In patients with acute ischemic stroke (AIS) elevated levels of cardiac troponin (cTn) are routinely detected as a biomarker for myocardial injury and are strongly associated with adverse patient outcomes (1–4). Consequently, national and international guidelines recommend the routine measurement of cTn levels in patients with AIS for the purpose of further risk stratification and diagnostics following hospital admission to a specialized stroke unit (5, 6). Latest research findings indicate that myocardial injury is more often attributable to abnormalities in the brain-heart interaction rather than being primarily caused by acute myocardial infarction (AMI) with coronary atherosclerotic plaque erosion or rupture (7–9).

Even though it is estimated that between 20 and 40% of patients with spontaneous intracerebral hemorrhage (sICH) exhibit elevated cTn levels at admission, only a limited number of studies have investigated this potential association with outcome (10, 11). Hemorrhagic stroke which includes sICH and subarachnoid hemorrhage is the second most common form of stroke and by itself associated with poor patient outcomes, which may be further exacerbated by cTn elevation at admission (10–12). Although there are current clinical practice guidelines and a recently updated diagnostic algorithm to determine the primary cause of cTn elevation in AIS patients, this approach has not yet been sufficiently established for patients with sICH (13–15). In contrast to established pathomechanisms of myocardial injury in AIS patients, preliminary research suggests that the release of cTn in sICH patients is primarily due to neurocardiogenic damage in the context of an autonomic dysfunction, which subsequently results in the release of catecholamines and, consequently, adrenergic overstimulation of the heart (16). Nevertheless, there is a paucity of data concerning the definitive causes of cTn elevation and the corresponding pattern of myocardial injury in patients with sICH. Furthermore, and in sharp contrast to patients with AIS, the influence of myocardial injury and the underlying mechanisms on outcomes with sICH, has not been sufficiently investigated.

The objective of this study was to examine patient characteristics and clinical parameters associated with cTn elevation in patients with sICH.

In the present study on a relevant population of sICH patients elevated hs-cTnI levels at admission were prevalent, consistent with prior studies on sICH patients. However, the frequency in our recent population was below the ones previously reported (10, 11, 19, 20). Baseline clinical characteristics revealed no significant differences between these patients and those without hs-cTnI elevation. A major finding of our data is that neither cardiac preconditions nor signs of structural heart disease, such as impaired LVEF or atrial fibrillation, nor neurological status were able to predict myocardial injury, with the exception of significant aortic valve stenosis. While sICH and CAD share several risk factors such as arterial hypertension, preexisting CAD in particular was relatively rare in our study population and did not predict hs-cTnI elevation.

Even though some clinical considerations suggest that elevated cTn levels in patients with sICH are associated with worse in-hospital functional and mortality-related outcome, there is still conflicting evidence on this topic, with some studies confirming this hypothesis (4, 10, 19, 21) and others failing to demonstrate this predictive value of cTn levels on outcome (22, 23). In our population, hs-cTnI elevation at admission was not associated with worse functional or mortality-related in-hospital outcomes. However, the short-term outcome of patients was poor overall with high levels of disability [median mRS at discharge 5 (IQR 3; 5) vs. 5 (IQR 3; 5)] and mortality.

While, consistent with prior studies, large hematoma volume was associated with a higher rate of in-hospital mortality, patients with large hematoma volume were not more likely to have elevated hs-cTnI levels (24, 25). Myocardial injury in sICH might therefore be triggered by more complex and interdependent mechanisms depending on bleeding location, hematoma volume, and dynamics potentiated by contributing factors such as IVH rather than hematoma volume alone.

Poor neurological status at admission may thus have contributed to the fact that hs-cTnI elevation at admission had no additional predictive influence on worse functional outcome in our population. Moreover, several other factors may have contributed to the novelty of our findings compared to previous findings:

Firstly, the inclusion criteria were heterogeneous and differed between prior studies, particularly with regard to the timing of cTn level measurement (at admission vs. within 24 h of admission vs. during hospitalization) and the cut-off values used to define elevated cTn levels. Additionally, older studies were subject to the limitation of unavailability of hs-cTnI assays (4). In the present study, all patients had hs-cTnI levels determined at the time of hospital admission and were acutely symptomatic with sICH. Previous studies did not employ a systematic approach to performing routine cTn level measurements at admission. Instead, these measurements were conducted at a later point in time, possibly introducing a selection bias for patients who were more medically unstable or more severely neurologically affected, or who were clinically suspected to suffer from AMI as the clinically derived reason for cTn level measurement, resulting in higher rates of poorer outcomes and mortality (10, 20, 26, 27). Several previous studies had a relatively small study population, with numbers ranging between 100 and 200 patients per study (20, 22, 27). In one of the earliest studies to identify an association between the prognosis of patients with sICH and the elevation of cTn levels, Hays and colleagues were compelled to exclude 37.7% of eligible patients due to the unavailability of cCT scans and an additional 15% due to the lack of cTn data (10). In this study, cTn level measurement within the first 24 h of hospitalization was subject to a significant selection bias, as patients with a history of cardiac disease or suspected AMI were more likely to receive cTn testing (10).

A further small study comprising 100 ICH patients, including those with traumatic ICH etiology, undergoing clot evacuation identified cTn elevation and the volume of hemorrhage as predictors of in-hospital mortality. In this study, cTn levels were not assessed systematically at admission: rather, they were only evaluated if specific criteria were met, such as the presence of electrocardiographic abnormalities and certain clinical parameters. Additionally, patients with a history of CAD were excluded (20). In this study, the neurological status of patients was not addressed in a systematic manner, and the short-term neurological outcomes were not compared. The interpretation of the results of this study is further complicated by the fact that surgical therapy in ICH is often restricted to young, previously healthy patients with superficial lesions and deteriorating neurological exams after admission, resulting in a severe selection bias for younger patients (20). In general, the majority of previous studies have comprised a significantly younger study population, with mean ages ranging between 50 and 60 years (19–21, 27). In comparison, the mean age of our study population was 75.0 ± 13.2. Consequently, elevated hs-cTnI levels at admission in an older study population may be indicative of overall multimorbidity, rather than neurological disability. Furthermore, at this juncture, it may not contribute significantly to neurological outcome and mortality, which are primarily caused by the initial “hit” suffered from the sICH.

In a more recent and larger prospective study, Gerner and colleagues found that peak cTn elevation at any point during hospitalization was associated with worse neurological outcome at admission and at discharge while interestingly, similar to our results, short-term mortality did not differ significantly between the groups (11). In their retrospective study, where only 63% of eligible patients with sICH had a cTn level measurement at admission, Tummala and colleagues found a higher mortality rate in patients with sICH and cTn elevation, but in a multivariate regression analysis cTn levels were no independent predictor of mortality (28).

Interestingly, in the recently published secondary observational analysis of the Factor Seven for Acute Hemorrhagic Stroke (FAST) Trial, Rosso and colleagues found increased mortality and worse neurological outcomes in patients with acute myocardial injury, defined as at least one cTn value above the upper reference limit with an increase or decrease of >20% within 48 h (21). Their data showed a very low incidence of significant cardiac complications in both patients with and without cTn elevation. In addition, no significant difference in outcomes was observed when comparing patients with cTn elevation but a decrease of cTn on subsequent measurement to patients with non-elevated cTn levels. One implication of this finding is that acute myocardial injury, rather than an isolated cTn elevation at admission, may be a potential predictor of poor outcome and mortality.

Elevated cTn levels indicate myocardial injury, but do not reveal the underlying pathology of myocardial cell damage, nor do elevated cTn levels unequivocally indicate AMI. In fact, the Fourth Universal Definition of Myocardial Infarction provides us with different types of myocardial injury, all of which are possible causes in sICH patients (29). Accordingly, myocardial injury may be caused by ischemic as well as non-ischemic pathologies or by chronic structural heart disease (29). Following the brain-heart axis, the cTn release, i.e., myocardial cell damage, can also be caused by dysregulation of the complex central autonomic network leading to enhanced stress responses, often referred to as stroke-heart syndrome as a consequence of stroke-induced heart injury (16). The central autonomic network, which includes cortical and subcortical regions and has a strong association with the insular cortex, particularly in the right hemisphere, induces responses in cardiovascular function via the autonomic nervous system and the hypothalamic-pituitary-adrenal axis (30–32). Studies have proposed that an overactivation of this network results in the release of excessive amounts of catecholamines that disrupt cardiomyocyte function, causing microcirculatory dysfunction and coronary insufficiency by vasoconstriction (13, 16). As patients with hs-cTnI elevation in the present study population did not have an overall more pronounced cerebrovascular risk profile and had a comparatively low prevalence of CAD, our findings support the growing evidence that cTn elevation in connection with sICH is primarily related to myocardial damage along the brain-heart axis and less to macrovascular ischemic conditions. However, further investigation is needed as cTn level measurement at admission may be insufficient in detecting myocardial injury. Serial cTn level measurements with the possibility to detect dynamic changes may provide a more suitable tool to identify patients suffering from acute myocardial injury.

The interpretation of our results is limited by the retrospective study design and the exclusion of 109 patients (18.0%) due to insufficient data. Specifically, there was no data available regarding pre-hospital delay times and therefore further analysis of its impact on in-hospital outcome could not be performed.

The findings of this study indicate that patients with sICH are at an elevated risk for myocardial injury, not specifically predicted by neurological status at admission or preexisting structural heart disease. Short-term outcome might not be further influenced by hs-cTnI elevation in severely affected sICH patients. However, the etiology and predictive value of cTn elevation remain uncertain, underscoring the need for continued research to identify risk factors for myocardial injury and diagnostic algorithms to detect patients who would benefit from an intensive cardiac work-up.