Background
Fighting heart disease and stroke is the agenda of the American Heart Association. What is more, the two diseases show intense connections as indicated by the high proportion of strokes with cardioembolic origin. Moreover, cardiac derangement has been observed in the context of acute neurological disorders causing myocardial dysfunction, arrhythmia, ECG alterations and rise of cardiac troponins [
1,
2].
The troponin protein complex consists of three subunits, namely troponin C, I and T, and contributes to the modulation of striated muscle contraction. Cardiac troponin C is identical to its skeletal isoform, but for troponin I and troponin T unique cardiac isoforms were identified. Monoclonal antibodies distinguish cardiac troponin T (cTnT) isoforms from fetal cardiac and skeletal isoforms without cross-reactivity, allowing the conclusion that elevation of cTnT in the blood stream always reflects myocardial injury [
3,
4]. However, the etiology of this myocardial injury is not revealed in the individual case, because increased cTnT was also found in the absence of thrombotic occlusion of a coronary vessel in other clinical conditions with cardiac injury or strain, such as heart failure, perimyocarditis, supraventricular tachycardias and pulmonary embolism [
5,
6]. Moreover, approximately 50% of the patients with renal insufficiency show increased cTnT values in the absence of symptoms of myocardial infarction [
7]. This may relate to associated left ventricular (LV) hypertrophy, "silent" micro-infarctions or decreased renal troponin excretion [
5,
7].
Interestingly, increased cTnT was also reported to occur in 5-34% of patients with acute ischemic stroke [
8]. In several studies, the elevation of cTnT was associated with stroke severity on hospital admission, insular cortex lesions, short- and long-term clinical outcome and increased risk of mortality [
9‐
12], indicating prognostic significance of increased cTnT in acute ischemic stroke.
In the individual stroke patient the cause of troponin elevation is uncertain. One possible explanation in some patients may be the coincidence of acute coronary syndrome (ACS) leading to ischemic myocardial necrosis. This notion is supported by the fact that stroke and myocardial infarction share common risk factors and by the high prevalence of coronary artery disease (CAD) in stroke patients [
13].
Neurogenic cardiac damage is another possible cause. Cardiac injury might result from autonomic imbalance after stroke affecting cortical areas controlling autonomic function, e.g. the insular cortex. A subsequent catecholamine surge may induce global LV dysfunction with ventriculographic findings of LV apical ballooning [
14,
15].
Due to the uncertainty regarding the underlying etiology of cTnT elevation in ischemic stroke patients the extent and time point of cardiologic work-up in this clinical situation is still under debate. Therefore, the aim of TRELAS is to determine the prevalence of troponin elevation in a prospective cohort of ischemic stroke patients and to display the frequency of underlying acute obstructive CAD, as defined by angiographic culprit lesions. Further objective is to clarify the frequency of associated neurocardiogenic LV dysfunction and insular cortex lesions.
Discussion
Elevated troponin levels are assumed to occur in up to 1 out of 6 patients presenting with acute cerebral ischemia and are associated with stroke severity, unfavorable short- and long-term clinical outcome [
2,
8]. Two candidate mechanisms are regarded to be relevant for troponin elevation in acute ischemic stroke when renal insufficiency is excluded. First, coincident ACS may lead to focal ischemic myocardial necrosis by means of thrombotic occlusion of a coronary vessel. Second, stroke-induced autonomic imbalance with subsequent surge of catecholamines could induce global damage and dysfunction of myocardial tissue and the release of cTnT. However, the underlying cause of cTnT elevation in the individual stroke patient remains questionable, leading to a diagnostic and therapeutic dilemma for the attending physician. In order to rule out coincident ACS reliably coronary status has to be clarified. However, estimated risks of cerebral bleeding complications limit the diagnostic work-up using CAG in patients with acute stroke.
Previous studies investigating troponin elevations in patients with ischemic stroke mainly described the prevalence and prognostic significance but data concerning co-existing acute CAD are scarce. Myocardial perfusion scintigraphy was carried out by Jensen et al. in 11 acute stroke patients with elevated cTnT, a cohort too small to produce significant results [
11]. So far, no study has used CAG to determine coronary status in patients with elevated cTnT and acute cerebral ischemia.
All stroke patients included in TRELAS will undergo CAG in order to determine the frequency of coronary culprit lesions associated to cTnT elevation. CAG is regarded to be the diagnostic gold standard for establishing the diagnosis of myocardial infarction [
30,
31]. Although non-invasive coronary CT imaging substantially improved over the last years, current guidelines recommend CAG in a clinical situation suggestive of myocardial infarction [
30]. Moreover, using CAG enables therapeutic intervention if a culprit lesion was identified. Within our study CAG will be done within 72 hours as recommended by guidelines of the American Heart Association and European Society of Cardiology for patients with NSTE-ACS and high likelihood of CAD [
30,
31] because patients with NSTE-ACS seem to benefit from early CAG [
32]. We have not defined typical chest pain as an inclusion criteria because one third of all myocardial infarctions in the elderly remain clinically "silent" [
33,
34]. In fact, cardiovascular disease is the most common cause of death in one-year stroke survivors [
35] and a substantial amount of stroke patients have asymptomatic coronary stenoses [
13] indicating CAD.
A reason for not performing CAG in stroke patients are safety concerns with an increased risk of brain hemorrhagic transformation and parenchymal hemorrhage because of anticoagulation during the procedure. However, only small amounts of heparin, if any, need to be administered during CAG and the increased risk of bleeding is rather caused by double-antiaggregation following application of coronary stents. In a recent study, CAG was performed in order to show previously unknown CAD in a large cohort of patients with ischemic stroke and proved to be safe even in the early phase of acute stroke (6-11 days after onset). In 315 stroke patients undergoing CAG no procedural adverse event was observed except one groin hematoma [
13].
A further objective of the TRELAS study is to investigate whether there is a correlation between troponin elevation and ischemia in the insular cortex which is regarded to play a crucial role in controlling the autonomic nervous system [
36]. In particular, right-sided insular lesions have been linked to disturbance of autonomic balance [
37]. Interestingly, Ay et al. conducted a voxel-wise analysis of diffusion weighted imaging lesions and reported a significant association of right insular cortex involvement and cTnT elevation [
12]. However, Barber et al. found no association of insular cortex stroke and increased serum cTnT [
38]. We hope the results of TRELAS to contribute to this issue.
Another aim of TRELAS is to assess the relation between neurogenic cardiac dysfunction and troponin elevation in ischemic stroke patients. Several studies reported disturbance of autonomic cardiac function with LV wall motion abnormalities in patients with acute ischemic stroke or subarachnoidal hemorrhage, respectively [
14,
39,
40]. In this context a unique kind of cardiomyopathy, termed
Takotsubo cardiomyopathy (TTC), seems noteworthy. Excessive catecholamine levels in the context of acute stressful events cause LV dysfunction with LV apical ballooning in TTC [
41], frequently combined with cTnT elevation despite of missing CAD [
26]. Diagnosis of TTC can be established via CAG and left ventriculography because the cardiac wall motion abnormalities associated with TTC can usually be shown and concomitant obstructive CAD can be ruled out simultaneously [
26]. The results of TRELAS will contribute to the question whether cTnT elevation in ischemic stroke is associated with myocardial LV dysfunction, and whether TTC is a relevant differential diagnosis in this clinical situation.
Impaired renal function is an exclusion criteria because diagnostic sensitivity to detect ACS is decreased in patients with renal failure [
42] and those patients are prone to adverse effects of the contrast agents administered for CAG. Nevertheless, only a few studies with troponin elevation in stroke excluded patients with renal insufficiency [
12,
15,
43].
To properly detect elevations of cTnT a high-sensitive troponin assay will be used. The assay was established recently to improve diagnostic precision, which is necessary according to the 2007 consensus definition of acute myocardial infarction [
44]. We do not expect significant inclusion of "false positive" patients in TRELAS because of the chosen cut-off, which is equal to cut-offs of former fourth cTnT assays [
25] and the exclusion of patients with impaired renal function.
There are some limitations of our study. First of all, CAG is conducted in a rather small cohort of 29 stroke patients. This sample size is adjusted to show a 50% difference in the occurrence of coronary culprit lesions between the matched-pairs. Thus, smaller differences are not detectable with a respective statistical power. Second, power estimation was carried out for finding significant results concerning the primary endpoint. Therefore, it might not be possible to present significant findings concerning the secondary endpoints. Third, the cerebral imaging modality will probably be heterogeneous in our study sample due to impossibility to ensure MRI in each stroke patient.
Taken together, troponin elevation is a frequent observation in patients with acute ischemic stroke and is associated with adverse outcome. As the underlying mechanism in the individual case is unclear there is a considerable diagnostic and therapeutic uncertainty. A focal cardiac ischemia due to acute rupture of coronary plaques requires urgent initiation of invasive cardiac diagnostics and intensified therapy. However, a proven stroke-mediated cardiomyopathy would open doors for heart protection strategies. The observational TRELAS trial will describe the prevalence of troponin elevation in a prospective cohort of acute ischemic stroke patients and will determine the frequency of possible etiological causes. Our findings may provide a basis for further recommendations regarding the extent and time point of cardiac work-up in this clinical setting.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors approved the final manuscript and contributed to its revision. CHN, BW and ME conceived the idea and together with JFS, HCM and BW conducted the design of the trial. CHN, HCM, ME, JFS, KGH, UL, HJA and HPS were involved in further planning. JFS drafted the manuscript. JFS, KGH, CHN and HCM will recruit patients. ME, HJA and HPS will participate in the supervision of the trial. PUH did and will do the statistical calculations.