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European Journal of Heart Failure 2005 7(1):57-61; doi:10.1016/j.ejheart.2004.04.009
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© 2004 European Society of Cardiology

Serum levels of different tumour markers in patients with chronic heart failure

Pompilio Faggiano*, Antonio D'Aloia, Loretta Brentana, Tommaso Bignotti, Claudia Fiorina, Enrico Vizzardi and Livio Dei Cas

Cattedra di Cardiologia, Università di Brescia Unità Operativa di Policardiografia e di Cardiologia Spedali Civili, Via S. Antonio 6, 25133 Brescia, Italy

* Corresponding author. Fax: +39-030-2007785. E-mail address: faggiano{at}numerica.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: serum levels of carbohydratic antigen 125 (CA 125), a tumour marker related to ovarian cancer, are increased in patients with heart failure (CHF). To our knowledge there are no data concerning the levels of other tumour markers in CHF.

Methods: we measured serum levels of Alpha-Fetoprotein (AFP), Carcinoembrionic antigen (CEA), CA 19.9, CA 15.3 and CA 125, in 191 pts (86 males, mean age 67±10 years) with mild to severe CHF due to left ventricular systolic dysfunction.

Results: Only CA-125 was increased in CHF patients: mean values were significantly higher (P<0.05) in NYHA classes III (60±22 UI/ml) and IV (192±115 UI/ml) compared to NYHA class I-II patients (16±11). Mean values of the other tumor markers were within the normal range. AFP was above the upper normal limit in 2/191 patients (1%), CEA in 5/191 (2.6%), CA 19.9 in 0, CA 15.3 in 2/191 (1%) and CA 125 in 126/191 patients (66%). In 30 NYHA IV patients, tumour markers were repeated after 5–20 days of aggressive medical treatment, when a clinical improvement (reduction of at least 1 NYHA class) was reached: mean serum levels of CA 125 decreased from 107±85 to 19±8 U/ml (P<0.05); no changes in other tumour markers were observed.

Conclusions: Of the tumour markers evaluated, only CA 125 seems to be related to the presence and severity of CHF and shows significant changes in response to medical therapy. The biologic and clinical relevance of this observation needs to be defined.

Key Words: Heart failure • Tumour markers • Carbohydrate antigen-125

Received October 24, 2003; Revised February 9, 2004; Accepted April 7, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In recent years, serum levels of several biological substances, such as neurohormones (particularly norepinephrine and atrial natriuretic peptides), markers of inflammation and cytokines (tumor necrosis factor and interleukin-6) have been shown to increase in patients with chronic heart failure (CHF) and to relate with an adverse outcome [1–5]. High levels of carbohydrate antigen 125 (CA 125), a tumour marker related to ovarian cancer, have been recently found in CHF patients and shown to relate to severity of clinical picture, hemodynamic abnormalities and short-term prognosis [6,7]. Data on the behaviour of other tumour markers in CHF are lacking. Accordingly, the aim of this study was to evaluate the serum levels of several tumour markers, commonly used in oncology for screening, diagnosis, prognostic stratification and therapeutic monitoring of different malignancies, in a large group of patients with mild to severe CHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The study population included 191 adult patients consecutively admitted with CHF to the Department of Cardiology, Spedali Civili and University of Brescia, Italy (Table 1). The diagnosis of CHF was based on clinical presentation and standard investigations and satisfied the European Society of Cardiology criteria; furthermore, all patients had at least one hospital admission for CHF prior to the inclusion in the study. Patients with recent acute coronary syndrome (<3 months), those awaiting coronary artery bypass or valvular surgery, those with any evidence of active infection or cancer, or end-stage liver disease or renal failure were excluded.


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  		Table 1 Demographic and clinical characteristics of the study population

 
Two-dimensional echocardiography was performed with commercially available equipment. Measured variables included: left ventricular end-diastolic (LVEDD) and end-systolic diameter (LVESD), using two-dimensional guided M-mode; and the left ventricular ejection fraction (LVEF), calculated using the Simpson method from the apical 4-chamber view. The severity of mitral and tricuspid regurgitation was evaluated by means of color Doppler flow imaging and semiquantitatively expressed using a scale from 0 to 4+ [8]. Systolic pulmonary artery pressure was non-invasively estimated by peak flow velocity of tricuspid regurgitation on continuous wave Doppler using a standard approach. On the pulsed Doppler tracing of transmitral blood flow, recorded at the tips of the mitral leaflets from the apical four-chamber view, the following parameters were measured: peak velocity in early filling (E) and during atrial systole (A), expressed in cm/s, and their ratio (E/A), and the deceleration time of early filling (DT), expressed in milliseconds; these parameters, particularly DT, have been shown to significantly correlate with invasively measured left atrial pressure [9].

Brain natriuretic peptide (BNP) serum levels were measured in all patients the day of hospital admission using a point-of-care method (Triage BNP Test, Biosite). Simultaneously, the serum levels of the following tumour markers were measured using commercially available kits: Alpha-Fetoprotein (AFP, Abbott Architect AFP, Abbott Laboratories, Abbott Park, Illinois, upper normal limit 7 UI/ml), Carcinoembryonic Antigen (CEA, Abbott Architect CEA, Abbott Laboratories, Abbott Park, Illinois, upper normal limit 7 ng/ml), Carbohydrate Antigen 19.9 (CA 19.9, AxSYM system, Abbott Laboratories, Abbott Park, Illinois, upper normal limit 40 U/ml), Carbohydrate antigen 15.3 (CA 15.3, AxSYM system, Abbott Laboratories, Abbott Park, Illinois, upper normal limit 30 U/ml), Carbohydrate Antigen 125 (CA 125, Tumor Marker CA 125, AxSYM system, Abbott Laboratories, Abbott Park, Illinois, upper normal limit 35 U/ml). For further information on the method of measurement, inter-assay and intra-assay coefficients of variations see a previous study from our group [7].

The study was approved by the local ethics committee and all patients gave written informed consent.

Statistical analysis: Data are expressed as mean values±standard deviation. Differences between the study groups were assessed by the Student t-test with Bonferroni correction and the two-way analysis of variance for repeated measures with post-hoc Scheffe correction was used. A P value <0.05 was considered statistically significant. Correlations were determined using linear regression analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Demographics and clinical characteristics of the study population are listed in Table 1. Doppler echocardiographic data and BNP values of study population divided according to New York Heart Association functional class are presented in Tables 2 and 3. Most patients showed symptoms of moderate to severe CHF (NYHA III and IV), marked left ventricular dilatation and systolic dysfunction with significant atrio-ventricular valve regurgitation and a relevant increase of BNP levels.


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  		Table 2 Doppler echocardiographic data of study population divided according to NYHA Functional class

 


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  		Table 3 Serum levels of tumoral markers and BNP in the population divided according to NYHA functional class

 
Mean values of serum levels of different tumour markers are reported in Table 3. Only the mean values of CA 125 were widely above upper normal limit in the study population considered as a whole. Furthermore, statistically significant higher values of CA 125 were observed in NYHA class III and IV compared to class I and II. An increase of AFP above upper normal limit (7 UI/ml, see Methods section) was found in 2 out of 191 patients (1%); two NYHA class IV patients showed a AFP value of 9 and 14 UI/ml, respectively. An increase of CEA above upper normal limit (7 ng/ml) was found in 5/191 patients (2.6%); 1 NYHA class II patient (CEA level 9 ng/ml), two NYHA class III patients (CEA levels 8 ng/ml and 13 ng/ml, respectively) and two NYHA class IV patients (CEA values 8 ng/ml and 11 ng/ml, respectively). CA 19.9 was within upper normal limit in all patients. An increase of CA 15.3 above upper normal limit (30 UI/ml) was found in 2/191 patients (1%); 1 NYHA class I patient and 1 NYHA class IV patient showed a CA 15.3 value of 33 UI/ml and 40 UI/ml, respectively. An increase of CA 125 above upper normal limit (35 UI/ml) was observed in 126 out of 191 patients (66%): 4/61 (6.5%) NYHA class I and II patients, 45/52 (86%) NYHA class III patients and 77/78 (98%) NYHA class IV patients.

CA 125 serum levels showed a statistically significant relation of at least moderate degree with BNP serum levels simultaneously assessed (r=0.75, P<0.05) (Fig. 1). However, the relation found between BNP and the other tumour markers was poor and not statistically significant (BNP vs. AFP r=0.15; BNP vs. CEA r=0.12; BNP vs. CA 19.9 r=0.10; BNP vs. CA15.3 r=0.13).


Figure 1
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  		Fig. 1 Linear regression analysis between CA 125 and BNP serum levels simultaneously assessed in CHF patients. See text for details.

 
Finally, serum levels of tumour markers were repeated in 30 NYHA class IV patients after 5–20 days of aggressive medical therapy with high doses of diuretics, intravenous vasodilators and dobutamine, when a clinical improvement was obtained (at least 1 NYHA Class reduction). In this group of 30 patients CA 125 significantly decreased from 107±85 (range 50–388) to 19±8 (range 8–32) UI/ml (P<0.005) and paralleled the concomitant reduction observed in serum BNP levels, from 941+355 (range 250–1300) to 187+109 (range 34–420) pg/ml (Fig. 2).


Figure 2
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  		Fig. 2 Changes in serum levels of CA 125 (upper panel) and of BNP (lower panel) observed after medical therapy optimization and clinical improvement in patients with severe CHF (NYHA IV class). See text for details.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The results of this study show that only the serum levels of the tumour marker CA 125 are significantly increased in patients with CHF, confirming previous data, while other commonly used tumour markers show minimal, non-significant changes.

CA 125, a glycoprotein initially related to ovarian cancer, has been subsequently found to increase in other malignant and non-malignant diseases, especially those with serosal involvement (which represents an important site of production) and peritoneal, pleural or pericardial effusion [10–15]. Recent studies have reported an increase of CA 125 levels in patients with moderate to severe CHF [6,7]; the changes observed in this tumour marker were related to the severity of the clinical picture, to the hemodynamic abnormalities and short-term prognosis [7]. Of interest, it has been reported that CA 125 and other tumour markers are produced and released from cancer cells when stimulated by cytokines [16–18], such as tumor necrosis factor (TNF-alfa) and interleukin-6 (IL-6), which are also elevated in heart failure [3–5]. Accordingly, we hypothesized that a generalized increase of several tumor markers could reflect an advanced stage of CHF with multiorgan failure and cachexia. To our knowledge, this is the first study that has evaluated systematically the behaviour of tumour markers in CHF patients.

The data here reported demonstrate that among the tumour markers commonly used in oncology, such as AFP, CEA, CA 19.9, CA 15.3 and CA 125, only the latter shows relevant changes in CHF patients. In fact, CA 125 serum levels slightly increased above normal limit in a few patients with mild CHF (NYHA I–II), were higher in most patients with moderate CHF (NYHA III) and markedly increased in almost all severe CHF (NYHA IV) patients. Furthermore, the CA 125 changes were unrelated to the body mass index, an indirect index of nutritional status, to the involvement of other organs, as patients with chronic liver disease were excluded and most patients had serum creatinine level within the normal range, and to associated serosal fluid accumulation (pleural and pericardial effusions were present only in three patients). However, CA 125 serum levels were significantly correlated with BNP serum levels. Finally, CA 125 serum levels significantly decreased after optimization of medical therapy, paralleling the clinical improvement and the simultaneous reduction of BNP levels. However, the other tumoral markers showed a slight increase in a minority of CHF patients (<3% of total study population), independently of the severity of the clinical picture and apparently indicating a chance variation (or subclinical malignancy?).

The changes we observed in CA 125 serum levels, compared to non-significant variations observed for the other tumour markers, and data from previous studies [6,7] allowed us to hypothesize a specific role for CA 125 in the management of patients with CHF, particularly in the evaluation of severity of the syndrome, in prognostic stratification and in monitoring the effects of therapy. However, several points regarding the interpretation of CA 125 elevations in CHF still need to be addressed. Particularly, the mechanism regulating its production, and the organs where it is produced, need to be clarified. It could be hypothesized that CA 125 might be produced from mesothelial cells as a consequence of even a subclinical, mild, fluid accumulation or of tissue stretching caused by either heart enlargement and/or hepatic and splanchnic congestion. The significant correlations between CA125 levels and right and left ventricular filling pressures, previously reported [7], and between CA 125 and BNP levels observed in this study are consistent with this mechanism. Alternatively, it may be hypothesized that CA125 is secreted by non-mesothelial cells in patients with CHF as a consequence of cytokine network activation (see above). It is also unknown whether the increase in CA 125 is simply an epiphenomenon of CHF progression or may actively contribute to the worsening of myocardial dysfunction and clinical conditions. The potential clinical role of these two mechanisms should be assessed in further studies.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Francis G.S., Cohn J.N., Johnson G., Rector T.S., Goldman S., Simon A. Plasma norepinephrine, plasma renin activity and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative studies group. Circulation (1993) 87:VI140, 148.
  2. Cheng V., Kazanegra R., Garcia A., et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol (2001) 37:368–391.
  3. Sharma R., Rauchhaus M., Ponikowski P.P., et al. The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Am Coll Cardiol (2000) 36:523–528.[Abstract/Free Full Text]
  4. Ferrari R., Bachetti T., Confortini R., et al. Tumor necrosis factor solubile receptors in patients with various degree of congestive heart failure. Circulation (1995) 92:1479–1486.[Abstract/Free Full Text]
  5. MacGowan G.A., Mann D.L., Kormos R.L., Feldman A.M., Murali S. Circulating interleukin-6 in severe heart failure. Am J Cardiol (1997) 79:1128–1131.[CrossRef][Web of Science][Medline]
  6. Nagele H., Bahlo M., Klapdor R., Schaeperkoetter D., Rodiger W. CA 125 and its relation to cardiac function. Am Heart J (1999) 137:1044–1049.[CrossRef][Web of Science][Medline]
  7. D'Aloia A., Faggiano P., Aurigemma G.P., Bontempi L., Ruggeri G., Metra M., et al. Serum levels of carbohydrate antigen 125 (CA 125) in patients with chronic heart failure. Relation with clinical severity, hemodynamic and Doppler echocardiographic abnormalities and short term prognosis. J Am Coll Cardiol (2003) 41:1805–1811.[Abstract/Free Full Text]
  8. Helmcke F., Nanda N.C., Hsiung M.C., et al. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation (1987) 75:175–183.[Abstract/Free Full Text]
  9. Giannuzzi P., Imparato A., Temporelli P.L., et al. Doppler-derived mitral deceleration time of early filling as a strong predictor of pulmonary capillary wedge pressure in postinfartion patients with left ventricular systolic dysfunction. J Am Coll Cardiol (1994) 23:1760–1767.
  10. Bast R.C., Klug T.L., John E.S., et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med (1983) 309:883–887.[Abstract]
  11. O'Brien T.J., Tanimoto H., Konishi I., Gee M. More than 15 years of CA 125: what is known about the antigen, its structure and its function. Int J Biol Markers (1998) 13:188–195.[Web of Science][Medline]
  12. Bates S.E. Clinical applications of serum tumor markers. Ann Intern Med (1991) 115:623–638.[Abstract/Free Full Text]
  13. Sjovall K., Nilsson B., Einhorn N. The significance of serum CA 125 elevation in malignant and non-malignant diseases. Gynecol Oncol (2002) 85:175–178.[CrossRef][Web of Science][Medline]
  14. Bergmann J.F., Bidart J.M., George M., Beaugrand M., Levy V.G., Bohuon C. Elevation of CA 125 in patients with benign and malignant ascites. Cancer (1987) 59:213–217.[CrossRef][Web of Science][Medline]
  15. Sevinc A., Buyukberger S., Sari R., Kiroglu Y., Turk H.M., Ates M. Elevated serum CA-125 in hemodialysis patients with peritoneal, pleural or pericardial fluids. Gynecol Oncol (2000) 77:254–257.[CrossRef][Web of Science][Medline]
  16. Zeimet A.G., Offner F.A., Marth C., et al. Modulation of CA 125 release by inflammatory cytokines in human peritoneal mesothelial and ovarian cancer cells. Anticancer Res (1997) 17:3129–3131.[Web of Science][Medline]
  17. Kubonishi I., Bandobaschi K., Murata N., Daibata M., Ido E., Sonobe H. High serum levels of CA 125 and interleukin-6 in a patient with Ki-1 lymphoma. Br J Haematol (1997) 98:450–452.[CrossRef][Web of Science][Medline]
  18. Marth C., Zeimet A.G., Widschwendter M., Daxenbichler G. Regulation of CA 125 expression in cultured human carcinoma cells. Int J Biol Markers (1998) 13:207–209.[Web of Science][Medline]

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