ST2 is a member of the interleukin (IL)-1 receptor family biomarker, and circulating soluble ST2 concentrations are believed to reflect cardiovascular stress. Recent studies have demonstrated soluble ST2 to be a strong predictor of cardiovascular outcomes in community-based populations free of cardiovascular disease. This report reviews the role of soluble ST2 in relation to cardiovascular risk factors and clinical outcomes in the general population. Furthermore, the recommendations regarding the role of soluble ST2 in general population-based testing, as formulated by the International ST2 Consensus Panel, are presented. There may be a role for soluble ST2 in improving current risk-stratification strategies for the prediction of cardiovascular outcomes, potentially in combination with other biomarkers in a multimarker strategy. However, the role of soluble ST2 testing in the general population has not yet been conclusively established. Future studies investigating the clinical utility of soluble ST2 screening in the general population are warranted.
It has been more than 50 years since Dr. William Kannel first coined the term “factors of risk” contributing to the development of coronary heart disease in participants of the Framingham Heart Study. Since that time, the assessment of cardiovascular risk factors has become a routine clinical practice. More recently, the 2013 American College of Cardiology–American Heart Association cholesterol treatment guidelines have incorporated cardiovascular risk assessment on the basis of individual factors, with direct implications on medical management and primary prevention of cardiovascular disease. Although risk factors such as diabetes mellitus, hypertension, tobacco use, and hyperlipidemia predict outcomes on the population level, it is also known that cardiovascular disease can occur in subjects with few or no traditional risk factors. In 1 study, 18% of subjects with coronary heart disease had no traditional cardiovascular risk factors, and more than half had 1 or less risk factors. This discrepancy between prevalent risk factors and those that develop cardiovascular events is occasionally termed the “prevention paradox”.
It is within this context that the use of biomarkers to improve on risk stratification based on traditional factors has become of great interest. One such biomarker, soluble ST2, has recently emerged as a strong predictor of cardiovascular outcomes. Biologic actions of ST2 have been summarized in a separate report within this Consensus document. In brief, ST2 is a member of the interleukin (IL)-1 receptor family, and expression in cardiomyocytes is increased in response to stress.
In clinical studies, elevated soluble ST2 concentrations have been associated with a worse prognosis in patients with existing cardiovascular disease. These observations have recently been extended to population-based cohorts free of cardiovascular disease, and we will review the role of soluble ST2 in relation to cardiovascular risk factors and clinical outcomes in the general population in this report. Furthermore, the recommendations regarding the role of soluble ST2 in general population-based testing, as formulated by the International ST2 Consensus Panel, will be presented.
Soluble ST2 Concentrations and Cardiovascular Risk Factors
Few studies have examined the cross-sectional association of soluble ST2 concentrations with cardiovascular risk factors in the general population. This is related to the fact that soluble ST2 concentrations in patients unaffected by cardiovascular disease tend to be lower than in those with disease. Before the development of more highly sensitive methods for measurement of circulating ST2 concentrations, less-sensitive research-use-only assays were unable to detect analyte in a substantial percentage of normal subjects. With the development of a more highly sensitive method for determining concentrations of soluble ST2, it was possible to assess the biomarker even in those without obvious cardiovascular disease.
Soluble ST2 concentrations were measured in 3,450 participants of the Framingham Heart Study Offspring cohort. Age- and gender-specific reference limits were examined for healthy subjects without major medical co-morbidities. In the broader sample, soluble ST2 concentrations were positively associated with older age, female gender, hypertension, and the presence of diabetes mellitus ( Table 1 , adapted with permission from Coglianese et al ). Other studies also support an association of soluble ST2 with diabetes mellitus and risk factors of diabetes cross sectionally. Notably, although linked in studies to asthma, no link between soluble ST2 and either asthma or obstructive physiology on pulmonary function testing was found. Despite being correlated with multiple traditional cardiovascular risk factors, soluble ST2 concentrations were found to be highly heritable in the Framingham Heart Study population, in which clinical factors accounted for only 14% of the interindividual variation in soluble ST2 concentrations, and genetic factors accounted for up to 45% of the remaining variation. The fact that clinical factors do not correlate strongly with soluble ST2 suggests that soluble ST2 may carry “orthogonal” information beyond traditional cardiovascular risk factors and thus may be useful to investigate in relation to risk prediction.
| Regression coefficient (s.e.) ∗ | P-value | |
|---|---|---|
| Female sex | -0.206 (0.013) | <0.001 |
| Age, per 10 years | 0.027 (0.007) | <0.001 |
| Body-mass index, per 5.2 kg/m 2 | 0.011 (0.007) | 0.09 |
| Systolic blood pressure, per 19 mmHg | 0.019 (0.007) | 0.006 |
| Antihypertensive treatment | 0.032 (0.017) | 0.03 |
| Diabetes mellitus | 0.104 (0.020) | <0.001 |
∗ Covariates included in the model are age, sex, body-mass index, systolic blood pressure, antihypertensive treatment, smoking status, total and HDL cholesterol, left ventricular hypertrophy, diabetes mellitus, and atrial fibrillation.
The association of soluble ST2 concentrations and the development of cardiovascular risk factors longitudinally has been examined for hypertension but not diabetes. In 1,834 normotensive Framingham Heart Study Offspring participants, baseline soluble ST2 concentrations were associated with the development of incident hypertension over 3 years. Specifically, subjects with soluble ST2 concentrations in the upper quartile had a 1.8-fold increased odds of developing hypertension compared with those in the lowest quartile (multivariable-adjusted odds ratio 1.77, 95% confidence interval [CI] 1.14 to 2.76, p = 0.01). Interestingly, sST2 concentrations predicted progression in systolic blood pressure and pulse pressure but not diastolic blood pressure in this study. This is compelling, given the link between ST2 biology and vascular disease, and at least raises the possibility that the link to the development of systolic hypertension might reflect stiffening of the vasculature in the context of progressive atherosclerosis.
Soluble ST2 as a Predictor of Cardiovascular Outcomes in the Community
Soluble ST2 concentrations have been examined in relation to cardiovascular outcomes in 3 community-based cohorts of adults free of cardiovascular disease at baseline: the Framingham Heart Study, the Dallas Heart Study, and the Cardiovascular Health Study. In 3,428 Framingham Heart Study Offspring cohort participants (mean age 59 years, 53% women) followed for a mean of 11.3 years, soluble ST2 was associated with both incident heart failure (multivariable-adjusted hazard ratio 1.45 per standard deviation increase in log-ST2, 95% CI 1.23 to 1.70, p <0.001) and all-cause mortality (hazard ratio 1.32, 95% CI 1.20 to 146, p <0.001). Subjects in the highest quartile of soluble ST2 had a 2.5-fold increased risk of incident heart failure compared with those in the lowest quartile ( Figure 1 ). When combined with growth differentiation factor 15, high-sensitivity troponin I, B-type natriuretic peptide, and C-reactive protein in a multimarker approach, soluble ST2 remained an independent predictor of outcomes. Furthermore, a multimarker score that included soluble ST2 improved cardiovascular risk prediction when added to a model containing clinical risk factors.
Soluble ST2 was measured using a less sensitive research-use-only method in 3,294 participants of the Dallas Heart Study, who were followed for a median of 8.3 years. In this analysis, most subjects did not have measurable soluble ST2. In contrast to data from other cohorts, soluble ST2 concentrations were not associated with most traditional cardiovascular risk factors cross sectionally. Despite the crude nature of the assay used, baseline soluble ST2 concentrations predicted all-cause mortality (adjusted hazard ratio 2.1 comparing the highest soluble ST2 quartile with undetectable soluble ST2, 95% CI 1.4 to 3.2, p = 0.0009) but not nonfatal cardiovascular events. The assay used in the Dallas Heart Study differed from that used in Framingham which might explain some of the discrepancy in the findings.
Most recently, soluble ST2 concentrations were measured in 3,915 participants of the Cardiovascular Health Study free of heart failure. During a median follow-up of 13.6 years, soluble ST2 concentrations at baseline predicted incident cardiovascular events in multivariable-adjusted analyses. Specifically, participants in the upper quintile of soluble ST2 had a greater risk of heart failure (adjusted hazard ratio 1.34, 95% CI 1.10 to 1.63, P for trend <0.001) and cardiovascular death (hazard ratio 1.40, 95% CI 1.13 to 1.72, P for trend <0.001) compared with participants in the lowest quintile ( Figure 2 ).
