Complementary roles for biomarkers of biomechanical strain ST2 and N-terminal prohormone B-type natriuretic peptide in patients with ST-elevation myocardial infarction

Abstract

Background: ST2 is a member of the interleukin-1 receptor family with a soluble form that is markedly upregulated on application of biomechanical strain to cardiac myocytes. Circulating ST2 levels are elevated in the setting of acute myocardial infarction, but the predictive value of ST2 independent of traditional clinical factors and of an established biomarker of biomechanical strain, N-terminal prohormone B-type natriuretic peptide (NT-proBNP), has not been established.

Methods and results: We measured ST2 at baseline in 1239 patients with ST-elevation myocardial infarction from the CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial. Per trial protocol, patients were to undergo coronary angiography after 2 to 8 days and were followed up for 30 days for clinical events. In contrast to NT-proBNP, ST2 levels were independent of clinical factors potentially related to chronic increased left ventricular wall stress, including age, hypertension, prior myocardial infarction, and prior heart failure; levels also were only modestly correlated with NT-proBNP (r=0.14). After adjustment for baseline characteristics and NT-proBNP levels, an ST2 level above the median was associated with a significantly greater risk of cardiovascular death or heart failure (third quartile: adjusted odds ratio, 1.42; 95% confidence interval, 0.68 to 3.57; fourth quartile: adjusted odds ratio, 3.57; 95% confidence interval, 1.87 to 6.81; P<0.0001 for trend). When both ST2 and NT-proBNP were added to a model containing traditional clinical predictors, the c statistic significantly improved from 0.82 (95% confidence interval, 0.77 to 0.87) to 0.86 (95% confidence interval, 0.81 to 0.90) (P=0.017).

Conclusions: In ST-elevation myocardial infarction, high baseline ST2 levels are a significant predictor of cardiovascular death and heart failure independently of baseline characteristics and NT-proBNP, and the combination of ST2 and NT-proBNP significantly improves risk stratification. These data highlight the prognostic value of multiple, complementary biomarkers of biomechanical strain in ST-elevation myocardial infarction.

Figure 1

Baseline and angiography levels of ST2 and NT-proBNP. Analyses were restricted to patients in whom measurements were available at both time points. NT-proBNP levels are plotted on a logarithmic scale. The median difference (Δ) and IQR for levels of each biomarker between the 2 time points are shown above the boxes. The bottom and top whiskers indicate the 5th and 95th percentile levels; the lower and upper boundaries of the boxes, the 25th and 75th percentile levels; and the horizontal line within the box, the median level.

Figure 2

A, Association between baseline ST2 levels and cardiovascular (CV) death (CVD) and heart failure. P values are for trends across ST2 quartiles. B, Association between baseline NT-proBNP levels and cardiovascular (CV) death (CVD) and heart failure. P values are for trends across NT-proBNP quartiles.

Figure 3

Association between serial biomarker levels and cardiovascular death (CVD) and heart failure. Patients in whom measurements were available at both time points were categorized into 4 groups on the basis of their biomarker levels (left, ST2; right, NT-proBNP) at baseline and at angiography (Angio). Solid bars indicate baseline values below the median; striped bars, baseline values above the median. White background indicates angiography values below the median; gray background, angiography values above the median. The number of patients in each group is as follows (from left to right and from back to front): 235, 207, 209, and 228 for ST2 and 276, 155, 138, and 266 for NT-proBNP. P values are for global χ² tests.

Figure 4

Multivariable-adjusted multimarker analysis of the association between baseline biomarker levels and cardiovascular (CV) death and heart failure. Adjusted ORs for cardiovascular death or heart failure through 30 days are depicted with red squares for ST2 quartiles and blue circles for NT-proBNP quartiles; vertical bars denote 95% CIs. The regression model included both biomarkers and age, sex, hypertension, diabetes mellitus, prior MI, prior CHF, creatinine clearance, infarct location, Killip class, time from symptom onset to lytic, type of lytic, and peak CK.

Figure 5

Combined risk stratification with the TIMI Risk Score for STEMI and NT-proBNP and ST2. Rate of cardiovascular death or heart failure in patients was categorized into 9 groups on the basis of the TIMI Risk Score for STEMI and biomarker status; the latter was categorized as neither ST2 and NT-proBNP above the median, 1 of the 2 above the median, or both above the median. The number of patients with events/ patients in each group is as follows (from left to right and from back to front): 36/141, 10/121, 5/59, 16/125, 9/226, 3/181, 4/38, 3/109, and 1/167.