Serum Soluble Tumor Necrosis Factor Receptors 1 and 2 Are Early Prognosis Markers After ST-Segment Elevation Myocardial Infarction

Abstract

Background: As inflammation following ST-segment elevation myocardial infarction (STEMI) is both beneficial and deleterious, there is a need to find new biomarkers of STEMI severity. Objective: We hypothesized that the circulating concentration of the soluble tumor necrosis factor α receptors 1 and 2 (sTNFR1 and sTNFR2) might predict clinical outcomes in STEMI patients. Methods: We enrolled into a prospective cohort 251 consecutive STEMI patients referred to our hospital for percutaneous coronary intervention revascularization. Blood samples were collected at five time points: admission and 4, 24, 48 h, and 1 month after admission to assess sTNFR1 and sTNFR2 serum concentrations. Patients underwent cardiac magnetic resonance imaging at 1 month. Results: sTNFR1 concentration increased at 24 h with a median of 580.5 pg/ml [95% confidence interval (CI): 534.4-645.6]. sTNFR2 increased at 48 h with a median of 2,244.0 pg/ml [95% CI: 2090.0-2,399.0]. Both sTNFR1 and sTNFR2 peak levels were correlated with infarct size and left ventricular end-diastolic volume and inversely correlated with left ventricular ejection fraction. Patients with sTNFR1 or sTNFR2 concentration above the median value were more likely to experience an adverse clinical event within 24 months after STEMI [hazards ratio (HR): 8.8, 95% CI: 4.2-18.6, p < 0.0001 for sTNFR1; HR: 6.1, 95% CI: 2.5 -10.5, p = 0.0003 for sTNFR2]. Soluble TNFR1 was an independent predictor of major adverse cardiovascular events and was more powerful than troponin I (p = 0.04 as compared to the troponin AUC). Conclusion: The circulating sTNFR1 and sTNFR2 are inflammatory markers of morphological and functional injury after STEMI. sTNFR1 appears as an early independent predictor of clinical outcomes in STEMI patients.

Keywords: TNF; biomarker; myocardial infarction; prognosis; soluble TNF receptor.

FIGURE 1

Soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 kinetics after STEMI. Circulating concentrations of sTNFR1 (A) and sTNFR2 (B) at admission and 4, 12, 48 h, and 1 month after PCI revascularization are presented. Time points were compared using the Kruskal–Wallis test. **p < 0.01, ****p < 0.0001 versus admission.

FIGURE 2

Adverse clinical events at 24 months after STEMI according to 48 h sTNFR1 and sTNFR2. (A, B) Adverse clinical events (all-cause mortality, hospitalization for heart failure, myocardial infarction, or stroke) over 24 months after admission for suspected STEMI in patients with sTNFR1 (A) or sTNFR2 (B) concentration at 48 h either below or above the median value of the study population.

FIGURE 3

Unadjusted hazards ratio (HR) and 95% confidence interval (CI) for experiencing a composite endpoint during the median of 24 months of follow-up when having high soluble tumor necrosis factor receptor (sTNFR) 1 or high sTNFR2 (>median), high C-reactive protein (CRP > median), high troponin peak (>median), and high creatine kinase (CK) peak (>median). The peak used is the maximum value of troponin, creatine kinase, or CRP measured for each patient individually (A). Receiver-operating characteristic (ROC) curves for discriminating between patients with or without a cardiac adverse event during the 24 months of follow-up after STEMI according to different markers (B). AUC: area under the curve, sTNFR1: soluble tumor necrosis factor receptor 1, and sTNFR2: soluble tumor necrosis factor receptor 2. *Hazards ratio adjusted in multivariable Cox regression analyses with models including age, sex, diabetes, hypertension, smoking, renal dysfunction, troponin peak, TIMI flow grade after PCI, and high levels of sTNFR1 (>median) or high levels of sTNFR2 (>median).