Antigen carbohydrate 125 as a prognostic biomarker in patients with stable chronic heart failure

Introduction

Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality worldwide, despite advances in pharmacological therapies and device interventions (1-3). Even during periods of clinical stability, patients often harbor subclinical congestion and inflammatory activity that may negatively impact their prognosis. Identifying objective biomarkers to stratify risk in these patients is therefore crucial. Several markers have been proposed, of which natriuretic peptides [B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP)] are the most extensively studied (4). However, there is a growing belief that a single parameter is insufficient to reflect the clinical and congestion status of patients with heart failure (HF) and guide their treatment. In this regard, both the search for new markers and multiparametric approaches have emerged, in patients with acute HF as well as in those with heart devices (5,6).

Carbohydrate antigen 125 (CA125) is a high-molecular-weight glycoprotein originally used in oncology, but it has emerged as a reliable biomarker for acute heart failure (AHF) (7-9). This glycoprotein is mainly synthesized in mesothelial cells in the peritoneum, pleura, and pericardium in response to mechanical stress and inflammation in HF (10). Previous studies have reported that plasma levels of this glycoprotein are associated with the severity of congestion and a higher risk of mortality and readmission related to HF, independently of other well-established prognostic factors, such as natriuretic peptides (11-13). However, its role in clinically stable, euvolemic patients with HFrEF has not been fully elucidated.

This study aims to assess whether baseline CA125 levels independently predict mortality and recurrent cardiovascular (CV) hospitalizations in clinically stable patients with HFrEF. We also explored the association between CA125 and markers of congestion and inflammation in this population. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-244/rc).

Methods

Study population

This was an observational prospective cohort study that enrolled all 116 consecutive patients diagnosed with HFrEF, who were visited in the outpatient HF clinic of a single center (University Hospital of Elche) during a 6 month period, from July 2018 to January 2019, and met the following inclusion criteria: patients with an ejection fraction (EF) of less than 40% and clinically stable. Stability was defined as the absence of hospital admissions due to HF symptoms or use of intravenous diuretics for at least 6 months before the inclusion date. It was required for all patients to be on optimal HF treatment as per current European Clinical Practice Guidelines (14), including medical therapy as well as cardiac resynchronization therapy pacemaker (CRT-P) or cardiac resynchronization therapy defibrillator (CRT-D), when indicated. Patients with a recent acute coronary syndrome (<6 months), hemodynamic instability or congenital heart disease and those with evidence of active infection or cancer were excluded. A detailed medical and drug history was obtained for each patient, and all of them underwent physical examination and laboratory testing. No patients were excluded after screening, as this outpatient program specifically enrolled clinically stable individuals with HFrEF.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Ethics Committee of the University Hospital of Elche (No. PI 29/2018). Written informed consent was obtained from all patients prior to their inclusion in the study.

Echocardiographic measurement

Echocardiography examination was carried out using standard transthoracic 2D and color Doppler by EPIQ 7, Phillips Ultrasound System equipment. Images were obtained in the parasternal long and short axis views as well as in the apical four, two, and three chamber views using a 3.5 MHz transducer. All studies were done by two expert echocardiographers. Measurements were obtained and analyzed as recommended by the European Society of Echocardiography (15). The following left ventricular (LV) function parameters were measured: LV end-diastolic volume index (LVEDVi), LV end-systolic volume index (LVESVi), and LV ejection fraction (LVEF) (using the Simpson method). Reduced LVEF was defined as less than 40%. Diastolic dysfunction was assessed according to the current available guidelines (16). Doppler examination was used to estimate systolic pulmonary arterial pressure (sPAP) and transmitral filling patterns (E and A velocities, E/A ratio, E/e’ ratio and early filling deceleration time (DT). Right ventricular function was estimated using the tricuspid annular plane systolic excursion (TAPSE).

Biomarker assessment

Laboratory determinations including NT-proBNP, hemoglobin, and CA125 were obtained on the inclusion date. Plasma CA125 level was determined using a commercially available immunoassay kit (VITROS^® Immunodiagnostic Products CA125 II™ Reagent Packs, ref 680 0038, Rochester, NY, USA).

Follow-up and outcomes

Patients had a median follow-up of 18 months [interquartile range (IQR), 13–19 months] after the CA125 assessment. The study’s primary endpoint was a composite of episodes of worsening HF, total CV admissions and all-cause of death. An episode of worsening HF was either an unplanned hospitalization or an urgent visit requiring intravenous therapy for HF. The personnel in charge of endpoint adjudication were not aware of the levels of the biomarkers.

Statistical analysis

All the data collected in the study are described in terms of central tendency, measures of dispersion, and relative frequencies. Continuous data are expressed as mean ± standard deviation (SD) or median (IQR) as appropriate and were compared between groups using Student’s t-test or analysis of variance (ANOVA). Categorical variables are presented percentages and were compared using the chi-square test. Due to a significant deviation from normality, CA125 was log-transformed for any analyses that include actual values.

Rates of events were presented as per 100 person-years. To account for the positive correlation between HF hospitalization and mortality, we fitted the Famoye bivariate Poisson regression model. The number of admissions (as counts) and mortality (as the terminal event) were modeled simultaneously and linked by shared frailty. We used the “Bivcnto” Stata module for multivariate and bivariate Poisson analyses.

For predictive purposes, the final covariates included in the models were: age, sex, hypertension, years since diagnosis, New York Heart Association (NYHA) class III vs. I-II, Charlson comorbidity index, heart rate, estimated glomerular filtration rate (eGFR), diuretics, and treatment with renin-angiotensin-aldosterone system inhibitors or angiotensin receptor neprilysin inhibitor (RAASi/ARNI), mineralocorticoid receptor antagonists (MRA), or beta-blockers. Risk estimates are presented as incidence rate ratios (IRRs). We set a two-tailed P value <0.05 as the threshold for significance.

For assessing the factors associated with CA125 values, a multivariable linear regression analysis was performed. Clinical, demographic, echocardiographic or medical treatment variables were tested based on previous knowledge, independent of the P value. We simultaneously tested the linearity assumption for all continuous variables and the variables were transformed with fractional polynomials when appropriate. Next, we derived a reduced and parsimonious model using backward step-down selection. The contribution of the exposures to the model’s predictability was assessed by the coefficient of determination (R²). All analyses were performed in Stata 15.1 (Stata Statistical Software, Release 15 [2017]; StataCorp LP, College Station, TX, USA).

In a post-hoc analysis, the sample size was calculated for the estimation of a single population proportion. We assumed an estimated mortality proportion of 11% (P=0.11) in patients with HF and an elevated CA125 level, with a 95% confidence level (Z=1.96) and an absolute precision of ±5% (d=0.05). The calculation yielded a minimum required sample size of 150 participants to achieve the study’s objectives.

Results

Baseline characteristics

From July 1, 2018 until January 31, 2019, a total of 118 patients met the inclusion criteria. Two of them did not undergo the blood test required for CA125 measurement and were therefore excluded from the analysis. Thus, the final cohort included 116 patients with complete baseline and follow-up data. There was no loss to follow-up during the study period. Half of the population had no previous admission due to cardiac decompensation. In those with a prior decompensation episode, the mean stability period was 26 months (IQR, 13.0–46.0 months). The mean age was 69±12 years, 71.6% were males, and ischemic cardiac disease was the main HF etiology (68.5%). Mean LVEF was 33.4%±7.1% and mean TAPSE was 19.6±5.7 mm. Approximately half of the study population were NYHA I class at baseline (52.6%). Median (IQR) values of CA125 and NT-proBNP were 9.15 (6.15–14.08) U/mL, and 1,110 (415–2,510) pg/mL, respectively. No enrolled patients showed pericardial or pleural effusion. The demographic and clinical characteristics across CA125 median values are represented in Tables 1,2.

Patients with levels of CA125 higher than 9.15 U/mL (median value) were older and showed greater comorbidities and had a longer time since HF diagnosis. They also showed worse renal function, higher NT-proBNP and interleukin-6 (IL-6) levels, and sPAP values (Tables 1,2). No differences were observed in either left or right systolic ventricle function, inferior vena cava (IVC) diameter or diastolic function parameters. No significant difference related to medical treatment was observed between the two groups except for lower use of RAASi/ARNI in patients with higher levels of CA125 (75.9% vs. 93.1%; P=0.02).

Mortality risk

During follow-up, 13 patients (11.2%) died, 10 of which were due to CV causes. Patients with higher CA125 values showed elevated unadjusted mortality rates (14.1 vs. 2.2 per 100 patient-years; P=0.02). In the adjusted model, CA125, modeled as a continuous non-linear variable, remained significantly associated with all-cause mortality (adjusted IRR 3.60; 95% confidence interval (CI): 1.08–12.02; P=0.03), as shown in Table 3 and illustrated in Figure 1A.

Figure 1 Functional form among the continuum of CA125 values and clinical outcomes. Non-linear association between CA125 levels and IRRs for all-cause mortality (A), total HF hospitalizations (B), and total CV hospitalizations (C), derived from fractional polynomial negative binomial models. For clinical interpretation, CA125 >9.15 U/mL was associated with higher rates of HF admissions (IRR 2.49, 95% CI: 1.14–5.44; P=0.02) and CV admissions (IRR 1.88, 95% CI: 1.01–3.52; P=0.04) compared with lower values, and CA125 showed a significant non-linear association with mortality risk (P=0.02). CA125, carbohydrate antigen 125; CI, confidence interval; CV, cardiovascular; HF, heart failure; IRR, incidence rate ratio.

Risk of total HF admissions

During follow-up, 47 episodes of total HF admission occurred. Most patients who were admitted showed a single HF admission (25.0%), while 6.9% and 4.3% had two and three admissions, respectively. In unadjusted analyses, patients with CA125 values above the median showed higher rates of HF hospitalization (3.9 vs. 2.0 per 10 patient-years; P=0.08). In the univariable negative binomial model, CA125 >9.15 U/mL was associated with a trend toward increased HF admission risk (IRR 1.93; 95% CI: 0.93–3.98; P=0.08), as shown in Table 3. After multivariable adjustment, this association remained significant (adjusted IRR 2.49; 95% CI: 1.14–5.44; P=0.02), as shown in Table 3. The gradient of risk attributable to CA125 followed a positive and non-linear pattern (Figure 1B).

Risk of CV admissions

A total of 60 episodes of CV admission were recorded during follow-up. Most patients experienced a single CV admission (31.0%), while 6.9% had two and another 6.9% had three admissions. In unadjusted analyses, patients with CA125 levels above the median showed higher rates of CV hospitalization (5.0 vs. 2.6 per 10 patient-years; P=0.04). In the univariable negative binomial model, CA125 >9.15 U/mL was associated with an increased rate of CV admissions (IRR 1.95; 95% CI: 1.03–3.71; P=0.04), as shown in Table 3. After multivariable adjustment, CA125 remained independently associated with CV admission risk (adjusted IRR 1.88; 95% CI: 1.01–3.52; P=0.04), as shown in Table 3. This association follows a positive, non-linear gradient (Figure 1C).

Independent predictor factors for high CA125 levels

To better understand the relationship of CA125 in the stable HF patients, linear regression analyses were performed. In a multivariable setting, 35% of the variability of CA125 was predicted by the full multivariate model. Ranked in order of importance (R², P value), three variables accounted for 80% of the model variability: lower sodium was associated with higher CA125 (48%, P<0.001), higher IL-6 (25%, P=0.01) and IVC diameter (9%, P=0.03) were also positive and linearly associated with higher CA125 levels. Graphics depicting the direction and magnitude of the relationship between CA125 and sodium, IL-6, and IVC are detailed in Figure 2. No significant association was observed between CA125 and demographic or blood test data such as age, NYHA, heart rate, renal function, bilirubin, NT-proBNP, hemoglobin, and echocardiographic parameters: LVEDVi, left atrial volume index (LAVi), TAPSE, LVEF and E/e’ ratio.

Figure 2 Relationship between CA125 levels and sodium (A), IL-6 (B), IVC diameter (C), and sPAP (D). CA125, carbohydrate antigen 125; IL-6, interleukin-6; IVC, inferior vena cava; sPAP, systolic arterial pulmonary pressure.

Discussion

This study shows that CA125, even in clinically stable patients with HFrEF, is associated with biomarkers of congestion and inflammation and predicts long-term mortality and CV hospitalizations. A visual summary of these findings is presented in Figure 3. In addition to previously published studies, our research has some remarkable findings. First, CA125 showed usefulness for risk stratification in patients with a long period of stability or even in patients who have never had an AHF episode. Second, it was also true in patients optimally treated. Finally, our findings suggest that CA125 values in a specific context, may play a role or act as a surrogate of residual congestion and inflammation.

Figure 3 During outpatient routine care, a CA125 above 9.15 U/mL, can recognize a subgroup of HF patients with a poorer mid-term prognosis. CA125, carbohydrate antigen 125; CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction.

One of the main strengths of this study is the highly selected and clinically stable outpatient population. All patients were carefully evaluated after at least six months of stability, allowing a true baseline evaluation of CA125 levels. The methodology used for evaluating recurrent events also adds to the robustness of the findings.

However, several limitations warrant discussion. First, it is a single-center study with a modest sample size of 116 patients; however, the mortality and hospitalization rates were similar to previously reported studies. Due to the inclusion time, the use of therapeutic options such as SGLT2i and sacubitril/valsartan is low and may affect the generalizability of our results. Finally, the lack of invasive pressure assessment prevented us from obtaining more insight into the pathophysiology of CA125 in this subset of patients.

Our results align with and expand upon previous investigations into CA125 as a prognostic marker. CA125 is a complex high-molecular glycoprotein that has been proposed as a potential cardiac biomarker for more than 20 years (17). Although it is widely used for ovarian cancer monitoring, high CA125 levels can be found in other malignant and nonmalignant diseases (18,19). The clinical factors related to the increase of CA125 levels are not yet well established and its mechanisms are still under research. It is well established that CA125 increases during HF decompensation (8,11,12,20). Núñez et al. have shown that CA125 is a proxy of fluid overload and inflammation and identifies a subset of higher risk of adverse events, including higher risk of death and HF readmissions (20). Indeed, CA125 emerged as an independent predictor factor of mortality in patients admitted with AHF and provided additional prognostic value to NT-proBNP (8,21). Furthermore, it also has been useful for monitoring and guiding diuretic therapy in patients with a recent episode of AHF, as shown in the CHANCE-HF trial (22,23).

To date, only a few studies have been published about the prognosis role of CA125 in chronic HF patients, just focusing on the stable phase and without fully optimized medical treatment (24,25). The current study suggests that CA125 may also be useful for risk stratification in patients with stable HF and optimally treated. Vizzardi et al. found that CA125 levels were associated with an increased risk of CV mortality and HF hospitalization (25,26). However, in that study, patients were enrolled just 3 months after the AHF episode. The present study extends this concept by proposing a longer stability period of at least 6 months to obtain a true basal CA125 level after the expected reduction following an AHF episode. Likewise, Ordu et al. showed that CA125 was a prognostic marker in stable HF patients comparable to NT-proBNP, however, given advances in therapy, that population is no longer comparable in terms of treatment (27,28). In our cohort, patients were more comprehensively managed with contemporary guideline-directed therapies, including ACEI/ARB, beta-blockers, MRAs, CRT devices, and newer agents such as sacubitril-valsartan, ivabradine, and SGLT2 inhibitors.

The mechanistic underpinnings of our findings appear closely linked to congestion and inflammation physiology. Previous studies have typically used a CA125 cut-off of 35 U/mL, based on oncology data (29). More recently, Núñez et al. proposed a threshold of <23 U/mL for lower short-term adverse event risk in AHF patients (30). In the absence of pleural/pericardial effusion and volume overload, it is reasonable to expect lower levels of CA125 in stable HF patients. In this population, even lower CA125 values—around 9.15 U/mL—were associated with increased risk of hospitalization, CV events, and mortality. While our cut-off was derived from the cohort median rather than an optimization of diagnostic performance metrics, the consistency of the observed risk differences, along with the non-linear relationship between CA125 and outcomes, supports the relevance of this lower threshold in the ambulatory setting. This suggests that even modest elevations in CA125 may reflect subclinical congestion and long-term risk, highlighting its utility as a prognostic biomarker in stable HF patients.

In the pathophysiological context of the present findings, CA125 is classically associated with fluid overload, and has been proposed to be upregulated in response to mesothelial cell activation triggered by inflammation or increased hydrostatic pressure (19,31-34). Notably, despite the clinically stable condition of our study population (52.6% in NYHA class I, no signs of congestion and normal IVC diameter), CA125 levels were significantly associated with surrogate markers of residual congestion (sodium levels and IVC diameter), and with a pro-inflammatory profile (IL-6). In this ambulatory setting, the inclusion of CA125 among the biomarker panel may enhance risk stratification by capturing a distinct dimension of HF pathophysiology.

The dynamic nature of CA125 in response to decongestive therapy further supports its biological relevance. Recent studies assessing dapagliflozin in stable chronic HFrEF demonstrated significant reductions in CA125 levels even in the absence of overt congestion or NT-proBNP changes (35,36). This reinforces the idea that CA125 reflects subclinical congestion or mesothelial inflammation and responds dynamically to therapy. These recent data strengthen our results by confirming that CA125 is not only a static predictor of adverse outcomes, but also a responsive marker of residual congestion in stable HF, even under optimized medical therapy.

An exploratory subgroup analysis was performed to evaluate whether baseline pharmacological or device-based therapies modified the association between CA125 levels and adverse clinical outcomes. No statistically significant differences were observed in the use of beta-blockers, RAASi/ARNI, MRAs, SGLT2i, or device therapies (implantable cardioverter-defibrillator or cardiac resynchronization therapy) between patients who did or did not experience adverse events. The only treatment showing a statistically significant difference was loop diuretic use, which was more common among patients who developed adverse outcomes (72.4% vs. 32.9%; P=0.001). These findings suggest that CA125 provides prognostic information that is independent of baseline medical therapy and device use.

This study suggests a potential role for CA125 in guiding clinical decision-making in stable HF patients. Given its association with adverse outcomes and its dynamic response to therapies such as SGLT2 inhibitors, CA125 may be useful for identifying patients with residual congestion, even when clinically compensated. Its integration into routine outpatient management could contribute to risk stratification and potentially guide diuretic or other tailored therapies.

While natriuretic peptides such as NT-proBNP remain central to HF diagnosis and monitoring, their levels primarily reflect myocardial stretch and may be influenced by age, renal function, or obesity. By contrast, CA125 is more specifically linked to serosal inflammation and third-space fluid accumulation, which may escape clinical detection. Its low cost, wide availability, and reproducibility support CA125 as a complementary biomarker that captures subclinical congestion and inflammation in stable, ambulatory settings.

Further studies are warranted to validate these findings in larger, diverse cohorts and to determine whether CA125-guided interventions can improve clinical outcomes in this population.

Conclusions

In patients with stable HFrEF, higher plasma CA125 levels were associated with an increase of mid-term morbidity. Further studies are warranted to confirm current findings and unravel the role of this biomarker as a signal of residual congestion and/or inflammatory status.

Acknowledgments

We would like to thank Dr. Valle Lozano, Specialist Physician of Clinical Analysis, and the Clinical Laboratory Department of the General University Hospital of Elche for CA125 levels measurements.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-244/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-244/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-244/prf

Funding: This work was partly supported by FISABIO (Fundació per al Foment de la Investigació Sanitària i Biomèdica de la Comunitat Valenciana) as well as grants from the Centro de investigación Biomédica en Red (CIBER) Cardiovascular (No. 16/11/00420, to J.N.V.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-244/coif). J.N.V. has received honoraria for lectures from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, NovoNordisk, Pfizer, Rovi, and Vifor Pharma. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the University Hospital of Elche (No. PI 29/2018). Written informed consent was obtained from all patients prior to their inclusion in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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