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J Stroke > Volume 23(2); 2021 > Article
Choi, Kim, Kim, Kang, Kim, Choi, Park, and Cho: Troponin Levels and Outcomes in Patients with Embolic Stroke of Undetermined Source
Dear Sir:
A new clinical construct of embolic stroke of undetermined source (ESUS) has been proposed to group heterogeneous patients with embolism of undetermined cause despite recommended diagnostic workup [1]. Although the emboli in ESUS may originate from various potential embolic sources (PESs), cardioembolic sources may account for most PESs in ESUS [1]. Cardiac troponin (cTn) is a sensitive and specific marker of cardiac dysfunction [2]. Recent studies have suggested that elevated cTn levels are more common in patients with ESUS than in those with noncardioembolic stroke [3]. Elevated cTn levels may be associated with worse clinical outcomes and a higher risk of vascular events after stroke [4,5]. Therefore, we investigated the effectiveness of conventional cTn I (cTnI) and high-sensitivity cTn T (hs-cTnT) levels in predicting clinical outcomes in patients with ESUS.
This single-center retrospective cohort study used a prospective registry. Subjects were divided into normal and high troponin groups according to sex-specific 99th percentile upper reference limits (Supplementary Figure 1). The primary outcome measure was the first occurrence of major adverse cerebrovascular and cardiovascular events (MACCE) according to the baseline cTn levels over a 1-year period after ESUS. The secondary outcomes included constituents of MACCE. We enrolled 1,838 consecutive patients with ESUS admitted to our center (Supplementary Figure 1). The baseline patient characteristics and annual number of patients in the cTnI and hs-cTnT groups are presented in Supplementary Tables 1-4. Elevated cTnI and hs-cTnT levels were detected in 20.2% (209/1,037) and 21.2% (170/801) patients, respectively. Detailed methodical descriptions and outcomes of interest are provided in Supplementary methods and results.
The rates of vascular events were higher in the high cTnI (Figure 1) and hs-cTnT (Figure 2) groups than in the respective normal groups. Multivariate Cox regression analyses revealed that patients in the high cTnI group had a significantly increased risk of MACCE compared to those in the normal cTnI group (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.13 to 3.44; P=0.016) (Figure 3 and Supplementary Table 5) after adjustment for confounders. Similarly, patients with high hs-cTnT levels had a significantly increased risk of MACCE compared to those with normal hs-cTnT levels (HR, 2.69; 95% CI, 1.44 to 5.01; P=0.002) (Figure 3 and Supplementary Table 5). In sensitivity analyses, prognostic values of both cTnI and hs-cTnT for predicting the risk of MACCE remained unchanged when cTn levels were analyzed using the overall cTn cutoff levels without sex-specific differences (Supplementary Table 6).
Regarding secondary outcomes, high cTnI and hs-cTnT levels were also significantly associated with the risk of vascular death (Figure 3 and Supplementary Table 5). High hs-cTnT levels were significantly associated with the risk of recurrent ischemic stroke (HR, 2.62; 95% CI, 1.05 to 6.57; P=0.039); this association was not observed for cTnI levels (HR, 1.40; 95% CI, 0.57 to 3.45; P=0.454) (Figure 3 and Supplementary Table 5). No significant differences were observed in the risk of acute myocardial infarction between the normal and high troponin groups (Figure 3 and Supplementary Table 5).
This is the first real-world cohort study on troponin levels in ESUS and validates the finding of a recent clinical trial substudy that the troponin level is a predictor of the risk of vascular events in patients with ESUS [5]. There is an urgent need to identify prognostic biomarkers related to potential cardiac dysfunction after ESUS [1]. In a recent randomized trial on ESUS, a high hs-cTnT level was associated with increased cardiovascular events [5]. Our data provide insights on the clinical significance of routine assessment of baseline troponin levels to predict vascular events after ESUS.
Our study has a few limitations. We were unable to perform all investigations for identifying PESs in ESUS, such as longterm cardiac monitoring, cardiac compound tomography, or magnetic resonance imaging. In addition, the predictive values of the two types of cTn were not compared. Since hs-cTnT assay has recently been introduced in clinical practice, patients who underwent hs-cTnT testing may have received more advanced treatment and better risk factor control than those who underwent cTnI testing. The risk of recurrent ischemic stroke was significantly associated with high hs-cTnT levels, but not with high cTnI levels. Further studies are needed to confirm whether hs-cTnT is superior to cTnI in predicting clinical outcomes and identify optimally tailored antithrombotics that reduce the risk of vascular events in patients with high cTn levels.
In conclusion, our findings suggest that high cTnI and hs-cTnT levels are significantly associated with MACCE and vascular death after ESUS. Our study also shows that high hs-cTnT levels are associated with a higher risk of recurrent ischemic stroke. Reducing the risk of MACCE after ESUS in individuals with high cTn levels is a challenge, and further studies are needed to improve patient care and clinical guidelines.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2021.00010.
Supplementary methods and results
jos-2021-00010-suppl1.pdf
Supplementary Table 1.
Baseline characteristics according to baseline cardiac troponin levels
jos-2021-00010-suppl2.pdf
Supplementary Table 2.
Transcranial and echocardiographic findings according to cardiac troponin levels
jos-2021-00010-suppl3.pdf
Supplementary Table 3.
Baseline characteristics according to troponin type
jos-2021-00010-suppl4.pdf
Supplementary Table 4.
The number of enrolled patients during cTn assays performed each year in this study
jos-2021-00010-suppl5.pdf
Supplementary Table 5.
Event rates and association estimates from Cox proportional hazard model according to baseline cardiac troponin levels
jos-2021-00010-suppl5.pdf
Supplementary Table 6.
Association between high cardiac troponin levels using the overall 99th percentile upper reference cutoff level and clinical outcomes
jos-2021-00010-suppl6.pdf
Supplementary Figure 1.
Subject enrollment and clinical outcome measures. ESUS, embolic stroke of undetermined source; hs, high-sensitivity.
jos-2021-00010-suppl6.pdf

Acknowledgments

This work was supported by a National Research Foundation of Korea grant funded by the Korean Government (NRF-2019M3A9E8020261, Kang-Ho Choi).

Notes

The authors have no financial conflicts of interest.

Figure 1.
Vascular events based on conventional troponin I levels. (A) Major adverse cerebrovascular and cardiovascular event (MACCE), (B) recurrent stroke, (C) acute myocardial infarction, (D) vascular death.
jos-2021-00010f1.jpg
Figure 2.
Vascular events based on high-sensitivity troponin T levels. (A) Major adverse cerebrovascular and cardiovascular event (MACCE), (B) recurrent stroke, (C) acute myocardial infarction, (D) vascular death.
jos-2021-00010f2.jpg
Figure 3.
Association between cardiac troponin levels and clinical outcomes after embolic stroke of undetermined source. (A) Troponin I, (B) high-sensitivity troponin I (hs troponin-T). MACCE, major adverse cerebrovascular and cardiovascular event.
jos-2021-00010f3.jpg

References

1. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-438.
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2. McCarthy CP, Raber I, Chapman AR, Sandoval Y, Apple FS, Mills NL, et al. Myocardial injury in the era of high-sensitivity cardiac troponin assays: a practical approach for clinicians. JAMA Cardiol 2019;4:1034-1042.
crossref pmid
3. Merkler AE, Gialdini G, Murthy SB, Salehi Omran S, Moya A, Lerario MP, et al. Association between troponin levels and embolic stroke of undetermined source. J Am Heart Assoc 2017;6:e005905.
crossref pmid pmc
4. Ahn SH, Lee JS, Kim YH, Kim BJ, Kim YJ, Kang DW, et al. Prognostic significance of troponin elevation for long-term mortality after ischemic stroke. J Stroke 2017;19:312-322.
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5. Scheitz JF, Pare G, Pearce LA, Mundl H, Peacock WF, Czlonkowska A, et al. High-sensitivity cardiac troponin T for risk stratification in patients with embolic stroke of undetermined source. Stroke 2020;51:2386-2394.
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