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Tumor marker levels in patients aged 85 years and older with chronic heart failure
European Journal of Internal Medicine 24 (2013) 440–443
Contents lists available at SciVerse ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Tumor marker levels in patients aged 85 years and older with chronic heart failure Jinling Ma 1, Yuexiang Zhao 1, Yutang Wang ⁎, Yuanyuan Guo, Jian Li First Geriatric Cardiology Division of South Building, Chinese PLA General Hospital, Beijing 100853, China
a r t i c l e
i n f o
Article history: Received 12 March 2013 Received in revised form 27 March 2013 Accepted 8 April 2013 Available online 1 May 2013 Keywords: Carbohydrate antigen-125 Heart failure Tumor markers Older patients
a b s t r a c t Background: Recent studies have suggested that carbohydrate antigen 125 (CA 125) serum levels are remarkably elevated in patients with heart failure. We hypothesized that there was a relationship between serum levels of tumor markers and the four stages of chronic heart failure (CHF) in patients aged 85 years and older with CHF. Methods: The retrospective study enrolled 2115 patients aged 85 years and older suffering from CHF between January 2004 and January 2011. The levels of various tumor markers, N-terminal proB-type natriuretic peptide (NT-proBNP) in the different stages of CHF, and clinical risk factors were analyzed. All patients were followed for 180 days, and major cardiovascular events were recorded. Results: Only the CA 125 level increased as the stage of CHF increased (p b 0.05) among the tumor markers. Significantly higher CA 125 serum levels were found in patients with pleural fluids or peripheral edema, compared with patients without pericardial effusion or peripheral edema (p b 0.01). During 180 days of follow-up, CA 125 values were significantly higher in patients who died or were rehospitalized, compared with those who remained alive or did not undergo rehospitalization. Linear regression analysis between CA 125 and NT-proBNP serum levels showed a statistically significant relation (r = 0.5103, p b 0.05). Conclusions: Among the tumor markers evaluated, only CA 125 appeared to be related to the severity of CHF and NT-proBNP, along with the presence of pleural fluid or peripheral edema in patients aged 85 years and older with CHF. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Serum tumor markers, except prostate-specific antigens, are normally used to follow-up patients with cancer [1], although the clinical use of these markers is partially limited because of low sensitivity. Recent studies have suggested that carbohydrate antigen 125 (CA 125) serum levels are remarkably elevated in patients with heart failure (HF), and the increase is related to the severity of the disease [2–8]. Serum CA 125 has been reported as an independent predictor of mortality up to the sixth month of follow-up [9]. This antigen has added prognostic value beyond the information provided by plasma B-type natriuretic peptide (BNP). The combination of these two molecules enables better six-month risk stratification [10]. Other serum tumor markers, such as carbohydrate antigen 199 (CA 19-9) and carcino embryonic antigen (CEA), are not influenced by circulatory disturbances [11,12]. Considering the various diseases in older patients, such as osteoporosis and arthritis, that cause difficulty in walking, the assessment of the New York Heart Association (NYHA) has been limited. Thus, the current research uses a new 4-stage classification, that is, four stages of chronic heart failure (CHF), to evaluate heart function. The four stages of CHF emphasize both the development and progression ⁎ Corresponding author. Tel.: +86 13901163874. E-mail address: [email protected] (Y. Wang). 1 Jinling Ma and Yuexiang Zhao contributed equally to this work.
of CHF, and this new classification scheme adds a useful dimension to the general view of HF [13]. The aim of the present study was to investigate the relationship between serum levels of tumor markers, including CA 125, carbohydrate antigen 15-3 (CA 15-3), CA 19-9, carbohydrate antigen 724 (CA 724), CEA, alpha-fetoprotein (AFP), neuron-specific enolase (NSE), and cytokeratin fragment 21-1 (CYFRA 21-1), and the four stages of CHF, as well as N-terminal proBNP (NT-proBNP), in patients aged 85 years and older with CHF. As a secondary objective, the present work aimed to monitor patients' major cardiac events after discharge, including deaths and re-hospitalizations due to decompensation of CHF. 2. Materials and methods 2.1. Subjects Data on 2115 consecutive patients aged 85 years and older with CHF between January 2004 and January 2011 were retrospectively collected from the hospital database. The patients who were admitted to the geriatric medical ward of Chinese PLA General Hospital were enrolled into final analysis within 2d of tumor marker and NT-proBNP sampling, and the presence or absence of pleural effusion and peripheral edema was noted. Data recorded in the database contained patient demographics, prescriptions, diagnoses, procedures, and hospitalizations. The diagnosis of CHF was based on medical history and initial investigation, including
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.04.002
J. Ma et al. / European Journal of Internal Medicine 24 (2013) 440–443
441
Table 1 Clinical characteristics, risk factors, and medications of 2115 patients. Age (years) Men/women Stages of CHF (%) A/B (%) C (%) D (%) History Diabetes mellitus (%) Hypertension (%) Smoking (%) Chronic pulmonary obstructive disease Coronary heart disease (%) Medications ACE inhibitors/ARB (%) Diuretics (%) Digitalis (%) Beta-blockers (%) Statins (%)
91 (85–100) 1783/332 53.0 28.3 18.7 32.3 35.6 64.2 41.6 57.7 65.5 43.1 23.9 81.2 78.6
ACE inhibitors, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker.
physical examination, electrocardiogram, chest X-ray, blood laboratory tests, and echocardiographic evaluation. Patients were assigned to stages A, B, C, or D according to the new classification of CHF. Patients diagnosed with malignancy, active inflammatory disease, end-stage renal failure, and liver cirrhosis were excluded from the analysis. Patients were followed up for six months. The discharged patients were followed up by telephone or community primary care physician. All rehospitalizations and cardiovascular mortality during this period were noted.
Fig. 1. Linear regression analysis between CA 125 and NT-proBNP serum levels in CHF patients.
(85–100) years. Upon admission, 1121 patients were in stage A/B (53.0%), 598 patients in stage C (28.3%), and 396 patients in stage D (18.7%). Patients in stages A/B were similar in terms of demographic characteristics and medication. Accordingly, they were considered together in the subsequent analysis. Table 1 shows the clinical characteristics, risk factors, and medications of the study population. Different serum tumor marker levels in all patients, classified according to the stage of CHF, are presented in Table 2. The median-interquartile range of CA 125 levels in stages C and D patients was significantly higher than that in the stage A/B group. No other tumor markers (CEA, AFP, CA 15-3, CA 19-9, CA 724, NSE, and CYFRA 21-1) were found to be significantly different in the various stages of CHF. 3.2. The relation between CA 125 and NT-proBNP levels
2.2. Statistical analysis The Statistical Package for Social Sciences 15 (SPSS 15) was used for the statistical analysis of the obtained data. The distribution of CA 125 was checked using the Kolmogorov–Smirnov test. All values were expressed as median-interquartile range because the measured data were markedly skewed. The differences between subgroups were analyzed using the non-parametric Mann–Whitney test. p b 0.05 was considered statistically significant. Correlations were determined using linear regression analysis.
Both CA 125 and NT-proBNP levels progressively increased as the stage of CHF increased, as illustrated in Table 2. Moreover, linear regression analysis revealed a significant relationship between CA 125 and NT-proBNP serum (r = 0.5103, p b 0.05). The dot plot of CA 125 vs. NT-proBNP serum levels was shown in Fig. 1. However, the relation found between NT-proBNP and the other tumor markers was not statistically significant (NT-proBNP vs. AFP, r = 0.0692; NT-proBNP vs. CEA, r = 0.0710; NT-proBNP vs. CA 19-9, r = 0.0565; NT-proBNP vs. CA 15-3, r = 0.0277; NT-proBNP vs. NSE r = 0.0727; NT-proBNP vs. CA 724 r = 0.0513; NT-proBNP vs. CYFRA, 21-1 r = 0.0069).
3. Results 3.3. Pleural fluids or peripheral edema 3.1. Demographic data The study population consisted of 2115 patients aged 85 years and older with CHF (1783 males and 332 females), with age range of 91
The CA 125 serum levels in patients with or without pleural effusion and peripheral edema are shown (Table 3). Significantly high CA 125 serum levels were found in CHF patients with pleural fluids,
Table 2 The levels of various tumor markers in the different stages of CHF.
Age (years) Male/female AFP (μg/l) CA 125 (U/ml) CA 153 (U/ml) CEA (μg/L) CA 724(U/ml) NSE (ng/ml) CA 199 (U/ml) CYFRA 21-1 (ng/ml) NT-pro BNP (pg/ml) a b c
p b 0.05 between Stages A/B and C. p b 0.05 between Stages A/B and D. p b 0.05 between Stages C and D.
Stage A/B n = 1121
Stage C n = 598
Stage D n = 396
90.8 (85–98) 945/176 2.8 (0.7–12.1) 11.1 (3.4–36.5)a 10.8 (2.0–37.3) 3.4 (0.5–7.9) 2.3 (0.8–9.2) 10.70 (4.8–20.1) 2.6 (1–12.1) 2.5 (0.9–13.4) 220.0 (50.9–1713.0)a
91.2 (85–100) 506/92 2.7 (0.5–21.6) 45.6 (31.2–179.3)b 10.8 (2.0–35.5) 3.5 (0.5–7.8) 1.7 (0.7–11.9) 10.8 (4.7–30.9) 15.5 (2.8–82.8) 2.7 (0.9–14.4) 1512.4 (104.0–9324.0)b
92.1 (85–100) 332/64 2.6 (0.5–21.2) 100.6 (20.2–459.0)c 10.8 (2.0–38.1) 3.4 (1.2–10.0) 2.0 (0.7–11.9) 10.9 (5.6–30.1) 15.6 (0.6–412.2) 2.6 (1–12.1) 4599.5 (790.4–19308.0)c
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J. Ma et al. / European Journal of Internal Medicine 24 (2013) 440–443
Table 3 Symptoms and clinical signs in association with CA 125 serum levels. Patients
n
CA 125 values
p value
Median-interquartile range (U/ml) Radiological pleural effusion Yes 438 No 1677 Peripheral edema Yes 727 No 1388
108.5 (20.2–459.0) 12.1 (3.0–141.3)
b0.01
78.4 (21.1–447.0) 11.9 (3.4–179.3)
b0.01
compared with those in CHF patients without pleural fluids. A statistically significant difference was observed between CHF patients with and without peripheral edema. 3.4. Follow-up Additionally, during the follow-up period of 180 days, 305 suffered from cardiovascular deaths and 461 were rehospitalized at least once for worsening CHF. CA 125 values were significantly higher (p b 0.01) in the patients who died or were rehospitalized [78.2 (20.2–459.0) U/ml], compared with those who remained alive or did not require rehospitalization [11.7 (3.4–179.3) U/ml]. Kaplan– Mayer curves showed survival in patients with normal and elevated CA 125 serum levels (Fig. 2). The curves demonstrated significant differences in survival across quartiles of CA125 (log-rank p b 0.005), which show the usefulness of CA125 as a short-term prognostic value in the oldest old patients. 4. Discussion CA 125, elevated particularly in patients with ovarian cancer, is a high-molecular weight glycoprotein used for monitoring the efficacy of therapy and for detecting recurrences [14,15]. Elevated CA 125 serum levels have also been reported in different types of both malignant and non-malignant diseases, such as cancers of the lung, breast, uterine, and gastrointestinal tract, non-Hodgkin's lymphoma, chronic liver diseases, nephrotic syndrome, and chronic renal diseases on hemodialysis with pleural, peritoneal, or pericardial effusion [16–18]. With regard to the cardiovascular system, the current study is the first to investigate the potential relationship between different serum tumor markers and CHF severity assessed by stage in oldest old patients with CHF. Multimorbidity is a current and real public health problem in the oldest old subjects [19]. According to the results of the present study, among the tumor markers, such as AFP, CEA, CA 724, NSE, CYFRA 21-1, CA 125, CA 19-9, and CA 15-3, only CA 125 serum levels were observed to correlate significantly with the clinical status of patients with CHF, as demonstrated by the higher values of CA 125 in stages C and D patients. Moreover, the
Fig. 2. Kaplan–Mayer curves showing survival in patients with normal and elevated CA 125 serum levels.
increase in CA 125 parallels the severity of CHF, which is consistent with the findings from previous studies [2–7], with a BNP-like behavior [3,4,6,7]. Kosar et al. found increased serum levels of CA 125 and CA 19-9 in HF patients, compared with those in the normal controls. CA 19-9 levels only had a tendency to increase with the severity of the disease, but this difference was not significant [20]. In the present study, CA 125 serum levels slightly increased above the normal limit in a few patients with mild CHF (stage A/B). Other tumor markers showed a slight increase in a minority of CHF patients, independent of the severity of the clinical stage. In the present research, increased levels of both CA 125 and NT-proBNP were found in patients aged 85 years and older with CHF. An important correlation was also observed between the levels of these two markers. The NT-proBNP value has been repeatedly reported to be a useful marker for the diagnosis of CHF, staging of severity, and prediction of patient outcomes [21–23]. Moreover, elevated CA 125 serum levels parallel to natriuretic peptides were reported in patients with heart failure as the NYHA functional class increases [24,25]. Therefore, the clinical implementation of CA 125 assay, combined with NT-proBNP, might be helpful in the early identification of patients with CHF at high risk. Furthermore, significant differences were found in CA 125 serum levels between patients aged 80 years and older with and without pleural fluid or ankle edema, in agreement with other published studies [2–5,7,24,26]. CA 125 is reportedly released from the pleura, peritoneum, or pericardium [27,28]. Núñez found that the main source of CA 125 elevations in HF can be from serosal effusions, especially from the pleura, and showed an important association between the presence of radiological pleural effusion and CA 125 serum concentrations [9]. Moreover, the pericardial tissue, obtained from the autopsy of 17 patients, was stained with anti-CA 125 antibodies, which suggested a pericardial production of this marker [29]. Riese speculated that, because of HF, bowel congestion may stimulate the peritoneal endotoxin and cytokines pathways to produce CA 125 [30]. Duman et al. suggested that elevated CA 125 levels in HF patients with mitral stenosis may be due to venous congestion and activation of peritoneal mesothelial cells or increased signal peptides [5]. Based on these reports, CA 125 might be produced from activated mesothelial cells, even in the absence of classical stimuli, as a consequence of tissue stretching caused by either heart enlargement and/or hepatic as well as splanchnic congestion. According to the current results, patients with elevated CA 125 serum levels showed higher mortality and rehospitalizations due to CHF decompensation, consistent with the results from other studies on patients with acute HF [9,10,31]. D'Aloia also demonstrated a significant increase in the combined end-point of mortality and HF hospitalization at six months among patients with increased CA 125 serum levels [7]. Luisa observed that a significant difference exists in the short-term outcome between patients with normal or elevated CA 125 serum levels obtained at the time of hospital admission [32]. These studies have demonstrated the independent effect of CA 125 in predicting mortality, which was also determined by the current work during 180 days of follow-up. The Kaplan–Mayer curves showed the usefulness of CA125 as a short-term prognostic value in the oldest old patients. The findings of the present research were limited by the retrospective means and the selected population. Two possible limitations need to be addressed. First, the population in this study came from a single center, which may limit the extrapolation of our results; the diagnostic and prognostic roles of CA125 need to be further validated in a wider range of populations before being recommended for clinical application. Secondly, the treatment regimen post-hospitalization was not standardized and might have been different between the patients. In conclusion, the determination of CA 125 is an easily obtainable and relatively inexpensive non-invasive test. CA 125 serum levels may be useful as a complementary laboratory tool for the functional
J. Ma et al. / European Journal of Internal Medicine 24 (2013) 440–443
staging of patients aged 85 years and older with CHF. Additionally, this tumor marker can reveal a short-term prognostic value. However, the biological role of CA 125 and the potential pathogenetic link between cytokine activation and production of CA 125 remain obscure. Studies with longer follow-up periods are required. Further studies are needed to better define the pathophysiology of CA 125 production. Learning points • The study enrolled 2115 patients aged 85 years and older suffering from CHF. • Only the CA 125 serum levels increased as the stage of CHF among the tumor markers. • Higher CA 125 serum levels were found in patients with pleural fluids or peripheral edema. • Linear regression analysis between CA 125 and NT-proBNP serum levels showed a significant relation. • During 180 days of follow-up, CA 125 values were significantly higher in patients who died or were rehospitalized. Conflict of interests All authors have no relevant conflict of interest to disclose, including any financial, personal or other relationships with other people or organizations within7 years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. References [1] Bates SE. Clinical applications of serum tumor markers. Ann Intern Med 1991;115: 623–8. [2] Turk HM, Pekdemir H, Buyukberber S, Sevinc A, Camci C, Kocabas R, et al. Serum CA 125 levels in patients with chronic heart failure and accompanying pleural fluid. Tumor Biol 2003;24:172–5. [3] Kouris NT, Zacharos ID, Kontogianni DD, Goranitou GS, Sifaki MD, Grassos HE, 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. [4] Varol E, OzaydNn M, Dogan A, Kosar F. Tumour marker levels in patients with chronic heart failure. Eur J Heart Fail 2005;7:840–3. [5] Duman C, Ercan E, Tengiz I, Bozdemir H, Ercan HE, Nalbantgil I. Elevated serum CA 125 levels in mitral stenotic patients with heart failure. Cardiology 2003;100: 7–10. [6] Nagele H, Bahlo M, Klapdor R, Schaeperkoetter D, Rodiger W. CA125 and its relation to cardiac function. Am Heart J 1999;137:1044–9. [7] D'Aloia A, Faggiano P, Aurigemma G, Bontempi L, Ruggeri G, Metra M, 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;41:1805–11. [8] Kouris NT, Kontogianni DD, Papoulia EP, Goranitou GS, Zaharos ID, Grassos HA, et al. Clinical and prognostic value of elevated CA125 levels in patients with congestive heart failure. Hellenic J Cardiol 2006;47:269–74. [9] Núñez J, Núñez E, Consuegra L, Sanchis J, Bodí V, Martínez-Brotons A, et al. Carbohydrate antigen 125: an emerging prognostic risk factor in acute heart failure? Heart 2007;93:716–21.
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[10] Núñez J, Sanchis J, Bodi V, Fonarow GC, Núñez E, Bertomeu-González V, et al. Improvement in risk stratification with the combination of the tumour marker antigen carbohydrate 125 and brain natriuretic peptide in patients with acute heart failure. Eur Heart J 2010;31:1752–63. [11] Varol E, Ozaydin M, Dogan A, Kosar F. Tumour marker levels in patients with chronic heart failure. Eur J Heart Fail 2005;7:840–3. [12] Nagele H, Bahlo M, Klapdor R, Rodiger W. Fluctuations of tumor markers in heart failure patients pre and post heart transplantation. Anticancer Res 1999;19:2531–4. [13] Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:1825. [14] Kenemans P, Yedema CA, Bon GG, von Mensdorff-Pouilly S. CA 125 in gynecological pathology: a review. Eur J Obstet Gynecol Reprod Biol 1993;49:115–24. [15] Vander Burg ME, Lammes FB, Verwei JJ. CA 125 in ovarian cancer. Neth J Med 1992;40:36–51. [16] Topalak O, Saygili U, Soyturk M, Karaca N, Batur Y, Uslu T, et al. Serum, pleural effusion, and ascites CA 125 levels in ovarian cancer and nonovarian benign and malignant diseases: a comparative study. Gynecol Oncol 2002;85:108–13. [17] Miralles C, Orea M, Espana P, Provencio M, Sánchez A, Cantos B, et al. Cancer antigen 125 associated with multiple benign and malignant pathologies. Ann Surg Oncol 2003;10:150–4. [18] Sjovall K, Nilsson B, Einhorn N. The significance of serum CA 125 elevation in malignant and nonmalignant diseases. Gynecol Oncol 2002;85:175–8. [19] Formiga F, Ferrer A, Sanz H, Marengoni A, Alburquerque J, Pujol R, et al. Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study. Eur J Intern Med 2013;24:40–4. [20] Kosar F, Aksoy Y, Ozguntekin G, Ozerol l, Varol E. Relationship between cytokines and tumour markers in patients with chronic heart failure. Eur J Heart Fail 2006;8: 270–4. [21] Hülsmann M, Berger R, Mörtl D, Gore O, Meyer B, Pacher R. Incidence of normal values of natriuretic peptides in patients with chronic heart failure and impact on survival: a direct comparison of N-terminal atrial natriuretic peptide, N-terminal brain natriuretic peptide and brain natriuretic peptide. Eur J Heart Fail 2005;7:552–6. [22] Masson S, Latini R, Anand IS, Vago T, Angelici L, Barlera S, et al. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Hear Failure (Val-HeFT) data. Clin Chem 2006;52:1528–38. [23] Aspromonte N, Valle R, Di Fusco SA, Santini M, Feola M. Prognostic value of B-type natriuretic peptide in patients with left bundle-branch block admitted for acute heart failure. Eur J Intern Med 2011;22:e152–4. [24] Faggiano P, D'Aloia A, Brentana L, Bignotti T, Fiorina C, Vizzardi E, et al. Serum levels of different tumour markers in patients with chronic heart failure. Eur J Heart Fail 2005;7:57–61. [25] Omland T, Persson A, Ng L, O'Brien R, Karlsson T, Herlitz J, et al. N-terminal pro-B B-type natriuretic peptide and long-term mortality in acute coronary syndrome. Circulation 2002;106:2913–8. [26] Sevinc A, Camci C, Turk HM, Buyukberber S. How to interpret serum CA 125 levels in patients with serosal involvement? A clinical dilemma. Oncology 2003;65:1–6. [27] Vergote IB, Onsrud M, Bormer OP, Sert BM, Moen M. CA125 in peritoneal fluid of ovarian cancer patients. Gynecol Oncol 1992;44:161–5. [28] Epiney M, Bertossa C, Weil A, Campana A, Bischof P. CA125 production by the peritoneum: in-vitro and in-vivo studies. Hum Reprod 2000;15:1261–5. [29] Seo T, Ikeda Y, Onaka H, Hayashi T, Kawaguchi K, Kotake C, et al. Usefulness of serum CA125 measurement for monitoring pericardial effusion. Jpn Circ J 1993;57:489–94. [30] Riese J, Schoolmann S, Denzel C, Herrmann O, Hobenberger W, Haupt W. Effect of abdominal infections on peritoneal and systemic production of interleukin 6 and monocyte chemoattractant protein-1. Shock 2002;17:361–7. [31] Mansour IN, Napan S, Tarek Alahdab M, Stamos TD. Carbohydrate antigen 125 predicts long-term mortality in African American patients with acute decompensated heart failure. Conqest Heart Fail 2010;16:15–20. [32] De Gennaro L, Brunetti ND, Bungaro R, Montrone D, Cuculo A, Pellegrino PL, et al. Carbohydrate antigen-125: additional accuracy in identifying patients at risk of acute heart failure in acute coronary syndrome. Coron Artery Dis 2009;20:274–80.
Contents lists available at SciVerse ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Tumor marker levels in patients aged 85 years and older with chronic heart failure Jinling Ma 1, Yuexiang Zhao 1, Yutang Wang ⁎, Yuanyuan Guo, Jian Li First Geriatric Cardiology Division of South Building, Chinese PLA General Hospital, Beijing 100853, China
a r t i c l e
i n f o
Article history: Received 12 March 2013 Received in revised form 27 March 2013 Accepted 8 April 2013 Available online 1 May 2013 Keywords: Carbohydrate antigen-125 Heart failure Tumor markers Older patients
a b s t r a c t Background: Recent studies have suggested that carbohydrate antigen 125 (CA 125) serum levels are remarkably elevated in patients with heart failure. We hypothesized that there was a relationship between serum levels of tumor markers and the four stages of chronic heart failure (CHF) in patients aged 85 years and older with CHF. Methods: The retrospective study enrolled 2115 patients aged 85 years and older suffering from CHF between January 2004 and January 2011. The levels of various tumor markers, N-terminal proB-type natriuretic peptide (NT-proBNP) in the different stages of CHF, and clinical risk factors were analyzed. All patients were followed for 180 days, and major cardiovascular events were recorded. Results: Only the CA 125 level increased as the stage of CHF increased (p b 0.05) among the tumor markers. Significantly higher CA 125 serum levels were found in patients with pleural fluids or peripheral edema, compared with patients without pericardial effusion or peripheral edema (p b 0.01). During 180 days of follow-up, CA 125 values were significantly higher in patients who died or were rehospitalized, compared with those who remained alive or did not undergo rehospitalization. Linear regression analysis between CA 125 and NT-proBNP serum levels showed a statistically significant relation (r = 0.5103, p b 0.05). Conclusions: Among the tumor markers evaluated, only CA 125 appeared to be related to the severity of CHF and NT-proBNP, along with the presence of pleural fluid or peripheral edema in patients aged 85 years and older with CHF. © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Serum tumor markers, except prostate-specific antigens, are normally used to follow-up patients with cancer [1], although the clinical use of these markers is partially limited because of low sensitivity. Recent studies have suggested that carbohydrate antigen 125 (CA 125) serum levels are remarkably elevated in patients with heart failure (HF), and the increase is related to the severity of the disease [2–8]. Serum CA 125 has been reported as an independent predictor of mortality up to the sixth month of follow-up [9]. This antigen has added prognostic value beyond the information provided by plasma B-type natriuretic peptide (BNP). The combination of these two molecules enables better six-month risk stratification [10]. Other serum tumor markers, such as carbohydrate antigen 199 (CA 19-9) and carcino embryonic antigen (CEA), are not influenced by circulatory disturbances [11,12]. Considering the various diseases in older patients, such as osteoporosis and arthritis, that cause difficulty in walking, the assessment of the New York Heart Association (NYHA) has been limited. Thus, the current research uses a new 4-stage classification, that is, four stages of chronic heart failure (CHF), to evaluate heart function. The four stages of CHF emphasize both the development and progression ⁎ Corresponding author. Tel.: +86 13901163874. E-mail address: [email protected] (Y. Wang). 1 Jinling Ma and Yuexiang Zhao contributed equally to this work.
of CHF, and this new classification scheme adds a useful dimension to the general view of HF [13]. The aim of the present study was to investigate the relationship between serum levels of tumor markers, including CA 125, carbohydrate antigen 15-3 (CA 15-3), CA 19-9, carbohydrate antigen 724 (CA 724), CEA, alpha-fetoprotein (AFP), neuron-specific enolase (NSE), and cytokeratin fragment 21-1 (CYFRA 21-1), and the four stages of CHF, as well as N-terminal proBNP (NT-proBNP), in patients aged 85 years and older with CHF. As a secondary objective, the present work aimed to monitor patients' major cardiac events after discharge, including deaths and re-hospitalizations due to decompensation of CHF. 2. Materials and methods 2.1. Subjects Data on 2115 consecutive patients aged 85 years and older with CHF between January 2004 and January 2011 were retrospectively collected from the hospital database. The patients who were admitted to the geriatric medical ward of Chinese PLA General Hospital were enrolled into final analysis within 2d of tumor marker and NT-proBNP sampling, and the presence or absence of pleural effusion and peripheral edema was noted. Data recorded in the database contained patient demographics, prescriptions, diagnoses, procedures, and hospitalizations. The diagnosis of CHF was based on medical history and initial investigation, including
0953-6205/$ – see front matter © 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.04.002
J. Ma et al. / European Journal of Internal Medicine 24 (2013) 440–443
441
Table 1 Clinical characteristics, risk factors, and medications of 2115 patients. Age (years) Men/women Stages of CHF (%) A/B (%) C (%) D (%) History Diabetes mellitus (%) Hypertension (%) Smoking (%) Chronic pulmonary obstructive disease Coronary heart disease (%) Medications ACE inhibitors/ARB (%) Diuretics (%) Digitalis (%) Beta-blockers (%) Statins (%)
91 (85–100) 1783/332 53.0 28.3 18.7 32.3 35.6 64.2 41.6 57.7 65.5 43.1 23.9 81.2 78.6
ACE inhibitors, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker.
physical examination, electrocardiogram, chest X-ray, blood laboratory tests, and echocardiographic evaluation. Patients were assigned to stages A, B, C, or D according to the new classification of CHF. Patients diagnosed with malignancy, active inflammatory disease, end-stage renal failure, and liver cirrhosis were excluded from the analysis. Patients were followed up for six months. The discharged patients were followed up by telephone or community primary care physician. All rehospitalizations and cardiovascular mortality during this period were noted.
Fig. 1. Linear regression analysis between CA 125 and NT-proBNP serum levels in CHF patients.
(85–100) years. Upon admission, 1121 patients were in stage A/B (53.0%), 598 patients in stage C (28.3%), and 396 patients in stage D (18.7%). Patients in stages A/B were similar in terms of demographic characteristics and medication. Accordingly, they were considered together in the subsequent analysis. Table 1 shows the clinical characteristics, risk factors, and medications of the study population. Different serum tumor marker levels in all patients, classified according to the stage of CHF, are presented in Table 2. The median-interquartile range of CA 125 levels in stages C and D patients was significantly higher than that in the stage A/B group. No other tumor markers (CEA, AFP, CA 15-3, CA 19-9, CA 724, NSE, and CYFRA 21-1) were found to be significantly different in the various stages of CHF. 3.2. The relation between CA 125 and NT-proBNP levels
2.2. Statistical analysis The Statistical Package for Social Sciences 15 (SPSS 15) was used for the statistical analysis of the obtained data. The distribution of CA 125 was checked using the Kolmogorov–Smirnov test. All values were expressed as median-interquartile range because the measured data were markedly skewed. The differences between subgroups were analyzed using the non-parametric Mann–Whitney test. p b 0.05 was considered statistically significant. Correlations were determined using linear regression analysis.
Both CA 125 and NT-proBNP levels progressively increased as the stage of CHF increased, as illustrated in Table 2. Moreover, linear regression analysis revealed a significant relationship between CA 125 and NT-proBNP serum (r = 0.5103, p b 0.05). The dot plot of CA 125 vs. NT-proBNP serum levels was shown in Fig. 1. However, the relation found between NT-proBNP and the other tumor markers was not statistically significant (NT-proBNP vs. AFP, r = 0.0692; NT-proBNP vs. CEA, r = 0.0710; NT-proBNP vs. CA 19-9, r = 0.0565; NT-proBNP vs. CA 15-3, r = 0.0277; NT-proBNP vs. NSE r = 0.0727; NT-proBNP vs. CA 724 r = 0.0513; NT-proBNP vs. CYFRA, 21-1 r = 0.0069).
3. Results 3.3. Pleural fluids or peripheral edema 3.1. Demographic data The study population consisted of 2115 patients aged 85 years and older with CHF (1783 males and 332 females), with age range of 91
The CA 125 serum levels in patients with or without pleural effusion and peripheral edema are shown (Table 3). Significantly high CA 125 serum levels were found in CHF patients with pleural fluids,
Table 2 The levels of various tumor markers in the different stages of CHF.
Age (years) Male/female AFP (μg/l) CA 125 (U/ml) CA 153 (U/ml) CEA (μg/L) CA 724(U/ml) NSE (ng/ml) CA 199 (U/ml) CYFRA 21-1 (ng/ml) NT-pro BNP (pg/ml) a b c
p b 0.05 between Stages A/B and C. p b 0.05 between Stages A/B and D. p b 0.05 between Stages C and D.
Stage A/B n = 1121
Stage C n = 598
Stage D n = 396
90.8 (85–98) 945/176 2.8 (0.7–12.1) 11.1 (3.4–36.5)a 10.8 (2.0–37.3) 3.4 (0.5–7.9) 2.3 (0.8–9.2) 10.70 (4.8–20.1) 2.6 (1–12.1) 2.5 (0.9–13.4) 220.0 (50.9–1713.0)a
91.2 (85–100) 506/92 2.7 (0.5–21.6) 45.6 (31.2–179.3)b 10.8 (2.0–35.5) 3.5 (0.5–7.8) 1.7 (0.7–11.9) 10.8 (4.7–30.9) 15.5 (2.8–82.8) 2.7 (0.9–14.4) 1512.4 (104.0–9324.0)b
92.1 (85–100) 332/64 2.6 (0.5–21.2) 100.6 (20.2–459.0)c 10.8 (2.0–38.1) 3.4 (1.2–10.0) 2.0 (0.7–11.9) 10.9 (5.6–30.1) 15.6 (0.6–412.2) 2.6 (1–12.1) 4599.5 (790.4–19308.0)c
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Table 3 Symptoms and clinical signs in association with CA 125 serum levels. Patients
n
CA 125 values
p value
Median-interquartile range (U/ml) Radiological pleural effusion Yes 438 No 1677 Peripheral edema Yes 727 No 1388
108.5 (20.2–459.0) 12.1 (3.0–141.3)
b0.01
78.4 (21.1–447.0) 11.9 (3.4–179.3)
b0.01
compared with those in CHF patients without pleural fluids. A statistically significant difference was observed between CHF patients with and without peripheral edema. 3.4. Follow-up Additionally, during the follow-up period of 180 days, 305 suffered from cardiovascular deaths and 461 were rehospitalized at least once for worsening CHF. CA 125 values were significantly higher (p b 0.01) in the patients who died or were rehospitalized [78.2 (20.2–459.0) U/ml], compared with those who remained alive or did not require rehospitalization [11.7 (3.4–179.3) U/ml]. Kaplan– Mayer curves showed survival in patients with normal and elevated CA 125 serum levels (Fig. 2). The curves demonstrated significant differences in survival across quartiles of CA125 (log-rank p b 0.005), which show the usefulness of CA125 as a short-term prognostic value in the oldest old patients. 4. Discussion CA 125, elevated particularly in patients with ovarian cancer, is a high-molecular weight glycoprotein used for monitoring the efficacy of therapy and for detecting recurrences [14,15]. Elevated CA 125 serum levels have also been reported in different types of both malignant and non-malignant diseases, such as cancers of the lung, breast, uterine, and gastrointestinal tract, non-Hodgkin's lymphoma, chronic liver diseases, nephrotic syndrome, and chronic renal diseases on hemodialysis with pleural, peritoneal, or pericardial effusion [16–18]. With regard to the cardiovascular system, the current study is the first to investigate the potential relationship between different serum tumor markers and CHF severity assessed by stage in oldest old patients with CHF. Multimorbidity is a current and real public health problem in the oldest old subjects [19]. According to the results of the present study, among the tumor markers, such as AFP, CEA, CA 724, NSE, CYFRA 21-1, CA 125, CA 19-9, and CA 15-3, only CA 125 serum levels were observed to correlate significantly with the clinical status of patients with CHF, as demonstrated by the higher values of CA 125 in stages C and D patients. Moreover, the
Fig. 2. Kaplan–Mayer curves showing survival in patients with normal and elevated CA 125 serum levels.
increase in CA 125 parallels the severity of CHF, which is consistent with the findings from previous studies [2–7], with a BNP-like behavior [3,4,6,7]. Kosar et al. found increased serum levels of CA 125 and CA 19-9 in HF patients, compared with those in the normal controls. CA 19-9 levels only had a tendency to increase with the severity of the disease, but this difference was not significant [20]. In the present study, CA 125 serum levels slightly increased above the normal limit in a few patients with mild CHF (stage A/B). Other tumor markers showed a slight increase in a minority of CHF patients, independent of the severity of the clinical stage. In the present research, increased levels of both CA 125 and NT-proBNP were found in patients aged 85 years and older with CHF. An important correlation was also observed between the levels of these two markers. The NT-proBNP value has been repeatedly reported to be a useful marker for the diagnosis of CHF, staging of severity, and prediction of patient outcomes [21–23]. Moreover, elevated CA 125 serum levels parallel to natriuretic peptides were reported in patients with heart failure as the NYHA functional class increases [24,25]. Therefore, the clinical implementation of CA 125 assay, combined with NT-proBNP, might be helpful in the early identification of patients with CHF at high risk. Furthermore, significant differences were found in CA 125 serum levels between patients aged 80 years and older with and without pleural fluid or ankle edema, in agreement with other published studies [2–5,7,24,26]. CA 125 is reportedly released from the pleura, peritoneum, or pericardium [27,28]. Núñez found that the main source of CA 125 elevations in HF can be from serosal effusions, especially from the pleura, and showed an important association between the presence of radiological pleural effusion and CA 125 serum concentrations [9]. Moreover, the pericardial tissue, obtained from the autopsy of 17 patients, was stained with anti-CA 125 antibodies, which suggested a pericardial production of this marker [29]. Riese speculated that, because of HF, bowel congestion may stimulate the peritoneal endotoxin and cytokines pathways to produce CA 125 [30]. Duman et al. suggested that elevated CA 125 levels in HF patients with mitral stenosis may be due to venous congestion and activation of peritoneal mesothelial cells or increased signal peptides [5]. Based on these reports, CA 125 might be produced from activated mesothelial cells, even in the absence of classical stimuli, as a consequence of tissue stretching caused by either heart enlargement and/or hepatic as well as splanchnic congestion. According to the current results, patients with elevated CA 125 serum levels showed higher mortality and rehospitalizations due to CHF decompensation, consistent with the results from other studies on patients with acute HF [9,10,31]. D'Aloia also demonstrated a significant increase in the combined end-point of mortality and HF hospitalization at six months among patients with increased CA 125 serum levels [7]. Luisa observed that a significant difference exists in the short-term outcome between patients with normal or elevated CA 125 serum levels obtained at the time of hospital admission [32]. These studies have demonstrated the independent effect of CA 125 in predicting mortality, which was also determined by the current work during 180 days of follow-up. The Kaplan–Mayer curves showed the usefulness of CA125 as a short-term prognostic value in the oldest old patients. The findings of the present research were limited by the retrospective means and the selected population. Two possible limitations need to be addressed. First, the population in this study came from a single center, which may limit the extrapolation of our results; the diagnostic and prognostic roles of CA125 need to be further validated in a wider range of populations before being recommended for clinical application. Secondly, the treatment regimen post-hospitalization was not standardized and might have been different between the patients. In conclusion, the determination of CA 125 is an easily obtainable and relatively inexpensive non-invasive test. CA 125 serum levels may be useful as a complementary laboratory tool for the functional
J. Ma et al. / European Journal of Internal Medicine 24 (2013) 440–443
staging of patients aged 85 years and older with CHF. Additionally, this tumor marker can reveal a short-term prognostic value. However, the biological role of CA 125 and the potential pathogenetic link between cytokine activation and production of CA 125 remain obscure. Studies with longer follow-up periods are required. Further studies are needed to better define the pathophysiology of CA 125 production. Learning points • The study enrolled 2115 patients aged 85 years and older suffering from CHF. • Only the CA 125 serum levels increased as the stage of CHF among the tumor markers. • Higher CA 125 serum levels were found in patients with pleural fluids or peripheral edema. • Linear regression analysis between CA 125 and NT-proBNP serum levels showed a significant relation. • During 180 days of follow-up, CA 125 values were significantly higher in patients who died or were rehospitalized. Conflict of interests All authors have no relevant conflict of interest to disclose, including any financial, personal or other relationships with other people or organizations within7 years of beginning the submitted work that could inappropriately influence, or be perceived to influence, their work. References [1] Bates SE. Clinical applications of serum tumor markers. Ann Intern Med 1991;115: 623–8. [2] Turk HM, Pekdemir H, Buyukberber S, Sevinc A, Camci C, Kocabas R, et al. Serum CA 125 levels in patients with chronic heart failure and accompanying pleural fluid. Tumor Biol 2003;24:172–5. [3] Kouris NT, Zacharos ID, Kontogianni DD, Goranitou GS, Sifaki MD, Grassos HE, 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. [4] Varol E, OzaydNn M, Dogan A, Kosar F. Tumour marker levels in patients with chronic heart failure. Eur J Heart Fail 2005;7:840–3. [5] Duman C, Ercan E, Tengiz I, Bozdemir H, Ercan HE, Nalbantgil I. Elevated serum CA 125 levels in mitral stenotic patients with heart failure. Cardiology 2003;100: 7–10. [6] Nagele H, Bahlo M, Klapdor R, Schaeperkoetter D, Rodiger W. CA125 and its relation to cardiac function. Am Heart J 1999;137:1044–9. [7] D'Aloia A, Faggiano P, Aurigemma G, Bontempi L, Ruggeri G, Metra M, 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;41:1805–11. [8] Kouris NT, Kontogianni DD, Papoulia EP, Goranitou GS, Zaharos ID, Grassos HA, et al. Clinical and prognostic value of elevated CA125 levels in patients with congestive heart failure. Hellenic J Cardiol 2006;47:269–74. [9] Núñez J, Núñez E, Consuegra L, Sanchis J, Bodí V, Martínez-Brotons A, et al. Carbohydrate antigen 125: an emerging prognostic risk factor in acute heart failure? Heart 2007;93:716–21.
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