Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD. STUDY DESIGN: Observational, case-cohort study design. SETTING & PARTICIPANTS: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study. EXPOSURES: Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile. OUTCOMES: The primary outcomes were incident HF and AF. ANALYTICAL APPROACH: Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker. RESULTS: The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF. LIMITATIONS: Observational study. CONCLUSIONS: In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.

The utility of growth differentiation factor-15, galectin-3, and sST2 as biomarkers for the diagnosis of heart failure with preserved ejection fraction and compared to heart failure with reduced ejection fraction: a systematic review.

The objective was to evaluate the diagnosis of heart failure with preserved ejection fraction (HFpEF) using the biomarkers, growth differentiation factor-15 (GDF-15), galectin-3 (Gal-3), and soluble ST2 (sST2), and to determine whether they can differentiate HFpEF from heart failure with reduced ejection fraction (HFrEF). Medline and Embase databases were searched with the terms diastolic heart failure or HFpEF, biomarkers, and diagnosis, limited to years 2000 to 2019. There were significantly and consistently higher levels of GDF-15, Gal-3, and sST2 in HFpEF compared to no heart failure. Importantly, the magnitude of the increase in GDF-15 or Gal-3 and possibly sST2,correlated with a greater degree of diastolic dysfunction. There were no significant differences between GDF-15, Gal-3, and sST2 in patients with HFpEF vs HFrEF. In the studies assessing these three biomarkers, BNP was significantly greater in heart failure than controls. Furthermore, BNP was significantly higher in HFrEF compared to HFpEF. The diagnostic utility of GDF-15, Gal-3, and sST2 compared to BNP was evaluated by comparing ROC curves. The data supports the contention that to distinguish HFpEF from HFrEF, an index is needed that incorporates GDF-15, Gal-3, or sST2 as well as BNP. The three biomarkers GDF-15, Gal-3, or sST2 can identify patients with HFpEF compared to individuals without heart failure but cannot differentiate HFpEF from HFrEF. BNP is higher in and is better at differentiating HFrEF from HFpEF. Indices that incorporate GDF-15, Gal-3, or sST2 as well as BNP show promise in differentiating HFpEF from HFrEF.

The Prognostic Value of Soluble ST2 in Maintenance Hemodialysis Patients: A Meta-Analysis.

BACKGROUND: Much controversy remains in the literature with respect to whether soluble suppression of tumorigenicity 2 (sST2) can serve to predict all-cause death in patients undergoing maintenance hemodialysis (MHD). This meta-analysis therefore sought to analyze extant datasets exploring the association between these 2 variables in MHD patients in order to draw relevant conclusions. METHODS: Articles published through December 2018 in PubMed and Embase were independently reviewed by 2 authors to identify relevant articles, and STATA 12.0 was used for statistical analyses of relevant results and study parameters. RESULTS: In total, we identified 4 relevant studies that were incorporated into this meta-analysis. These studies included a total of 1,924 participants (60% male, mean follow-up 911 days). The combined study results suggested that increased levels of sST2 were significantly linked to a 2.23 fold rise in all-cause mortality (hazard ratio [HR] 2.23, 95% CI 1.81-2.75). Subgroup analyses confirmed that this same association was true in patients undergoing hemodialysis (HR 2.17, 95% CI 1.74-2.71), which indicated that the increased levels of sST2 were significantly linked to a 2.17 fold rise in all-cause mortality. CONCLUSIONS: This analysis suggests that there is a significant link between elevated levels of sST2 and death in patients undergoing MHD. Further large-scale trials, however, will be needed to fully validate these findings and their clinical relevance.

GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD.

RATIONALE & OBJECTIVE: Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study). EXPOSURES: Circulating GDF-15, Gal-3, and sST2 measured at baseline. OUTCOMES: Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident. ANALYTIC APPROACH: Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function. RESULTS: Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m2. Higher GDF-15 (adjusted HR [aHR] per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events. LIMITATIONS: Event rates for heart failure and atherosclerotic CVD were low. CONCLUSIONS: Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.

Soluble ST2 Is a Sensitive and Specific Biomarker for Fulminant Myocarditis.

Background The aim of the study was to identify biomarkers that can facilitate early diagnosis and treatment of fulminant myocarditis (FM) in order to reduce mortality. Methods and Results First, the expression profiles of circulating cytokines were determined in the plasma samples from 4 patients with FM and 4 controls using human cytokine arrays. The results showed that 39 cytokines from patients with FM were changed at admission. Among them, 8 cytokines returned to normal levels at discharge, including soluble ST2 (sST2), which showed the most marked dynamic changes from disease onset to resolution. Then, in a cohort of 76 patients with FM, 57 patients with acute hemodynamic dysfunction attributable to other causes, and 56 patients with non-FM, receiver operating characteristic curve analyses suggested that plasma sST2 level was able to differentiate FM from non-FM or other FM-unrelated acute heart failure more robustly N-terminal pro-B-type natriuretic peptide or cardiac troponin I. Moreover, longitudinal analysis of plasma sST2 was performed in 10 patients with FM during hospitalization and 16 patients with FM during follow-up. Finally, the diagnostic value was validated in an additional 26 patients with acute onset of unstable hemodynamics. The cutoff value of plasma sST2 for optimal diagnosis of FM was established at 58.39 ng/mL, where a sensitivity of 85.7% and specificity of 94.7% were achieved. Conclusions Elevated sST2 level was associated with mechanical stress or inflammation. Especially, sST2 might be used as a potential biomarker for the rapid diagnosis of FM, which was characterized by strong mechanical stretch stimulation and severe inflammatory response. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03268642.

Immediate Renal Denervation After Acute Myocardial Infarction Mitigates the Progression of Heart Failure via the Modulation of IL-33/ST2 Signaling.

Objective: Previous studies have demonstrated the protective effects of renal denervation (RDN) in pre-existing heart failure, but the effects of immediate RDN after acute myocardial infarction (AMI) on subsequent cardiac remodeling have not been reported. This study aimed to investigate the cardioprotective effects of immediate RDN after AMI and its underlying mechanism. Methods: AMI was induced by intracoronary gelatin sponge embolization in 14 Shanghai white pigs that were randomized to undergo either renal angiography (AMI+sham group) or RDN (AMI+RDN group) after 1 h of hemodynamic monitoring. Cardiac function of the two groups was measured at baseline, 1 h post-AMI and at the 1 month follow-up (1M-FU) by transthoracic echocardiography (TTE). Plasma NT-proBNP, soluble ST2 (sST2), norepinephrine (NE), and renin-angiotensin-aldosterone system activity were detected simultaneously. The renal cortex was harvested for NE measurement after the 1M-FU, and the renal arteries were stained with tyrosine hydroxylase for the evaluation of sympathetic activity. Heart tissues in the non-ischemic areas were collected to assess histological and molecular left ventricular (LV) remodeling by pathological staining, RT-PCR, and western blotting. Results: There was no difference in the hemodynamic stability or cardiac function between the two groups at baseline and 1 h post-AMI. Six pigs from each of the two groups completed the 1M-FU. TTE analysis revealed the improved cardiac function of immediate RDN in the AMI+RDN group and circulating NT-proBNP levels were lower than those in the AMI+sham group. Further analysis showed significantly less interstitial fibrosis in the remote non-ischemic myocardium after immediate RDN, together with decreased cardiomyocyte hypertrophy and inflammatory cell infiltration. sST2 levels in circulating and myocardial tissues of animals in the AMI+RDN group were significantly higher than those in the AMI+sham group, accompanied by corresponding alterations in IL-33/ST2 and downstream signaling. Conclusions: Immediate RDN can improve cardiac function and myocardial remodeling after AMI via modulation of IL-33/ST2 and downstream signaling.

Soluble ST2, Galectin-3 and clinical prognosis of patients with hypertrophic cardiomyopathy undergoing ventricular septal myectomy: a correlation analysis.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common chromosomal abnormal heart disease. The pathophysiological mechanism of HCM is complex. Several studies have suggested that the level of Soluble ST2 (sST2) may be a biomarker of chronic systolic heart failure, however, the role of sST2 in HCM remains unclear. So we performed this study to analyze the role of Soluble ST2 (sST2), Galectin-3 (Gal-3) and its correlations with clinical prognosis of patients with hypertrophic cardiomyopathy (HCM) undergoing ventricular septal myectomy. METHODS: HCM patients who underwent modified Morrow surgery in our hospital during June 2016-June 2018 were included. We divided the patients into different groups stratified by sST2 and Gal-3 level. Besides, we included volunteers without heart disease for medical examination as normal controls. Biochemical analyses were conducted to identify the biomarkers difference. The predictive value of sST2 and Gal-3 on all-cause mortality was evaluated with Cox regression analysis. RESULTS: A total of 125 HCM patients were included in this present study. The sST2 and Gal-3 levels in HCM patients were significantly higher than that in control group (all P<0.001); there were significant differences in the incidence of all-cause mortality for HCM patients stratified by the sST2 and Gal-3 level; Cox univariate regression survival analysis showed that the hypertension (HR =1.19, 95% CI: 1.01-1.38), maximum wall thickness (HR =1.48, 95% CI: 1.04-1.98), Log sST2 (HR =1.02, 95% CI: 1.01-1.05), Log Gal-3 (HR =1.17, 95% CI: 1.09-1.32) were the predictors for all-cause mortality in patients with HCM, and Cox multivariate risk regression showed that maximum wall thickness was the independent predictors of all-cause mortality in patients with HCM (HR =1.63, 95% CI: 1.35-1.97). CONCLUSIONS: Even through sST2 and Gal-3 were not associated with clinical prognosis of patients with HCM undergoing ventricular septal myectomy, it may be involved in the progress of HCM, more studies are warranted to identify the potential mechanism and reverence value.

Soluble ST2 (sST2) as potential marker for hepatic cystic echinococcosis activity.

OBJECTIVES: this study aims to identify the potential marker for hepatic cystic echinococcosis (CE) activity. METHODS: totally 97 CE patients and 47 health control (HC) subjects were included. Based on the ultrasound (US) images, CE patients were further categorized as active CE (ACE; 52 cases) and inactive CE (IACE; 45 cases). The sST2 and IL (interleukin)-33 levels were measured by enzyme-linked immunosorbent assay. Univariate, multivariate and subgroup analysis were performed. The relationship between sST2 and CE activity was analyzed by the smooth curve fitting. The receiver operating characteristic (ROC) curve analysis was also performed. RESULTS: the serum sST2 level in the CE patients was significantly higher than the HC subjects. Moreover, there was significant difference in the serum sST2 level between the ACE and IACE group. However, no significant difference was observed in the IL-33 level between the ACE and IACE groups. Univariate analysis showed that CE activity was significantly correlated with the sST2 level when the sST2 was greater than 1496.6 pg/mL. Multivariable analysis after adjustment for potential confounding factors, and subgroup analysis showed that sST2 had independent effect on CE activity. ROC curve showed that sST2 could differentially diagnose CE activity at the cut-off value of 1246.550 pg/mL with an AUC of 0.770. CONCLUSION: the sST2 could be used as a biomarker for hepatic CE activity. High levels of sST2 suggest that the hepatic CE is more likely to be active. Our findings have important guiding significance for the diagnosis of CE activity and the choice of treatment methods.

Combined use of high-sensitivity ST2 and NT-proBNP for predicting major adverse cardiovascular events in coronary heart failure.

BACKGROUND: Elevated serum soluble ST2 (sST2) level is marker of poor prognosis in chronic heart failure (HF). N-terminal pro-brain natriuretic peptide (NT-proBNP) is an important biomarker in cardiovascular diseases. This study aimed to address the incremental usefulness of the combined use of high-sensitivity sST2 and NT-proBNP for predicting the risk of major adverse cardiovascular events (MACEs) in patients with coronary heart disease (CHD). METHODS: We used patient data along with data established by our research group to compare the performance of a combination of biomarkers reflecting ventricular fibrosis, remodeling, stretch and deterioration of cardiac function (sST2 and NT-proBNP) with that of established mortality risk factors [age, diabetes, systolic blood pressure, diastolic blood pressure, left ventricular ejection fraction (LVEF), body mass index (BMI), creatinine (Cr), uric acid (UA), glucose (Glu)] in stratifying the risk of MACEs in CHD patients. RESULTS: The median follow-up period was 3.9 years, during which time there were 3,724 cases with CHD, 113 cases of cardiovascular death, 30 cases with myocardial infarction, 49 cases with stroke, 39 cases of non-cardiovascular death, 6 cases of peripheral arterial occlusion, 55 cases with HF, and 73 cases of revascularization. A total of 365 cases had MACEs. In the multivariate Cox proportional hazard model, both sST2 and NT-proBNP were significant predictors of MACEs. Both sST2 and NT-proBNP were separately incorporated into the model with established MACE risk factors, which significantly improved the C-statistics for predicting MACEs [0.758 (0.724-0.792)] and saw an estimated net improvement in reclassification of 1.03% (P<0.001) and an integrated discrimination improvement of 0.48% (P<0.001). The Hosmer-Lemeshow test showed that the models were well calibrated with and without the two biomarkers (P>0.344 for all comparisons). Moreover, the model incorporating the two biomarkers was shown to have a better global fit than the model with only the established MACE risk factors (P<0.001). CONCLUSIONS: A model incorporating sST2 and NT-proBNP was shown to outperform a model based on established MACE risk factors alone in stratifying risk of MACEs in a group of CHD patients.