Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction

Omar F AbouEzzeddine, Paul M McKie, Shannon M Dunlay, Susanna R Stevens, G Michael Felker, Barry A Borlaug, Horng H Chen, Russell P Tracy, Eugene Braunwald, Margaret M Redfield, Omar F AbouEzzeddine, Paul M McKie, Shannon M Dunlay, Susanna R Stevens, G Michael Felker, Barry A Borlaug, Horng H Chen, Russell P Tracy, Eugene Braunwald, Margaret M Redfield

Abstract

Background: Soluble suppression of tumorigenicity 2 (sST2) receptor is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity-driven microvascular inflammation is postulated to play a key role in heart failure with preserved ejection fraction (HFpEF) pathophysiology, but data on how sST2 relates to clinical characteristics or inflammatory conditions or biomarkers in HFpEF are limited. We sought to determine circulating levels and clinical correlates of sST2 in HFpEF.

Methods and results: At enrollment, patients (n=174) from the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial of sildenafil in HFpEF had sST2 levels measured. Clinical characteristics; cardiac structure and function; exercise performance; and biomarkers of neurohumoral activation, systemic inflammation and fibrosis, and myocardial necrosis were assessed in relation to sST2 levels. Median sST2 levels in male and female HFpEF patients were 36.7 ng/mL (range 30.9-49.2 ng/mL; reference range 4-31 ng/mL) and 30.8 ng/mL (range 25.3-39.3 ng/mL; reference range 2-21 ng/mL), respectively. Among HFpEF patients, higher sST2 levels were associated with the presence of diabetes mellitus; atrial fibrillation; renal dysfunction; right ventricular pressure overload and dysfunction; systemic congestion; exercise intolerance; and biomarkers of systemic inflammation and fibrosis, neurohumoral activation, and myocardial necrosis (P<0.05 for all). sST2 was not associated with left ventricular structure or left ventricular systolic or diastolic function.

Conclusions: In HFpEF, sST2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function. These data suggest that ST2 may be a marker of systemic inflammation in HFpEF and potentially of extracardiac origin.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.

Keywords: biomarker; diastolic heart failure.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Frequency distribution of suppression of tumorigenicity 2 (ST2) levels in heart failure with preserved ejection fraction overall and by sex (insert). The distribution of baseline ST2 levels in the RELAX trial cohort (n=174). Overall, median ST2 levels were 34.3 ng/mL (25th–75th percentiles 26.9–46.6 ng/mL) and were higher in male participants (36.7 ng/mL [25th–75th percentiles 30.9–49.2 ng/mL]) than in female participants (30.8 ng/mL [25th–75th percentiles 25.3–39.3 ng/mL]).
Figure 2
Figure 2
The relationship between suppression of tumorigenicity 2 (ST2) and biomarkers in heart failure with preserved ejection fraction. ST2 was associated with endothelin 1, high‐sensitivity C‐reactive protein (CRP), C‐telopeptide for type I collagen (CITP), and troponin I but not aldosterone or pro–collagen III N‐terminal peptide (PIIINP) levels. *Adjusted for sex. Ln indicates log transformed.

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