Association of Troponin T levels and functional outcome 3 months after subarachnoid hemorrhage

TroponinT levels are frequently elevated after subarachnoid hemorrhage (SAH). However, their clinical impact on long term outcomes still remains unclear. This study evaluates the association of TroponinT and functional outcomes 3 months after SAH. Data were obtained in the frame of a randomized controlled trial exploring the association of Goal-directed hemodynamic therapy and outcomes after SAH (NCT01832389). TroponinT was measured daily for the first 14 days after admission or until discharge from the ICU. Outcome was assessed using Glasgow Outcome Scale (GOS) 3 months after discharge. Logistic regression was used to explore the association between initial TroponinT values stratified by tertiles and admission as well as outcome parameters. TroponinT measurements were analyzed in 105 patients. TroponinT values at admission were associated with outcome assessed by GOS in a univariate analysis. TroponinT was not predictive of vasospasm or delayed cerebral ischemia, but an association with pulmonary and cardiac complications was observed. After adjustment for age, history of arterial hypertension and World Federation of Neurosurgical Societies (WFNS) grade, TroponinT levels at admission were not independently associated with worse outcome (GOS 1–3) or death at 3 months. In summary, TroponinT levels at admission are associated with 3 months-GOS but have limited ability to independently predict outcome after SAH.

www.nature.com/scientificreports/ Besides, some patients develop a severe form of stress-induced cardiomyopathy, neurogenic stunned myocardium (NSM) characterized by depressed ventricular function and regional wall motion abnormality (RWMA) 4 . Numerous studies have explored the association of these findings with complications and outcome 3,5,6 . RWMAs, elevated NT-proBNP levels as well as some ECG changes, for example ST-segment depression, were significantly associated with an increased risk of death 7 . Although the elevation of cardiac troponins has been the topic of several investigations, its impact on outcome remains unclear. While there are studies linking cardiac troponin elevation with long-term outcome 8 , the association was not present after discharge in other trials 3 . Therefore, the aim of this study was to evaluate whether hsTroponinT values after SAH are associated with functional outcome at 3 months.

Methods
Study design. Troponin T measurements were obtained prospectively in the frame of a randomized, controlled clinical trial exploring the association of goal-directed hemodynamic therapy and outcomes after SAH at a University Hospital in Germany (Klinikum rechts der Isar, Technical University Munich) 9 . The study was approved by the local ethics committee (Ethics Commission of the Medical faculty, Technical University of Munich, ID: 5425-12) and was first registered at 16/04/2013 at clinicaltrials.gov; Identifier: NCT01832389. All research was performed in accordance with the Declaration of Helsinki.
Patients older than 18 with an aneurysmal SAH diagnosed by CT and confirmed by angiography were eligible for enrollment. Exclusion criteria were: traumatic SAH, congestive heart failure, severe diseases of aorta or aortic valve, pregnancy, calcium antagonist intolerance. Written consent was obtained from each patient or their legal representative. Clinical management was performed according to current guidelines and was described previously in detail 9,10 . Data collection. Outcome was assessed 3 months after discharge using Glasgow Outcome Scale (GOS): GOS 1 = death, GOS 2 = persistent vegetative state, GOS 3 = severe disability, GOS 4 = moderate disability and GOS 5 = good recovery 11 . The participants were usually seen in the neurosurgical outpatient department by a neurosurgical consultant unaware of measurement results, otherwise they were contacted by telephone.
To describe medical history at admission the following factors were considered: arterial hypertension, history of coronary artery disease, arrhythmia, history of cerebrovascular disease, tobacco use, history of asthma/chronic obstructive pulmonary disease (COPD), diabetes mellitus and chronic kidney disease. Further, the severity of SAH was assessed using Hunt-Hess grade, World Federation of Neurologic Surgeons (WFNS) grade and modified Fisher scale, taking into consideration the amount of blood in the initial CT scan [12][13][14] .
Complications were assessed as follows: cardiac complications (myocardial infarction, hemodynamic relevant arrhythmia, heart failure), pulmonary complications (pulmonary edema, pneumonia, pulmonary embolism), cerebrovascular complications (vasospasm, delayed cerebral ischemia (DCI), need for intra-arterial vasodilator therapy). Cardiac and pulmonary complications were assessed based on the current clinical practice involving symptoms, laboratory and radiological parameters, as well as current guidelines 15 . Vasospasm was diagnosed by daily transcranial Doppler measurements and defined as peak-value increase by > 50 cm/sec/24 h compared to the previous result or a mean value > 120 cm/sec in one of the main supply branches 16 . DCI was defined as a new focal neurological deficit or a cerebral infarction in the presence of vasospasm revealed by radiologic imaging, or both. Other causes of neurological aggravation had to be excluded 17,18 . Troponin T measurement. Troponin T was measured daily starting from admission for consecutive 14 days or, if shorter, until discharge from ICU. For troponin T measurements the Roche high-sensitive troponin T Elecsys-assay was used in our laboratory.

Statistical analysis.
Variables are presented as median and interquartile ranges or as mean and standard deviation, as appropriate. Continuous, normally distributed variables were compared using a two-sided Student's t test, and a Mann Whitney-U-test was used for variables with skewed distributions. Spearman rank test was used to test correlations in non-normally distributed variables. Troponin T values at admission were divided into tertiles. Logistic regression models were applied to assess the relation between initial troponin T values and admission as well as outcome parameters. In order to test whether troponin T is an independent risk factor for worse outcome, a multivariate regression was performed considering age, history of arterial hypertension and WFNS score according to SAHIT core criteria 19 . All statistical tests were done using SPSS statistics 27 (IBM SPSS, Inc.). A p value < 0.05 was considered statistically significant.

Results
Patients were enrolled between March 2013 and December 2015 9 . Both, outcome and troponin t data, were available in 106 patients. From the initially included 108 patients two were excluded: one due to missing outcome data, the other due to missing troponin T data.
The median age was 55 years and 81% of the patients were female. Almost half of the patients had a history of arterial hypertension and 8% had a history of coronary artery disease. An overview of baseline characteristics is presented in Table 1 There was a close correlation between the initial troponin T measurement and the peak troponin T value (r = 0.79, p < 0.01). Mean troponin T values were higher (p < 0.001) on days 1-3 (0.054 ± 0.14 µg/L; mean ± SD) compared to days 4-7 (0.027 ± 0.053 µg/L) and days 8-14 (0.016 ± 0.021 µg/L). An overview of troponin T distribution over time is shown in Fig. 1. Troponin T levels at admission were significantly higher in patients with Hunt-Hess grades 3-5 (p < 0.001) and WFNS grades 4-5 (p < 0.001), whereas there was no difference in modified Fisher scale (p = 0.054).

Discussion
In this prospective study, we were able to show that troponin T levels measured for the first 14 days are associated with 3 months outcomes assessed by GOS. However, when adjusted for age and Hunt-Hess scores, troponin T levels at admission were not independently predictive of death (GOS 1) or worse outcomes (GOS 1-3) at 3 months. Cardiac impairment and its impact on outcomes after SAH has been an object of great interest in recent years [20][21][22][23] . While there is widely agreement about the mechanism behind these findings involving abnormal sympathetic innervation with an excessive norepinephrine release, their impact on short and long term outcome remains controversial 24 . There are only very few studies who have prospectively evaluated the association between cardiac troponins and outcome after SAH, and only two of them used a high sensitive troponin essay similar to the one in the present study 8,25 . To the best of our knowledge, the present study is the first one prospectively conducting serial hs troponin T measurements for 14 days after admission.
We were able to show that initial troponin T levels are strongly correlated to peak troponin T levels. Additionally, there was an association in the univariate analysis between troponin T levels at admission and severity scores like Hunt-Hess and WFNS grade. Both findings confirm previously published results and support the hypothesis that troponin T elevation is likely to reflect an initial SAH severity with its influence on myocardial dysfunction 26 . Neither vasospasm nor DCI nor the need for intra-arterial vasodilator therapy showed an association with initial troponin T levels in our study. Neither did the modified Fisher scale which is closely related to vasospasm 14 . Due to the disparity of definitions of vasospasm and DCI in previous trials, the results in this field are poorly comparable. While no association between cardiac troponins and vasospasm was found by some investigators 27 , other reported a relation between cardiac troponins and DCI 7,8 . For further research, standardized definitions and approaches are needed in this field and, according to our data, considerably larger sample sizes are warranted in order to draw robust conclusions considering vasospasm and DCI. Further, our work confirms an association between troponin T levels and cardiac as well as pulmonary complications 28 . Finally, while there was an association in the univariate analysis between troponin T levels and 3 months outcomes at all 14 days of measurement, the relation between troponin T tertiles at admission and death as well as worse outcome was no longer present in the multivariate analysis. This finding is in line with previously published retrospective data and even expands those due to the prospective approach 3,5 . Moreover, in a multicenter cohort study, regional wall motion abnormalities (RWMA) after SAH were found to be an independent predictor of outcome after SAH while troponin T elevation was not 7 . Our results confirm the latter observation, but there are also trials suggesting a causal relationship between the early biomarker release such as troponin T and outcome after SAH 8,25 .  www.nature.com/scientificreports/ Further research in a preferably multicenter setting is warranted to clarify the impact of the elevated biomarker levels on the outcome after SAH. Our study has several limitations. First, this study does not investigate the mechanisms behind the biomarker elevation nor does it consider other cardiac parameters. Second, it is a single center trial with a limited number of patients. Nevertheless, the data were obtained prospectively and continuously. Besides, troponin T as well as 3 months outcome data were collected in all included patients. Third, our follow-up period ended at 3 months. We cannot preclude that a longer follow-up might have led to different results.
Nevertheless, our results add to previous literature as the high sensitive troponin T essay was used as suggested by the current guidelines 29 . We were able to show that troponin T measurements are associated with outcome after SAH as well as cardiovascular and pulmonary complications and might be useful in risk stratification of SAH patients. However, our results suggest that troponin T has limited ability to independently predict outcome after SAH. Further studies are needed to test the utility of hsTroponin T measurements in the early phase after SAH.