The Expanding Role of Carbohydrate Antigen 125 in Heart Failure: From Tumour Marker to a Cornerstone of Heart Failure Management. An Updated Narrative Review

Abstract

Congestion is central to heart failure (HF) but remains difficult to quantify. Carbohydrate antigen 125 (CA125), also known as mucin 16, released by mesothelial cells, captures two pathways relevant to HF: fluid overload and inflammation. This narrative review summarises biological mechanisms and clinical applications. Across acute and chronic settings, CA125 tracks systemic and right-sided congestion, complements natriuretic peptides and shows lower dependence on renal function. Higher levels identify patients at risk for death and readmission; in ambulatory HF with reduced ejection fraction it predicts events, while in HF with preserved ejection fraction its signal is strongest in congestion-dominant phenotypes. Serial testing mirrors decongestion and clinical course; CA125-guided care has reduced rehospitalisations and improved renal function measures in selected populations. Advantages, wide availability, standardisation and low cost, support use in practice. Key gaps include phenotype-specific threshold, sampling interval and integration into actionable algorithms. Overall, CA125 has moved from tumour marker to practical tool that refines congestion assessment, improves risk stratification and informs individualised therapy in contemporary HF care.

Carbohydrate antigen 125 (CA125), a high-molecular-weight glycoprotein also known as mucin 16 (MUC16), has long been established in the oncological lexicon as a principal biomarkerforthe monitoring ofepithelial ovarian cancer.1 Beyond malignancy, accumulating evidence has expanded its clinical relevance into cardiovascular medicine, particularly in the complex syndrome of heart failure (HF).2,3 An emerging body of evidence reinforces CA125 as a useful biomarker for diagnosis, HF phenotyping, risk stratification, monitoring and tailoring of decongestive strategies in HF.4 This glycoprotein, synthesised by mesothelial cells in the pleura, pericardium and peritoneum, appears to be upregulated in response to fluid overload and inflammation.5 The wide availability, low cost and standardised measurement of testing further underscore its potential for seamless integration into routine clinical practice, offering a valuable adjunct to other biomarkers.

The journey of CA125 toward cardiovascular utility began with observations of its elevation in non-malignant states characterised by serosal fluid accumulation.6 Early seminal studies systematically explored this in HF, showing that serum CA125 is mainly upregulated in acute HF and advanced disease, with direct correlation to clinical severity first described in 1999 by Nägele et al.7 In a pivotal study, Faggiano et al. compared several tumour markers in chronic HF and found that, unlike others, CA125 rose in direct proportion to New York Heart Association (NYHA) class and fell with effective therapy, suggesting a dynamic link to haemodynamic status and volume overload.8 Subsequent multicentre analyses confirmed that CA125, among other cancer-related biomarkers, is associated with increasing HF severity.9 Importantly, CA125 and natriuretic peptides capture distinct pathobiology: in acute HF, CA125 relates mainly to clinical congestion and tricuspid regurgitation severity, whereas N-terminal pro-B-type natriuretic peptide (NT-proBNP) is driven by renal dysfunction, left ventricular (LV) ejection fraction and age.10

The elevation of circulating CA125 in HF is likely to reflect intertwined mechanisms central to disease progression, primarily mesothelial mechanical stress and systemic inflammation.11 Mesothelial cells lining serous cavities are the principal source of CA125. In acute HF, increased hydrostatic pressure and vascular permeability promote interstitial fluid accumulation and serosal stimulation, often leading to effusion.6 This mechanical and inflammatory stress upregulates MUC16 expression, increasing CA125 release into the circulation and serosal spaces. In chronic HF, CA125 elevation is strongly associated with serous effusions, and in vitro mechanical stretch was found to directly upregulate MUC16 in human mesothelial cells.12 Consistently, CA125 correlates with invasive haemodynamic indices of congestion (right atrial pressure, pulmonary capillary wedge pressure) and sonographic signs of fluid overload, including reduced inspiratory collapse of the inferior vena cava.7,13 It also serves as a proxy for increased intra-abdominal pressure in acute HF.14 Collectively, these data position CA125 as a marker of venous and serosal congestion that complements intravascular pressure surrogates.

Beyond volume overload, inflammatory activation in failing myocardium and congested tissues provides a second driver.15 Pro-inflammatory cytokines (e.g. interleukin-1β, tumour necrosis factor-α) stimulate CA125 secretion by mesothelial cells, independent of mechanical stretch.16,17 Foundational work demonstrated constitutive mesothelial CA125 secretion with robust upregulation in response to cytokines or bacterial lipopolysaccharide, linking inflammation to elevated CA125.18 In patients with HF, serum CA125 correlates positively with key pro-inflammatory cytokines, embedding the biomarker in the cytokine milieu of cardiac dysfunction.15,19 Given its relatively prolonged half-life (~7–12 days), CA125 integrates sustained inflammatory and permeability signals rather than transient cytokine surges, offering complementary pathophysiologic insight into natriuretic peptides that primarily reflect wall stress and intravascular load.16,17,20,21

Finally, recent tissue-level data localise MUC16 in the epicardial layer (particularly epicardial adipose tissue), where its expression coexists with inflammatory infiltrates and fibrosis-related markers (transforming growth factor-β, collagen I). Higher MUC16 expression is associated with increased local cytokines and extracellular matrix remodelling proteins, suggesting that CA125 may not only reflect systemic biology but could participate in local cardiac inflammatory and fibrotic processes relevant to HF (Figure 1).22

Figure 1: Mechanisms of Carbohydrate Antigen 125 Elevation in Heart Failure.

Schematic showing mesothelial MUC16/CA125 upregulation driven by venous or serosal congestion and systemic inflammation; mechanical stretch and cytokine signalling increase CA125 release into circulation. CA125 = carbohydrate antigen 125; HF = heart failure; IL = interleukin; LPS = lipopolysaccharide; MUC16 = mucin 16; TNF = tumour necrosis factor.

Clinical Applications of CA125 in Heart Failure

Assessment of Haemodynamics and Fluid Overload

The clinical use of CA125 in haemodynamic assessment is to translate serosal and peripheral congestion into actionable information, complementing examination, imaging and natriuretic peptides. Nägele et al. first linked CA125 trajectories with recovery of cardiac function, noting normalisation after successful heart transplantation.7 This observation supports its role as a dynamic readout of decongestion rather than a static cancer marker.

In chronic HF, D’Aloia et al. showed that CA125 correlates with invasive filling pressures (right atrial pressure and pulmonary capillary wedge pressure) and Doppler indices, and aligns with NYHA functional class.23 Kouris et al. validated these associations in a European cohort, reinforcing that higher CA125 accompanies greater global congestion burden.24 Beyond chamber pressures, Duman et al. related elevated CA125 to left atrial volume, a surrogate of chronically raised LV filling pressures, indicating value for chronic load profiling.25

Importantly, registry-based work emphasises what CA125 captures at the bedside: compared with NT-proBNP, CA125 shows a tighter linkage to extravascular congestion (i.e. peripheral oedema, pleural effusion and pulmonary B-lines on lung ultrasound), while natriuretic peptides more closely reflect intravascular pressure surrogates.26 In acute care, CA125 can also flag venous hypertension at the organ level: Núñez-Marín et al. demonstrated that CA125 predicts congestive intrarenal venous flow (a Doppler marker of renal venous hypertension), whereas NT-proBNP did not.27 Extending these insights, Gayán Ordás et al. reported, in a large registry, that CA125 maintains a stronger association than NT-proBNP with extravascular congestion proxies, while natriuretic peptides dominate intravascular domains, supporting a complementary dual-marker strategy.26

Heart Failure Diagnosis

While natriuretic peptides remain the primary diagnostic biomarkers for HF, CA125 provides complementary information, particularly in contexts in which natriuretic peptide interpretation is confounded (e.g. obesity, renal dysfunction, AF). The first systematic synthesis of CA125 in HF diagnosis was presented by Zhuang et al., who demonstrated in a meta-analysis that CA125 levels were significantly higher in HF patients than in controls, with consistent associations across studies.28

Chen et al. reported that combining CA125 with BNP improved diagnostic accuracy for HF compared with NT-proBNP alone, particularly in patients presenting with dyspnoea of uncertain aetiology.29 In the acute setting, Miró et al. showed that CA125 level measured upon arrival to the emergency department correlated with clinical and laboratory markers of acute decompensation.30 More recently, in a prospective study of 210 ambulatory patients with suspected HF, CA125 showed comparable diagnostic accuracy to NT-proBNP for HF with preserved ejection fraction (HFpEF). A CA125 level ≥23 U/ml provided high specificity (96.6%) and positive predictive value (80.8%), while <9 U/ml yielded high negative predictive value (85.7%). These findings suggest that CA125 may complement NT-proBNP in HFpEF diagnosis.31

Risk Stratification

CA125 provides consistent prognostic information across the HF spectrum, with the strongest signal in acute or worsening presentations and a phenotype-dependent contribution in the ambulatory setting. Its value stems from integrating serosal and extravascular congestion and inflammatory activation (pathways that are complementary to natriuretic peptides), and from its behaviour when interpreted serially and in combination with other biomarkers.

Worsening or Acute Heart Failure

Early single-centre cohorts positioned CA125 as an independent predictor of mortality after worsening HF, with higher admission quartiles portending worse 6-month outcomes.32 These observations have been reproduced in pooled analyses, confirming robustness across diverse acute HF populations.33 Emergency department studies extend this signal to real-world triage: admission CA125 tracks decompensation severity and identifies patients at increased 1-year mortality, particularly at upper-tercile levels.30 A practical discharge threshold (<23 U/ml) delineates a lower-risk subgroup with high negative predictive value for early events, informing early post-discharge planning.34 Large-scale validation from BIOSTAT-CHF corroborated that CA125 independently predicts 1-year mortality and the composite of death or HF rehospitalisation, even after adjustment for clinical scores and a standardised congestion score.35 Prognostic performance is preserved irrespective of pleural effusion status.36 Beyond single-marker use, biomarker synergy is salient: combining CA125 with NT-proBNP refines 6-month mortality risk, producing a graded pattern (both high > one high > both low).37 This gradient has been reproduced externally in non-western acute HF populations.38

Chronic Heart Failure with Reduced Ejection Fraction

In ambulatory cohorts, elevated CA125, despite optimised therapy and mild-to-moderate symptoms, anticipated cardiovascular events and HF hospitalisations, probably reflecting residual extravascular congestion not fully captured by natriuretic peptides or standard clinical assessment.2,24 In DAPA-HF, baseline CA125 >35 U/ml identified a subgroup at higher adjusted risk of worsening HF or cardiovascular death; risk rose across quartiles and increased over 12 months (including ‘low → high’ transitions), aligned with adverse outcomes.39 In contrast, phenotype-specific analyses suggested heterogeneity across the ejection fraction (EF) spectrum: in chronic HF with reduced EF (HFrEF), higher CA125 is associated with HF hospitalisation or cardiovascular death, whereas this relationship was not observed in HFpEF in the trial populations.40

Heart Failure with Preserved Ejection Fraction

Observational data indicate that CA125 aligns with congestion and fibrosis-related markers and predicts HF hospitalisation or cardiovascular death after multivariable adjustment, pointing to utility in congestion-dominant phenotypes.41 In women with HFpEF, higher CA125 relates to adverse left atrial remodelling and independently predicts hospitalisation.42 In larger acute HF cohorts enriched for preserved EF, CA125 forecasts recurrent readmissions independently of NT-proBNP, underscoring additive value for total HF events over time.43 This signal may be accentuated in comorbidity-rich subsets (e.g. HFpEF with renal dysfunction), in which CA125 better tracks functional limitation.44,45 Conversely, in EMPEROR-Preserved, baseline CA125 was not associated with the primary outcome, suggesting that biomarker performance in HFpEF is sensitive to disease stage, congestion burden and background therapy.40

Multi-marker Context and Biological Interactions

CA125 appears to modulate the prognostic expression of other pathways. Galectin-3 predicted long-term adverse outcomes primarily in patients with elevated CA125, consistent with an interplay between fibrotic signalling and sustained congestion.46 A similar effect modification has been observed with soluble ST2, in which risk enhancement was concentrated in the high-CA125 strata, aligning with a strain–inflammation amplifier model.47,48 Following MI, the combination of CA125, NT-proBNP and TIMP-3 improved discrimination for adverse remodelling versus any single marker, supporting an extracellular matrix–congestion composite.49 Finally, the adverse impact of hypoalbuminemia in acute HF depended on concurrent CA125 elevation, suggesting an interaction between systemic inflammation, nutritional status and serosal congestion.50

Clinical Framing

In acute care, CA125 aids early risk stratification (admission and discharge), complements natriuretic peptides and supports transition planning (e.g. a <23 U/ml discharge threshold).32–37,51 In ambulatory HFrEF, it identifies residual risk and refines phenotyping beyond wall-stress markers.2,24,39,40 In HFpEF, its contribution appears strongest when congestion and fibrotic remodelling are prominent, with neutral signals in selected randomised trial populations.40–43 Overall, CA125 strengthens risk stratification when interpreted together with clinical assessment, natriuretic peptides and, when appropriate, other pathway biomarkers.

The accumulated prognostic evidence across different HF phenotypes, stages and study designs is summarised in Table 1.

Table 1: Prognostic Value of Carbohydrate Antigen 125 in Heart Failure.

Reference	Design/Setting	Population	n	Endpoint(s)	CA125 Analysis/Cut-off	Key Findings
Nägele et al. 19997	Observational, serial pre/post heart transplantation	HF patients pre- and post-HTx	71	Changes in CA125 across clinical states	Continuous (absolute U/l values)	CA125 decreased after transplant and stabilisation, increased with worsening; correlated with filling pressures and neurohormones.
D’Aloia et al. 200323	Prospective cohort	Chronic HF (NYHA II–IV)	286	6-month death/HF readmission	Continuous	Strong correlation with right atrial pressure, PCWP, NYHA class; independent predictor of outcome.
Faggiano et al. 20058	Prospective observational	CHF (NYHA I–IV)	182	Correlation with therapy response	Continuous	CA125 increased with NYHA class and decreased after effective therapy; stronger than other tumour markers.
Kouris et al. 200524	Observational cohort	CHF	110	Haemodynamic and echo parameters	Continuous	CA125 levels rose proportionally with HF severity; higher with pulmonary and systemic congestion.
Duman et al. 200825	Observational	Advanced CHF	84	BNP, LA volume	Continuous	CA125 correlated with BNP and LA volume, a surrogate of chronic elevated LV filling pressures.
Núñez et al. 200732	Prospective cohort	AHF	529	6-month mortality	Quartiles	Higher CA125 quartiles independently predicted mortality.
Davutoglu et al. 201036	Observational	ADHF	158	In-hospital and long-term mortality	Continuous	Prognostic value independent of pleural effusion.
Vizzardi et al. 20122	Ambulatory cohort	Mild–moderate CHF	144	CV events, HF hospitalisations	Continuous	Elevated CA125 independently predicted long-term adverse outcome.
Miñana Escrivá et al. 201254	Serial biomarker study	Post-AHF	293	Early readmissions	ΔCA125 (discharge–follow-up)	Persistent/increasing CA125 predicted higher risk of early readmission.
Núñez et al. 201264	Observational	Post-AHF	447	Mortality	Continuous; interaction with BUN	Mortality association of loop diuretics depended on BUN and CA125 levels.
Núñez et al. 201752	Joint modelling	AHF	667	Long-term mortality	Serial trajectories	Persistently elevated CA125 predicted poor outcome; decline associated with survival benefit.
Li et al. 201833	Systematic review and meta-analysis	16 studies of AHF	8,401	Mortality, HF readmission	High versus low	↑68% mortality and ↑77% readmission risk with high CA125.
Yoon et al. 201982	Prospective cohort	ADHF	413	2-year mortality	Continuous; combination with NT-proBNP	CA125 independently predicted mortality; combination improved risk prediction.
Soler et al. 202066	Cohort	AHF with severe TR	300	Mortality	Continuous	Outperformed NT-proBNP for long-term mortality prediction.
Núñez et al. 202035 (BIOSTAT-CHF)	Multicentre prospective registry	WHF	2,356	1-year death/HF readmission	Quartiles	Independent predictor beyond congestion scores and validated risk scores.
de la Espriella et al. 202265	Cohort	AHF with full eGFR spectrum	4,595	Mortality	Continuous	Prognostic accuracy maintained across renal function strata; NP declined with renal dysfunction.
Núñez-Marín et al. 202127	Cohort	AHF	213	Congestive intrarenal venous flow	Continuous	CA125 (not NT-proBNP) predicted intrarenal venous congestion.
Menghoum et al. 202441	Prospective	HFpEF	139	Mortality or first HF hospitalisation	≥35 U/ml	Elevated CA125 predicted HF hospitalisation; stronger than NT-proBNP.
Miñana et al. 202243	Prospective	HFpEF	2,369	Recurrent HF readmissions	Continuous	Strong predictor of recurrent HF readmissions independent of NT-proBNP.
Ferreira et al. 202440 (EMPEROR)	RCT biomarker analysis	HF spectrum	1,111	CV death/HF hospitalisation	Continuous	No significant prognostic signal in HFpEF; present in HFrEF.
Llàcer et al. 202245	Cohort	Elderly HFpEF	348	Mortality, rehospitalisation	Continuous	Independent predictor even after adjustment for comorbidities.
Zhang et al. 202369	Cohort	Stage D HF	176	All-cause death, CV death, HF readmission	Continuous	Strong predictor of all outcomes, independent of LVEF.
Revuelta-López et al. 202548	Cohort	AHF	160	Long-term morbidity	CA125 × sST2 interaction	Prognostic impact of sST2 evident mainly in patients with elevated CA125.
Docherty et al. 202339	Post-hoc biomarker analysis of RCT	HFrEF	3,123	Primary: first worsening HF (hospitalisation or urgent IV HF therapy) or CV death; secondary: CV death, HF events, total HF hospitalisations + CV death, all-cause death, KCCQ-TSS, renal slope	Quartiles (Q1 ≤8.78; Q2 8.79–13.04; Q3 13.05–21.13; Q4 ≥21.14 U/ml); cut-off ≤35 versus >35 U/ml; median 13.04 U/ml	Median 13.04 U/ml; 12.2% >35 U/ml. CA125 >35 U/ml: adjusted HR 1.59 (95% CI [1.29–1.96]) for primary outcome; Q4 versus Q1 HR 1.63; doubling at 12 months → HR 1.77. Dapagliflozin benefit consistent across CA125 strata (no interaction).

AHF = acute heart failure; ADHF = acute decompensated heart failure; BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CA125 = carbohydrate antigen 125; CHF = chronic heart failure; CV = cardiovascular; eGFR = estimated glomerular filtration rate; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HTx = heart transplant; KCCQ-TSS = Kansas City Cardiomyopathy Questionnaire total symptom score; LA = left atrium; LV = left ventricle; LVEF = left ventricular ejection fraction; NP = natriuretic peptide; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; PCWP = pulmonary capillary wedge pressure; RCT = randomised controlled trial; sST2 = soluble ST2; TR = tricuspid regurgitation; WHF = worsening heart failure. Cut-offs of 23 and 35 U/ml correspond to thresholds most frequently applied in prognostic studies. Δ = change in CA125 between admission, discharge or follow-up.

Monitoring and Biomarker-guided Therapy

Historical observations first suggested the dynamic behaviour of CA125 in relation to congestion relief: levels normalised after successful heart transplantation, aligning with haemodynamic recovery.7 This concept was later substantiated by longitudinal analyses showing that serial trajectories (rather than single measurements) carry powerful prognostic information in both acute and chronic settings. Persistently elevated CA125 after an episode of acute HF is associated with higher long-term mortality, whereas declining concentrations over follow-up identify patients with improved outcomes; combined modelling with NT-proBNP further enhances risk prediction.52 In categorical pre–post assessments, patients whose CA125 remains elevated or increases between discharge and early ambulatory review have substantially higher rates of death and HF readmission versus those whose CA125 normalises.53,54

Given its relatively prolonged half-life (~7–12 days), CA125 is best suited for medium- to long-term monitoring (weeks to months), capturing the integrated effect of decongestive strategies and disease-modifying therapies. In a single-centre cohort of hospitalised patients with acute HF, both admission and discharge CA125 independently predicted 1-year mortality; among those with paired samples, decreases in CA125 were linked to a markedly lower risk of death, with the prognostic benefit evident mainly in hospital stays exceeding 10 days, consistent with the time required for meaningful biological change.55 In chronic ambulatory HFrEF, a biomarker analysis from DAPA-HF showed that patients transitioning from low (≤35 U/ml) to high (>35 U/ml) CA125 at 12 months had a substantially greater risk of death or HF hospitalisation, and that a doubling in CA125 conferred higher event rates, reinforcing the value of trajectories over time.39

Beyond monitoring, CA125 has been prospectively evaluated to guide therapy. In the randomised CHANCE-HF trial, recently discharged patients with acute HF and elevated CA125 were assigned to biomarker-guided care versus usual care; the CA125-guided algorithm, that is, favouring more aggressive diuretic titration when CA125 remained >35 U/ml, reduced the composite of death or HF readmission at 1 year, with the greatest benefit driven by fewer rehospitalisations.56 In a high-risk cardiorenal cohort (IMPROVE), CA125-guided diuretic dosing improved short-term renal outcomes (higher glomerular filtration at 72 hours) while achieving effective decongestion.57

Therapy-related CA125 trajectories align with interventions that sustain decongestion. With sodium-glucose cotransporter 2 inhibitors (SGLT2Is), empagliflozin and dapagliflozin have been associated with downward CA125 trends in chronic and post-acute settings, in some studies accompanied by improvements in exercise capacity.58–60 In more advanced or refractory HF, CA125 may assist in identifying candidates for adjunctive strategies such as acetazolamide or peritoneal dialysis when conventional diuresis is insufficient.61,62 Operationally, elevated discharge levels can support decisions to extend the length of stay to consolidate decongestion and reduce early readmissions, and integration with parameters like blood urea nitrogen helps identify patients who may tolerate and benefit from higher-intensity diuretic regimens.63,64

Taken together, CA125 offers a pragmatic framework that links monitoring with action:

1. establish a baseline and reassess after a biologically meaningful interval;

2. interpret serial changes alongside clinical examination, natriuretic peptides, renal function and imaging; and

3. consider therapy escalation or consolidation when levels remain elevated or rise, particularly in the early post-discharge period.

These principles are consistent with its pathophysiological footprint (i.e. extravascular or serosal congestion and inflammation), and with trial-level signals supporting CA125-guided decongestive strategies in selected populations (Figure 2 and Table 2).

Figure 2: Clinical Applications of Carbohydrate Antigen in Heart Failure.

Summary of roles in congestion assessment, diagnosis, risk stratification, medium-term monitoring (weeks–months) and therapy guidance (diuretic titration, discharge planning); interpret alongside clinical exam and NT-proBNP. CA125 = carbohydrate antigen 125; CKD = chronic kidney disease; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; MUC16 = mucin 16; NP = natriuretic peptide; NT-proBNP = N-terminal pro-B-type natriuretic peptide.

Table 2: Studies on Monitoring and Carbohydrate Antigen 125-guided Therapy in Heart Failure.

Reference	Design	Population	Intervention (CA125-guided)	Control	Endpoints	Key Results
Núñez et al. 201656 (CHANCE-HF)	RCT	380 post-AHF with CA125 >35	Diuretic/statin intensification until ≤35 U/ml	Usual care	Death or HF readmission (1 year)	The guided group had a lower risk, driven by fewer rehospitalisations.
Núñez et al. 202057	RCT	160 AHF + renal dysfunction	Loop diuretics titrated by CA125 (>35: higher doses)	Usual care	eGFR at 72 h; decongestion	Better renal outcomes with guided approach.
Núñez et al. 201253	Serial measurement	293 post-AHF patients	Serial CA125 measurement from discharge to early outpatient follow-up	–	Mortality	Persistent elevation or failure of CA125 to normalise was associated with a higher risk of mortality.
Miñana Escrivá et al. 201254	Serial measurement	293 post-AHF patients	Serial CA125 measurement from discharge to early outpatient follow-up	–	Early HF readmission	Persistent elevation or an increase in CA125 was associated with a higher risk of early HF readmission.
Lourenço et al. 20225	Cohort	AHF	Paired CA125 at admission and discharge	–	Mortality at 1 year	Decline is associated with 68% lower mortality, but only if LOS >10 days.
de la Espriella et al. 202158	Observational	CHF + T2D	Empagliflozin	Pre-initiation levels	CA125 trajectory	Significant decline in CA125, consistent with decongestion.
Amiguet et al. 202360 (DAPA-VO₂)	RCT sub-analysis	87 stable HFrEF	Dapagliflozin	Placebo	VO₂, CA125 change	Dapagliflozin reduced CA125; mediation analysis linked the reduction with improved VO₂.
Miñana et al. 202559	Observational	956 AHF	Dapagliflozin at discharge	No dapagliflozin	CA125 change, 6-month outcomes	Greater CA125 reduction and fewer events.
Núñez et al. 201861	Observational	Refractory CHF	Acetazolamide	–	Decongestion	Useful adjunct in refractory congestion.
Núñez et al. 201262	Observational	Advanced CHF	CAPD	–	Clinical outcomes	CAPD was associated with a marked reduction in CA125 at 6 and 24 weeks, improved functional status and fewer days hospitalised for AHF.
Lorenzo et al. 202163	Cohort	AHF	CA125-based discharge planning	–	Readmission	Elevated discharge CA125 identified patients needing longer stay.
Núñez et al. 201264	Observational	Post-AHF	BUN × CA125 stratification	–	Mortality	Identified patients tolerating high diuretic doses with survival benefit.

AHF = acute heart failure; BUN = blood urea nitrogen; CA125 = carbohydrate antigen 125; CAPD = continuous ambulatory peritoneal dialysis; CHF = chronic heart failure; eGFR = estimated glomerular filtration rate; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LOS = length of stay; RCT = randomised controlled trial; T2D = type 2 diabetes; VO₂ = peak oxygen consumption. Thresholds of 23 U/ml and 35 U/ml represent the most widely used cut-offs in therapeutic algorithms.

CA125 in Other Cardiovascular Scenarios

Beyond its established role in HF, CA125 has shown prognostic and therapeutic potential across a range of other cardiovascular conditions.

Chronic Kidney Dysfunction

In patients with kidney impairment, de la Espriella et al. reported in a large acute HF cohort that CA125 retained robust prognostic accuracy for all-cause mortality across the entire spectrum of renal dysfunction (even when estimated glomerular filtration rate is lower than 30 ml/min/1.73 m²), whereas the predictive performance of NT-proBNP declined with worsening estimated glomerular filtration rate.65 This relative independence from renal clearance suggests that CA125 may serve as a more reliable congestion-linked biomarker in cardiorenal syndromes.

Right-sided Heart Failure and Pulmonary Hypertension

In right-sided HF and severe tricuspid regurgitation, CA125 shows particular prognostic strength. Soler et al. showed that in acute HF patients with severe tricuspid regurgitation, CA125 outperformed NT-proBNP in predicting long-term mortality.66 This superiority is likely to reflect CA125’s tighter correlation with serosal and peripheral congestion markers, including pleural effusions and ascites, which are characteristic of advanced right-sided overload. Sahin et al. observed that elevated CA125 predicted mortality in pulmonary arterial hypertension, reinforcing its applicability in conditions in which right-sided congestion is a dominant pathophysiological driver.67

Congenital Heart Disease and Fontan Circulation

In adult congenital heart disease, particularly Fontan physiology, chronic systemic venous congestion and inflammatory activation are central to clinical deterioration. Buendía et al. reported that CA125 levels were significantly elevated in Fontan patients and correlated with NYHA functional class, objective markers of systemic congestion and adverse clinical events.68

Advanced Heart Failure and Transplant Populations

In stage D HF, in which identifying patients at highest risk is critical for timely referral to advanced therapies, CA125 has shown consistent prognostic value. Zhang et al. reported that elevated CA125 independently predicted both mortality and rehospitalisation, irrespective of LV ejection fraction.69 Similarly, Monteiro et al. confirmed its predictive capacity in patients with refractory HF awaiting mechanical circulatory support or transplantation.70

In surgical contexts, Nan et al. found that preoperative CA125 level predicted adverse outcome after surgical LV reconstruction, highlighting its potential perioperative risk-stratification role.71 In transplant recipients, López-Vilella et al. proposed that CA125 may assist in detecting cellular rejection, potentially reflecting mesothelial inflammatory activation in response to graft injury.72

Aortic Stenosis

In aortic stenosis, elevated CA125 levels have been associated with advanced disease stage and poorer prognosis, both in surgical and transcatheter settings. In patients undergoing transcatheter aortic valve implantation (TAVI), higher preprocedural CA125 predicted increased mortality and rehospitalisation rates, independently of traditional risk scores.71,73–75 The biomarker appears to capture systemic congestion and inflammatory activation often missed by standard indices. A recent single-centre study demonstrated that a CA125-guided pre-TAVI optimisation strategy, focused on individualised decongestion before intervention, led to improved quality of life and fewer adverse events.76

Acute Coronary Syndromes

In acute coronary syndromes (ACS), particularly acute MI, CA125 has emerged as an independent predictor of adverse outcome. Elevated concentration at presentation has been linked to higher rates of in-hospital complications, early post-acute MI pulmonary congestion and long-term mortality.77–79 Furthermore, Cordero et al. demonstrated that combining CA125 with other biomarkers significantly improves the prediction of early LV remodelling after ACS, underscoring its potential role in guiding post-infarction management strategies.80 These associations are likely to reflect the biomarker’s sensitivity to acute haemodynamic stress, systemic inflammation and serosal involvement.

Amyloidosis

In cardiac amyloidosis, especially light-chain cardiorenal forms, CA125 elevation is common and strongly associated with advanced diastolic dysfunction, higher natriuretic peptide levels and reduced survival.81 Its performance in this context is particularly relevant given the confounding influence of renal dysfunction on traditional congestion markers.

The role of CA125 in specific HF phenotypes and other cardiovascular conditions is summarised in Table 3, and its clinical applications are shown in Figure 2.

Table 3: Carbohydrate Antigen 125 in Special Cardiovascular Populations.

Context	References	n	Key Findings
Aortic stenosis/TAVI	Husser et al. 2013;73 Romeo et al. 2021;74 Rheude et al. 2018;75 García-Blas et al. 202476	111–363 (per study)	Elevated baseline CA125 predicted mortality and rehospitalisation; additive to frailty and NP. Patients who did not respond to CA125-guided pre-TAVI optimisation (persistently elevated CA125) had poorer functional recovery and clinical outcomes, suggesting that the response to decongestion is a key prognostic factor.
Acute coronary syndromes	Falcão et al. 2019,77 2020;78 Yndigegn et al. 2024;79 Cordero et al. 202480	200–1,500	CA125 predicted pulmonary congestion, in-hospital complications, remodelling and mortality; improved prediction when combined with other biomarkers.
Cardiac amyloidosis (AL)	Wu et al. 202381	186	High CA125 strongly associated with diastolic dysfunction, higher NP and reduced survival.
Right-sided HF/severe TR	Soler et al. 202066	300	CA125 superior to NT-proBNP in predicting mortality in TR-dominant AHF.
Pulmonary hypertension	Sahin et al. 202167	93	Elevated CA125 predicted mortality in PAH.
Chronic kidney dysfunction	de la Espriella et al. 202265	4,595	Prognostic accuracy maintained across eGFR spectrum, unlike NT-proBNP.
Fontan circulation	Buendía Fuentes et al. 202368	103	Elevated CA125 correlated with NYHA class, systemic congestion and adverse events.
Stage D/advanced HF	Zhang et al. 202369; Monteiro et al. 201070	176–225	CA125 predicted mortality and HF events irrespective of LVEF.
Surgical contexts	Nan et al. 2023;71 López-Vilella et al. 202172	180; 63	Pre-operative CA125 predicted adverse outcomes after LV reconstruction; may assist in diagnosing graft rejection post-HTx.
Mechanistic (epicardial fat)	Eiras et al. 202422	–	MUC16 expressed in epicardial fat, co-localised with inflammatory infiltrates and fibrosis markers.

AHF = acute heart failure; AL = amyloid light-chain; eGFR = estimated glomerular filtration rate; CA125 = carbohydrate antigen 125; HF = heart failure; HTx = heart transplant; LV = left ventricular; LVEF = left ventricular ejection fraction; NP = natriuretic peptide; NT-proBNP = N-terminal pro-B-type natriuretic peptide; MUC16 = mucin 16; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; TAVI = transcatheter aortic valve implantation; TR = tricuspid regurgitation.

Future Directions and Research Gaps

Despite strong evidence for CA125 in HF, several research gaps remain before routine adoption. Its dual reflection of congestion and inflammation positions it as a tool for more precise HF phenotyping and for guiding targeted therapies. Integration into multi-marker panels, alongside biomarkers of fibrosis, injury and neurohormonal activation, could enhance risk stratification, as shown in elderly and high-risk populations. CA125’s role in monitoring response to emerging therapies (e.g. SGLT2Is, angiotensin receptor–neprilysin inhibitors) and guiding novel interventions targeting inflammation or fibrosis warrants further study.

Large, prospective randomised trials are needed to confirm that CA125-guided management improves outcomes and is cost-effective, and to define its value versus, or in combination with, natriuretic peptide-guided strategies. Standardised protocols for timing, thresholds and incorporation into risk scores are essential.

Unresolved challenges include the absence of universally accepted HF-specific cut-offs, incomplete understanding of why some severe HF patients have normal CA125, and uncertainty about whether CA125 is purely a marker or an active player in disease progression. Comparative studies with novel congestion biomarkers, integration with imaging tools (e.g. venous excess ultrasound, lung ultrasound, etc.) and exploration of confounding factors such as sarcopenia are critical next steps to fully harness CA125’s clinical potential.

Conclusion

CA125 is an accessible biomarker that integrates congestion and inflammation and provides incremental prognostic value in HF, especially in acute or worsening episodes. Used alongside natriuretic peptides, it refines assessment of systemic congestion, supports trajectory monitoring and enables individualised decongestion, with signals of benefit when guiding diuretic therapy. The availability, standardisation and low cost of testing favour clinical adoption, but larger pragmatic trials should define phenotype-specific cut-offs, optimal sampling intervals and actionable algorithms; overall, current evidence supports its use in routine care.

Funding Statement

This work was supported by grants from CIBER Cardiovascular (grant no. 16/11/00420).