Topical Review Application and Interpretation of High-Sensitivity Cardiac Troponin Assays in Patients With Acute Ischemic Stroke Jan F. Scheitz, MD; Christian H. Nolte, MD; Ulrich Laufs, MD; Matthias Endres, MD
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erebrovascular and cardiovascular diseases are major causes of death and disability worldwide. Ischemic stroke is a frequent complication in cardiac disease and, vice versa, cardiac complications commonly cause early clinical worsening and death after stroke.1 Adverse cardiac events account for the second largest group of deaths during the acute phase after stroke and are important determinants of long-term survival.2 Because of the close association between stroke and cardiac disease, current AHA/ASA guidelines for the early management of patients with acute ischemic stroke recommend assessment of cardiac biomarkers (preferably cardiac troponin [cTn]) in all patients presenting with acute ischemic stroke.3 Although the guidelines point out the potential prognostic significance of cTn, there are currently no recommendations on how to interpret cTn levels in the setting of ischemic stroke. Practice guidelines for interpretation of cTn generally include patients with stroke; specific recommendations, however, are scarce.4 Interpretation of cTn elevation in patients primarily presenting with ischemic stroke is complex because other conditions apart from acute thrombotic coronary artery disease (CAD) may also lead to the finding of an elevated cTn.4–6 What is more, clinical complaints associated with acute coronary syndromes may be atypical or masked by neurological deficits. Although early invasive coronary revascularization and potent antithrombotic therapy are lifesaving in patients with myocardial infarction (MI), caution is warranted in the context of an acute ischemic cerebral lesion. Recently, high-sensitivity cTn assays were developed, which enable detection of small amounts of circulating cTn.7,8 However, the marked increase in sensitivity for myocardial injury is accompanied by a reduced specificity for diagnosis of acute CAD. Consequently, the above-mentioned practice guidelines for applying highly sensitive cTn assays refer to stroke as one of the multiple clinical conditions, in which cTn testing has created clinical uncertainty.4 In this review, we summarize possible mechanisms of cTn elevation in ischemic stroke and provide stroke clinicians with
tools for interpreting and applying the controversial high-sensitivity cTn assays.
Evolution of cTn Assays and Their Application in Patients With Stroke It has long been recognized that acute cerebrovascular events may coincide with or trigger cardiac dysfunction and elevation of cardiac biomarkers. Already in the 1960s, creatine kinase was found to be transiently elevated in 56% of patients with cerebrovascular accidents, especially in patients with poor outcome.9 A large step forward was made in 1989 with the introduction of cTn in clinical practice.10 cTn soon became the preferred biomarker for diagnosing MI, and elevation above the 99th percentile of a normal reference population (with a coefficient of variation, 50% is recommended for identifying acute elevation, whereas in patients with higher baseline cTn levels a rise or fall pattern of cTn >20% is suggested.4,32 In a study by Anders et al,24 172 consecutive ischemic stroke patients with elevated cTn were serially measured with a high-sensitivity assay within a period of 3 hours. Sixty percent of patients with elevated cTn levels on admission showed a stable pattern of cTn levels (rise or fall 25% of patients with ischemic stroke and with no known history of CAD show coronary stenosis in coronary angiography.35 Importantly, patients with stroke represent an elderly population with atypical clinical presentation or impaired ability to report symptoms of acute coronary syndromes. Consequently, the frequency of coincident type 1 MI in patients with ischemic stroke remains unclear. The TRoponin ELevation in Acute ischemic Stroke (TRELAS) study, which aims to assess the frequency of culprit coronary lesions in stroke patients with cTn elevation, will afford more insight into the frequency of concomitant type 1 MI and concomitant stable CAD.36 Type 2 MI represents cardiac ischemia based on a mismatch between oxygen demand and supply. Common medical complications after stroke, such as tachyarrhythmia, hypertensive crisis, or respiratory failure with oxygen desaturation have been related to type 2 MI.1,37,38 A recent observational study showed that 26% of patients diagnosed with MI according to the universal definition of MI had type 2 MI.38 A cTn elevation in patients with stroke might, therefore, mirror ischemic myocardial injury ascribable to these medical complications.
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Figure 1. Possible mechanisms of acute troponin elevation in patients with ischemic stroke. Acute troponin elevation (with rise/fall pattern over time) might originate from ischemic and nonischemic myocardial injury (MI). It should be noted that the mechanisms are not mutually exclusive. As indicated by the arrows, neurocardiogenic mechanisms may promote demand ischemia or sudden cardiac death.
Type 2 MI might be promoted by the presence of a fixed coronary stenosis because of concomitant CAD. It is probable that a high proportion of acutely elevated cTn in patients with ischemic stroke is caused by type 2 MI, although more research is needed to accurately define frequency and treatment of this subgroup. Sudden cardiac death because of MI is termed type 3 MI.33 Type 4 MI (procedure-related) and type 5 MI (related to coronary artery bypass grafting) will usually have been documented in medical charts and thus not likely to cause clinical uncertainty.
Neurogenic Heart Syndrome: When a Stroke Hits the Heart One possible mechanism of acute cardiac injury in ischemic stroke, which pertains exclusively to patients with acute disease of the central nervous system is neurogenic myocardial damage. The magnitude of the effects of the central nervous system on cardiac function can be conceived in the context of cardiovascular events after severe emotional or physical stress. Already in 1942, Walter B. Cannon39 suggested that death because of a voodoo curse in ancient cultures with strong belief in external forces may be real and caused by a “persistent excessive activity of the sympathico-adrenal system.”39 In cultures of the modern era, examples for this phenomenon include the 2-fold increase of ventricular arrhythmias in patients with implantable cardioverter–defibrillators after the terrorist attack on the World Trade Center or the increased incidence of sudden cardiac death after the tsunami catastrophe in Japan 2011.40,41 Acute alterations in the autonomic control of the heart with exaggerated catecholamine release are thought to be the pathophysiologic explanation.42 Figure 2 displays the cascade of events linking autonomic imbalance after stroke with cTn elevation. Acute lesions within the central autonomic network may result in acute disturbance of normal sympathetic and parasympathetic neural outflow to the heart. A consequence of increased sympathetic activity is excessive catecholamine release in cardiac sympathetic nerves, with subsequent (over)activation of calcium channels. This results
in hypercontraction of sarcomeres, reduced muscle relaxation, and metabolic disturbance. The histopathologic finding in this context is called coagulative myocytolysis (also known as contraction band necrosis or myofibrillar degeneration).43 These lesions occur close to intracardiac nerves and are producible in animal models with application of stress hormones or catecholamine infusion.42 The same histopathologic findings can be seen in patients with takotsubo cardiomyopathy (TTC, also known as stress cardiomyopathy).44,45 TTC is a common mimic of MI with acute left ventricular dysfunction.44 Typically, cTn is mildly elevated in patients with TTC, whereas catecholamine levels markedly exceed those found in patients with MI.45 TTC was also observed in patients with ischemic stroke, in particular in those with insular cortex lesions.46,47 The insula is a crucial player within the central autonomic network. Because of the blood supply via the middle cerebral artery, the insula is frequently affected in anterior circulation stroke. Experimental stimulation of the insula produced sympathetic (right-sided stimulation) or parasympathetic (left-sided stimulation) alterations of heart rate and blood pressure.48 Of note, a voxel-based imaging study revealed an association between right insula cortex stroke and cTn elevation.49 Interestingly, patients with stroke affecting the insular cortex have higher catecholamine levels than do those without.50 In addition, it has been demonstrated that stroke patients with cTn elevation have higher circulating catecholamine levels than those without.51 In summary, autonomic imbalance with exaggerated sympathetic activity after stroke may lead to cardiac contraction band necrosis, and cardiac dysfunction with subsequent cTn release. Direct stroke-induced myocardial injury is thus likely to contribute to a relevant proportion of cTn elevation in patients with ischemic stroke. In addition to neurogenic mechanisms of cTn release, exaggerated catecholamine exposure may also lead to type 2 MI via coronary vasoconstriction and tachyarrhythmia. Preexisting cardiac morbidities may exacerbate the deleterious effects of autonomic imbalance. From this
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Figure 2. Neurogenic heart syndrome. Strokemediated troponin release triggered by autonomic imbalance: Altered sympathetic and parasympathetic activity may lead directly to myocardial contraction band necroses with or without the clinical phenotype of takotsubo cardiomyopathy (TTC). Alternatively, troponin release may be provoked indirectly via demand ischemia. PS indicates parasympathetic; and S, sympathetic.
perspective, acute brain injury could be viewed as a stress test for the heart.
Additional Causes of Acute Nonischemic Myocardial Injury Further causes of nonischemic myocardial injury in patients with stroke are acutely impaired renal function, acute HF, severe infection, and pulmonary embolism.4 These conditions are common complications in patients with acute stroke, and it is important that they be excluded.1 The mechanisms and therapeutic implications of cTn elevation in these conditions have been described elsewhere.4,5,22
Troponin Elevation in Stroke: “Troponinosis” or Prognostically Relevant? cTn elevation in patients without apparent acute coronary syndromes has been regarded as “troponinosis” or “troponinemia”.52 In patients with stroke, however, there is evidence that irrespective of the underlying mechanism cTn contains prognostic information about short- and long-term functional outcome and survival.13,14,27,53,54 A recent retrospective study showed that patients within the highest quartile of cTn measured with a high-sensitivity assay on hospital admission had a 1.6-fold increased risk of all-cause mortality during a follow-up period of 1.5 years when adjusted for age, baseline stroke severity, and comorbidities.53 In a prospective study of 1016 consecutive patients with ischemic stroke measured serially with a high-sensitivity cTn assay, the rate of unfavorable functional outcome at discharge (modified Rankin Scale >1) increased significantly with higher peak cTn levels.27 The adjusted odds ratio for unfavorable outcome was 1.8 (95% confidence interval [CI], 1.3–2.8) in patients with moderate cTn elevation (1–2 times the URL) and 3.4 (95% CI, 2.2–5.4) in patients with highly elevated cTn (>2 times the URL). C-statistics for prediction of functional short-term outcome were improved with addition of cTn to age, stroke severity, and comorbidities,
although the overall improvement was low (area under the curve, 0.85 versus 0.84; P=0.05). Of note, stroke patients with dynamic changes in cTn levels (>50%) within 24 hours showed a higher risk for in-hospital mortality (hazard ratio [HR], 2.3; 95% CI, 1.1–4.7) than patients with increased cTn levels who were stable over time.27 Further data are urgently needed to establish a clinically reliable prognostic threshold of cTn in the context of stroke for the prediction of unfavorable functional outcome or mortality.
Clinical Work-Up of Stroke Patients With Elevated cTn A possible algorithm for classification of elevated cTn in patients with ischemic stroke is shown in Figure 3. Figures 4 through 6 illustrate 3 typical clinical scenarios, in which application of cTn in stroke patients without apparent chest pain may cause uncertainty. General recommendations suggest that outpatient screening for structural or coronary heart disease (ie, echocardiography, exercise ECG, or coronary angiography) should be considered if cTn is elevated but stable over time (ie, nonacute).4,52 If there is evidence of heart disease, cardiovascular prevention measures should be intensified or reevaluated. This recommendation is based on the strong association between cTn levels and (subclinical) heart disease, future cardiovascular events and mortality.16,17,56 If there is evidence of acute ischemic myocardial injury (dynamic pattern), clinicians should promptly attempt to identify the most probable cause of cTn elevation.4,52 The pretest probability for MI increases with the presence of cardiovascular risk factors, ECG alterations suggestive of myocardial ischemia, typical chest discomfort, or dyspnea.4 Absolute cTn levels may help in identifying the most probable cause of myocardial damage.57 Patients with type 1 MI usually show higher cTn values than those with type 2 MI or TTC, and display more pronounced ECG alterations.37,57 Additional noninvasive cardiac diagnostics should be performed at a low threshold
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Figure 3. Possible algorithm for classification of elevated cardiac troponin (cTn) in acute ischemic stroke. The algorithm is based on the literature4,52 and has not been validated. Data on cut-offs of cTn for prediction of coronary ischemia in patients with stroke is limited. ACS indicates acute corornary syndrome; EF, ejection fraction; HRV, heart rate variability; PE, pulmonary embolism; SIRS, systemic inflammatory response; and TTC, takotsubo cardiomyopathy. *Note that the 99th percentile cut-off for definition of cTn elevation is likely to be 2 to 3 times higher in the elderly, especially in men.55 †Acute elevation of cTn (δ>50% within 24 hours) has been associated with in-hospital death,27 whereas chronic elevations have been linked to unfavorable short-term (optimal cut-off for high-sensitivity cTn [hs-cTn], 16 ng/L) and long-term (optimal cut-off for hs-cTn, 39 ng/L) outcomes.53 ‡Current cardiological guidelines suggest that a δ>20% within 3 to 6 hours is indicative of acute myocardial injury, whereas a δ criterion >50% should be applied in patients with low baseline cTn.4 §In general, absolute cTn and relative change in cTn is higher and ECG changes are more distinct in type 1 myocardial infarction (MI) compared with type 2 MI; absolute cTn and relative change in cTn is higher in MI than in noncoronary causes.37
in patients with high absolute cTn levels or with dynamic change in cTn because echocardiography or cardiac magnetic resonance imaging or computed tomography may help to identify patients with unstable CAD or other acute cardiac dysfunctions caused by HF or stress cardiomyopathy. If there is evidence for type 1 MI, potent platelet inhibition and revascularization are indicated in principle. However, depending on the size of acute ischemic brain lesion, these aggressive treatments might be contraindicated in patients with acute ischemic stroke. This remains a clinical dilemma and demands careful clinical judgment. More data are required to provide clinicians with a diagnostic cut-off for diagnosis of MI in patients with stroke. A recent analysis of large population-based studies suggested that the 99th percentile of cTn is highly age-dependent and that application of a uniform cut-off across all age groups is likely to lead to overdiagnosis of MI in the elderly.55 If type 2 MI or acute nonischemic myocardial injury has been caused by disorders, such as tachyarrhythmia, hypertensive emergencies, oxygen desaturation in acute HF or decompensated obstructive pulmonary disease, or severe infections, the respective disorders should be treated accordingly.
The possibility of neurogenic heart syndrome (with and without TTC) should be kept in mind, especially in insular cortex stroke. Absolute levels of cTn are usually lower than would be the case in MI.37,45,57 Although the best treatment of neurogenic heart syndrome has not yet been determined, β-blockers, α-blockers, or angiotensin-converting enzyme inhibitors might be considered.44
Future Perspectives: Possible Applications High-sensitivity cTn assays allow for detection of small degrees of myocardial injury that may precede the clinical manifestation of heart disease. It is tempting to speculate about its potential use as a biomarker for predicting and monitoring cardiovascular and cerebrovascular diseases. It has been shown that risk of incident HF and mortality was associated with the pattern of cTn levels during a period of 2 to 3 years. Patients with decreasing levels (>50%) during 2 to 3 years showed reduced risks of incident HF (HR, 0.73; 95% CI, 0.54–0.97) and cardiovascular death (HR, 0.71; 95% CI, 0.52–0.97), whereas patients with increasing cTn levels over time were at increased risk of incident HF
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Figure 4. Findings of neuroimaging and coronary angiography: stable cardiac troponin (cTn) levels over time because of chronic congestive heart failure. Imagine an 82-year-old woman with a history of hypertension presenting with acute middle cerebral artery stroke (A, Magnetic resonance imaging showing acute left middle cerebral artery infarction). Clinical examination shows mild pretibial edema and mild pulmonary rales. cTn is 46 ng/L on admission (upper reference limit 14, ng/L) and 48 ng/L 3 hours later (B, Time course of high-sensitivity cTn [hs-cTn] measured serially on admission, after 3 hours and after 24 hours, dashed line indicates 99th percentile, 14 ng/L). ECG shows negative T waves in V1–V3. Echocardiography displays reduced ejection fraction of 40%. Outpatient elective coronary angiography 3 weeks after stroke reveals stable coronary 1-vessel disease (C, Coronary angiography, arrow indicates stable 1-vessel coronary artery disease). This results in intensified secondary prevention measures (ie, lower cholesterol and blood pressure targets).
(HR, 1.61; 95% CI, 1.32–1.97) or death (HR, 1.65; 95% CI, 1.35–2.03).18 Interestingly, a longitudinal populationbased study showed that elevated cTn at baseline not only predicted cardiovascular death within the 10-year follow-up period (HR, 7.4; 95% CI, 4.6–11.6) but to a lower degree also death from stroke (HR, 3.3; 95% CI, 1.3–8.7), and cancer (HR, 1.6; 95% CI, 1.1–2.4).56 Furthermore, cTn was independently associated with increased risk of incident stroke in the general population (HR, 1.13; 95% CI, 1.1–1.2; follow-up 20 years).58 In patients with atrial fibrillation included in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, annual rates of stroke or systemic embolism during follow-up of 2 years ranged from 0.9% in the lowest cTn quartile to 2.1% in the highest quartile (HR, 1.9; 95% CI, 1.4–2.8).59 Of note, patients with atrial fibrillation and persistent levels of detectable cTn at 3 months after randomization within the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial had
significantly higher risk of incident stroke compared with patients with transient elevations (2.0% versus 0.8%).60 Elevation of cTn has also been linked to cognitive function in a recent community-based study.61 Subclinical myocardial injury as measured with highly sensitive cTn was associated with lower cognitive function at baseline. During follow-up for a median of 13 years, higher baseline cTn levels were also associated with incident hospitalization for dementia (HR, 2.7 for elevated versus undetectable cTn; 95% CI, 1.9–3.8), in particular vascular dementia. An explanation may be shared risk factors for small and large vessel disease that constitute a common pathway for simultaneous heart and brain damage. Moreover, heart disease may harm the brain via cardiac emboli or reduced cerebral perfusion in congestive HF. As described above, brain disease may, vice versa, cause neurogenic heart syndrome with myocardial injury.62 Overall, the concept of cTn as a staging biomarker or biomarker for monitoring of treatment success is appealing but needs further validation.
Figure 5. Findings of neuroimaging and coronary angiography: rising cardiac troponin (cTn) levels over time because of acute type 1 myocardial infarction (MI). Imagine a 71-year-old smoker with history of diabetes mellitus who presents with aphasia and right-sided hemiparesis after acute left middle cerebral artery stroke (A) Magnetic resonance imaging showing acute left middle cerebral artery infarction). Admission cTn is 183 ng/L (upper reference limit, 14 ng/L) and increases to 320 ng/L within 3 hours (B, Time course of high-sensitivity cTn [hs-cTn] measured serially on admission, after 3 hours and after 24 hours, dashed line indicates 99th percentile, 14 ng/L). ECG shows negative T waves in I, II, and aVF. Because echocardiography shows regional wall motion abnormalities, coronary angiography is performed and reveals acutely unstable coronary artery disease (type 1 MI) (C, Coronary angiography, arrow indicates unstable coronary lesion). The patient underwent percutaneous coronary intervention and is being treated with dual antiplatelet therapy. aVF indicates lead augmented vector foot.
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Figure 6. Findings of neuroimaging and coronary angiography: cardiac troponin (cTn) levels rising mildly over time because of takotsubo cardiomyopathy. Imagine a 76-year-old woman with right-sided insular cortex stroke (A, Magnetic resonance imaging showing acute right middle cerebral artery infarction with insular involvement). Resting heart rate at admission is 98 per minute. There are signs of mild heart failure (dyspnea and pretibial edema), whereas ECG shows no pathological findings. Initial cTn is 78 ng/L rising to 110 ng/L within 3 hours (B, Time course of high-sensitivity cTn [hs-cTn] measured serially on admission, after 3 hours and after 24 hours, dashed line indicates 99th percentile, 14 ng/L). This is accompanied by worsening of dyspnea. Echocardiography shows global wall motion abnormalities with reduced ejection fraction. Coronary angiography demonstrates left apical ballooning but no evidence of coronary artery disease (C, Ventriculography of coronary angiography, arrow indicates apical balooning). The patient is treated with β-blockers, and cardiac function is closely monitored with echocardiography.
Conclusions With the use of highly sensitive cTn assays, the vast majority of patients with acute ischemic stroke show detectable (ie, measurable) circulating cTn, and approximately half of patients show cTn levels elevated above the URL. cTn serum concentrations in patients with stroke provide strong prognostic information about short- and long-term functional outcome and mortality. The extent of cTn release is highly dependent on patient age and burden of chronic concurrent comorbidities. Serial measurements should be performed to establish whether cTn is acutely or chronically elevated. The majority of patients with ischemic stroke have stable cTn levels over time because of clinically (silent) stable comorbidities. Given the prognostic relevance of cTn in various stable disease states, screening for structural or coronary heart disease is advisable in these patients. If present, cardiovascular prevention measures should be intensified or reevaluated. Underlying mechanisms of acute cTn elevation after stroke include type 1 or (probably more often) type 2 MI, but the contribution of nonischemic myocardial injury via neurogenic-mediated mechanisms should also be considered. Acute cTn elevations with a dynamic pattern of cTn levels over time warrant careful clinical observation (chest pain, ECG alterations, thorough screening for complications leading to demand ischemia, or nonischemic myocardial injury). Whether cTn can be used for prediction of stroke recurrence or cognitive decline needs further investigation.
Acknowledgments We thank Catherine Aubel for editing the article for language and grammar.
Funding Sources Dr Scheitz is a participant in the Charité Clinical Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health. Dr Nolte received a research grant from the German Bundesministerium für Bildung und Forschung (BMBF, Center for Stroke Research Berlin) on research on cardiac complications after stroke. Dr Endres receives funding from the Deutsche Forschungsgemeinschaft
(DFG, NeuroCure, SFB TR 43, KFO 247, KFO 213), BMBF, Deutsches Zentrum für Herzkreislaufforschung (DZHK), European Union (European Stroke Network, WakeUp, Counterstroke), Corona Foundation (Vascular Senescence). The other authors report no conflicts.
Disclosures None.
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8 Stroke April 2015 detection of acute myocardial infarction in patients. J Mol Cell Cardiol. 1989;21:1349–1353. 11. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined–a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36:959–969. 12. Feher G, Tibold A, Koltai K, Szapary L. The clinical importance of troponin elevation in ischaemic cerebrovascular events: a clinical review. J Cardiol Therapy. 2014;7:141–149. 13. Kerr G, Ray G, Wu O, Stott DJ, Langhorne P. Elevated troponin after stroke: a systematic review. Cerebrovasc Dis. 2009;28:220–226. doi: 10.1159/000226773. 14. Scheitz JF, Endres M, Mochmann HC, Audebert HJ, Nolte CH. Frequency, determinants and outcome of elevated troponin in acute ischemic stroke patients. Int J Cardiol. 2012;157:239–242. doi: 10.1016/j. ijcard.2012.01.055. 15. Wu AH, Jaffe AS. The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing. Am Heart J. 2008;155:208–214. doi: 10.1016/j.ahj.2007.10.016. 16. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304:2503–2512. doi: 10.1001/jama.2010.1768. 17. Saunders JT, Nambi V, de Lemos JA, Chambless LE, Virani SS, Boerwinkle E, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation. 2011;123:1367–1376. doi: 10.1161/CIRCULATIONAHA.110.005264. 18. deFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA. 2010;304:2494–2502. doi: 10.1001/ jama.2010.1708. 19. Eggers KM, Lind L, Ahlström H, Bjerner T, Ebeling Barbier C, Larsson A, et al. Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects. Eur Heart J. 2008;29:2252–2258. doi: 10.1093/eurheartj/ehn327. 20. Iversen K, Køber L, Gøtze JP, Dalsgaard M, Nielsen H, Boesgaard S, et al. Troponin T is a strong marker of mortality in hospitalized patients. Int J Cardiol. 2013;168:818–824. doi: 10.1016/j.ijcard.2012.10.006. 21. Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM, Jablonski KA, et al; Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med. 2009;361:2538–2547. doi: 10.1056/NEJMoa0805299. 22. Januzzi JL Jr, Filippatos G, Nieminen M, Gheorghiade M. Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur Heart J. 2012;33:2265–2271. doi: 10.1093/eurheartj/ ehs191. 23. Faiz KW, Thommessen B, Einvik G, Brekke PH, Omland T, Rønning OM. Determinants of high sensitivity cardiac troponin T elevation in acute ischemic stroke. BMC Neurol. 2014;14:96. doi: 10.1186/1471-2377-14-96. 24. Anders B, Alonso A, Artemis D, Schäfer A, Ebert A, Kablau M, et al. What does elevated high-sensitive troponin I in stroke patients mean: concomitant acute myocardial infarction or a marker for high-risk patients? Cerebrovasc Dis. 2013;36:211–217. doi: 10.1159/000353875. 25. Jensen JK, Ueland T, Aukrust P, Antonsen L, Kristensen SR, Januzzi JL, et al. Highly sensitive troponin T in patients with acute ischemic stroke. Eur Neurol. 2012;68:287–293. doi: 10.1159/000341340. 26. Král M, Šaňák D, Veverka T, Hutyra M, Vindiš D, Kunčarová A, et al. Troponin T in acute ischemic stroke. Am J Cardiol. 2013;112:117–121. doi: 10.1016/j.amjcard.2013.02.067. 27. Scheitz JF, Mochmann HC, Erdur H, Tütüncü S, Haeusler KG, Grittner U, et al. Prognostic relevance of cardiac troponin T levels and their dynamic changes measured with a high-sensitivity assay in acute ischaemic stroke: analyses from the TRELAS cohort. Int J Cardiol. 2014;177:886–893. doi: 10.1016/j.ijcard.2014.10.036. 28. Bleier J, Vorderwinkler KP, Falkensammer J, Mair P, Dapunt O, Puschendorf B, et al. Different intracellular compartmentations of cardiac troponins and myosin heavy chains: a causal connection to their different early release after myocardial damage. Clin Chem. 1998;44:1912–1918.
29. White HD. Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis? J Am Coll Cardiol. 2011;57:2406–2408. doi: 10.1016/j.jacc.2011.01.029. 30. Vafaie M, Biener M, Mueller M, Schnabel PA, André F, Steen H, et al. Analytically false or true positive elevations of high sensitivity cardiac troponin: a systematic approach. Heart. 2014;100:508–514. doi: 10.1136/heartjnl-2012-303202. 31. Lindner G, Pfortmueller CA, Funk GC, Leichtle AB, Fiedler GM, Exadaktylos AK. High-sensitive troponin measurement in emergency department patients presenting with syncope: a retrospective analysis. PLoS One. 2013;8:e66470. doi: 10.1371/journal.pone.0066470. 32. Thygesen K, Mair J, Giannitsis E, Mueller C, Lindahl B, Blankenberg S, et al; Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J. 2012;33:2252–2257. doi: 10.1093/ eurheartj/ehs154. 33. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al; Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction; Authors/Task Force Members Chairpersons; Biomarker Subcommittee; ECG Subcommittee; Imaging Subcommittee; Classification Subcommittee; Intervention Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; Trials & Registries Subcommittee; ESC Committee for Practice Guidelines (CPG); Document Reviewers. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581–1598. doi: 10.1016/j.jacc.2012.08.001. 34. Pepi M, Evangelista A, Nihoyannopoulos P, Flachskampf FA, Athanassopoulos G, Colonna P, et al; European Association of Echocardiography. Recommendations for echocardiography use in the diagnosis and management of cardiac sources of embolism: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr. 2010;11:461–476. doi: 10.1093/ejechocard/ jeq045. 35. Amarenco P, Lavallée PC, Labreuche J, Ducrocq G, Juliard JM, Feldman L, et al. Prevalence of coronary atherosclerosis in patients with cerebral infarction. Stroke. 2011;42:22–29. doi: 10.1161/ STROKEAHA.110.584086. 36. Scheitz JF, Mochmann HC, Nolte CH, Haeusler KG, Audebert HJ, Heuschmann PU, et al. Troponin elevation in acute ischemic stroke (TRELAS)–protocol of a prospective observational trial. BMC Neurol. 2011;11:98. doi: 10.1186/1471-2377-11-98. 37. Alpert JS, Thygesen KA, White HD, Jaffe AS. Diagnostic and therapeutic implications of type 2 myocardial infarction: review and commentary. Am J Med. 2014;127:105–108. doi: 10.1016/j.amjmed.2013.09.031. 38. Saaby L, Poulsen TS, Hosbond S, Larsen TB, Pyndt Diederichsen AC, Hallas J, et al. Classification of myocardial infarction: frequency and features of type 2 myocardial infarction. Am J Med. 2013;126:789–797. doi: 10.1016/j.amjmed.2013.02.029. 39. Cannon WB. “Voodoo” death. American Anthropologist. 1942;44(new series):169–181. Am J Public Health. 2002;92:1593–1596. 40. Steinberg JS, Arshad A, Kowalski M, Kukar A, Suma V, Vloka M, et al. Increased incidence of life-threatening ventricular arrhythmias in implantable defibrillator patients after the World Trade Center attack. J Am Coll Cardiol. 2004;44:1261–1264. doi: 10.1016/j. jacc.2004.06.032. 41. Niiyama M, Tanaka F, Nakajima S, Itoh T, Matsumoto T, Kawakami M, et al. Population-based incidence of sudden cardiac and unexpected death before and after the 2011 earthquake and tsunami in Iwate, northeast Japan. J Am Heart Assoc. 2014;3:e000798. doi: 10.1161/ JAHA.114.000798. 42. Samuels MA. ‘Voodoo’ death revisited: the modern lessons of neurocardiology. Cleve Clin J Med. 2007;74(suppl 1):S8–S16. 43. Baroldi G. Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J. 1975;89:742–752. 44. Akashi YJ, Goldstein DS, Barbaro G, Ueyama T. Takotsubo cardiomyopathy: a new form of acute, reversible heart failure. Circulation. 2008;118:2754–2762. doi: 10.1161/CIRCULATIONAHA.108.767012. 45. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539–548. doi: 10.1056/NEJMoa043046. 46. Yoshimura S, Toyoda K, Ohara T, Nagasawa H, Ohtani N, Kuwashiro T, et al. Takotsubo cardiomyopathy in acute ischemic stroke. Ann Neurol. 2008;64:547–554. doi: 10.1002/ana.21459.
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Scheitz et al Use of Cardiac Troponins in Ischemic Stroke 9 47. Scheitz JF, Mochmann HC, Witzenbichler B, Fiebach JB, Audebert HJ, Nolte CH. Takotsubo cardiomyopathy following ischemic stroke: a cause of troponin elevation. J Neurol. 2012;259:188–190. doi: 10.1007/s00415-011-6139-1. 48. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology. 1992;42: 1727–1732. 49. Ay H, Koroshetz WJ, Benner T, Vangel MG, Melinosky C, Arsava EM, et al. Neuroanatomic correlates of stroke-related myocardial injury. Neurology. 2006;66:1325–1329. doi: 10.1212/01.wnl.0000206077.13705.6d. 50. Sander D, Winbeck K, Klingelhöfer J, Etgen T, Conrad B. Prognostic relevance of pathological sympathetic activation after acute thromboembolic stroke. Neurology. 2001;57:833–838. 51. Barber M, Morton JJ, Macfarlane PW, Barlow N, Roditi G, Stott DJ. Elevated troponin levels are associated with sympathoadrenal activation in acute ischaemic stroke. Cerebrovasc Dis. 2007;23:260–266. doi: 10.1159/000098325. 52. de Lemos JA. Increasingly sensitive assays for cardiac troponins: a review. JAMA. 2013;309:2262–2269. doi: 10.1001/jama.2013.5809. 53. Faiz KW, Thommessen B, Einvik G, Omland T, Rønning OM. Prognostic value of high-sensitivity cardiac troponin T in acute ischemic stroke. J Stroke Cerebrovasc Dis. 2014;23:241–248. doi: 10.1016/j. jstrokecerebrovasdis.2013.01.005. 54. James P, Ellis CJ, Whitlock RM, McNeil AR, Henley J, Anderson NE. Relation between troponin T concentration and mortality in patients presenting with an acute stroke: observational study. BMJ. 2000;320:1502–1504. 55. Gore MO, Seliger SL, Defilippi CR, Nambi V, Christenson RH, Hashim IA, et al. Age- and sex-dependent upper reference limits for the highsensitivity cardiac troponin T assay. J Am Coll Cardiol. 2014;63:1441– 1448. doi: 10.1016/j.jacc.2013.12.032. 56. Oluleye OW, Folsom AR, Nambi V, Lutsey PL, Ballantyne CM; ARIC Study Investigators. Troponin T, B-type natriuretic peptide, C-reactive
protein, and cause-specific mortality. Ann Epidemiol. 2013;23:66–73. doi: 10.1016/j.annepidem.2012.11.004. 57. Twerenbold R, Jaffe A, Reichlin T, Reiter M, Mueller C. High-sensitive troponin T measurements: what do we gain and what are the challenges? Eur Heart J. 2012;33:579–586. doi: 10.1093/eurheartj/ehr492. 58. Zeller T, Tunstall-Pedoe H, Saarela O, Ojeda F, Schnabel RB, Tuovinen T, et al; MORGAM Investigators. High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort. Eur Heart J. 2014;35:271–281. doi: 10.1093/eurheartj/eht406. 59. Hijazi Z, Wallentin L, Siegbahn A, Andersson U, Alexander JH, Atar D, et al; ARISTOTLE Investigators. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol. 2014;63:52–61. doi: 10.1016/j. jacc.2013.07.093. 60. Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, et al. Importance of persistent elevation of cardiac biomarkers in atrial fibrillation: a RE-LY substudy. Heart. 2014;100:1193– 1200. doi: 10.1136/heartjnl-2013-304872. 61. Schneider AL, Rawlings AM, Sharrett AR, Alonso A, Mosley TH, Hoogeveen RC, et al. High-sensitivity cardiac troponin T and cognitive function and dementia risk: the atherosclerosis risk in communities study. Eur Heart J. 2014;35:1817–1824. doi: 10.1093/eurheartj/ ehu124. 62. Nolte CH, Endres M. The heart of the matter: a link between troponin and dementia? Eur Heart J. 2014;35:1779–1781. doi: 10.1093/eurheartj/ ehu198. Key Words: cerebral infarction ◼ myocardial ischemia ◼ stroke ◼ takotsubo cardiomyopathy ◼ troponin ◼ troponin T
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Application and Interpretation of High-Sensitivity Cardiac Troponin Assays in Patients With Acute Ischemic Stroke Jan F. Scheitz, Christian H. Nolte, Ulrich Laufs and Matthias Endres Stroke. published online March 3, 2015; Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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erebrovascular and cardiovascular diseases are major causes of death and disability worldwide. Ischemic stroke is a frequent complication in cardiac disease and, vice versa, cardiac complications commonly cause early clinical worsening and death after stroke.1 Adverse cardiac events account for the second largest group of deaths during the acute phase after stroke and are important determinants of long-term survival.2 Because of the close association between stroke and cardiac disease, current AHA/ASA guidelines for the early management of patients with acute ischemic stroke recommend assessment of cardiac biomarkers (preferably cardiac troponin [cTn]) in all patients presenting with acute ischemic stroke.3 Although the guidelines point out the potential prognostic significance of cTn, there are currently no recommendations on how to interpret cTn levels in the setting of ischemic stroke. Practice guidelines for interpretation of cTn generally include patients with stroke; specific recommendations, however, are scarce.4 Interpretation of cTn elevation in patients primarily presenting with ischemic stroke is complex because other conditions apart from acute thrombotic coronary artery disease (CAD) may also lead to the finding of an elevated cTn.4–6 What is more, clinical complaints associated with acute coronary syndromes may be atypical or masked by neurological deficits. Although early invasive coronary revascularization and potent antithrombotic therapy are lifesaving in patients with myocardial infarction (MI), caution is warranted in the context of an acute ischemic cerebral lesion. Recently, high-sensitivity cTn assays were developed, which enable detection of small amounts of circulating cTn.7,8 However, the marked increase in sensitivity for myocardial injury is accompanied by a reduced specificity for diagnosis of acute CAD. Consequently, the above-mentioned practice guidelines for applying highly sensitive cTn assays refer to stroke as one of the multiple clinical conditions, in which cTn testing has created clinical uncertainty.4 In this review, we summarize possible mechanisms of cTn elevation in ischemic stroke and provide stroke clinicians with
tools for interpreting and applying the controversial high-sensitivity cTn assays.
Evolution of cTn Assays and Their Application in Patients With Stroke It has long been recognized that acute cerebrovascular events may coincide with or trigger cardiac dysfunction and elevation of cardiac biomarkers. Already in the 1960s, creatine kinase was found to be transiently elevated in 56% of patients with cerebrovascular accidents, especially in patients with poor outcome.9 A large step forward was made in 1989 with the introduction of cTn in clinical practice.10 cTn soon became the preferred biomarker for diagnosing MI, and elevation above the 99th percentile of a normal reference population (with a coefficient of variation, 50% is recommended for identifying acute elevation, whereas in patients with higher baseline cTn levels a rise or fall pattern of cTn >20% is suggested.4,32 In a study by Anders et al,24 172 consecutive ischemic stroke patients with elevated cTn were serially measured with a high-sensitivity assay within a period of 3 hours. Sixty percent of patients with elevated cTn levels on admission showed a stable pattern of cTn levels (rise or fall 25% of patients with ischemic stroke and with no known history of CAD show coronary stenosis in coronary angiography.35 Importantly, patients with stroke represent an elderly population with atypical clinical presentation or impaired ability to report symptoms of acute coronary syndromes. Consequently, the frequency of coincident type 1 MI in patients with ischemic stroke remains unclear. The TRoponin ELevation in Acute ischemic Stroke (TRELAS) study, which aims to assess the frequency of culprit coronary lesions in stroke patients with cTn elevation, will afford more insight into the frequency of concomitant type 1 MI and concomitant stable CAD.36 Type 2 MI represents cardiac ischemia based on a mismatch between oxygen demand and supply. Common medical complications after stroke, such as tachyarrhythmia, hypertensive crisis, or respiratory failure with oxygen desaturation have been related to type 2 MI.1,37,38 A recent observational study showed that 26% of patients diagnosed with MI according to the universal definition of MI had type 2 MI.38 A cTn elevation in patients with stroke might, therefore, mirror ischemic myocardial injury ascribable to these medical complications.
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Scheitz et al Use of Cardiac Troponins in Ischemic Stroke 3
Figure 1. Possible mechanisms of acute troponin elevation in patients with ischemic stroke. Acute troponin elevation (with rise/fall pattern over time) might originate from ischemic and nonischemic myocardial injury (MI). It should be noted that the mechanisms are not mutually exclusive. As indicated by the arrows, neurocardiogenic mechanisms may promote demand ischemia or sudden cardiac death.
Type 2 MI might be promoted by the presence of a fixed coronary stenosis because of concomitant CAD. It is probable that a high proportion of acutely elevated cTn in patients with ischemic stroke is caused by type 2 MI, although more research is needed to accurately define frequency and treatment of this subgroup. Sudden cardiac death because of MI is termed type 3 MI.33 Type 4 MI (procedure-related) and type 5 MI (related to coronary artery bypass grafting) will usually have been documented in medical charts and thus not likely to cause clinical uncertainty.
Neurogenic Heart Syndrome: When a Stroke Hits the Heart One possible mechanism of acute cardiac injury in ischemic stroke, which pertains exclusively to patients with acute disease of the central nervous system is neurogenic myocardial damage. The magnitude of the effects of the central nervous system on cardiac function can be conceived in the context of cardiovascular events after severe emotional or physical stress. Already in 1942, Walter B. Cannon39 suggested that death because of a voodoo curse in ancient cultures with strong belief in external forces may be real and caused by a “persistent excessive activity of the sympathico-adrenal system.”39 In cultures of the modern era, examples for this phenomenon include the 2-fold increase of ventricular arrhythmias in patients with implantable cardioverter–defibrillators after the terrorist attack on the World Trade Center or the increased incidence of sudden cardiac death after the tsunami catastrophe in Japan 2011.40,41 Acute alterations in the autonomic control of the heart with exaggerated catecholamine release are thought to be the pathophysiologic explanation.42 Figure 2 displays the cascade of events linking autonomic imbalance after stroke with cTn elevation. Acute lesions within the central autonomic network may result in acute disturbance of normal sympathetic and parasympathetic neural outflow to the heart. A consequence of increased sympathetic activity is excessive catecholamine release in cardiac sympathetic nerves, with subsequent (over)activation of calcium channels. This results
in hypercontraction of sarcomeres, reduced muscle relaxation, and metabolic disturbance. The histopathologic finding in this context is called coagulative myocytolysis (also known as contraction band necrosis or myofibrillar degeneration).43 These lesions occur close to intracardiac nerves and are producible in animal models with application of stress hormones or catecholamine infusion.42 The same histopathologic findings can be seen in patients with takotsubo cardiomyopathy (TTC, also known as stress cardiomyopathy).44,45 TTC is a common mimic of MI with acute left ventricular dysfunction.44 Typically, cTn is mildly elevated in patients with TTC, whereas catecholamine levels markedly exceed those found in patients with MI.45 TTC was also observed in patients with ischemic stroke, in particular in those with insular cortex lesions.46,47 The insula is a crucial player within the central autonomic network. Because of the blood supply via the middle cerebral artery, the insula is frequently affected in anterior circulation stroke. Experimental stimulation of the insula produced sympathetic (right-sided stimulation) or parasympathetic (left-sided stimulation) alterations of heart rate and blood pressure.48 Of note, a voxel-based imaging study revealed an association between right insula cortex stroke and cTn elevation.49 Interestingly, patients with stroke affecting the insular cortex have higher catecholamine levels than do those without.50 In addition, it has been demonstrated that stroke patients with cTn elevation have higher circulating catecholamine levels than those without.51 In summary, autonomic imbalance with exaggerated sympathetic activity after stroke may lead to cardiac contraction band necrosis, and cardiac dysfunction with subsequent cTn release. Direct stroke-induced myocardial injury is thus likely to contribute to a relevant proportion of cTn elevation in patients with ischemic stroke. In addition to neurogenic mechanisms of cTn release, exaggerated catecholamine exposure may also lead to type 2 MI via coronary vasoconstriction and tachyarrhythmia. Preexisting cardiac morbidities may exacerbate the deleterious effects of autonomic imbalance. From this
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Figure 2. Neurogenic heart syndrome. Strokemediated troponin release triggered by autonomic imbalance: Altered sympathetic and parasympathetic activity may lead directly to myocardial contraction band necroses with or without the clinical phenotype of takotsubo cardiomyopathy (TTC). Alternatively, troponin release may be provoked indirectly via demand ischemia. PS indicates parasympathetic; and S, sympathetic.
perspective, acute brain injury could be viewed as a stress test for the heart.
Additional Causes of Acute Nonischemic Myocardial Injury Further causes of nonischemic myocardial injury in patients with stroke are acutely impaired renal function, acute HF, severe infection, and pulmonary embolism.4 These conditions are common complications in patients with acute stroke, and it is important that they be excluded.1 The mechanisms and therapeutic implications of cTn elevation in these conditions have been described elsewhere.4,5,22
Troponin Elevation in Stroke: “Troponinosis” or Prognostically Relevant? cTn elevation in patients without apparent acute coronary syndromes has been regarded as “troponinosis” or “troponinemia”.52 In patients with stroke, however, there is evidence that irrespective of the underlying mechanism cTn contains prognostic information about short- and long-term functional outcome and survival.13,14,27,53,54 A recent retrospective study showed that patients within the highest quartile of cTn measured with a high-sensitivity assay on hospital admission had a 1.6-fold increased risk of all-cause mortality during a follow-up period of 1.5 years when adjusted for age, baseline stroke severity, and comorbidities.53 In a prospective study of 1016 consecutive patients with ischemic stroke measured serially with a high-sensitivity cTn assay, the rate of unfavorable functional outcome at discharge (modified Rankin Scale >1) increased significantly with higher peak cTn levels.27 The adjusted odds ratio for unfavorable outcome was 1.8 (95% confidence interval [CI], 1.3–2.8) in patients with moderate cTn elevation (1–2 times the URL) and 3.4 (95% CI, 2.2–5.4) in patients with highly elevated cTn (>2 times the URL). C-statistics for prediction of functional short-term outcome were improved with addition of cTn to age, stroke severity, and comorbidities,
although the overall improvement was low (area under the curve, 0.85 versus 0.84; P=0.05). Of note, stroke patients with dynamic changes in cTn levels (>50%) within 24 hours showed a higher risk for in-hospital mortality (hazard ratio [HR], 2.3; 95% CI, 1.1–4.7) than patients with increased cTn levels who were stable over time.27 Further data are urgently needed to establish a clinically reliable prognostic threshold of cTn in the context of stroke for the prediction of unfavorable functional outcome or mortality.
Clinical Work-Up of Stroke Patients With Elevated cTn A possible algorithm for classification of elevated cTn in patients with ischemic stroke is shown in Figure 3. Figures 4 through 6 illustrate 3 typical clinical scenarios, in which application of cTn in stroke patients without apparent chest pain may cause uncertainty. General recommendations suggest that outpatient screening for structural or coronary heart disease (ie, echocardiography, exercise ECG, or coronary angiography) should be considered if cTn is elevated but stable over time (ie, nonacute).4,52 If there is evidence of heart disease, cardiovascular prevention measures should be intensified or reevaluated. This recommendation is based on the strong association between cTn levels and (subclinical) heart disease, future cardiovascular events and mortality.16,17,56 If there is evidence of acute ischemic myocardial injury (dynamic pattern), clinicians should promptly attempt to identify the most probable cause of cTn elevation.4,52 The pretest probability for MI increases with the presence of cardiovascular risk factors, ECG alterations suggestive of myocardial ischemia, typical chest discomfort, or dyspnea.4 Absolute cTn levels may help in identifying the most probable cause of myocardial damage.57 Patients with type 1 MI usually show higher cTn values than those with type 2 MI or TTC, and display more pronounced ECG alterations.37,57 Additional noninvasive cardiac diagnostics should be performed at a low threshold
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Figure 3. Possible algorithm for classification of elevated cardiac troponin (cTn) in acute ischemic stroke. The algorithm is based on the literature4,52 and has not been validated. Data on cut-offs of cTn for prediction of coronary ischemia in patients with stroke is limited. ACS indicates acute corornary syndrome; EF, ejection fraction; HRV, heart rate variability; PE, pulmonary embolism; SIRS, systemic inflammatory response; and TTC, takotsubo cardiomyopathy. *Note that the 99th percentile cut-off for definition of cTn elevation is likely to be 2 to 3 times higher in the elderly, especially in men.55 †Acute elevation of cTn (δ>50% within 24 hours) has been associated with in-hospital death,27 whereas chronic elevations have been linked to unfavorable short-term (optimal cut-off for high-sensitivity cTn [hs-cTn], 16 ng/L) and long-term (optimal cut-off for hs-cTn, 39 ng/L) outcomes.53 ‡Current cardiological guidelines suggest that a δ>20% within 3 to 6 hours is indicative of acute myocardial injury, whereas a δ criterion >50% should be applied in patients with low baseline cTn.4 §In general, absolute cTn and relative change in cTn is higher and ECG changes are more distinct in type 1 myocardial infarction (MI) compared with type 2 MI; absolute cTn and relative change in cTn is higher in MI than in noncoronary causes.37
in patients with high absolute cTn levels or with dynamic change in cTn because echocardiography or cardiac magnetic resonance imaging or computed tomography may help to identify patients with unstable CAD or other acute cardiac dysfunctions caused by HF or stress cardiomyopathy. If there is evidence for type 1 MI, potent platelet inhibition and revascularization are indicated in principle. However, depending on the size of acute ischemic brain lesion, these aggressive treatments might be contraindicated in patients with acute ischemic stroke. This remains a clinical dilemma and demands careful clinical judgment. More data are required to provide clinicians with a diagnostic cut-off for diagnosis of MI in patients with stroke. A recent analysis of large population-based studies suggested that the 99th percentile of cTn is highly age-dependent and that application of a uniform cut-off across all age groups is likely to lead to overdiagnosis of MI in the elderly.55 If type 2 MI or acute nonischemic myocardial injury has been caused by disorders, such as tachyarrhythmia, hypertensive emergencies, oxygen desaturation in acute HF or decompensated obstructive pulmonary disease, or severe infections, the respective disorders should be treated accordingly.
The possibility of neurogenic heart syndrome (with and without TTC) should be kept in mind, especially in insular cortex stroke. Absolute levels of cTn are usually lower than would be the case in MI.37,45,57 Although the best treatment of neurogenic heart syndrome has not yet been determined, β-blockers, α-blockers, or angiotensin-converting enzyme inhibitors might be considered.44
Future Perspectives: Possible Applications High-sensitivity cTn assays allow for detection of small degrees of myocardial injury that may precede the clinical manifestation of heart disease. It is tempting to speculate about its potential use as a biomarker for predicting and monitoring cardiovascular and cerebrovascular diseases. It has been shown that risk of incident HF and mortality was associated with the pattern of cTn levels during a period of 2 to 3 years. Patients with decreasing levels (>50%) during 2 to 3 years showed reduced risks of incident HF (HR, 0.73; 95% CI, 0.54–0.97) and cardiovascular death (HR, 0.71; 95% CI, 0.52–0.97), whereas patients with increasing cTn levels over time were at increased risk of incident HF
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6 Stroke April 2015
Figure 4. Findings of neuroimaging and coronary angiography: stable cardiac troponin (cTn) levels over time because of chronic congestive heart failure. Imagine an 82-year-old woman with a history of hypertension presenting with acute middle cerebral artery stroke (A, Magnetic resonance imaging showing acute left middle cerebral artery infarction). Clinical examination shows mild pretibial edema and mild pulmonary rales. cTn is 46 ng/L on admission (upper reference limit 14, ng/L) and 48 ng/L 3 hours later (B, Time course of high-sensitivity cTn [hs-cTn] measured serially on admission, after 3 hours and after 24 hours, dashed line indicates 99th percentile, 14 ng/L). ECG shows negative T waves in V1–V3. Echocardiography displays reduced ejection fraction of 40%. Outpatient elective coronary angiography 3 weeks after stroke reveals stable coronary 1-vessel disease (C, Coronary angiography, arrow indicates stable 1-vessel coronary artery disease). This results in intensified secondary prevention measures (ie, lower cholesterol and blood pressure targets).
(HR, 1.61; 95% CI, 1.32–1.97) or death (HR, 1.65; 95% CI, 1.35–2.03).18 Interestingly, a longitudinal populationbased study showed that elevated cTn at baseline not only predicted cardiovascular death within the 10-year follow-up period (HR, 7.4; 95% CI, 4.6–11.6) but to a lower degree also death from stroke (HR, 3.3; 95% CI, 1.3–8.7), and cancer (HR, 1.6; 95% CI, 1.1–2.4).56 Furthermore, cTn was independently associated with increased risk of incident stroke in the general population (HR, 1.13; 95% CI, 1.1–1.2; follow-up 20 years).58 In patients with atrial fibrillation included in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, annual rates of stroke or systemic embolism during follow-up of 2 years ranged from 0.9% in the lowest cTn quartile to 2.1% in the highest quartile (HR, 1.9; 95% CI, 1.4–2.8).59 Of note, patients with atrial fibrillation and persistent levels of detectable cTn at 3 months after randomization within the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial had
significantly higher risk of incident stroke compared with patients with transient elevations (2.0% versus 0.8%).60 Elevation of cTn has also been linked to cognitive function in a recent community-based study.61 Subclinical myocardial injury as measured with highly sensitive cTn was associated with lower cognitive function at baseline. During follow-up for a median of 13 years, higher baseline cTn levels were also associated with incident hospitalization for dementia (HR, 2.7 for elevated versus undetectable cTn; 95% CI, 1.9–3.8), in particular vascular dementia. An explanation may be shared risk factors for small and large vessel disease that constitute a common pathway for simultaneous heart and brain damage. Moreover, heart disease may harm the brain via cardiac emboli or reduced cerebral perfusion in congestive HF. As described above, brain disease may, vice versa, cause neurogenic heart syndrome with myocardial injury.62 Overall, the concept of cTn as a staging biomarker or biomarker for monitoring of treatment success is appealing but needs further validation.
Figure 5. Findings of neuroimaging and coronary angiography: rising cardiac troponin (cTn) levels over time because of acute type 1 myocardial infarction (MI). Imagine a 71-year-old smoker with history of diabetes mellitus who presents with aphasia and right-sided hemiparesis after acute left middle cerebral artery stroke (A) Magnetic resonance imaging showing acute left middle cerebral artery infarction). Admission cTn is 183 ng/L (upper reference limit, 14 ng/L) and increases to 320 ng/L within 3 hours (B, Time course of high-sensitivity cTn [hs-cTn] measured serially on admission, after 3 hours and after 24 hours, dashed line indicates 99th percentile, 14 ng/L). ECG shows negative T waves in I, II, and aVF. Because echocardiography shows regional wall motion abnormalities, coronary angiography is performed and reveals acutely unstable coronary artery disease (type 1 MI) (C, Coronary angiography, arrow indicates unstable coronary lesion). The patient underwent percutaneous coronary intervention and is being treated with dual antiplatelet therapy. aVF indicates lead augmented vector foot.
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Scheitz et al Use of Cardiac Troponins in Ischemic Stroke 7
Figure 6. Findings of neuroimaging and coronary angiography: cardiac troponin (cTn) levels rising mildly over time because of takotsubo cardiomyopathy. Imagine a 76-year-old woman with right-sided insular cortex stroke (A, Magnetic resonance imaging showing acute right middle cerebral artery infarction with insular involvement). Resting heart rate at admission is 98 per minute. There are signs of mild heart failure (dyspnea and pretibial edema), whereas ECG shows no pathological findings. Initial cTn is 78 ng/L rising to 110 ng/L within 3 hours (B, Time course of high-sensitivity cTn [hs-cTn] measured serially on admission, after 3 hours and after 24 hours, dashed line indicates 99th percentile, 14 ng/L). This is accompanied by worsening of dyspnea. Echocardiography shows global wall motion abnormalities with reduced ejection fraction. Coronary angiography demonstrates left apical ballooning but no evidence of coronary artery disease (C, Ventriculography of coronary angiography, arrow indicates apical balooning). The patient is treated with β-blockers, and cardiac function is closely monitored with echocardiography.
Conclusions With the use of highly sensitive cTn assays, the vast majority of patients with acute ischemic stroke show detectable (ie, measurable) circulating cTn, and approximately half of patients show cTn levels elevated above the URL. cTn serum concentrations in patients with stroke provide strong prognostic information about short- and long-term functional outcome and mortality. The extent of cTn release is highly dependent on patient age and burden of chronic concurrent comorbidities. Serial measurements should be performed to establish whether cTn is acutely or chronically elevated. The majority of patients with ischemic stroke have stable cTn levels over time because of clinically (silent) stable comorbidities. Given the prognostic relevance of cTn in various stable disease states, screening for structural or coronary heart disease is advisable in these patients. If present, cardiovascular prevention measures should be intensified or reevaluated. Underlying mechanisms of acute cTn elevation after stroke include type 1 or (probably more often) type 2 MI, but the contribution of nonischemic myocardial injury via neurogenic-mediated mechanisms should also be considered. Acute cTn elevations with a dynamic pattern of cTn levels over time warrant careful clinical observation (chest pain, ECG alterations, thorough screening for complications leading to demand ischemia, or nonischemic myocardial injury). Whether cTn can be used for prediction of stroke recurrence or cognitive decline needs further investigation.
Acknowledgments We thank Catherine Aubel for editing the article for language and grammar.
Funding Sources Dr Scheitz is a participant in the Charité Clinical Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health. Dr Nolte received a research grant from the German Bundesministerium für Bildung und Forschung (BMBF, Center for Stroke Research Berlin) on research on cardiac complications after stroke. Dr Endres receives funding from the Deutsche Forschungsgemeinschaft
(DFG, NeuroCure, SFB TR 43, KFO 247, KFO 213), BMBF, Deutsches Zentrum für Herzkreislaufforschung (DZHK), European Union (European Stroke Network, WakeUp, Counterstroke), Corona Foundation (Vascular Senescence). The other authors report no conflicts.
Disclosures None.
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Application and Interpretation of High-Sensitivity Cardiac Troponin Assays in Patients With Acute Ischemic Stroke Jan F. Scheitz, Christian H. Nolte, Ulrich Laufs and Matthias Endres Stroke. published online March 3, 2015; Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
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