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Increased Plasma Concentrations of Soluble ST2 Independently Predict Mortality but not Cardiovascular Events in Stable Coronary Heart Disease Patients: 13-Year Follow-up of the KAROLA Study

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Abstract

Purpose

sST2 (soluble suppression of tumorigenicity 2), a member of the interleukin-1 family, has been suggested to play a role in cardiac remodeling and inflammatory signaling. We assessed the association between sST2 in patients with stable coronary heart disease (CHD) with multiple cardiovascular outcomes and total mortality, simultaneously controlling for a large number of potential confounders.

Methods

Plasma concentrations of sST2 (ELISA, Critical Diagnostics) were measured at baseline in a cohort of 1081 patients. The Cox-proportional hazards model was used to determine the prognostic value of sST2 on a combined cardiovascular disease (CVD) endpoint, on cardiovascular death, and on total mortality after adjustment for covariates.

Results

The median sST2 level was 28.9 ng/mL (IQR 23.8, 35.1) (mean age at baseline 58.9 years, 84.6% male). sST2 concentration was positively correlated with inflammatory markers and emerging risk factors, e.g., cystatin C, N-terminal probrainnatriuretic peptide (NT-proBNP), high-sensitivity (hs)-Troponin T and I, mid-regional pro-atrial natriuretic peptide (MR-proANP), and growth differentiation factor 15 (GDF-15). Results after short- and long-term (4.5 and 12.3 years, respectively) follow-up (FU) displayed no statistically significant association with the combined endpoint of non-fatal and fatal CVD events when the top quartile (Q4) of sST2 concentration was compared to the bottom quartile (Q1). A relationship during long-term FU was seen with CVD mortality even after multivariable adjustments including clinical risk variables (HR 1.65; 95% CI 1.02–2.86), but not in a fully adjusted model whereas, in contrast, it was still highly significant after short-term FU (HR (5.97 (95%CI 1.32–27.06)). In addition, the sST2 concentration was still strongly associated with total mortality in the fully adjusted model including clinical variables and cystatin C based estimated glomerular filtration rate, NT-proBNP, hsCRP and hs-TnI comparing Q4 vs Q1 during long-term FU (HR of 1.48 (95% CI 1.03–2.13)) and short-term FU (HR 3.06 (95% CI 1.29–7.24)).

Conclusions

Elevated levels of sST2 concentration in stable CHD patients may independently predict short- and long-term risk for fatal CVD events and total mortality but not non-fatal CVD events.

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Acknowledgements

Funding from the KAROLA study was received from the German Federal Ministry of Education and Research (01GD9820/0 and 01ER0814), the Willy Robert Pitzer Foundation, Bad Nauheim, Germany, and by the Waldburg-Zeil Clinics Isny, Germany. Reagents for high-sensitivity troponin I was generously provided for free by Abbott, Wiesbaden, Germany. The funders played no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

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    Authors and Affiliations

    1. Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany

      Vanessa Pfetsch, Veronika Sanin & Wolfgang Koenig

    2. Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany

      Andrea Jaensch & Dietrich Rothenbacher

    3. AGAPLESION Bethesda Clinic, Geriatric Center Ulm/Alb-Donau, Research Unit on Aging, Ulm University, Ulm, Germany

      Dhayana Dallmeier

    4. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany

      Ute Mons, Hermann Brenner & Dietrich Rothenbacher

    5. Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm, Germany

      Wolfgang Koenig

    6. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

      Wolfgang Koenig

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    1. Vanessa Pfetsch
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    2. Veronika Sanin
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    Correspondence to Wolfgang Koenig.

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    Conflict of Interest

    The authors declare that they have no conflict of interest.

    Informed Consent

    Informed consent was obtained from all individual participants included in the study (see also page 3).

    Funding

    This study was funded by the German Federal Ministry of Education and Research (01GD9820/0 and 01ER0814) the Willy Robert Pitzer Foundation, Bad Nauheim, Germany, and by the Pitzer Foundation, Bad Nauheim, Germany. Reagents for hs-TnI were provided for free by Abbott, Wiesbaden, Germany.

    Ethical Approval

    All procedures performed in this study, which involves human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments of comparable ethical standards (see also page 3).

    Additional information

    Wolfgang Koenig and Dietrich Rothenbacher contributed equally to this work.

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    Pfetsch, V., Sanin, V., Jaensch, A. et al. Increased Plasma Concentrations of Soluble ST2 Independently Predict Mortality but not Cardiovascular Events in Stable Coronary Heart Disease Patients: 13-Year Follow-up of the KAROLA Study. Cardiovasc Drugs Ther 31, 167–177 (2017). https://doi.org/10.1007/s10557-017-6718-1

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