Blood Biomarkers for the Differentiation of Cardiac Ischemic Stroke Subtypes: A Systematic Review

Author(s): Abhishek Pathak*, Surya P. Pandey, Prasoon Madhukar, Priya Dev, Deepika Joshi, Vijay N. Mishra, Rameshwar N. Chaurasia.

Journal Name: Cardiovascular & Hematological Disorders-Drug Targets
(Formerly Current Drug Targets - Cardiovascular & Hematological Disorders)

Volume 19 , Issue 3 , 2019

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Graphical Abstract:


Background: Blood biomarkers are a cost-effective and valid method to diagnose ischemic stroke and differentiate its subtypes in countries with poor resources.

Objective: To perform a systematic review of published literature evaluating the diagnostic utility of blood-based biomarkers to diagnose and differentiate the etiology of ischemic stroke.

Methods: A comprehensive literature search was carried out till December 2017 in major scientific and medical databases including PubMed, Cochrane, OVID and Google Scholar. Modified Quality Assessment of Diagnostic Accuracy Studies questionnaire was used to assess the methodological quality of each study.

Results: Twenty-six studies were identified relevant to our systematic review. Various biomarkers have been studied, though only a few biomarkers such as a B-type natriuretic peptide (BNP) and Ddimer have proved their clinical utility. None of the other tested biomarkers appeared to have consistent results to diagnose ischemic stroke subtypes. Most of the studies had limitations in the classification of ischemic stroke, sample size, sample collection time, methods, biomarker selection and data analysis.

Conclusion: Our systematic review does not recommend the use of any blood biomarker for clinical purposes based on the studies conducted to date. BNP and D-dimer may present optimal biomarker for diagnosis and differentiation of ischemic stroke. However, large well-designed clinical studies are required to validate utility of these biomarkers to differentiate subtypes of ischemic stroke.

Keywords: Biomarkers, blood proteins, ischemia, natriuretic peptide brain, stroke, haemorrhagic stroke.

Donnan, G.A.; Fisher, M.; Macleod, M.; Davis, S.M. Stroke. Lancet, 2008, 371, 1612-1623.
Fonseca, A.C.; Matias, J.S.; Pinho e Melo, T.; Falcão, F.; Canhão, P.; Ferro, J.M. N-terminal probrain natriuretic peptide as a biomarker of cardioembolic stroke. Int. J. Stroke, 2011, 6, 398-403.
Kamalakannan, S.; Gudlavalleti, A.S.V.; Gudlavalleti, V.S.M.; Goenka, S.; Kuper, H. Incidence & prevalence of stroke in India: A systematic review. Indian J. Med. Res., 2017, 146, 175-185.
Wasay, M.; Khatri, I.A.; Kaul, S. Stroke in South Asian countries. Nat. Rev. Neurol., 2014, 10, 135-143.
Banerjee, T.; Das, S. Fifty years of stroke researches in India. Ann. Indian Acad. Neurol., 2016, 19, 1.
Yan, L.L.; Li, C.; Chen, J.; Miranda, J.J.; Luo, R.; Bettger, J.; Zhu, Y.; Feigin, V.; O’Donnell, M.; Zhao, D.; Wu, Y. Prevention, management, and rehabilitation of stroke in low- and middle-income countries. Neurol. Sci., 2016, 2, 21-30.
Whiteley, W.; Tseng, M.C.; Sandercock, P. Blood biomarkers in the diagnosis of ischemic stroke: A systematic review. Stroke, 2008, 39, 2902-2909.
Chaudhuri, J.R.; Sharma, V.K.; Mridula, K.R.; Balaraju, B.; Bandaru, V.C. Association of plasma brain natriuretic peptide levels in acute ischemic stroke subtypes and outcome. J. Stroke Cerebrovasc. Dis., 2015, 24, 485-491.
Shibazaki, K.; Kimura, K.; Okada, Y.; Iguchi, Y.; Uemura, J.; Terasawa, Y.; Aoki, J. Plasma brain natriuretic peptide as an independent predictor of in-hospital mortality after acute ischemic stroke. Intern. Med., 2009, 48, 1601-1606.
Naya, T.; Yukiiri, K.; Hosomi, N.; Takahashi, T.; Ohkita, H.; Mukai, M.; Koziol, J.A.; Kohno, M. Brain natriuretic peptide as a surrogate marker for cardioembolic stroke with paroxysmal atrial fibrillation. Cerebrovasc. Dis., 2008, 26, 434-440.
Yukiiri, K.; Hosomi, N.; Naya, T.; Takahashi, T.; Ohkita, H.; Mukai, M.; Masugata, H.; Murao, K.; Ueno, M.; Nakamura, T.; Dobashi, H.; Miki, T.; Kuroda, Y.; Kohno, M. Plasma brain natriuretic peptide as a surrogate marker for cardioembolic stroke. BMC Neurol., 2008, 8, 45.
Berntsson, J.; Zia, E.; Borné, Y.; Melander, O.; Hedblad, B.; Engström, G. Plasma natriuretic peptides and incidence of subtypes of ischemic stroke. Cerebrovasc. Dis., 2014, 37, 444-450.
Rodríguez-Yáez, M.; Sobrino, T.; Blanco, M.; de la Ossa, N.P.; Brea, D.; Rodríguez-González, R.; Leira, R.; Dávalos, A.; Castillo, J. High serum levels of pro-brain natriuretic peptide (pro BNP) identify cardioembolic origin in undetermined stroke. Dis. Markers, 2009, 26, 189-195.
Hajsadeghi, S.; Kashani Amin, L.; Bakhshandeh, H.; Rohani, M.; Azizian, A.R.; Jafarian Kerman, S.R. The diagnostic value of N-terminal pro-brain natriuretic peptide in differentiating cardioembolic ischemic stroke. J. Stroke Cerebrovasc. Dis., 2013, 22, 554-560.
Zecca, B.; Mandelli, C.; Maino, A.; Casiraghi, C.; Bolla, G.; Consonni, D.; Santalucia, P.; Torgano, G. A bioclinical pattern for the early diagnosis of cardioembolic stroke. Emerg. Med. Int., 2014, 2014242171
Fonseca, A.C.; Matias, J.S.; Pinho e Melo, T.; Falcão, F.; Canhão, P.; Ferro, J.M. N-terminal probrain natriuretic peptide as a biomarker of cardioembolic stroke. Int. J. Stroke, 2011, 6, 398-403.
Montaner, J.; Perea-Gainza, M.; Delgado, P.; Ribó, M.; Chacón, P.; Rosell, A.; Quintana, M.; Palacios, M.E.; Molina, C.A.; Alvarez-Sabín, J. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke, 2008, 39, 2280-2287.
Zi, W-J.; Shuai, J. Plasma D-dimer levels are associated with stroke subtypes and infarction volume in patients with acute ischemic stroke. PLoS One, 2014, 9e86465
Isenegger, J.; Meier, N.; Lämmle, B.; Alberio, L.; Fischer, U.; Nedeltchev, K.; Gralla, J.; Kohler, H.P.; Mattle, H.P.; Arnold, M. D-dimers predict stroke subtype when assessed early. Cerebrovasc. Dis., 2009, 29, 82-86.
Ageno, W.; Finazzi, S.; Steidl, L.; Biotti, M.G.; Mera, V.; Melzi D’Eril, G.; Venco, A. Plasma measurement of d-dimer levels for the early diagnosis of ischemic stroke subtypes. Arch. Intern. Med., 2002, 162, 2589-2593.
Liu, L-B.; Li, M.; Zhuo, W-Y.; Zhang, Y.S.; Xu, A.D. The role of hs-CRP, D-dimer and fibrinogen in differentiating etiological subtypes of ischemic stroke. PLoS One, 2015, 10e0118301
Rajeshwar, K.; Kaul, S.; Al-Hazzani, A.; Babu, M.S.; Balakrishna, N.; Sharma, V.; Jyothy, A.; Munshi, A. C-reactive protein and nitric oxide levels in ischemic stroke and its subtypes: Correlation with clinical outcome. Inflammation, 2012, 35, 978-984.
Ladenvall, C.; Jood, K.; Blomstrand, C.; Nilsson, S.; Jern, C.; Ladenvall, P. Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke, 2006, 37, 2018-2023.
Eikelboom, J.W.; Hankey, G.J.; Baker, R.I.; McQuillan, A.; Thom, J.; Staton, J.; Cole, V.; Yi, Q. C-reactive protein in ischemic stroke and its etiologic subtypes. J. Stroke Cerebrovasc. Dis., 2003, 12, 74-81.
Bang, O.Y.; Saver, J.L.; Liebeskind, D.S.; Pineda, S.; Ovbiagele, B. Association of serum lipid indices with large artery atherosclerotic stroke. Neurology, 2008, 70, 841-847.
Chei, C-L.; Yamagishi, K.; Kitamura, A.; Kiyama, M.; Imano, H.; Ohira, T.; Cui, R.; Tanigawa, T.; Sankai, T.; Ishikawa, Y.; Sato, S.; Hitsumoto, S.; Iso, H. CIRCS Investigators. High-density lipoprotein subclasses and risk of stroke and its subtypes in Japanese population: The Circulatory Risk in Communities Study. Stroke, 2013, 44, 327-333.
Vibo, R.; Kõrv, J.; Roose, M.; Kampus, P.; Muda, P.; Zilmer, K.; Zilmer, M. Acute phase proteins and oxidised low-density lipoprotein in association with ischemic stroke subtype, severity and outcome. Free Radic. Res., 2007, 41, 282-287.
Brea, D.; Sobrino, T.; Blanco, M.; Fraga, M.; Agulla, J.; Rodríguez-Yáñez, M.; Rodríguez-González, R.; Pérez de la Ossa, N.; Leira, R.; Forteza, J.; Dávalos, A.; Castillo, J. Usefulness of haptoglobin and serum amyloid A proteins as biomarkers for atherothrombotic ischemic stroke diagnosis confirmation. Atherosclerosis, 2009, 205, 561-567.
Turgut, B.; Turgut, N.; Çelik, Y.; Tekgündüz, E.; Pamuk, G.E.; Demir, M. Differences in platelet-leukocyte aggregates among subtypes of acute cerebral ischemia. J. Neurol. Sci., 2011, 305, 126-130.
Lin, S-P.; Lin, P-Y.; Jiang, H-L.; Long, Y.M.; Chen, X.H. Is serum total bilirubin useful to differentiate cardioembolic stroke from other stroke subtypes? Neurol. Res., 2015, 37, 727-731.
Tuttolomondo, A.; Di Raimondo, D.; Di Sciacca, R.; Casuccio, A.; Bivona, G.; Bellia, C.; Barreca, L.; Serio, A.; D’Aguanno, G.; Ciaccio, M.; Licata, G.; Pinto, A. Fetuin-A and CD40 L plasma levels in acute ischemic stroke: Differences in relation to TOAST subtype and correlation with clinical and laboratory variables. Atherosclerosis, 2010, 208, 290-296.
Kim, B.J.; Lee, S.H.; Ryu, W.S.; Kim, C.K.; Yoon, B.W. Adipocytokines and ischemic stroke: Differential associations between stroke subtypes. J. Neurol. Sci., 2012, 312, 117-122.
Tsai, N-W.; Chang, Y-T.; Huang, C-R.; Lin, Y.J.; Lin, W.C.; Cheng, B.C.; Su, C.M.; Chiang, Y.F.; Chen, S.F.; Huang, C.C.; Chang, W.N.; Lu, C.H. Association between oxidative stress and outcome in different subtypes of acute ischemic stroke. BioMed Res. Int., 2014, 2014, 1-7.
Naya, T.; Yukiiri, K.; Hosomi, N.; Takahashi, T.; Ohkita, H.; Mukai, M.; Koziol, J.A.; Kohno, M. Brain natriuretic peptide as a surrogate marker for cardioembolic stroke with paroxysmal atrial fibrillation. Cerebrovasc. Dis., 2008, 26, 434-440.
Nakamura, M.; Ishibashi, Y.; Tanaka, F.; Omama, S.; Onoda, T.; Takahashi, T.; Takahashi, S.; Tanno, K.; Ohsawa, M.; Sakata, K.; Koshiyama, M.; Ogasawara, K.; Okayama, A. Iwate-KENCO Study Group. Ability of B-type natriuretic peptide testing to predict cardioembolic stroke in the general population- comparisons with c-reactive protein and urinary albumin. Circ. J., 2018, 82, 1017-1025.
Monbailliu, T.; Goossens, J.; Hachimi-Idrissi, S. Blood protein biomarkers as diagnostic tool for ischemic stroke: A systematic review. Biomarkers Med., 2017, 11(6), 503-512.
Katan, M.; Elkind, M.S.V. The potential role of blood biomarkers in patients with ischemic stroke: An expert opinion. Clin. Trans. Neurosci, e2018, 1-7.

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Article Details

Year: 2019
Page: [215 - 227]
Pages: 13
DOI: 10.2174/1871529X18666180829142354
Price: $58

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