Cardiac troponins are sensitive and specific markers of myocardial necrosis, and are measured routinely in the diagnosis of acute myocardial infarction (MI). The universal definition of acute MI requires detection of rise and/or fall of cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99^th percentile of the upper reference limit [1]. The highly sensitive troponin assays meet the analytical criteria required, as they have a limit of detection lower than the 99^th percentile of a general population, and a coefficient of variation of 10% or less at this concentration [2]. The National Academy of Clinical Biochemistry has recommended the use of δ 20% in sensitive assays when cardiac troponin is above the 99^th percentile [3, 4], while Mueller et al [5] have proposed the use of an absolute change of at least 9.2 ng/L. In acute MI, values may remain elevated for two weeks or more following the onset of myocardial necrosis [1].

More widespread use of the highly sensitive assays have led to substantial increase in the detection of elevated levels of cardiac troponin, even among patients admitted for other conditions [6], such as end-stage renal disease (ESRD) [3, 7], pulmonary embolism (PE) [8] and epileptic seizures [9]. Several studies have shown elevation of markers of myocardial damage in a proportion of patients with acute stroke [10–13], and elevated levels are associated with mortality [11, 13, 14]. In a systematic review [15], the prevalence of cardiac troponin elevation in stroke patients was reported to vary from 0 to 34%, but the studies reviewed were heterogeneous and difficult to compare due to different troponin assays and cut-offs. Furthermore, it is uncertain whether this elevation is transient or chronic and whether the etiology is acute myocardial ischemia or comorbidities. In addition, stroke patients often manifest electrocardiography (ECG) changes suggestive of cardiac injury [16, 17], but the etiology is unclear.

The aims of the present study were to identify possible determinants associated with high sensitivity cardiac troponin T (hs-cTnT) elevation and to determine the prevalence of ECG changes in patients with acute ischemic stroke. In addition, we wanted to examine whether hs-cTnT values on admission or dynamic changes in hs-cTnT are related to in-hospital mortality.

In this retrospective study, all patients aged 18 and above, discharged from Department of Neurology, Akershus University Hospital, with a diagnosis of acute ischemic stroke (ICD-10 I63.x [International Classification of Diseases, 10th revision]) between June 1, 2009 and May 31, 2010, were identified by a systematic search in our clinical database. In the case of multiple admissions during the study period, only the first admission was included. Patients admitted from other hospitals were excluded because of incomplete data. In this patient cohort, we have previously shown admission hs-cTnT levels to be a predictor of all-cause mortality [14].

In total, 367 patients were identified. In the present study, patients were excluded if admission was delayed more than 24 hours after symptom onset (n = 61), if they were diagnosed with acute MI within the last 7 days before admission or during hospitalization (n = 16), or if they were diagnosed with acute PE during hospitalization (n = 3). Patients with a diagnosis of ESRD requiring dialysis were not eligible (n = 0).

Patient characteristics were extracted by chart review and included age, gender and history of cerebrovascular disease (CVD), coronary heart disease (CHD), congestive heart failure, atrial fibrillation, diabetes mellitus, smoking, hypertension and hyperlipidemia. Stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS) [18]. Values regarding pulse and blood pressure (BP) were registered, and it was recorded whether the patients received intravenous thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA). Stroke etiology was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria [19].

Serum concentrations of hs-cTnT were routinely measured on admission and the following morning (up to 24 hours after the first measurement), or earlier at the discretion of the physician on call. The hs-cTnT analyses were performed using a commercially available assay (Roche Diagnostics, Mannheim, Germany). The limit of detection (LoD) was 5 ng/L (pg/mL), and values under this limit were routinely classified as 4.99 ng/L. According to the manufacturer, the upper reference limit (URL; the 99^th percentile in a normal reference population) was 14 ng/L. Recently, gender specific 99^th percentiles have been published [20]; 13 ng/L in females and 20 ng/L in males.

Biochemical analyses for blood leukocyte count and estimated glomerular filtration rate (eGFR) were performed on admission. eGFR was estimated using the Modification of Diet in Renal Disease (MDRD) formula.

Standard 12-lead ECGs recorded on admission were evaluated by two investigators (GE and PHB), blinded for patient data. Inter-observer differences were resolved by consensus. The following ECG parameters were analyzed: heart rate and rhythm, PR interval, QRS interval, QTc interval, Q wave, ST segment elevation and/ or depression [21], T-wave inversion [21], Sokolow-Lyon voltage [22] and the Cornell product [23]. The definitions of the ECG parameters are presented in Additional file 1: Table S1. Electrocardiographic left ventricular hypertrophy (LVH) was defined as fulfilling the Sokolow-Lyon voltage and/or the Cornell product criteria. Only heart rate and rhythm were evaluated in patients with pacemakers. PR interval was not evaluated in patients with atrial fibrillation/flutter. Sokolow Lyon voltage and the Cornell product were not evaluated in patients with left bundle branch block (LBBB). ST segment elevation, ST segment depression and T-wave inversion were not evaluated in patients with LBBB or LVH.

In-hospital mortality was used as the outcome measure.

Elevation of hs-cTnT in the entire study population was associated with older age (p < 0.001), history of CVD (p = 0.004) and CHD (p < 0.001), congestive heart failure (p < 0.001), atrial fibrillation (p < 0.001), diabetes mellitus (p = 0.007), non-smoking (p < 0.001) and hypertension (p < 0.001) in the univariate analyses. Patients with elevated hs-cTnT had more severe strokes (p = 0.001) and worse renal function (p < 0.001). There were no significant differences regarding pulse and BP.

The median value of the second hs-cTnT concentration was 16.9 ng/L (IQR 9.2-33.4). The median time interval between the two hs-cTnT measurements was 16.0 hours (IQR 10.7-19.8).

Of the 264 patients with serial measurements, 81 (30.7%) patients had dynamic relative change greater than 20%, while 46 (17.4%) patients had absolute change greater than 9.2 ng/L.

The hs-cTnT level was strongly correlated to age (Spearman’s ρ = 0.55, p < 0.001) and eGFR (Spearman’s ρ = - 0.40, p < 0.001).

The principal findings in this study among patients admitted with acute ischemic stroke are: i) hs-cTnT was higher than the URL in 53.4% of the patients; ii) 6.6% of the patients met the criteria of acute MI; iii) patients with elevated hs-cTnT more frequently had ST segment depression and T-wave inversion on ECG, and iv) higher age, history of CHD and congestive heart failure, presence of diabetes mellitus and renal dysfunction were variables significantly associated with hs-cTnT elevation.

Both the median hs-cTnT concentration and the prevalence of detectable hs-cTnT were considerably higher in this population of patients with acute ischemic stroke than previously reported in population-based cohorts and patients with stable CHD [20, 24, 25]. Previously, it has been demonstrated that elevated hs-cTnT is a predictor of 90-day clinical outcome [26] and long-term mortality [14] in ischemic stroke, thus it is of clinical relevance to identify determinants of elevated hs-cTnT. In a retrospective study, Scheitz et al [27] demonstrated that renal insufficiency, CHD, hypercholesterolemia, higher stroke severity and insular cortex involvement were significantly associated with elevated admission cTnT levels in ischemic stroke patients. A fourth generation assay was used to measure cTnT. In previous studies measuring cardiac troponin with conventional assays in patients with acute stroke, elevated levels have been reported as high as 34% [28]. In a meta-analysis from 2009 by Kerr et al [15], 18% of the patients had elevated troponin level, and these patients were more likely to have ECG changes suggestive of acute MI (OR 3.0). The present study shows that by using a highly sensitive assay with a lower limit of detection, more than 50% of acute ischemic stroke patients have elevated levels of cardiac troponin, even after exclusion of patients diagnosed with acute MI during hospitalization or prior to admission. Interestingly, patients with elevated hs-cTnT more frequently had ST segment depression and T-wave inversion, which are typical ECG manifestations of non-ST elevation MI (NSTEMI). We did not record patient symptoms such as chest pain or shortness of breath, but the presence of hs-cTnT elevation and ECG manifestations of myocardial ischemia indicate that acute MI is likely underdiagnosed in patients with acute ischemic stroke, although the findings are insufficient to conclude whether the ischemia has been caused by type 1 or type 2 MI [1]. Language or cognitive impairments and silent acute MIs before or in concert with the ischemic stroke could be possible explanations. In addition, congestive heart failure and renal failure could be responsible for the troponin elevation.

In a recently published study by Kral et al. [29], 36% of the patients had hs-cTnT higher than the URL, and 22% of the patients presented with elevated hs-cTnT with new or presumed new significant ST-T segment changes or new LBBB.

The etiology of troponin elevation in stroke is not completely understood and still debated. It has been suggested that elevated levels of cardiac markers in acute stroke patients could be related to myocytolysis due to activation of the sympathetic nervous system [30, 31]. However, earlier studies have focused on patients with subarachnoidal hemorrhage and arrhythmias. In patients with ischemic stroke, it is difficult to assess whether troponin elevation is due to the acute cerebral injury exerting myocardial stress or to pre-existing comorbidities associated with troponin elevation. Previously, epinephrine [12] and cortisol [28] have been associated with troponin elevation in acute stroke, indicating an imbalance between the parasympathetic and sympathetic nervous system. In our study, there were no significant differences in pulse or BP when comparing patients with normal and elevated hs-cTnT levels. Some studies have highlighted the association between insular cortex involvement and cTnT elevation [27, 32], suggesting neurologically induced myocardial injury. We did not assess the possible role of the insular cortex in troponin elevation.

In the study by Scheitz et al. [27], elevated cTnT on admission was an independent predictor of in-hospital mortality, but we could not confirm that a single value obtained on admission was independently associated with short-term outcome However, a novel finding is that dynamic changes in hs-cTnT levels (both relative and absolute change) seem to predict in-hospital mortality, which may indicate that dynamic changes in troponin levels rather than stable elevation related to chronic diseases could be related to poor short-term prognosis.

Our study has certain limitations. First, the retrospective collection of data limits the interpretation of the results, and prospective studies are required to confirm our findings. Second, there was a variation in time between the two hs-cTnT measurements, and the results regarding dynamic changes should therefore be interpreted with caution. It is recommended that blood samples for the measurement of cardiac troponins should be drawn on first assessment and repeated 3–6 hours later [1], while the median time interval was 16 hours in our study. In addition, because of the low number in-hospital mortality events, the results from the multivariate analyses should be considered preliminary, and larger studies are needed to clarify this issue. Future studies should focus on standardized serial measurements of hs-cTnT concentration to determine whether dynamic changes are related to poor short-term prognosis. On the other hand, the strict exclusion criteria excluded patients expected to have elevated troponin levels on admission or during hospitalization.

We have identified determinants and ECG changes associated with hs-cTnT elevation in patients with acute ischemic stroke, and this study demonstrates a possible role of dynamic changes in hs-cTnT for prediction of in-hospital mortality. Acute MI is likely underdiagnosed in patients with acute ischemic stroke. These results need to be verified in larger prospective studies.