Fibrosis Marker HE4 Predicts Death and Heart Attacks a Decade Out in Coronary Patients

A protein long known to gynecologists as a tumor marker is now emerging as one of the most intriguing signals in cardiovascular medicine. Human epididymis protein 4, better known as HE4 and encoded by the WFDC2 gene, was originally characterized as a secreted glycoprotein overproduced by ovarian and endometrial cancers. But a decade-long study of nearly 400 patients with confirmed coronary artery disease now shows that the same molecule, measured in a simple blood sample, can flag who is most likely to die or suffer a major cardiovascular event over the following ten years. The findings, published in the Journal of Molecular Medicine, suggest that fibrosis — the scarring process HE4 appears to drive — may be a powerful and underappreciated force shaping the long-term fate of heart patients.

The research team, led by Axel Muendlein of the Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT) in Feldkirch, Austria, followed 395 patients whose coronary artery disease had been confirmed by angiography, the gold-standard imaging technique that visualizes the coronary arteries directly. At the start of the study, the investigators measured circulating HE4 concentrations in every participant and then tracked them for a full decade, recording cases of major adverse cardiovascular events — a composite of outcomes such as cardiovascular death, heart attack, and stroke — as well as deaths from any cause. This prospective design, in which the biomarker is measured before outcomes occur, is critical for establishing that a marker genuinely carries predictive information rather than merely reflecting disease that has already declared itself.

The statistical architecture of the study was deliberately rigorous. The researchers analyzed HE4 in two complementary ways: as a continuous variable after log2 transformation, which allows the risk associated with each doubling of the protein’s concentration to be quantified, and as a categorical variable using a cut-off of 8.0 nanograms per milliliter derived from Youden’s index, a standard method for choosing the threshold that best separates patients who experience an event from those who do not. Both approaches told the same story. Each doubling of HE4 concentration was associated with a 20 to 40 percent increase in the risk of major adverse cardiovascular events and of all-cause mortality, with hazard ratios in that range holding steady across every level of statistical adjustment the team applied.

Those adjustment levels are where the study gains its real force. In a first model, the researchers corrected for the traditional cardiovascular risk factors: age, body mass index, hypertension, type 2 diabetes, LDL cholesterol, HDL cholesterol, and the presence of significant coronary stenoses on the angiogram. In a second, more demanding model, they additionally adjusted for kidney function, C-reactive protein, fibrinogen, and N-terminal pro–B-type natriuretic peptide, or NT-proBNP — a battery that covers renal impairment, systemic inflammation, coagulation activity, and cardiac wall stress. The association between HE4 and adverse outcomes survived all of it. In other words, HE4 was not simply acting as a proxy for poor kidney function, chronic inflammation, or an already strained heart; it carried prognostic information that those established markers could not capture.

Beyond the hazard ratios, the team examined whether adding HE4 to a fully adjusted baseline model improved risk reclassification — a statistical test of whether the new marker actually moves individual patients into more accurate risk categories rather than just nudging population-level statistics. It did, across all endpoints. For clinicians, this matters because the central problem in secondary prevention is not identifying that a coronary patient is at risk; it is deciding which coronary patient is at highest risk and therefore deserves intensified therapy, closer surveillance, or more aggressive revascularization. A marker that refines that sorting beyond what age, lipids, diabetes status, CRP, and NT-proBNP already provide is precisely the kind of tool the field has been hunting for.

Why would an epididymal protein track cardiovascular death so faithfully? The most compelling answer lies in fibrosis. Seminal work published in Nature Medicine in 2013 identified HE4 as a fibroblast-derived mediator of fibrosis, a secreted factor that promotes the accumulation of extracellular matrix and the stiffening of tissue. Fibrosis is the common endpoint of many chronic diseases of the heart and kidney: after a heart attack, in heart failure with preserved ejection fraction, in hypertensive remodeling, and in progressive kidney disease, the gradual replacement of functioning tissue with scar is what ultimately erodes organ reserve and kills patients. HE4, in this framework, is not an innocent bystander but a molecular signature of an active scarring program — one that unfolds silently over years while standard markers of inflammation and hemodynamic stress remain comparatively quiet.

The new coronary findings fit into a rapidly expanding literature on HE4 across the cardiovascular spectrum. The protein has been shown to predict progressive fibrosis and cardiovascular events in patients with dilated cardiomyopathy, to carry diagnostic and prognostic weight in patients undergoing transcatheter aortic valve implantation, to correlate with heart failure severity in chronic heart failure, and to flag poor prognosis in heart failure with preserved ejection fraction and in acute myocardial infarction. Elevated HE4 has also been documented in cystic fibrosis, where it behaves as an inflammatory biomarker, and in renal fibrosis after kidney transplantation, where hypoxia-induced HE4 in tubular epithelial cells drives extracellular matrix accumulation via the NF-κB pathway. The same Austrian group has separately reported that circulating HE4 predicts ten-year mortality and major adverse cardiovascular events in patients with peripheral artery disease, indicating that the signal extends beyond the coronary circulation to atherosclerotic disease in general.

The biology of the molecule itself adds a layer of irony to the story. HE4 was first molecularly characterized in the early 1990s as a major epididymis-specific protein with sequence homology to extracellular proteinase inhibitors, belonging to the whey acidic protein family, whose members carry a distinctive four-disulfide core domain and participate in innate immune defense. Comprehensive tissue surveys later showed expression not only in the epididymis but in the respiratory tract and female reproductive epithelia. Its clinical debut, however, came through oncology: because serous and endometrioid ovarian carcinomas overexpress it, HE4 entered routine practice as part of the ROMA algorithm for distinguishing malignant from benign pelvic masses. That a protease inhibitor with innate immune functions would turn out to be a fibrosis driver and a cardiovascular prognostic marker illustrates how a single molecule can sit at the crossroads of tissue repair, immunity, and chronic disease.

For the millions of people living with established coronary artery disease, the practical implications are worth stating carefully. This was an observational study, so it demonstrates prediction, not causation, and it does not establish that lowering HE4 would improve outcomes. No HE4-lowering therapy exists, and the authors note that their datasets are not publicly available due to institutional data protection policies, which means independent validation in other cohorts will be essential before any guideline change. Still, the marker is measurable with existing immunoassay infrastructure, the cut-off of 8.0 ng/mL offers a concrete clinical threshold, and the prognostic gain held even after accounting for NT-proBNP, the strongest cardiorenal marker currently in routine use. As proteomics increasingly supplies cardiovascular medicine with new candidate biomarkers, HE4 stands out because it points to a mechanism — fibrotic remodeling — that is both plausible and potentially targetable.

The study, conducted under the auspices of the VIVIT research institute with ethics approval from the University of Innsbruck and informed consent from all participants, adds a striking entry to the growing argument that the next leap in cardiovascular risk prediction will come from understanding tissue scarring, not just plaque and lipids. If larger trials confirm these results, a blood test originally designed to help detect ovarian cancer could find a second life identifying which coronary patients are quietly heading toward heart failure and death a decade before it happens — and, perhaps, which of them would benefit most from the anti-fibrotic therapies now being developed across medicine.

Subject of Research: Prognostic value of the profibrotic biomarker HE4 for long-term outcomes in coronary artery disease

Article Title: Human epididymis protein 4 is a predictor of long-term mortality and major adverse cardiovascular events in patients with coronary artery disease

Article References: Muendlein, A., Heinzle, C., Geiger, K., Brandtner, E. M., Schnetzer, L., Hammerer-Lercher, A., Saely, C. H., Drexel, H., & Leiherer, A. (2026). Human epididymis protein 4 is a predictor of long-term mortality and major adverse cardiovascular events in patients with coronary artery disease. Journal of Molecular Medicine, 104(1), Article 117. https://doi.org/10.1007/s00109-026-02727-0

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02727-0

Keywords: HE4, WFDC2, coronary artery disease, biomarkers, cardiovascular risk prediction, major adverse cardiovascular events, all-cause mortality, fibrosis, NT-proBNP, C-reactive protein, prognosis, Journal of Molecular Medicine