Soluble ST2 (sST2) is a novel biomarker implicated in myocardial remodeling and fibrosis. Recent studies in normal subjects have suggested that the biologic variability (BV) of sST2 is significantly lower than that of the B-type natriuretic peptides and N-terminal pro B-type natriuretic peptide (NTproBNP). It may, consequently, be a better biomarker for monitoring patients with chronic heart failure (CHF). To date, no published studies have examined the BV of sST2 in a heart failure population. Blood samples from 50 outpatients with pharmacologically optimized stable CHF and persistent left ventricular dysfunction (ejection fraction <40%) were collected at baseline, 1 hour, 1 month, 3 months, and 6 months. Using log-transformed data, mean intra-individual coefficients of variation (CV I ) and subsequent reference change values were calculated for both NTproBNP and sST2. Results demonstrate significantly lower CV I and reference change values for sST2 compared with NTproBNP at 1 month (12.02 [36%] vs 36.75 [103%]), p <0.001, 3 months (12.23 [36%] vs 40.98 [114%]), p <0.001, and 6 months (16.41 [47%] vs 46.02 [128%]), p <0.001. In conclusion, the BV of sST2 is significantly lower than that of NTproBNP in patients with CHF. These results support previous indications that sST2 may be a better biomarker for monitoring such patients.
Soluble ST2 (sST2) is a member of the interleukin 1 receptor family that has recently been identified as a novel biomarker for cardiac remodeling and fibrosis. Raised concentrations are known to be predictive of mortality in patients with acutely decompensated heart failure (ADHF). Moreover, several studies have provided evidence for the prognostic role of serial measures of sST2 in patients with ADHF. The role of sST2 in chronic heart failure (CHF) is, however, less well defined. Recently, Wu et al have demonstrated that the reference change values (RCV) of sST2 in healthy volunteers to be much lower than that of B-type natriuretic peptide (BNP) or N-terminal pro B-type natriuretic peptide (NTproBNP), indicating that it may be a better marker for serial monitoring. Despite such promising results, it is likely that variation among patients with disease will be greater than that in healthy subjects. To date, no studies analyzing the biologic variability (BV) or RCV of sST2 in CHF have been reported.
Methods
Fifty patients with CHF, New York Heart Association class I to III, and left ventricular ejection fraction ≤40% were recruited from the heart failure clinics at Kings College Hospital, London. A subset of this cohort has been previously described. All were on optimum tolerated heart failure medications. Target dose levels were defined according to current guidelines. Main exclusion criteria were an acute cardiovascular admission or change in prognostically indicated medication within 4 weeks of recruitment, a planned cardiovascular admission, significant renal impairment (estimated glomerular filtration rate <20), or the inability or unwillingness to consent.
Clinical review and blood sampling took place at 5 time points—baseline, 1 hour, 1 month, 3 months, and 6 months. Reviews took place at the same time of day for each visit. Vital signs and New York Heart Association class were recorded together with medications and details of any hospital admissions.
Blood samples were obtained by venepuncture after 30 minutes of semi-recumbent rest. Serum samples for creatinine were analyzed immediately. After centrifugation at 3,000 rpm, 2-ml aliquots of plasma were stored at −30°C until analyzed.
sST2 was measured by enzyme-linked immunosorbent assay (R&D Systems Europe, Ltd, Abingdon, United Kingdom). The sST2 assay contains NS0-expressed recombinant human sST2 and has been shown to accurately quantitate the recombinant factor. The intra-assay precision was 5.6%, 4.4%, and 4.5% and the inter-assay precision was 7.1%, 5.4%, and 6.3% at 5.4, 12.6, and 20.6 μg/L, respectively. The limit of detection was 0.005 μg/L. Reference range is 6.74 to 20.4 μg/L.
NTproBNP was measured by 2-site chemiluminescence immunoassay (Immulite 2000; Siemens Healthcare Diagnostics Ltd, Camberley, Surrey, United Kingdom). The intra-assay precision was 5.4%, 3.0%, and 4.1% and the inter-assay precision was 6.4%, 4.0%, and 4.7% at 35.6, 1,430 and 29,725 ng/L, respectively. The limit of detection was 10 ng/L. Reference range is 125 and 450 ng/L at age <75 and >75 years, respectively.
The total coefficient of variation (CV T ) is composed of both analytic and biologic variation. Each patient’s 1 hour, 1 month, 3 months, and 6 months CV T s for both NTproBNP and sST2 were calculated from the standard deviation of the respective values at baseline and 1 hour, baseline and 1 month, baseline and 3 months, and baseline and 6 months. As concentrations of all biomarkers were not normally distributed, data were log transformed before analysis.
Analytical coefficient of variation (CV A ) describes the reproducibility of the measurement of an analyte. Where possible, samples were analyzed in a single series to minimize the contribution of inter-assay analytical variation.
CV I is the random variation that occurs around a homeostatic setting point in a subject. CV I was calculated according to the formula:
RCVs at a 95% confidence level were calculated from median CV I values according to the formula:
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