BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to be associated with poor prognosis after cardiovascular events. We aimed to assess the dynamic changes in TRAIL levels and the relation of TRAIL level to stroke severity, its impact on the short-term outcomes, and its association with markers of cardiac injury in patients after acute stroke. METHODS: Between August 2020 and August 2021, 120 consecutive patients, 104 after acute ischemic stroke (AIS), 76 receiving reperfusion therapy, and 16 patients after intracerebral hemorrhage (ICH) were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 h later, and 48 h later to determine the plasma level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitive Troponin I (hs-TnI). Twelve-lead ECGs were obtained at the time of admission, 24 h later, 48 h later, and at the release of the patients. Evaluations were performed using the National Institutes of Health Stroke Scale (NIHSS) at the time of admission and using the modified Rankin Scale (mRS) 90 days following the patient's discharge from the hospital. RESULTS: We observed a connection between lower TRAIL levels and stroke severity evaluated using the NIHSS (p = 0.044) on the first day. Lower TRAIL showed an association with severe disability and death as evaluated using the mRS at 90 days, both after 24 (p = 0.0022) and 48 h (p = 0.044) of hospitalization. Moreover, we observed an association between lower TRAIL and NT-proBNP elevation at the time of admission (p = 0.039), after 24 (p = 0.043), and after 48 h (p = 0.023) of hospitalization. In the ECG analysis, lower TRAIL levels were associated with the occurrence of premature ventricular extrasystoles (p = 0.043), and there was an association with prolonged QTc interval (p = 0.052). CONCLUSIONS: The results show that lower TRAIL is associated with stroke severity, unfavorable functional outcome, and short-term mortality in patients after acute ischemic stroke. Moreover, we described the association with markers of cardiac injury and ECG changes.

Cardiocenter 3rd Faculty of Medicine Charles University 100 34 Prague Czech Republic

Department of Neurology 3rd Faculty of Medicine University Hospital Kralovske Vinohrady Charles University 100 34 Prague Czech Republic

Medtronic Czechia Partner of INTERCARDIS Project 190 00 Prague Czech Republic

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Wiley S.R., Schooley K., Smolak P.J., Din W.S., Huang C.P., Nicholl J.K., Sutherland G.R., Smith T.D., Rauch C., Smith C.A., et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3:673–682. doi: 10.1016/1074-7613(95)90057-8. PubMed DOI

Stuckey D.W., Shah K. TRAIL on trial: Preclinical advances in cancer therapy. Trends Mol. Med. 2013;19:685–694. doi: 10.1016/j.molmed.2013.08.007. PubMed DOI PMC

Gasparini C., Vecchi Brumatti L., Monasta L., Zauli G. TRAIL-based therapeutic approaches for the treatment of pediatric malignancies. Curr. Med. Chem. 2013;20:2254–2271. doi: 10.2174/0929867311320170009. PubMed DOI

Corallini F., Rimondi E., Secchiero P. TRAIL and osteoprotegerin: A role in endothelial physiopathology? Front. Biosci. 2008;13:135–147. doi: 10.2741/2665. PubMed DOI

Kavurma M.M., Bennett M.R. Expression, regulation and function of trail in atherosclerosis. Biochem. Pharmacol. 2008;75:1441–1450. doi: 10.1016/j.bcp.2007.10.020. PubMed DOI

Kakareko K., Rydzewska-Rosolowska A., Zbroch E., Hryszko T. TRAIL and Cardiovascular Disease-A Risk Factor or Risk Marker: A Systematic Review. J. Clin. Med. 2021;10:1252. doi: 10.3390/jcm10061252. PubMed DOI PMC

Teringova E., Kozel M., Knot J., Kocka V., Benesova K., Tousek P. Relationship between TRAIL and Left Ventricular Ejection Fraction in Patients with ST-Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention. BioMed Res. Int. 2018;2018:3709084. doi: 10.1155/2018/3709084. PubMed DOI PMC

Volpato S., Ferrucci L., Secchiero P., Corallini F., Zuliani G., Fellin R., Guralnik J.M., Bandinelli S., Zauli G. Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults. Atherosclerosis. 2011;215:452–458. doi: 10.1016/j.atherosclerosis.2010.11.004. PubMed DOI PMC

Mori K., Ikari Y., Jono S., Shioi A., Ishimura E., Emoto M., Inaba M., Hara K., Nishizawa Y. Association of serum TRAIL level with coronary artery disease. Thromb. Res. 2010;125:322–325. doi: 10.1016/j.thromres.2009.11.024. PubMed DOI

Secchiero P., Corallini F., Ceconi C., Parrinello G., Volpato S., Ferrari R., Zauli G. Potential prognostic significance of decreased serum levels of TRAIL after acute myocardial infarction. PLoS ONE. 2009;4:e4442. doi: 10.1371/journal.pone.0004442. PubMed DOI PMC

Niessner A., Hohensinner P.J., Rychli K., Neuhold S., Zorn G., Richter B., Hulsmann M., Berger R., Mortl D., Huber K., et al. Prognostic value of apoptosis markers in advanced heart failure patients. Eur. Heart J. 2009;30:789–796. doi: 10.1093/eurheartj/ehp004. PubMed DOI

Skau E., Henriksen E., Wagner P., Hedberg P., Siegbahn A., Leppert J. GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction. Eur. J. Prev. Cardiol. 2017;24:1576–1583. doi: 10.1177/2047487317725017. PubMed DOI

Ferreira J.P., Sharma A., Mehta C., Bakris G., Rossignol P., White W.B., Zannad F. Multi-proteomic approach to predict specific cardiovascular events in patients with diabetes and myocardial infarction: Findings from the EXAMINE trial. Clin. Res. Cardiol. 2021;110:1006–1019. doi: 10.1007/s00392-020-01729-3. PubMed DOI

Arcidiacono M.V., Rimondi E., Maietti E., Melloni E., Tisato V., Gallo S., Valdivielso J.M., Fernandez E., Betriu A., Voltan R., et al. Relationship between low levels of circulating TRAIL and atheromatosis progression in patients with chronic kidney disease. PLoS ONE. 2018;13:e0203716. doi: 10.1371/journal.pone.0203716. PubMed DOI PMC

Voltan R., Secchiero P., Casciano F., Milani D., Zauli G., Tisato V. Redox signaling and oxidative stress: Cross talk with TNF-related apoptosis inducing ligand activity. Int. J. Biochem. Cell Biol. 2016;81:364–374. doi: 10.1016/j.biocel.2016.09.019. PubMed DOI

Xia P., Liu Y., Cheng Z. Signaling Pathways in Cardiac Myocyte Apoptosis. BioMed Res. Int. 2016;2016:9583268. doi: 10.1155/2016/9583268. PubMed DOI PMC

Tisato V., Gonelli A., Voltan R., Secchiero P., Zauli G. Clinical perspectives of TRAIL: Insights into central nervous system disorders. Cell. Mol. Life Sci. 2016;73:2017–2027. doi: 10.1007/s00018-016-2164-7. PubMed DOI PMC

Tufekci K.U., Vurgun U., Yigitaslan O., Keskinoglu P., Yaka E., Kutluk K., Genc S. Follow-up Analysis of Serum TNF-Related Apoptosis-Inducing Ligand Protein and mRNA Expression in Peripheral Blood Mononuclear Cells from Patients with Ischemic Stroke. Front. Neurol. 2018;9:102. doi: 10.3389/fneur.2018.00102. PubMed DOI PMC

Pan X., Pang M., Ma A., Wang K., Zhang Z., Zhong Q., Yang S. Association of TRAIL and Its Receptors with Large-Artery Atherosclerotic Stroke. PLoS ONE. 2015;10:e0136414. doi: 10.1371/journal.pone.0136414. PubMed DOI PMC

Kang Y.H., Park M.G., Noh K.H., Park H.R., Lee H.W., Son S.M., Park K.P. Low serum TNF-related apoptosis-inducing ligand (TRAIL) levels are associated with acute ischemic stroke severity. Atherosclerosis. 2015;240:228–233. doi: 10.1016/j.atherosclerosis.2015.03.028. PubMed DOI

Soto-Camara R., Gonzalez-Santos J., Gonzalez-Berna J., Trejo-Gabriel-Galan J.M. Factors associated with a rapid call for assistance for patients with ischemic stroke. Emergencias. 2020;32:33–39. PubMed

Scheitz J.F., Nolte C.H., Laufs U., Endres M. Application and interpretation of high-sensitivity cardiac troponin assays in patients with acute ischemic stroke. Stroke. 2015;46:1132–1140. doi: 10.1161/STROKEAHA.114.007858. PubMed DOI

Kerr G., Ray G., Wu O., Stott D.J., Langhorne P. Elevated troponin after stroke: A systematic review. Cerebrovasc. Dis. 2009;28:220–226. doi: 10.1159/000226773. PubMed DOI

Faiz K.W., Thommessen B., Einvik G., Omland T., Ronning O.M. 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. PubMed DOI

de Lemos J.A., Morrow D.A., Bentley J.H., Omland T., Sabatine M.S., McCabe C.H., Hall C., Cannon C.P., Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N. Engl. J. Med. 2001;345:1014–1021. doi: 10.1056/NEJMoa011053. PubMed DOI

Wang T.J., Larson M.G., Levy D., Benjamin E.J., Leip E.P., Omland T., Wolf P.A., Vasan R.S. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N. Engl. J. Med. 2004;350:655–663. doi: 10.1056/NEJMoa031994. PubMed DOI

Fonarow G.C., Peacock W.F., Phillips C.O., Givertz M.M., Lopatin M., ADHERE Scientific Advisory Committee and Investigators Admission B-type natriuretic peptide levels and in-hospital mortality in acute decompensated heart failure. J. Am. Coll. Cardiol. 2007;49:1943–1950. doi: 10.1016/j.jacc.2007.02.037. PubMed DOI

Cushman M., Judd S.E., Howard V.J., Kissela B., Gutierrez O.M., Jenny N.S., Ahmed A., Thacker E.L., Zakai N.A. N-terminal pro-B-type natriuretic peptide and stroke risk: The reasons for geographic and racial differences in stroke cohort. Stroke. 2014;45:1646–1650. doi: 10.1161/STROKEAHA.114.004712. PubMed DOI PMC

Di Castelnuovo A., Veronesi G., Costanzo S., Zeller T., Schnabel R.B., de Curtis A., Salomaa V., Borchini R., Ferrario M., Giampaoli S., et al. NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) and the Risk of Stroke. Stroke. 2019;50:610–617. doi: 10.1161/STROKEAHA.118.023218. PubMed DOI

Osmancik P., Teringova E., Tousek P., Paulu P., Widimsky P. Prognostic value of TNF-related apoptosis inducing ligand (TRAIL) in acute coronary syndrome patients. PLoS ONE. 2013;8:e53860. doi: 10.1371/journal.pone.0053860. PubMed DOI PMC

Shichita T., Ito M., Yoshimura A. Post-ischemic inflammation regulates neural damage and protection. Front. Cell. Neurosci. 2014;8:319. doi: 10.3389/fncel.2014.00319. PubMed DOI PMC

Mabuchi T., Kitagawa K., Ohtsuki T., Kuwabara K., Yagita Y., Yanagihara T., Hori M., Matsumoto M. Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke. 2000;31:1735–1743. doi: 10.1161/01.STR.31.7.1735. PubMed DOI

Martin-Villalba A., Herr I., Jeremias I., Hahne M., Brandt R., Vogel J., Schenkel J., Herdegen T., Debatin K.M. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J. Neurosci. 1999;19:3809–3817. doi: 10.1523/JNEUROSCI.19-10-03809.1999. PubMed DOI PMC

Giannakoulas G., Hatzitolios A., Karvounis H., Koliakos G., Charitandi A., Dimitroulas T., Savopoulos C., Tsirogianni E., Louridas G. N-terminal pro-brain natriuretic peptide levels are elevated in patients with acute ischemic stroke. Angiology. 2005;56:723–730. doi: 10.1177/000331970505600610. PubMed DOI

Di Angelantonio E., Fiorelli M., Toni D., Sacchetti M.L., Lorenzano S., Falcou A., Ciarla M.V., Suppa M., Bonanni L., Bertazzoni G., et al. Prognostic significance of admission levels of troponin I in patients with acute ischaemic stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76:76–81. doi: 10.1136/jnnp.2004.041491. PubMed DOI PMC

Christensen H., Fogh Christensen A., Boysen G. Abnormalities on ECG and telemetry predict stroke outcome at 3 months. J. Neurol. Sci. 2005;234:99–103. doi: 10.1016/j.jns.2005.03.039. PubMed DOI

Christensen H., Boysen G., Christensen A.F., Johannesen H.H. Insular lesions, ECG abnormalities, and outcome in acute stroke. J. Neurol. Neurosurg. Psychiatry. 2005;76:269–271. doi: 10.1136/jnnp.2004.037531. PubMed DOI PMC

Eom Y.W., Jung H.Y., Oh J.E., Lee J.W., Ahn M.S., Youn Y.J., Ahn S.G., Kim J.Y., Lee S.H., Yoon J., et al. Isoproterenol Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Embryonic Kidney Cells through Death Receptor 5 up-Regulation. Korean Circ. J. 2016;46:93–98. doi: 10.4070/kcj.2016.46.1.93. PubMed DOI PMC

Secchiero P., Gonelli A., Corallini F., Ceconi C., Ferrari R., Zauli G. Metalloproteinase 2 cleaves in vitro recombinant TRAIL: Potential implications for the decreased serum levels of TRAIL after acute myocardial infarction. Atherosclerosis. 2010;211:333–336. doi: 10.1016/j.atherosclerosis.2010.02.024. PubMed DOI

Secchiero P., Gonelli A., Carnevale E., Milani D., Pandolfi A., Zella D., Zauli G. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation. 2003;107:2250–2256. doi: 10.1161/01.CIR.0000062702.60708.C4. PubMed DOI

Zauli G., Pandolfi A., Gonelli A., Di Pietro R., Guarnieri S., Ciabattoni G., Rana R., Vitale M., Secchiero P. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sequentially upregulates nitric oxide and prostanoid production in primary human endothelial cells. Circ. Res. 2003;92:732–740. doi: 10.1161/01.RES.0000067928.83455.9C. PubMed DOI

Secchiero P., Candido R., Corallini F., Zacchigna S., Toffoli B., Rimondi E., Fabris B., Giacca M., Zauli G. Systemic tumor necrosis factor-related apoptosis-inducing ligand delivery shows antiatherosclerotic activity in apolipoprotein E-null diabetic mice. Circulation. 2006;114:1522–1530. doi: 10.1161/CIRCULATIONAHA.106.643841. PubMed DOI

Secchiero P., Corallini F., di Iasio M.G., Gonelli A., Barbarotto E., Zauli G. TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release. Blood. 2005;105:3413–3419. doi: 10.1182/blood-2004-10-4111. PubMed DOI

Prevalence of myocardial injury in patients after acute ischaemic stroke according to standard criteria