Galectin-3 and ST2

Galectin-3 and soluble ST2 (sST2, suppression of tumourigenicity 2) are biomarkers of myocardial fibrosis, remodelling and mechanical stress. They are not diagnostic of heart failure, unlike natriuretic peptides. They give prognostic information in patients with established heart failure and add to natriuretic peptides for risk stratification.

Galectin-3 is a beta-galactoside-binding lectin secreted by activated macrophages that promotes fibroblast activation and collagen deposition. ST2 is a member of the interleukin-1 receptor family. Its soluble form acts as a decoy receptor for interleukin-33, which blocks the cardioprotective IL-33 signalling, and its concentration rises with myocardial strain.

Heart failure affects over 64 million people worldwide, with 5-year mortality of about 50%. The prognostic value of ST2 is better established than galectin-3. Raised ST2 (over 35 ng/mL) predicts death and hospitalisation independently of natriuretic peptides, and ST2 is less affected by age, renal function and body mass index than NT-proBNP. Galectin-3 is raised in renal impairment, obesity, ageing and fibrotic disease, which limits its specificity.

Indications. Risk stratification of patients with chronic or acute heart failure. Monitoring response to therapy in heart failure in selected patients. Prognosis after myocardial infarction. Added to natriuretic peptides when the NT-proBNP result is difficult to interpret (obesity, renal failure, atrial fibrillation). Not for screening or for diagnosis.

Specimen. Serum or EDTA or heparin plasma, 1 mL, no fasting. Stable for 24 hours at room temperature and 7 days at 2 to 8 °C. ST2 is measured on a high sensitivity ELISA or automated immunoassay. Galectin-3 on automated immunoassay platforms.

Reference values.

• Galectin-3: under 17.8 ng/mL (normal), 17.9 to 25.9 ng/mL (intermediate), over 25.9 ng/mL (high risk) by the commonly used cut offs.
• ST2: median 18 ng/mL in men and 14 ng/mL in women in healthy people. Prognostic cut off over 35 ng/mL for adverse events in both sexes. Levels of 20 to 35 ng/mL are intermediate.

Interpretation in heart failure.

• ST2 over 35 ng/mL: markedly higher risk of death, hospitalisation and transplant over 1 year (hazard ratio 2 to 3 compared with lower values). In acute heart failure, ST2 at discharge over 35 ng/mL predicts early readmission.
• Falling ST2 with treatment (a drop of 15% or more, or to under 35 ng/mL) indicates favourable remodelling and lower risk. Persisting high values suggest inadequate treatment, and dose optimisation of beta blockers, renin angiotensin system inhibitors and mineralocorticoid antagonists is reviewed.
• Galectin-3 over 25.9 ng/mL: higher risk of readmission and death. The test is more useful in heart failure with preserved ejection fraction and in ambulatory patients, but less independent of renal function.
• Combined use: raised natriuretic peptide with raised ST2 identifies the highest risk group, and both normal identifies low risk.

Other conditions.

• ST2 rises in acute myocardial infarction (peaks at 12 hours), pulmonary embolism, acute respiratory distress syndrome, sepsis, trauma and inflammatory diseases, so it is not cardiac specific.
• Galectin-3 rises in chronic kidney disease, hepatic and pulmonary fibrosis, rheumatoid arthritis, some cancers and diabetes.

Role in practice. Both are optional additions for prognosis in heart failure, and they do not replace natriuretic peptides for diagnosis or for directing therapy.

Critical values and findings needing immediate action.

• ST2 over 35 ng/mL at discharge after acute heart failure: close follow up within 7 to 14 days, treatment optimisation, and consideration of advanced heart failure therapy.
• Persistently very high ST2 (over 70 ng/mL) with symptoms: referral to a heart failure specialist, and assessment for devices, transplant or palliative care.
• Rising values on treatment: investigation for ischaemia, arrhythmia, adherence and precipitants.

Interferences and pitfalls.

• Neither marker diagnoses heart failure. NT-proBNP or BNP remains the first test for diagnosis.
• Galectin-3 is raised by renal impairment (eGFR under 60 mL/min/1.73 m²), age, obesity and fibrotic disease, so results in these settings overestimate risk.
• ST2 is raised in non-cardiac inflammatory and critical illness, so values are read with the clinical state.
• Values differ between assays, and published cut offs apply only to the assay used.
• Biological variation of galectin-3 is lower than for natriuretic peptides, but serial changes are small, and thresholds for a meaningful change are assay specific.
• Sacubitril-valsartan raises BNP but not NT-proBNP, galectin-3 or ST2, and the latter are better markers on this drug.
• Frozen storage is acceptable, but repeated freeze thaw cycles degrade ST2.
• Cost and limited availability restrict use in many centres.

Special groups.

• Older adults: galectin-3 rises with age, and the cut offs are not age adjusted.
• Renal disease: ST2 is less affected by renal function than galectin-3 or NT-proBNP, and is preferred.
• Obesity: natriuretic peptides are lower and ST2 is unaffected.
• Women: baseline ST2 is lower, though a single prognostic cut off is used.
• Regions: availability is limited, and clinical scoring with natriuretic peptides remains the main approach.

Follow up tests. NT-proBNP or BNP, high sensitivity troponin, echocardiography with ejection fraction, creatinine and eGFR, electrolytes, full blood count, ferritin and transferrin saturation, thyroid function, HbA1c and lipids, ECG and rhythm monitoring, cardiac MRI where fibrosis assessment is needed.