	Selected Abbreviations and Acronyms

 

AAA = abdominal aortic aneurysm CHD = coronary heart disease IFN- = interferon- PIIINP = propeptide of type III procollagen TNF- = tissue necrosis factor-

	Acknowledgments

 
This work was supported by a grant from the Sigrid Juselius Foundation, Finland. The authors thank Michael Nurzia, BA, for assistance in the preparation of the manuscript.

Received July 2, 1996; accepted April 7, 1997.

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