ST2 (for growth STimulation expressed gene 2) is a member of the interleukin-1 (IL1) receptor family of proteins, which play a central role in the regulation of immune and inflammatory response. Also referred to as cytokines, because of their cell-signaling capacity, the IL1 family was largely studied to elucidate the link between fever and infection or inflammation. Since initial elucidation, it’s diverse physiologic role now includes the stimulation and inhibition of cells in organs including the heart. In the heart, ST2 has a biological role in the innate immunological process and is also directly involved in a cardiac signaling pathway, which, under healthy conditions, serves to protect the heart during pressure overload or stretch.²

Soluble ST2 is an emerging biomarker that has been shown to predict adverse outcomes and death in individuals with established heart failure and is also a powerful prognostic marker for future cardiovascular disease in the general population. Higher levels of circulating ST2 (comparable to those found in hospitalized patients) can be detected in apparently healthy individuals and precede adverse outcomes.¹ Circulating ST2 is a sensitive marker of cardiac stress or ischemic injury, as suggested by experimental studies showing marked upregulation of ST2 gene expression in heart tissue induced by myocardial stretch or mechanical overload.²

The two key isoforms of ST2 are ST2L (a membrane-bound receptor) and sST2 (a soluble form found in the bloodstream). The response of healthy cardiac tissue to injury or mechanical stress involves the production and binding of interleukin-33 (IL-33) to ST2L, which stimulates a cardioprotective signaling cascade that defends against fibrosis, stiffening of the heart (cardiac remodeling), and heart failure (HF).³ Heart failure is a progressive disease which requires ongoing treatment. When sST2 levels are elevated, however, sST2 will bind to IL-33, thus reducing the beneficial effect of IL-33 through the ST2L receptor, so that cardiac fibrosis starts to develop (Fig.1). In this way sST2 is a biomarker for worse prognosis in patients with cardiovascular disease.

Fig. 1  Soluble ST2 blocks cardioprotective effect of IL-33

While all individuals have a normal level of ST2 in their circulation, an elevated concentration of ST2 is a powerful predictor of adverse outcomes, mortality or hospital-ization, not only in patients with heart failure as well as other forms of cardiac disease, but also in the general population. The median normal concentration for ST2 is 18 ng/ml, while concentrations greater than 35 ng/ml are strongly indicative of increased risk.^2,4

ST2 concentration elevation precedes an overt change in a patient’s symptoms, reflecting a worsening in the patient’s disease status. Plasma ST2 thus predicts which chronic HF patients are progressing towards worsening HF and cardiac remodeling, so that treatment can be implemented to improve the risk profile.

ST2 has prognostic value across a range of clinical settings:

1) Primary disease prevention in asymptomatic members of the general population

Recent findings indicate that asymptomatic patients with elevated ST2 levels are at increased risk for the development of hypertension, HF, and cardiovascular mortality, and thus become candidates for therapeutic intervention.^1,5 A recent analysis of the Framingham Heart Study Cohort found that ST2 is upregulated in up to 25% of asymptomatic individuals in the general population. After an average of 11.3 years, the highest quartile of ST2 levels alone were strongly associated with death (45% increased risk), HF (32% increased risk), and major CV events.¹ ST2 was shown to be a powerful ischemic marker, specifically predictive of the more hypertensive, cardiomyopathic, and heart failure-type etiologies. These emerging findings support the notion that CV dysfunction can exist for many years before the onset of clinical symptoms in ambulatory individuals. Importantly, proper risk classification of patients using ST2 may result in significantly improved outcomes for such individuals.¹

2) Patients with heart failure

The Penn Heart Failure Study (PHFS) illustrates the significance of a high ST2 value for predicting clinically relevant outcomes, death, heart transplant or hospitalization in patients with HF (Fig. 2). Patients with ST2 >35 ng/ml have a 2.8x higher risk of adverse outcomes within 30 days than patients with low ST2 concentrations. The relative risk of adverse events in patients with ST2 > 35ng/ml persists at a level of at least 1.8 for a follow up period of 4 years.^4,6

Fig. 2 Effect of high ST2 levels on clinical outcomes in the Penn Heart Failure Study (PHFS).

3) Secondary disease prevention after acute coronary syndromes

In addition to HF, circulating ST2 levels have clinical prognostic value in cases of acute coronary syndromes. Patients can show elevated ST2 levels, and increased risk of death, as early as 2-3 hours after an ischemic event or cardiac injury, with elevated risk persisting throughout the follow-up period. The initial ST2 level at presentation after a myocardial infarction (MI) has been independently linked to the incidence of 30-day mortality.^7,8

References

1. Wang TJ, Wollert KC, Larson MG, Coglianese E, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation 2012 Aug 20. [Epub ahead of print].
2. Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Disc 2008;7(10):827-840.
3. Ahmad, Fiuzat M, Felker GM, O’Connor C. Novel biomarkers in chronic heart failure. Nat Rev Cardiol 2012 Mar 27 [E-pub ahead of print].
4. Ky B, et al. High sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure. Circ Heart Fail 2011;4(2):180-7.
5. AbouEzzeddine OF, Kane GC, Rodeheffer RJ, Chen HH, et al. Plasma levels of ST2 in the community: association with cardiac remodeling, heart failure incidence and mortality (abstract to be presented at AHA meeting, Nov 2012).
6. Felker GM, et al. Soluble ST2 in ambulatory patients with heart failure: association with functional capacity and long term outcomes. (Manuscript submitted for publication, 2012).
7. Shrimpo M, et al. Serum levels of the interleukin-1 receptor family ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 2002;109:2961-2966.
8. Kohli P, Bonaca MP, Kakkar R, et al. Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 Trial. Clin Chem 2012;58(1):257-266.
9. Broch K, Ueland T, Nymo SH, et al. Soluble ST2 is associated with adverse outcomes in patients with heart failure of ischaemic aetiology. Eur J Heart Failure 2012;14:268-277.

ST2 (for growth STimulation expressed gene 2; also known as IL1RL1, or Interleukin 1 Receptor-Like 1) is a member of the interleukin 1 receptor family. Early studies suggested that expression of this receptor can be induced by various stimuli, and may also be involved in the function of helper T-cells.

The ST2 protein has two isoforms directly implicated in the progression of cardiac disease: a soluble form (referred to as soluble ST2 or sST2) and a membrane-bound receptor form (referred to as the ST2 receptor or ST2L). The ligand for ST2 is the cytokine Interleukin-33(IL-33). Binding of IL-33 to the ST2 receptor, in response to cardiac disease or injury, such as an ischemic event, elicits a cardioprotective effect resulting in preserved cardiac function.

This cardioprotective IL-33 signal is counter-balanced by the level of soluble ST2, which binds IL-33 and makes it unavailable to the ST2 receptor for cardioprotective signaling. As a result, the heart is subjected to greater stress in the presence of high levels of soluble ST2, leading to cellular death and tissue fibrosis, reduced cardiac function, and increasing the rate of disease progression.

The Presage® ST2 Assay quantitatively measures the concentration of soluble ST2, providing a physician with an accurate tool to assess prognosis in patients with cardiovascular disease.