Tumour biomarkers in heart failure: is there a role for CA-125?

Introduction

Biomarkers, informative signals derived from the body, are used in clinical practice to indicate the diagnosis, prognosis, or status of a specific disease or to guide therapy. Biomarkers were first defined as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention'1 by the Biomarkers Definitions Working Group in 2001. Till date many biomarkers, including natriuretic peptides, proadrenomedullin and ST2, have been proposed as diagnostic and prognostic factors in heart failure (HF).2 Most of these markers reflect a specific pathophysiological aspect of the disease.2 More recently, some biomarkers from the field of oncology have been tested in HF.3–5 As such, CA-125, CA 15–3, CA 19–9, carcinoembryonic antigen, alpha-feto protein, tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS),6 cytokeratin 19 fragment (CYFRA 21–1),7 and chromogranin A and B,8 which have been used as tumour markers in various different pathologies, have all been tested in HF studies.3,9,10

Of the initial HF biomarker portfolio, CEA, TPA, CA 72–4, CA 15.3, and AFP have been ruled out as possible candidates in HF.9,10 However, other tumour biomarkers could be of interest. One study showed that CA-19–9 was higher in patients with HF than in healthy controls,3 although other studies have not reported similar findings.9,10 Another study has shown that TPS is correlated with New York Heart Association (NYHA) class in patients with HF, although this has not been studied further by others.9 Members of the chromogranin family, neuroendocrine protective modulators of cardiac function, have also been shown to be increased in patients with HF in relation to functional status and brain natriuretic peptide (BNP) levels.11 However, it has recently been shown that chromogranin (A) measurements may not provide incremental prognostic information in addition to physical examination and current routine analyses.12 Another study found that chromogranins (A and B)13 might have a role in the stratification and prognosis of HF.14 However, although the chromogranin family of biomarkers has been tested in neuroendocrine neoplasia, they are not solely considered as tumour markers. The role of other potential candidates requires further exploration.

Of all tumour biomarkers, CA-125 has been the most consistently designated marker with a potential role in HF. Hence, we conducted a review with a specific focus on CA-125.

Description of CA-125

CA-125 is a member of the mucin (MUC) family and is also known as MUC 16. Mucins are high-molecular-weight glycoproteins that protect the epithelial luminal surfaces via a process of hydration and lubrication.15 CA-125 is a tumour antigen that is expressed on the surface of ovarian cancer cells and is a well-established biomarker for monitoring ovarian cancer growth.16–18 It is a large membrane-bound MUC and is normally expressed by cells of different tissues derived from coelomic epithelium, such as the pericardium, pleura, peritoneum, and Müllerian epithelium.19,20 CA-125 is a heavily glycosylated transmembrane molecule with two parts15: an intracytoplasmic-transmembrane part made of protein and an extracellular domain made of O- and N-linked oligosaccharide chains. It is thought that CA-125 facilitates attachment and adhesion for metastasizing cancer cells and thus may have a biological role in the metastasis of ovarian cancer cells.16 It is a soluble glycoprotein and is thought to be shed from surfaces or produced in response to various stimuli, including mechanical stress, and inflammatory stimuli.16,21 Elevated serum CA-125 levels have been identified in other malignancies such as lung cancer, gastrointestinal cancer, and non-malignant conditions such as abdominal miliary tuberculosis, endometriosis, and pelvic inflammatory disease.22–24

Currently, CA-125 is used to screen women at high-risk of developing ovarian cancer,25 to monitor the status of ovarian cancer26 and in post-therapy stratification and prognosis.27 Various studies have found that the half-life of CA-125 varies from 5–7 days to several days28–30 and it appears to reflect the cancer stage, response to therapy, and hence patient prognosis.30 Patients with a longer CA-125 half-life after cancer therapy seem to have a poorer prognosis than those with a shorter half-life.31 However, these findings should be interpreted with caution as the studies were heterogeneous in terms of disease stage. Care should thus be taken in generalizing the results to other pathological states.

Increased serum CA-125 levels have also been documented in patients with HF along with other biomarkers.3,10,32–38 Recently, CA-125 has been shown to be prognostically important in patients with acute HF (AHF).39 However, from a cardiac viewpoint, the pathophysiological value of an increase in CA-125 remains unclear. Hence, there is a need to better understand the pathobiology underlining CA-125 secretion.

Clinical and haemodynamic associations of CA-125 in heart failure

The first study investigating possible clinical and haemodynamic associations of tumour markers with chronic HF was published by Nagele et al.37 The authors investigated various tumour markers in patients with severe HF both before and after cardiac transplantation. They showed a direct correlation of CA-125 with right atrial pressure (r=0.41, P<0.0001) and pulmonary capillary wedge pressure (r=0.27, P<0.001). Subsequent studies found CA-125 to be elevated in patients with chronic congestive HF.3,34,35 In a study by Kouris et al.,35 CA-125 levels were shown to be associated with the severity of chronic HF, and there was a weak correlation between CA-125 levels and pulmonary artery pressure; however, there was no association between left-sided haemodynamics and CA-125.33 In contrast, a study by D'Aloia et al.34 showed that the CA-125 level was related not only to right atrial pressure, systolic pulmonary artery pressure, and pulmonary artery capillary wedge pressure but also to left ventricular (LV) diastolic function parameters. This latter study did not show a significant correlation between CA-125 and LV ejection fraction or LV end diastolic diameter although CA-125 was associated with the NYHA class of patients with HF.34 On the other hand, Vizzardi et al.32 showed that CA-125 was related both to systolic and LV diastolic function in a study that included a well-defined echocardiographic approach. Furthermore, in another study, CA-125 was also shown to be associated with left atrial volume in addition to severity indices of diastolic dysfunction along with BNP levels.33 In a recent study which enrolled ‘all comers’, CA-125 levels were shown to be independently associated with LVEF, presence of pericardial effusions, and right ventricular (RV) dilatation.40 Along with haemodynamic associations, CA-125 levels seem to designate the clinical status of patients with HF, such as congestive status (pulmonary or systemic), functional class, and more importantly positive or negative response to therapy (Table 1).

CA-125 levels have also been shown to be linked to the type of presentation of AHF.37,39 In one study, CA-125 was differentially elevated in patients with acutely decompensated HF in contrast to patients presenting with acute pulmonary oedema.39 However, another recent study found that patients presenting with acute pulmonary oedema were better identified with a combination of CA-125 and BNP in the setting of acute coronary syndrome-associated AHF.46 In this study, CA-125 levels identified patients with pulmonary oedema with a higher positive predictive value and better accuracy than BNP. In addition to these studies, CA-125 has also been detected in secretions of normal human airways.47 Further studies are required to elucidate this controversy.

Elevated CA-125 levels have also been observed in other cardiac pathologies such as tricuspid stenosis, mitral stenosis, mitral valve endocarditis, atrial septal defect, pulmonary hypertension, aortic stenosis, and acute coronary syndromes.48–54

In summary, the specific characteristics of CA-125 might make it a useful indicator to help diagnose different presentations of AHF particularly if it is combined with other biomarkers.

Prognostic associations of CA-125 in heart failure

Recent studies have shown that CA-125, as a biomarker with a characteristic half-life, could be a prognostic indicator in HF. In a study by D'Aloia et al.34 CA-125 levels were associated with the combined end-point of HF hospitalization and mortality after 6 months of follow-up. Furthermore, CA-125 was related to an improvement in NYHA class by treatment. In a recent study, patients with high CA-125 levels were shown to have more frequent hospitalization and mortality as well as atrial fibrillation (51.9 vs. 13.4%, P<0.001).40 In addition, in a very recent study by Nunez et al.39 CA-125 was shown to provide additional prognostic value in patients with AHF in addition to a clinical model with and without BNP.

In summary, CA-125 could be a useful additional prognostic marker in HF and might also be used in the stratification of HF and the monitoring of therapy. However, its exact role in prognostic stratification remains to be established.

Association with other biomarkers and pathophysiological links

CA-125 seems to be moderately associated with BNP even though they have different half-lives.5,10,33 CA-125 levels have also been shown to be related to serum tumour necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 levels, suggesting a pathobiological link with the activation of cytokines.55 It has recently been purported that congestion and systemic inflammatory activity are interrelated and that CA-125 might therefore be a surrogate for both processes.56 Congestion, as a haemodynamic parameter, is integrated into the vicious cycle of the inflammatory process of HF and thus contributes to HF progression.21,57 In theory, congestion is related to HF progression via activation of the neurohumoral axis and induction of myocardial necrosis/apoptosis.58 As a result of organ cross talk in HF, congestion is also related to the cardiorenal syndrome that might result from a reduced perfusion gradient through the kidney, secondary to elevated right atrial pressure.59 Under the influence of this syndrome, the splanchnic bed, where there is an abundance of mesothelial cells that can produce CA-125, is exposed to high-venous pressure and congestion. However, whether it simply reflects the stimulation of the cytokine pathway or other pathophysiological pathways, or whether CA-125 as an active substance is truly responsible for myocardial and/or peripheral dysfunction remains to be established.60 It is hypothesized that normal, or so-called ‘stressed’, mesothelial cells produce CA-125 in response to haemodynamic and/or inflammatory stimuli.61 In the pathophysiological link, translocation of bacteria and/or endotoxins during exacerbation of HF—possibly more severe in patients with RV failure—along with impaired functioning of the gastrointestinal system secondary to impaired perfusion, might be critically important in the ‘stress’ response of mesothelial cells.57 On the other hand, it seems that CA-125 levels are directly related to RV dysfunction,40 which is a well-established prognostic indicator in systolic HF.62 Therefore, CA-125 may help further risk stratification along with information derived from right heart in addition to clinical models.63 Furthermore, there are data suggesting that CA-125 levels could be modulated via some cytokines such as IL-1β or TNF-α, and thus therapies that affect cytokines might be monitored via CA-125 levels.61

Conclusion

Tumour biomarkers appear to be an interesting area for researchers in heart failure. Heart failure is a complex syndrome, in which several systems play a role. Hence, along with the understanding of its complex pathophysiology, a collaborative biomarker-based approach might help physicians to manage HF better. Tumour biomarkers might prove to be useful indicators for the diagnosis, stratification, or prognosis of patients with HF in the near future. On the other hand, CA-125, a complex glycoprotein with established value in ovarian cancer but a more recently discovered role in HF, seems to be emerging as both a haemodynamically and prognostically important biomarker.

However, some questions remain open to investigation: (i) is CA-125 released as a result of passive congestion or pathophysiologically actively linked to the process of cardiac failure and (ii) is it a good biomarker of congestion that can be used to tailor therapy (‘fine-tuning’) during follow-up or in-hospital management given its low price (40)? Satisfactory answers to these questions are required before CA-125 can be introduced as a routine biomarker in HF management. In light of the potential role of other cancer biomarkers in the field of cardiovascular medicine, oncologists and cardiologists need to collaborate in multidisciplinary teams and develop analyses with modern methods such as the net reclassification improvement,64 in order to define the clinical value of these biomarkers in addition to other routine markers such as natriuretic peptides.

Conflict of interest: none declared.