Aiding in prognosis for patients diagnosed with chronic heart failure
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Heart failure is a chronic, progressive, complex cardiovascular disorder with a variety of etiologies and heterogeneity with respect to the clinical presentation of the patient. Heart failure is significantly increasing in prevalence with an aging population and is associated with high short- and long-term mortality rate. Over 80% of patients diagnosed and treated for acute heart failure syndromes in the emergency department are readmitted within the forthcoming year, incurring costly treatments and therapies.(1)
The development and progression of heart failure is a clinically silent process until manifestation of the disorder, which typically occurs late and irreversibly into its progression. Mechanistically heart failure, whether due to systolic or diastolic dysfunction, is thought to progress primarily through adverse cardiac remodeling and fibrosis in response to cardiac injury or stress.(2) Soluble ST2 is a biomarker that appears to be actively involved with IL-33 in modulating cardiac remodeling and ventricular function via effects in the inflammatory and apoptosis pathways.(3)
ST2 is a member of the interleukin-1 receptor family and has 2 isoforms that are directly implicated in progression of cardiac disease: soluble ST2 (sST2) and a transmembrane-bound form, ST2 ligand (ST2L). IL-33 is the hormone that interacts with ST2L, protecting against left ventricular hypertrophy and myocardial fibrosis to effectively preserve cardiac function. Therefore, when sST2 concentrations are high, IL-33 is unavailable for cardioprotective signaling, leaving the heart vulnerable to the effects of sST2. High concentrations of sST2 result in cellular death, tissue fibrosis, reduced cardiac function, and an increase in the rate of disease progression.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
<18 years: not established
> or =18 years: < or =52.0 ng/mL
<18 years: not established
> or =18 years: < or =38.7 ng/mL
Clinically, ST2 concentrations in the HF-ACTION heart failure study were a significant predictor of mortality, all-cause hospitalization, mortality due to cardiovascular disease, and hospitalization due to cardiovascular disease using a cutpoint of 35 ng/mL. In addition, mortality risk was significantly higher in patients with ST2 >35 ng/mL.(4) The risk appears early and persists throughout the follow-up period.
Clinical risk categories are substantiated by results from several large chronic heart failure studies:
-Low risk: < or =35.0 ng/mL
-High risk: >35.0 ng/mL (high risk)
Results should be interpreted in the context of the individual patient presentation. Elevated ST2 results indicate an increased risk for adverse outcomes and signal the adverse remodeling and progression of disease.
The reference interval was derived from normal donors without a history of cardiovascular disease, stroke, diabetes, renal disease, liver disease, or autoimmune diseases. The reference range is gender dependent; however, it is the clinical cutpoint that is recognized as providing the most utility.
Knowledge of ST2 results in a heart failure patient may assist in cardiovascular risk stratification and lead to more aggressive management. There are no specific ST2 inhibitors available at this time and heart failure patients with elevated ST2 concentrations should be treated and monitored according to established guidelines. Angiotensin receptor blockers (ARBs) and aldosterone antagonists are thought to be particularly effective.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
ST2 has not been shown to be useful in the acute diagnosis of heart failure; natriuretic peptides (BNP or NT-proBNP) should be utilized for this purpose in the context of appropriate clinical suspicion of acute heart failure. ST2 and natriuretic peptides are measures of separate and distinct biological processes, providing independent and complimentary prognostic information.
There are no significant analytical interferences reported for ST2 from bilirubin, hemoglobin, triglycerides, cholesterol, or total protein. Forty-nine therapeutic substances were tested for analytical interference and none had significant interference with the ST2 assay.(5)
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Weintraub NL, Collins SP, Pang PS, et al: Acute heart failure syndromes: emergency department presentation, treatment, and disposition: Current approaches and future aims: a scientific statement from the American Heart Association. Circulation 2010;122:1975-1996
2. Kakkar R, Lee R: The IL-33/ST2 Pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov 2008;7:827-8403
3. Seki K, Sanada S, Kudinova AY, et al: Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circ Heart Fail 2009;2(6):684-691
4. Whellan DJ, O’Connor CM, Lee, KL, et al: HF-ACTION Trial Investigators. Heart failure and a controlled trial investigating outcomes of exercise training (HF-ACTION): design and rationale. Am Heart J 2007;153(2):201-221
5. Dieplinger B, Januzzi J, Steinmair M, et al: Analytical and clinical evaluation of a novel high-sensitivity assay for measurement of soluble ST2 in human plasma - The Presage ST2 Assay. Clin Chim Acta 2009;409:33-40