High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Ky, Bonnie; French, Benjamin; McCloskey, Kristin; Rame, J. Eduardo; McIntosh, Erin; Shahi, Puja; Dries, Daniel L.; Tang, W.H. Wilson; Wu, Alan H.B.; Fang, James C.; Boxer, Rebecca S.; Sweitzer, Nancy K.; Levy, Wayne C.; Goldberg, Lee R.; Jessup, Mariell; Cappola, Thomas P.

doi:10.1161/circheartfailure.110.958223

Cited by 337 publications

(288 citation statements)

References 30 publications

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“…The circulating biomarker, soluble ST2 (sST2) has been shown to be a powerful independent prognosticator for patients with acute myocardial infarction (AMI)1, 2 as well as acute decompensated3, 4 and chronic5, 6, 7, 8, 9 HF. sST2, a member of the interleukin (IL)‐1 receptor‐like family of proteins, is released in response to myocyte stretch, and functions as a decoy receptor, neutralizing its ligand, IL‐33.…”

Section: Introductionmentioning

confidence: 99%

Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community‐Dwelling Population

Parikh

Seliger

Christenson

et al. 2016

JAHA

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BackgroundSoluble ST2 (sST2), a marker of myocyte stretch and fibrosis, has prognostic value in many cardiovascular diseases. We hypothesized that sST2 levels are associated with incident heart failure (HF), including subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fraction, and cardiovascular death.Methods and ResultsBaseline serum sST2 was measured in 3915 older, community‐dwelling subjects from the Cardiovascular Health Study without prevalent HF. sST2 levels were associated with older age, male sex, black race, traditional cardiovascular risk factors, other biomarkers of inflammation, cardiac stretch, myocardial injury, and fibrosis, and abnormal echocardiographic parameters. In longitudinal analysis, greater sST2 was associated with a higher risk of incident HF and cardiovascular death; however, in multivariate models adjusting for other cardiac risk factors and the cardiac‐specific biomarker, N‐terminal pro–type B natriuretic peptide, these associations were attenuated. In these models, an sST2 level above the US Food and Drug Administration–approved cut‐off value (>35 ng/mL) was significantly associated with incident HF (hazard ratio [HR], 1.20; 95% CI, 1.02–1.43) and cardiovascular death (HR, 1.21; 95% CI, 1.02–1.44), and greater sST2 was continuously associated with cardiovascular death (per 1‐ln increment: HR, 1.24; 95% CI, 1.02–1.50). sST2 was not associated with the HF subtypes of HFpEF and HFrEF in adjusted analysis. Addition of sST2 to existing risk models of HF and cardiovascular death modestly improved discrimination and reclassification into a higher risk.ConclusionsThe predictive value of sST2 for HF of all subtypes and cardiovascular death is modest in an elderly population despite strong cross‐sectional associations with risk factors and underlying cardiac pathology.

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Section: Introductionmentioning

confidence: 99%

Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community‐Dwelling Population

Parikh

Seliger

Christenson

et al. 2016

JAHA

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“…The soluble receptor ST2 is a prognostic biomarker in patients with cardiovascular disease (4,5), and serum ST2 levels also predict changes in blood pressure in the community (6). ST2, also known as IL1RL1 (IL-1 receptor like 1), is a member of the IL-1 receptor family, which plays a major role in immune and inflammatory responses (7).…”

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confidence: 99%

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

Chen

Hong

Gannon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

132

125

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Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart's response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.H ypertension is the most common cardiovascular risk factor and contributes to widespread morbidity and mortality worldwide (1), but the pathological and molecular mechanisms by which elevated blood pressure promotes vascular disease remain uncertain. Inflammation has been hypothesized to play a role in hypertension as well as the progression of vascular disease (2, 3). Although the association between hypertension and inflammation has now been clearly demonstrated, molecular mechanisms that link hypertension to systemic inflammation are unclear.The soluble receptor ST2 is a prognostic biomarker in patients with cardiovascular disease (4, 5), and serum ST2 levels also predict changes in blood pressure in the community (6). ST2, also known as IL1RL1 (IL-1 receptor like 1), is a member of the IL-1 receptor family, which plays a major role in immune and inflammatory responses (7). At least two forms of ST2 are known, including the transmembrane receptor (ST2L) and the soluble form (sST2) that circulates in blood (8). Membrane-bound ST2L interacts with IL-33, an IL-1 family ligand (9), and IL-33 can have antihypertrophic and antifibrotic effects in the myocardium (10). In contrast, sST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits (10-12). IL-33 is also expressed in endothelial cells (ECs) (13-16), in which it induces angiogenesis (17), expression of adhesion molecules, and inflammatory activation (18). Here we report the surprising finding that endothelial IL-33 from pressure overload induces a selective systemic response, potentially linking hypertension with circulating factors that can affect the vasculature and other organs. Results ST2 Deficiency Exacerbates Pressure Overload-Induced CardiacHypertrophy. Communication between cardiomyocytes, fibroblasts, and ECs is important for normal cardiac function as well as pathophysiology (19,20). We explored intercellular communication in...

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“…Given NT‐proBNP's strong associations with heart failure, mortality attributable to cardiovascular events, and mortality after cardiac surgery, its inclusion in a prediction model of in‐hospital mortality may serve to improve the model's predictive ability 13, 14, 15, 16. Galectin‐3, a member of the lectin family of proteins, and ST2, a biomarker for cardiac stress, have also been found to be strongly associated with heart failure 17, 18, 19, 20, 21, 22. Additionally, Galectin‐3 has been found to be associated with increased risk for all‐cause mortality in the Framingham Offspring Cohort 23.…”

Section: Introductionmentioning

confidence: 99%

Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin‐3, and NT‐ProBNP Before Cardiac Surgery

Polineni

Parker

Alam

et al. 2018

JAHA

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BackgroundCurrent preoperative models use clinical risk factors alone in estimating risk of in‐hospital mortality following cardiac surgery. However, novel biomarkers now exist to potentially improve preoperative prediction models. An assessment of Galectin‐3, N‐terminal pro b‐type natriuretic peptide (NT‐ProBNP), and soluble ST2 to improve the predictive ability of an existing prediction model of in‐hospital mortality may improve our capacity to risk‐stratify patients before surgery.Methods and ResultsWe measured preoperative biomarkers in the NNECDSG (Northern New England Cardiovascular Disease Study Group), a prospective cohort of 1554 patients undergoing coronary artery bypass graft surgery. Exposures of interest were preoperative levels of galectin‐3, NT‐ProBNP, and ST2. In‐hospital mortality and adverse events occurring after coronary artery bypass graft were the outcomes. After adjustment, NT‐ProBNP and ST2 showed a statistically significant association with both their median and third tercile categories with NT‐ProBNP odds ratios of 2.89 (95% confidence interval [CI]: 1.04–8.05) and 5.43 (95% CI: 1.21–24.44) and ST2 odds ratios of 3.96 (95% CI: 1.60–9.82) and 3.21 (95% CI: 1.17–8.80), respectively. The model receiver operating characteristic score of the base prediction model (0.80 [95% CI: 0.72–0.89]) varied significantly from the new multi‐marker model (0.85 [95% CI: 0.79–0.91]). Compared with the Northern New England (NNE) model alone, the full prediction model with biomarkers NT‐proBNP and ST2 shows significant improvement in model classification of in‐hospital mortality.ConclusionsThis study demonstrates a significant improvement of preoperative prediction of in‐hospital mortality in patients undergoing coronary artery bypass graft and suggests that biomarkers can be used to identify patients at higher risk.

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High-Sensitivity ST2 for Prediction of Adverse Outcomes in Chronic Heart Failure

Cited by 337 publications

References 30 publications

Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community‐Dwelling Population

Soluble ST2 for Prediction of Heart Failure and Cardiovascular Death in an Elderly, Community‐Dwelling Population

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin‐3, and NT‐ProBNP Before Cardiac Surgery

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