Elsevier

American Heart Journal

Volume 161, Issue 6, June 2011, Pages 1163-1170
American Heart Journal

Clinical Investigation
Acute Ischemic Heart Disease
Interleukin 33 and ST2 in non–ST-elevation myocardial infarction: Comparison with Global Registry of Acute Coronary Events Risk Scoring and NT-proBNP

https://doi.org/10.1016/j.ahj.2011.03.025Get rights and content

Background

Soluble ST2 is a marker of biomechanical strain for which the natural ligand is interleukin 33 (IL-33). They have not been studied together in non–ST-elevation myocardial infarction (NSTEMI). We investigated their relationship with death, heart failure (HF) readmission, and reinfarction combined (termed major adverse cardiac events [MACE]) and, separately, in unselected patients using Global Registry of Acute Coronary Events Risk Scoring (GRACE-RS) and n terminal pro B type natriuretic peptide (NT-proBNP) as benchmark comparators.

Methods

ST2 and IL-33 were measured in 577 patients 3 to 5 days after admission. Mean follow-up was 532 (150-1059) days, during which 156 patients (27%) reached the primary end point.

Results

ST2 was higher in those who experienced MACE when compared with event-free survivors (median 782 pg/mL vs 596, P < .001), but there was no difference in IL-33 levels across any end point. Multivariate Cox regression analysis reveals that elevated ST2 is independently associated with increased risk of MACE during the long term (hazard ratio [HR] 2.01, P = .005). This relationship continues on further adjustment for either GRACE risk score or NT-proBNP individually but not on adjustment for both. ST2 also independently predicts reinfarction (HR 2.48, P = .03) and 30-day mortality (HR 4.43, P = .02, c-statistic 0.73, P < .001). Adding ST2 to GRACE or to NT-proBNP did not lead to significant improvements in the c-statistic for MACE for long-term follow-up (P = .27 and P = .57, respectively) or the net reclassification index. Neither IL-33 nor its ratio with ST2 was associated with study end points.

Conclusions

Elevated ST2 predicts adverse outcome in non–ST-elevation myocardial infarction but does not significantly improve risk stratification for established markers. Interleukin 33 was not related to adverse events.

Section snippets

Study Population

We studied 577 consecutive patients with NSTEMI admitted to University Hospitals of Leicester National Health Service Trust between February 1, 2005, and May 1, 2007. The study complied with the Declaration of Helsinki and was approved by the local ethics committee; written informed consent was obtained from all patients. Non–ST-elevation myocardial infarction was diagnosed according to the established criteria9 when cardiac troponin I (Advia Centaur Troponin-I assay; Siemens, Deerfield, IL)

Patient characteristics

We recruited 577 patients whose characteristics are recorded in Table I. Mean follow-up was 532 days (range 150-1059 days) during which 156 patients (27%) reached the primary end point (MACE) of which 75 (13%) died, 52 (9%) were readmitted with HF, and 62 (11%) had a reinfarction. No patient was lost to follow-up.

ST2 levels and clinical variables

Median ST2 in the whole cohort was 638 pg/mL (range 82-18875). ST2 was elevated in patients who experienced the primary end point (median 782 pg/mL, P < .001) (Figure 1) and the

Discussion

In 2005, IL-33 was found to be the natural ligand for membrane-bound ST2L2; and this is the first study assessing the relationship between both IL-33 and soluble ST2 levels and adverse events in real-world patients with NSTEMI. The findings of this study are 4-fold. Firstly, we have demonstrated that elevated ST2 is associated with a poor prognosis during the longer term in NSTEMI. Secondly, on evaluating the end points separately, we showed that the relationship with adverse outcome is

Limitations

Our findings were based on a single-center population with 2 admitting hospitals. Plasma samples were obtained at a single time 3 to 5 days postevent by which point 304 patients (52.7%) had IL-33 levels below the lower detection limit of the assay (5.40 pg/mL), affecting the ratio of IL-33 to ST2 and any calculations using that variable. More sensitive IL-33 assays or earlier sampling may have yielded different results. We have shown that measuring ST2 3 to 5 days postevent continues to offer

Conclusion

In consecutive patients with NSTEMI, ST2 is predictive of death and reinfarction but does not yield sufficient incremental benefit for GRACE scoring or NT-proBNP to warrant clinical use for risk stratification. We have evaluated IL-33, for the first time, and report that a significant proportion of patients with NSTEMI mount a low IL-33 response and neither IL-33 nor its ratio with ST2 was related to adverse outcome.

Acknowledgements

Prof Ng, Prof Squire, and Dr. J. Davies are supported by the Leicester National Institute for Health Research Cardiovascular Biomedical Research Unit, UK.

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Dr Dhillon was supported by a British Heart Foundation Junior Research Fellowship (grant no. FS/03/028/15486).

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