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European Journal of Heart Failure 2008 10(6):556-559; doi:10.1016/j.ejheart.2008.04.012
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© 2008 European Society of Cardiology

Serum carbohydrate antigen 125 levels in advanced heart failure: Relation to B-type natriuretic peptide and left atrial volume

Dursun Dumana,*, Fatih Palitb, Ergun Simsekb and Karadag Bilgehanc

a Haydarpasa Numune Training and Research Hospital, Department of Cardiology, Tibbiye Caddesi Kadiköy/Istanbul, Turkey
b Haydarpasa Numune Training and Research Hospital, Department of Internal Medicine Istanbul, Turkey
c University of Istanbul, Cerrahpasa School of Medicine, Department of Cardiology Istanbul, Turkey

* Corresponding author. Tel.: +90 216 640 2061; fax: +90 216 640 2713. E-mail address: drduman{at}excite.com


   Abstract
Top
 Abstract
1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
Aims: To assess the relation between serum levels of carbohydrate antigen 125 (CA 125) and parameters of left ventricular (LV) filling pressure in patients with advanced heart failure (AHF).

Methods: Forty-nine patients (mean age 67±10 years) with LV ejection fraction (EF) ≤0.35 and New York Heart Association (NYHA) class III or IV symptoms of heart failure were enrolled. Left atrial volume indexed to body surface area (LAVI) and the ratio of mitral inflow early diastolic velocity to annulus velocity (E/e) were evaluated with pulsed wave and tissue Doppler. Plasma B-type natriuretic peptide (BNP) was also measured.

Results: The median overall CA 125 value was 44.0 (17.7–140) U/ml. CA 125 above the normal value (<35U/ml) was found in 28 of the 49 patients (57%). Compared to patients with normal CA 125 levels, those with elevated CA 125 had a higher NYHA class and increased serum BNP levels, LAVI and E/e. In multivariate analysis, serum CA 125 levels were significantly associated with BNP (standardized β coefficient=0.58, p<0.001) and LAVI (standardized β coefficient 0.34, p<0.005).

Conclusion: Our study demonstrates that elevated serum CA 125 levels are associated with increased LAVI in parallel to increased neurohormonal activation in patients with AHF.

Key Words: Carbohydrate antigen 125 • Left atrial volume • B-type natriuretic peptide • Advanced heart failure

Received February 16, 2008; Revised April 8, 2008; Accepted April 28, 2008


   1. Background
Top
 Abstract
 1. Background
2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 
Carbohydrate antigen 125 (CA 125) is a high-molecular-weight soluble glycoprotein synthesized by epithelial serosal cells. It has been shown that in patients with systolic heart failure increased levels of CA 125 are related to severity of clinical symptoms, haemodynamic alterations and short-term prognosis [1-6].

The mechanism of serum CA 125 elevation in acute heart failure is not well understood. Studies have reported that this elevation may be related to fluid retention with pleural, pericardial, or peritoneal effusions [1,6]. Other studies, however, have found elevated serum CA 125 levels in moderate to severe heart failure with no serosal fluid accumulation [2,5]. Previous studies have also demonstrated that elevated serum levels of CA 125 were significantly correlated with LV end diastolic pressure and B-type natriuretic peptide (BNP) levels, which were produced mainly in response to left ventricular (LV) wall pressure and volume overload [1,7]. During the diastolic period, the left atrial chamber is exposed to LV pressures. Impaired diastolic function causes the elevation of LV end diastolic pressure, which may over time lead to dilation of the left atrium [8]. Left atrial volume index (LAVI), is therefore presumed to reflect the severity and duration of LV diastolic dysfunction [9,10]. Previous studies have found that LAVI is significantly associated with increased neurohormonal activation in patients with heart failure [11]; however, the relationship between CA 125 and LAVI has never been investigated.


   2. Aims
Top
 Abstract
 1. Background
 2. Aims
3. Materials and methods
 4. Results
 5. Conclusion
 References
 
We postulated that elevated serum CA 125 is related to LAVI which reflects increased chronic LV filling pressure in patients with AHF. In this study we therefore investigated the relation between CA 125 and LAVI and neurohormonal activation in patients with AHF.


   3. Materials and methods
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
4. Results
 5. Conclusion
 References
 
We recruited 49 consecutive patients admitted to the emergency room with LV ejection fraction (EF) ≤0.35 and New York Heart Association class III or IV symptoms of heart failure. Exclusion criteria were: moderate and severe valvular disease, heart failure due to restrictive or hypertrophic cardiomyopathy, the presence of acute or chronic inflammatory or infectious diseases, recent myocardial infarction (within 8 weeks) or chest pain at the time of recruitment, hepatic or renal impairment (creatinine>2.5 mg/dl), the use of immunosuppressive drugs, serious arrhythmias, atrial fibrillation, cardiac tamponade and those with any evidence of cancer. All patients were in sinus rhythm.

The study was approved by the local ethics committee and written informed consent was obtained from each patient.

Left atrial volumes were calculated according to the Dodge method [12] and were corrected for body surface area. Peak velocities of early (E) and late (A) diastolic filling, isovolumic relaxation time (IVRT) and deceleration time (DT) were estimated from transmitral Doppler recordings. TDI-derived systolic, early (e), and late (a) diastolic velocities were estimated from the septal and lateral mitral annulus Doppler recordings and E/e ratio was also computed as a marker of LV filling pressures [9]. For standard echo/PW-Doppler measurements and TDI-derived variables, the intraobserver coefficients of variation ranged from 2.7% to 9.5%.

Natriuretic peptide levels were measured using an Enzyme-Linked Immunosorbent Assay (Biosite Diagnostics, San Diego, CA, USA) by an observer who was blinded to patient identity and treatments.

Skewed data (such as CA 125 and BNP values) were logarithmically transformed (ln), and the ln values were then used in correlation and regression analyses.


   4. Results
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
5. Conclusion
 References
 
Fifty-seven percent of the patients (n=28) had a CA 125 level >35 U/ml (Table 1). Compared to patients with normal CA 125 levels (n=21), those with elevated CA 125 had a higher NYHA class and increased serum BNP levels. E/e ratio and LAVI were also significantly increased in patients with elevated CA 125 (Table 1). Pleural effusion was observed on the chest X-ray in 5 patients; mild pericardial effusion was detected in 2 patients; no patients had ascites. All patients with pleuro-pericardial effusion had elevated levels of CA 125.


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  		Table 1 Baseline and clinical characteristics according to CA 125 levels, using 35 U/ml as a cut-off value

 
The correlations between ln CA 125 and other measured variables are listed in Table 2. Ln CA 125 was significantly correlated with ln BNP (r=0.78, p=0.0001), LAVI (r=0.58, p=0.001) and E/e (r=0.37, p=0.009), but not with EF, mitral DT, IVRT, mitral E-wave velocity or E/A. There was also a significant correlation between ln BNP and LAVI (r=0.55, p=0.001).


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  		Table 2 Correlation between logarithmically transformed (ln) CA 125 and other measured variables

 
The relationship between ln CA 125 and ln BNP and LAVI is shown in Fig. 1. In forward linear regression analyses (including NYHA class IV, E/e, LAVI, BNP and IVRT), the only independent predictors of ln CA 125 were ln BNP (standardized β coefficient=0.58, p<0.001) and LAVI (standardized β coefficient 0.34, p<0.005).


Figure 01
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  		Fig. 1 Correlation between logarithmically transformed (ln) CA 125 and ln BNP (A) and LAVI (B).

 

   5. Conclusion
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
References
 
The principal result of this study, in patients with AHF but with no severe valvular disease, was that serum levels of CA 125 were related to LAVI, BNP and E/e ratio. In particular, the only independent predictors of CA 125 in multivariate analysis were BNP and LAVI, which supports the theory that increased chronic LV filling pressure and neurohormonal activation may be more important than the acute changes of LV filling for the elevation of CA 125 in these patients.

We detected pleural and pericardial effusion in 7 of the 49 patients (14%), all of whom had elevated CA 125 levels, although the majority of patients with elevated CA 125 levels (75%) had no pleural or pericardial effusions. In agreement with our finding, D'Aloia et al. showed elevated serum CA 125 levels both in the few patients with pleural, pericardial or peritoneal effusion and in most patients with moderate to severe heart failure with no effusion [2].

Circulating levels of cytokines and/or cytokine receptors have been shown to be elevated in patients with AHF and to predict adverse outcomes [13]. Kosar et al. demonstrated that CA 125 is markedly elevated in patients with heart failure, and correlates with cytokines such as TNF-{alpha}, IL-6 and IL-10 [14]. Based on these reports and our findings, we speculate that CA 125 might be produced from activated mesothelial cells, even in the absence of classical stimuli (such as fluid retention) as a consequence of tissue stretching caused by increased chronic LV filling pressure and cytokine stimulation. However, the potential pathophysiological link between LAVI, cytokine activation and production of CA 125 in patients with AHF needs further study.


   References
Top
 Abstract
 1. Background
 2. Aims
 3. Materials and methods
 4. Results
 5. Conclusion
 References
 

  1. Kouris N.T., Zacharos I.D., Kontogianni D.D., et al. The significance of CA 125 levels in patients with chronic congestive heart failure. Correlation with clinical and echocardiographic parameters. Eur J Heart Fail (2005) 7:199–203.[Abstract/Free Full Text]
  2. D'Aloia A., Faggiano P., Aurigemma G., et al. Serum levels of carbohydrate antigen 125 in patients with chronic heart failure: relation to clinical severity, hemodynamic and Doppler echocardiographic abnormalities, and short-term prognosis. J Am Coll Cardiol (2003) 41:1805–1811.[Abstract/Free Full Text]
  3. Nagele H., Bahlo M., Klapdor R., Rödiger W. Tumor marker determination after orthotopic heart transplantation. J Heart Lung Transplant (1999) 18:957–962.[CrossRef][Web of Science][Medline]
  4. Nagele H., Bahlo M., Klapdor R., et al. Fluctuations of tumor markers in heart failure patients pre and post heart transplantation. Anticancer Res (1999) 19:2531–2534.[Web of Science][Medline]
  5. Nagele H., Bahlo M., Klapdor R., Schaeperkoetter D., Rödiger W. CA 125 and its relation to cardiac function. Am Heart J (1999) 137:1044–1049.[CrossRef][Web of Science][Medline]
  6. Turk H.M., Pekdemir H., Buyukberber S., et al. Serum CA 125 levels in patients with chronic heart failure and accompanying pleural fluid. Tumour Biol (2003) 24:172–175.[CrossRef][Medline]
  7. Faggiano P., D'Aloia A., Brentana L., et al. Serum levels of different tumour markers in patients with chronic heart failure. Eur J Heart Fail (2005) 7:57–61.[Abstract/Free Full Text]
  8. Simek C.L., Feldman M.D., Haber H.L., Wu C.C., Jayaweera A.R., Kaul S. Relationship between left ventricular wall thickness and left atrial size comparison with other measures of diastolic function. J Am Soc Echocardiogr (1995) 8:37–47.[CrossRef][Medline]
  9. Douglas P.S. The left atrium. A biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol (2003) 42:1206–1207.[Free Full Text]
  10. Pritchett A.M., Jacobsen S.J., Mahoney D.W., Bailey R.J., Rodeheffer K.R., Redfield M.M. Left atrial volume as an index of left atrial size a population based study. J Am Coll Cardiol (2003) 41:1036–1043.[Abstract/Free Full Text]
  11. Barclay J.L., Kruszewski K., Croal B.L., Cuthbertson B.H., Oh J.K., Hillis G.S. Relation of left atrial volume to B-type natriuretic peptide levels in patients with stable chronic heart failure. Am J Cardiol (2006) 98:98–101.[CrossRef][Web of Science][Medline]
  12. Dodge H.T., Sandler H., Ballew D.W., Lord D.J. Jr. The use of biplane angiocardiography for the measurements of left ventricular volumes in man. Am Heart J (1960) 60:762–776.[CrossRef][Web of Science][Medline]
  13. Deswal A., Petersen N.J., Feldman A.M., et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation (2001) 103:2055–2059.[Abstract/Free Full Text]
  14. Kosar F., Aksoy Y., Ozguntekin G., Ozerol I., Varol E. Relationship between cytokines and tumour markers in patients with chronic heart failure. Eur J Heart Fail (2006) 8:270–274.[Abstract/Free Full Text]

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This Article
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