Baseline characteristics
From October 2015 to June 2018, 452 consecutive patients with TIA/ischemic stroke were eligible for prospective enrollment. After excluding 15 patients without blood samples, 3 with active inflammation, 2 with malignant tumor, 2 with history of trauma or surgery within the last year, and 17 lost to the 1-year follow-up, a total of 413 patients were included in the final analysis (Fig. 1).
Baseline characteristics are shown in Table 1. Among the 413 patients, the average age was 60.34 ± 11.48 years and 128 patients (30.99%) were female. The median NIHSS score on admission and serum sST2 levels of the cohort were 2 (0–4) and 17.74 (9.16–28.72) ng/mL, respectively.
Table 1
Baseline characteristics of TIA/ischemic stroke patients included according to 1-year prognostic outcomes
Baseline characteristics | Total (n = 413) | 1-year prognostic outcomes after TIA/ischemic stroke |
Composite adverse outcomes (n = 38) | Non-composite adverse outcomes (n = 375) | P value | | mRS, 3–6 (n = 40) | mRS, 0–2 (n = 373) | P value |
Female, n (%) | 128 (30.99) | 12 (31.58) | 116 (30.93) | 0.935 | | 16 (40.00) | 112 (30.03) | 0.195 |
Age, mean ± SD | 60.34 ± 11.48 | 64.55 ± 11.56 | 59.92 ± 11.40 | 0.018 | | 66.20 ± 11.89 | 59.72 ± 11.27 | 0.001 |
Current smoking, n (%) | 121 (29.30) | 11 (28.95) | 110 (29.33) | 0.960 | | 10 (25.00) | 111 (29.76) | 0.530 |
Medical history, n (%) |
Hypertension | 283 (68.52) | 26 (68.42) | 257 (68.53) | 0.989 | | 34 (85.00) | 249 (66.76) | 0.018 |
Diabetes mellitus | 113 (27.36) | 10 (26.32) | 103 (27.47) | 0.879 | | 15 (37.50) | 98 (26.27) | 0.130 |
Hyperlipidemia | 101 (24.46) | 7 (18.42) | 94 (25.07) | 0.364 | | 6 (15.00) | 95 (25.47) | 0.143 |
Prior ischemic stroke | 91 (22.03) | 15 (39.47) | 76 (20.27) | 0.006 | | 14 (35.00) | 77 (20.64) | 0.037 |
Coronary heart disease | 69 (16.71) | 9 (23.68) | 60 (16.00) | 0.226 | | 9 (22.50) | 60 (16.09) | 0.301 |
Atrial fibrillation | 26 (6.30) | 3 (7.89) | 23 (6.13) | 0.940 | | 6 (15.00) | 20 (5.36) | 0.041 |
NIHSS on admission, median (IQR) | 2 (0–4) | 2 (0–3) | 2 (0–4) | 0.593 | | 4 (2–9) | 2 (0–4) | < 0.0001 |
sST2 (ng/mL), median (IQR) | 17.74 (9.16–28.72) | 24.02 (12.99–43.06) | 16.97 (8.98–27.57) | 0.035 | | 24.82 (13.93–43.74) | 16.70 (8.99–26.70) | 0.003 |
IQR, interquartile range; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; sST2, soluble ST2; TIA, transient ischemic stroke. |
Association of serum sST2 with the severity of TIA/ischemic stroke
Serum sST2 levels were positively correlated with the NIHSS score on admission (r = 0.247 P < 0.0001). Stratified by a NIHSS score of 3 [16], the patients were divided into the mild group (NIHSS ≤ 3, n = 293) and severe group (NIHSS > 3, n = 120). The sST2 levels were significantly higher in the severe group than in the mild group (P < 0.001, Fig. 2a). Among the 413 patients, 312 had ischemic stroke and 101 had TIA according to the tissue-based definitions. Serum sST2 levels were markedly higher in patients with ischemic stroke than in those with TIA (P < 0.0001, Fig. 2b).
Association between serum sST2 and prognostic outcomes after TIA/ischemic stroke
During the 1-year follow-up period, 38 (9.20%) patients experienced composite adverse events (Table 1). Serum sST2 levels were higher in patients with composite adverse events. (P = 0.035, Fig. 2c). Kaplan-Meier analysis according to the optimal sST2 cut-off value of 22.97 ng/mL revealed that patients with higher sST2 levels had higher incidence of composite adverse events at 1 year (log-rank test P = 0.006, Fig. 3a). Using sST2 dichotomized by the cut-off value, the univariate Cox proportional hazards regression showed that elevated sST2 levels were associated with increased risk of composite adverse events (HR = 2.356, 95% CI: 1.246–4.453, P = 0.008). After adjusting for age, sex, smoking status, medical history (hypertension, diabetes mellitus, hyperlipidemia, prior ischemic stroke, coronary heart disease, and atrial fibrillation) and baseline NIHSS score, serum sST2 levels could still independently predict 1-year composite adverse events (HR: 2.517, 95% CI: 1.279–4.956, P = 0.008, Table 2). Additional significant predictors were age (HR: 1.041, 95% CI: 1.006–1.077, P = 0.022) and prior ischemic stroke (HR: 2.182, 95% CI: 1.100-4.332, P = 0.026).
Table 2
Multivariate analyses for the association between serum sST2 and prognostic outcomes at 1 year
Variables | Composite adverse events | | A combination of major disability and death |
HRa | 95% CI | P value | | ORb | 95% CI | P value |
Sex (female) | 1.235 | 0.571–2.670 | 0.592 | | 1.569 | 0.670–3.674 | 0.299 |
Age | 1.041 | 1.006–1.077 | 0.022 | | 1.060 | 1.018–1.103 | 0.005 |
Current smoking | 1.246 | 0.554–2.802 | 0.594 | | 0.915 | 0.336–2.492 | 0.862 |
Hypertension | 0.777 | 0.379–1.589 | 0.489 | | 2.340 | 0.888–6.165 | 0.085 |
Diabetes mellitus | 0.737 | 0.350–1.551 | 0.421 | | 1.337 | 0.607–2.948 | 0.471 |
Hyperlipidemia | 1.021 | 0.424–2.456 | 0.964 | | 1.033 | 0.370–2.883 | 0.951 |
Prior ischemic stroke | 2.182 | 1.100-4.332 | 0.026 | | 2.197 | 0.994–4.857 | 0.052 |
Coronary heart disease | 1.052 | 0.472–2.341 | 0.902 | | 0.681 | 0.258–1.794 | 0.436 |
Atrial fibrillation | 0.845 | 0.238–2.997 | 0.794 | | 0.963 | 0.264–3.519 | 0.955 |
NIHSS on admission | 0.932 | 0.825–1.052 | 0.255 | | 1.263 | 1.140–1.399 | < 0.0001 |
sST2 (> cut-off value ng/mL)c | 2.517 | 1.279–4.956 | 0.008 | | 3.126 | 1.452–6.728 | 0.004 |
aHR was adjusted ratio calculated by multivariate Cox proportional hazards regression. |
bOR was adjusted ratio calculated by multivariate logistic regression. |
csST2 was dichotomized according to optimal cut-off values obtained by ROC curve analysis. |
CI, confidence interval; HR, hazard ratio; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; sST2, soluble ST2. |
Within 1 year after TIA/ischemic stroke, composite outcomes of major disability and death occurred in 40 (9.69%) patients (Table 1). Higher sST2 levels were observed in patients with mRS of 3–6 (P = 0.003, Fig. 2d). Unadjusted logistic regression, dichotomizing sST2 levels with a cut-off value of 24.61 ng/mL, showed that serum sST2 levels were associated with a combination of major disability and death within 1 year (OR: 3.408, 95% CI: 1.751–6.634, P < 0.001). The association remained significant in multivariate logistic regression. The adjusted OR for the higher versus lower sST2 levels was 3.126 (95% CI: 1.452–6.728, P = 0.004, Table 2). In addition, age (OR: 1.060, 95% CI: 1.018–1.103, P = 0.005) and baseline NIHSS scores (OR: 1.263, 95% CI: 1.140–1.399, P < 0.0001) were also significantly associated with major disability or death.
We also examined the association between sST2 and 1-year stroke recurrence (including ischemic and hemorrhagic stroke, n = 30). There was a significant difference in the risk of recurrent stroke between the low-level (≤ 7.92 ng/mL) and high-level (> 7.92 mg/mL) categories (log-rank test P = 0.049, Fig. 3b). However, after adjusting for confounders, there was no significance but only a trend toward an association between higher sST2 levels and higher risk of stroke recurrence (P = 0.055).
Incremental predictive value of sST2 for TIA/ischemic stroke outcomes
Adding serum sST2 to the NIHSS score, we evaluated whether sST2 would further increase the predictive value for TIA/ischemic stroke outcomes (Table 3). For the composite adverse events, the C statistic by sST2 combined with NIHSS showed a significant improvement (from 0.526 to 0.669, P = 0.021) and the IDI was 1.91% (P = 0.042). Only the NRI of 32.82% by NIHSS with the addition of sST2 appeared to be substantially better than NIHSS alone (P = 0.042) for major disability or death.
Table 3
Reclassification and discrimination statistics for prognostic outcomes within 1 year by serum sST2
Outcomes within 1 year | C statistic | | NRI (continuous), % | | IDI, % |
Estimate (95% CI) | P value | | Estimate (95% CI) | P value | | Estimate (95% CI) | P value |
Composite adverse events |
NIHSS | 0.526 (0.438–0.613) | | | Reference | | | Reference | |
NIHSS + sST2 | 0.669 (0.598–0.740) | 0.021 | | 31.48 (-0.77-63.73) | 0.056 | | 1.91 (0.07–3.75) | 0.042 |
A combination of major disability and death (mRS, 3–6) |
NIHSS | 0.710 (0.628–0.793) | | | Reference | | | Reference | |
NIHSS + sST2 | 0.726 (0.641–0.810) | 0.378 | | 32.82 (1.25–64.38) | 0.042 | | 1.61 (-0.42-3.65) | 0.120 |
CI, confidence interval; IDI, integrated discrimination index; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; NRI, net reclassification index; sST2, soluble ST2. |