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European Journal of Heart Failure 2005 7(2):199-203; doi:10.1016/j.ejheart.2004.07.015
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© 2005 European Society of Cardiology

The significance of CA125 levels in patients with chronic congestive heart failure. Correlation with clinical and echocardiographic parameters

Nikos T. Kourisa,*, Ioannis D. Zacharosb, Dimitra D. Kontogiannia, Georgia S. Goranitoua, Maria D. Sifakia, Haris E. Grassosa, Eleni M. Kalkandia and Dimitris K. Babalisa

a Cardiology Department, Western Attica General Hospital Athens, Greece
b Social Security Institution, Piraeus Unit Greece

* Corresponding author. Tel.: +30 210 8041601; fax: +30 210 5698465. E-mail address: nikoskou{at}otenet.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Objective: To assess serum levels of carbohydrate antigen 125 (CA125) in patients with chronic congestive heart failure (CHF) and to assess any correlation with clinical symptoms and echocardiographic indices.

Patients and methods: We enrolled 77 male patients (mean age: 73±10 years) admitted to the Cardiology Emergency Department (ED) with cardiac symptoms requiring hospitalization. Diagnosis of CHF was based upon medical history or initial echocardiographic evaluation on current admission. Serum CA125 was measured by an enzyme immunoradiometric assay, on admission and before discharge.

Results: The median overall CA125 value was 22.4 (11.5–48.9) U/ml. Serum CA125 levels were related to the severity of CHF [New York Heart Association (NYHA) class I: 19.2 (7.2–31) U/ml, NYHA class II: 17.6 (10–23) U/ml, NYHA class III: 32 (25–77) U/ml and NYHA class IV: 34.3 (18.6–77) U/ml (p<0.04)]. Patients in NYHA classes III and IV had significantly higher mean values of CA125, than patients in class II (p<0.005 and p<0.05, respectively). Moreover, patients with fluid congestion (pulmonary congestion, ankle edema) had higher levels of serum CA125 than patients without congestion (p=0.002 and p<0.03, respectively). Finally, levels of serum CA125 correlated weakly with right ventricular systolic pressure (RVSP) and renal function, while no significant correlation was found between CA125 and E wave deceleration time on Doppler echocardiography, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), liver function and the medical treatment prescribed.

Conclusion: Serum CA125 is associated with the clinical severity of CHF and the symptoms and signs of fluid congestion and therefore may be a useful additional tool for the evaluation and clinical staging of these patients.

Key Words: Tumor marker • CA125 • Congestive heart failure

Received July 29, 2003; Revised December 16, 2003; Accepted July 5, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Serum carbohydrate antigen 125 (CA125) is a tumor marker used for monitoring the clinical course of patients with ovarian cancer [1,2]. Increased serum CA125 values have also been reported in other malignancies including acute leukemia [3], non-Hodgkin's lymphoma [4–6], melanoma [7], breast [8] and lung cancers [9] and gastrointestinal carcinoma [10], as well as in some non-malignant conditions such as abdominal surgery [11], bacterial peritonitis [12], pelvic inflammatory disease [13], endometriosis [14], tuberculosis [15,16] and pericardial effusion [17]. Recently, elevation of CA125 serum levels has been reported in patients with congestive heart failure (CHF) [18,25].

In this study, we measured serum CA125 in a group of patients with CHF, who were admitted to our cardiology department with symptoms of CHF. We also studied the correlation between serum CA125 levels and clinical symptoms and findings on admission, as well as laboratory and echocardiographic indices.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
We evaluated 77 consecutive male patients, with or without a history of CHF, admitted to the Cardiology Emergency Department (ED) of the Western Attica General Hospital in Athens with symptoms of decompensated CHF or other cardiac symptoms such as angina, syncope or palpitations. The diagnosis of CHF was based on medical history and initial investigation, which included physical examination, electrocardiogram, chest X-ray, blood and urine laboratory tests and echocardiographic evaluation. Patients were assigned to either NYHA classes I, II, III or IV according to the New York Heart Association (NYHA) classification of heart failure. All patients were screened for diseases that could influence levels of CA125 such as malignancies, active infection and liver or renal failure. Symptoms on admission and physical findings, such as rales on chest auscultation and the presence of ankle edema, were also recorded. Additionally, the presence of pulmonary congestion and pleural fluid on chest X-ray, the renal functional status and medications prescribed during hospitalization were evaluated. All patients underwent a two-dimensional Doppler echocardiographic examination within 4 h of admission. Echocardiographic examination included measurement of left ventricular end-diastolic (LVEDD) and end-systolic diameters (LVESD), estimation of left ventricular ejection fraction (LVEF) using the Simpson method and the existence of pericardial fluid. On Doppler examination, E and A velocities, E/A ratio and early filling deceleration time (DTE) were measured on transmitral filling pattern. Right ventricular systolic pressure (RVSP) was estimated from the maximum velocity of tricuspid regurgitation on continuous Doppler using the Bernoulli equation: RVSP=4Vmax2+RAP, where RAP is the right atrial pressure, approximately 10 mm Hg.

The clinical characteristics of patients are shown in Table 1.


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  		Table 1 Clinical characteristics of the whole cohort of patients

 
2.1. Serum CA125 measurements
Serum levels of CA125 were determined on admission and before hospital discharge. The assessment of CA125 levels was made by an enzyme immunoradiometric assay (Immunotech CA125 Antigen IRMA kit, ref. 2233; Beckman Coulter, USA) with an upper normal limit of 35 U/ml. The intra-assay and inter-assay coefficient of variation were 2.1% and 4.4%, respectively. A two-site ‘sandwich— assay with two mouse monoclonal labeled antibodies directed against two different epitopes of the molecule was performed for each patient in duplicate. The bound radioactivity, measured in a gamma counter, was proportional to the CA125 concentration.

2.2. Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software [19]. Normal distribution of CA125 was checked with Kolmogorov–Smirnov test. Due to the fact that measured data were markedly skewed, all values are expressed as median–interquartile range. Analysis of the differences between subgroups was performed using the non-parametric Mann–Whitney U-test. Correlations between CA125 and clinical, laboratory and echocardiographic parameters were measured using Spearman's rho method. A p value<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
The median value of serum CA125 in the whole cohort of patients was 22.4 (11.5–48.9) U/ml. Median values of CA125 in each group were: NYHA I: 19.2 (7.2–31) U/ml; NYHA II: 17.6 (10–23) U/ml; NYHA III: 32 (25–77) U/ml and NYHA IV: 34.3 (18.6–77) U/ml. Clinical, laboratory and echocardiographic parameters and serum levels of CA125 in all patients, classified according to NYHA functional class, are presented in Tables 2 and 3. Patients in NYHA classes III and IV demonstrated higher values of CA125, than patients in NYHA class II (p<0.005 and p<0.05, respectively) (Table 3, Fig. 1). Additionally, serum levels of CA125 were higher in patients with pulmonary congestion (p=0.002) and with ankle edema (p<0.03). A trend towards higher values of CA125 was also found, in patients with pleural effusion (p=0.06; Table 2).


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  		Table 2 Symptoms on admission, clinical signs and laboratory findings

 


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  		Table 3 Laboratory and echocardiographic parameters and serum levels of CA125 in patients with CHF

 


Figure 1
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  		Fig. 1 Boxplot for differences of CA125 between NYHA classes I, II, III and IV.

 
Echocardiographic indices, renal and liver functional status and the use of medications (before and during hospitalization) were evaluated for their correlation to serum CA125 levels. Forty-three patients (55%) were receiving ACE inhibitors at the time of admission, 49 (63%) were receiving diuretics, 18 (23%) digitalis and 10 (23%) b-blockers. Four patients (5%) were not receiving any medication. A weak correlation was found between levels of CA125 and renal function (r=0.3, p=0.02), as well as RVSP (r=0.25, p=0.05). No significant correlation was found between the levels of CA125 on admission and LVEDD, EF, DTE, liver function and the patient's pre-admission medications. Similarly, there was no correlation between the levels of CA125 before discharge and the medications prescribed during hospitalization.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
Serum levels of CA125 are used for the diagnosis and follow-up of patients with ovarian carcinoma [1,2]. Several studies have reported elevation of serum CA125 in patients with other malignancies [3,7–10], but the clinical significance of these observations remains unclear. Recently, levels of serum CA125 were found to be of prognostic significance in patients with non-Hodgkin's lymphoma [6]. Moreover, elevation of serum CA125 has been found in some non-malignant diseases [11–17]. In most of these reports, high levels of serum CA125 were associated with the presence of pleural and/or pericardial and/or ascetic fluid [3,5,6]. Seo et al. [17] suggested that sequential measurements of serum CA125 are useful for monitoring pericardial effusion. Nagele et al. [18] and D'Aloia et al. [25] found that CA125 is increased in patients with left ventricular dysfunction and that these values were related to the severity of CHF.

The underlying mechanism for the production and secretion of CA125 antigen remains unclear. Apel and Fernandes [20] and Camera et al. [21] have reported that neoplastic cells do not produce CA125. This provides additional support to the theory that increased serum CA125 may represent a reaction of pleuropericardial or peritoneal mesothelial cells to the tumor. Cytokines, such as interleukin-1β and tumor necrosis factor-{alpha} derived from malignant cells in patients with peritoneal involvement, may be responsible for the stimulation of mesothelial cells to secrete CA125 [22]. In non-malignant disease, it seems that peritoneal irritation due to inflammation or trauma stimulates peritoneal mesothelial cells to secrete CA125 antigen. As far as the relationship between CA125 and cardiac dysfunction is concerned, interleukin-6, which has been found to be elevated in CHF [22], might play an important role, since there are data suggesting that proliferation of CA125-producing cells is stimulated by this cytokine [23].

According to the results of our study, serum CA125 levels correlate significantly with the clinical status of patients with CHF, as demonstrated by the higher values of CA125 in NYHA classes III and IV patients, compared to those in NYHA classes I and II. Moreover, serum CA125 correlates with the presence of fluid congestion, based on rales on auscultation, signs of congestion on chest X-ray and ankle edema. This finding is verified by the fact that in patients with dyspnea of cardiac origin as the predominant symptom on admission, levels of serum CA125 were higher compared to those who were admitted due to angina, acute coronary syndrome, syncope or ventricular arrhythmias, regardless of the severity of CHF. Interestingly, there were two patients with a history of severe CHF (NYHA IV) who were hospitalized twice: the reasons for their first hospitalization were sustained VT and paroxysmal atrial fibrillation, while the second admissions were due to decompensated CHF. CA125 serum levels were within normal range in both patients when they were admitted due to arrhythmias, but levels were elevated when fluid congestion was the reason for admission. Only four patients had evidence of mild to moderate pericardial effusion on echocardiography. In these patients, levels of CA125 were high, a finding consistent with the report of Seo et al. [17], who also reported that levels of CA125 were related to the amount of pericardial effusion.

Two recent studies [24,25] also report higher levels of CA125 in patients with fluid congestion. Our findings are in agreement with D'Aloia et al. [25] who also indicated fluid congestion as the main cause for CA125 elevation, but in contrast to the results of Nagele et al. [18] who reported that acute congestion was probably not the cause of CA125 secretion. On the other hand, D'Aloia et al. reported a significant negative correlation between CA125 and DTE. The reason for this discrepancy may be the fact that our study also included patients with advanced CHF, who were admitted for reasons other than fluid congestion (e.g., VT or syncope), in whom levels of CA125 were normal. Another discrepancy between Nagele's report and the present study are the lower CA125 values found in our study. This is due to the different assay used for serum CA125 measurement (ELISA method in Nagele's report, monoclonal antibodies in the present study).

Additionally, Nagele et al. and D'Aloia et al., found a significant decrease in CA125 values after proper therapeutic intervention and compensation of CHF. In our study, values of serum CA125 prior to hospital discharge were lower than values on admission, but the difference was not statistically significant (p=0.09). This discrepancy might be due to the fact that the mean time for repeating measurement of CA125 in our study was only 5.8 days (range 4–7) after admission. The short duration of the follow-up period in our study, is also a considerable limitation, since clinical endpoints, such as mortality (total and cardiovascular) or hospitalization for cardiovascular causes, cannot be evaluated over such a short period of time. Prolongation of the follow-up period and consideration of the aforementioned clinical endpoints might provide valuable information concerning the potential use of serum CA125 levels, as a prognostic marker in patients with CHF.

Finally, it has been reported that serum levels of CA125 are elevated in parallel to natriuretic peptides and norepinephrine in patients with CHF [18]. The fact that determination of CA125 is both easier and cheaper may make it a valuable diagnostic "blood test" for patients admitted with symptoms of congestion.

We conclude that serum CA125 appears to be useful as a complementary laboratory tool for the functional staging of patients with CHF. However, the biologic role of CA125 antigen remains obscure and the potential prognostic value of this biologic marker require further investigation in studies with longer follow-up periods.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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