Soluble ST2 and Prognosis in Chronic and Acute Heart Failure
Soon after its relation to the CV system was described, sST2 was suggested to be associated with prognosis in CHF; in 161 patients with severe CHF (New York Heart Association (NYHA) III-IV, LV ejection fraction [LVEF] <30 %) from the Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2) study, Weinberg et al. found sST2 changes from baseline to 2 weeks to be significantly associated with mortality or heart transplantation, independent of BNP or proANP;98 in this first study, however, baseline sST2 was not significantly associated with events, unlike BNP.98 Later studies with larger cohorts and longer follow-up, including analyses from the Penn HF Study, CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure) or Val-HeFT studies, among others, have supported higher baseline sST2 to be a predictor of adverse outcomes, such as all-cause, CV or HF death, sudden cardiac death or hospitalisation.46,47,99–102 In these prognostic studies, sST2 levels have been found to be higher in subjects with more advanced disease, such as increased NYHA class, higher NTproBNP or worse renal function;46,101 some studies also suggest its levels to be higher in males,46,99,101 though the effect of gender as well as other factors such as the ethnicity or HF aetiology are not well established. However, the prognostic value of sST2 in CHF seems not to be significantly influenced by renal function.103 The role of sST2 compared with NP remains more controversial. In many of the studies, sST2 was reported to be a significant predictor of adverse events in multivariable adjusted models including NP and it improved risk stratification;46,100–102,104 however, in the CORONA study this relationship was no longer significant after including NTproBNP (together with C-reactive protein) in the models (except for the secondary outcomes of HF death or CV or HF hospitalisation).47 In analyses from Val-HeFT, when NTproBNP was included in the models, sST2 did not add significant prognostic information.99 And in HF-ACTION, sST2 did not improve significantly reclassification of risk in models already containing NTproBNP.101 Most of the prognostic studies in CHF have been focused mainly in patients with systolic HF, with low LVEF (mean/median around 30 %), so its value in HF with preserved LVEF is uncertain; finally, many of them are post hoc analysis or sub-studies from previous larger trials not specifically designed to assess sST2.
Apart from CHF, sST2 has been reported to be consistently associated with prognosis in AHF as well as in patients attending the emergency department (ED) with dyspnoea. In a large cohort of over 1,000 subjects presenting with dyspnoea at ED, Socrates et al. found higher sST2 to be predictive of mortality at 1 year even when including NP in multivariable adjusted models (in both all participants with dyspnoea and in those with AHF as the cause for such symptoms).48 This association with mortality was consistently confirmed in other studies;49,105–107 also with in-hospital mortality;108 and in the PRIDE study the predictive value remained significant at a longer follow-up of 4 years.109 In these reports, the baseline levels of sST2 have been repeatedly found to be higher in those patients with AHF as the cause of dyspnoea and among decedents during the follow-up than in survivors.48,49,106,108 Likewise, results suggest that its levels are lower in HF with preserve LVEF compared with systolic HF,48,107 though it remained an independent predictor of mortality in both situations.107 Changes in the decompensated status of patients following management and therapy of AHF could have its reflection in the levels of biomarkers. In this respect, serial measurements of sST2 from presentation to a variable time (e.g. first 48 hours,108 admission to discharge110 or baseline to 2 weeks111) have been reported. In these studies, a failure of sST2 levels to decrease from baseline (a certain percentage reduction, again variable depending on the study) has been associated with subsequent mortality108,110 or cardiac events111 in the following months. These observed dynamic changes of sST2 according to the clinical status and response to HF management may suggest a potential role of this biomarker for monitoring the course of the disease and response to therapy,53,111 though this aspect needs to be specifically studied and confirmed.