, Volume 35, Issue 3, pp 978–984 | Cite as

C-Reactive Protein and Nitric Oxide Levels in Ischemic Stroke and Its Subtypes: Correlation with Clinical Outcome

  • K. Rajeshwar
  • Subhash Kaul
  • Amal Al-Hazzani
  • M. Sai Babu
  • N. Balakrishna
  • Vandana Sharma
  • A. Jyothy
  • Anjana Munshi


Studies in different populations have shown that ischemic stroke can trigger an acute phase response resulting in a rise of plasma concentration of C-reactive protein (CRP). However, there are very limited studies on CRP and first ischemic stroke divided into subtypes. High levels of CRP may also be associated with poor outcome. The present study was taken up to investigate the prognostic value of CRP within 24 h of onset of ischemic stroke. Five hundred and eighty one patients with first stroke and 575 age- and sex-matched healthy controls were involved in the study. High-sensitivity C-reactive protein (hsCRP) levels were estimated, and follow-up interviews were conducted with patients at 3, 6, and 12 months post-event to determine stroke outcome. In addition to this plasma, NO x (nitrate and nitrite) was measured to detect the serum NO (an important biomarker of inflammation and oxidative stress) levels in ischemic stroke patients and controls. The relationship between CRP value and poor outcome (>2 on modified Rankin Scale Score and <5 on an extended Glasgow outcome scale) was studied. There was a significant association between elevated levels of CRP and NO with the disease. A stepwise multiple logistic regression analysis confirmed these findings after adjustment for potential confounders [adjusted odds ratio = 2.890, 95% CI (1.603–5.011) with p < 0.01 and adjusted odds ratio = 2.364, 95% CI (1.312–3.998) with p < 0.01 for hsCRP and NO, respectively]. After adjustment of potential confounders, patients with high CRP levels had a significant increased risk of poor outcome [adjusted odds ratio = 3.50, 95% CI (1.312–6.365) and p < 0.001]. Elevated levels of hsCRP associated significantly with all stroke subtypes classified according to Trial of ORG 10172 in Acute Stroke Treatment classification except for lacunar stroke and stroke of other determined etiology. In conclusion, hsCRP and NO levels predict the incidence of ischemic stroke and hsCRP is an independent prognostic factor of poor outcome at 3 months.


high-sensitivity C-reactive protein (hsCRP) nitric oxide (NO) ischemic stroke stroke subtypes poor outcome 


  1. 1.
    Du Clos, T.W. 2000. Function of C-reactive protein. Annals of Medicine 32(4): 274–278.PubMedCrossRefGoogle Scholar
  2. 2.
    Calabro, P., J.T. Willerson, and E.T. Yeh. 2003. Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells. Circulation 108: 1930–1932.PubMedCrossRefGoogle Scholar
  3. 3.
    Verma, S., C.H. Wang, S.H. Li, A.S. Dumont, P.W.M. Fedak, M.V. Badiwala, B. Dhillon, R.D. Weisel, R. Li, D.A.G. Mickle, and D.J. Stewart. 2002. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106: 913–919.PubMedCrossRefGoogle Scholar
  4. 4.
    Danenberg, H.D., A.J. Szalai, R.V. Swaminathan, L. Peng, Z. Chen, P. Seifert, W.P. Fay, D.I. Simon, and E.R. Edelman. 2003. Increased thrombosis after arterial injury in human C-reactive proteintransgenic mice. Circulation 108: 512–515.PubMedCrossRefGoogle Scholar
  5. 5.
    Ridker, P.M., J.E. Buring, J. Shih, M. Matias, and C.H. Hennekens. 1998. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently woman. Circulation 98: 731–733.PubMedGoogle Scholar
  6. 6.
    Ford, E.S., and W.H. Giles. 2000. Serum C-reactive protein and self-repoted stroke. Findings from the third National health and nutrition examination survey. Arteriosclerosis, Thrombosis, and Vascular Biology 20(4): 1052–1056.PubMedCrossRefGoogle Scholar
  7. 7.
    Ridker, P.M., C.H. Hennekens, J.E. Buring, and N. Rifai. 2000. C reactive protein and other markers of inflammation in the prediction of cardio vascular disease in women. The New England Journal of Medicine 342: 836–843.PubMedCrossRefGoogle Scholar
  8. 8.
    Rost, N.S., P.A. Wolf, C.S. Kase, M. Kelly-hayes, H. Silbershatz, J.M. Massaro, R.B. Angostino, C. Franzblau, and P.W. Wilson. 2001. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack. The Framingham study. Stroke 32(11): 2575–2579.PubMedCrossRefGoogle Scholar
  9. 9.
    van Exel, E., J. Gussekloo, A.J. de Craen, A. Bootsma-vander Weil, M. Frolich, and R.G. Westendorp. 2002. Inflammation and stroke: the Leiden 85-plus study. Stroke 33: 1135–1138.PubMedCrossRefGoogle Scholar
  10. 10.
    Arenillas, J.F., J. Alavarez-sabin, C.A. Molinaatal, P. Chacon, J. Montaner, A. Rovira, B. Ibarra, and M. Quintana. 2003. C-reactive protein predicts further ischemic events in first-ever transient ischaemic attack or stroke patients with intracranial large artery occlusive disease. Stroke 34(10): 2463–2468.PubMedCrossRefGoogle Scholar
  11. 11.
    Ridker, P.M., N. Rifai, M.A. Pfeffer, F.M. Sacks, L.A. Moye, S. Goldman, G.C. Flaker, and E. Braunwald. 1998. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events (CARE) investigators. Circulation 98: 839–844.PubMedGoogle Scholar
  12. 12.
    Haverkate, F., S.G. Thompson, S.D. Pyke, J.R. Gallimore, and M.B. Pepys. 1997. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet 349(9050): 462–466.PubMedCrossRefGoogle Scholar
  13. 13.
    Retterstol, L., L. Eikvar, M. Bohn, A. Bakken, J. Erikssen, and K. Berg. 2002. C-reactive protein predicts death in patients with previous premature myocardial infarction—a 10-year follow-up study. Atherosclerosis 160(2): 433–440.PubMedCrossRefGoogle Scholar
  14. 14.
    Muir, K.W., C.J. WeirJ, W. Alwan, I.B. Squire, and K.R. Lees. 1999. C-reactive protein and outcome after ischemic stroke. Stroke 30: 981–985.PubMedCrossRefGoogle Scholar
  15. 15.
    Canova, C.R., C. Courtin, and W.H. Reinhart. 1999. C-reactive protein (CRP) in cerebro-vascular events. Atherosclerosis 147(1): 49–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Di Napoli, M., G. Di Gianfilippo, A. Sollecito, and V. Bocola. 2000. C-reactive protein and outcome after first-ever ischemic stroke. Stroke 31: 238–239.PubMedGoogle Scholar
  17. 17.
    Di Napoli, M., F. Papa, and V. Bocola. 2001. Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 32: 133–138.PubMedCrossRefGoogle Scholar
  18. 18.
    Anuk, T., E.B. Assayag, R. Rotstein, R. Fusman, D. Zeltser, S. Berliner, D. Avitzour, I. Shapira, N. Arber, and N.M. Bornstein. 2002. Prognostic implications of admission inflammatory profile in acute ischemic neurological events. Acta Neurologica Scandinavica 106(4): 196–199.PubMedCrossRefGoogle Scholar
  19. 19.
    Ceccarelli, E., C. Donati, S. Forconi, R. Cappelli, and L. Masotti. 2002. C-reactive protein, physical disability, and prognosis in very old patients with ischemic stroke. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 57(8): 520–522.CrossRefGoogle Scholar
  20. 20.
    Winbeck, K., H. Poppert, T. Etgen, B. Conrad, and D. Sander. 2002. Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke 33: 2459–2464.PubMedCrossRefGoogle Scholar
  21. 21.
    Emsley, H.C., C.J. Smith, C.M. Gavin, R.F. Georgiou, A. Vail, E.M. Barberan, J.M. Hallenbeck, G.J. del Zoppo, N.J. Rothwell, P.J. Tyrrell, and S.J. Hopkins. 2003. An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis. Journal of Neuroimmunology 139(1–2): 93–101.PubMedCrossRefGoogle Scholar
  22. 22.
    Di Napoli, M., F. Papa, and V. Bocola. 2001. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke 32: 917–924.PubMedCrossRefGoogle Scholar
  23. 23.
    Di Napoli, M., M. Schwaninger, R. Cappelli, E. Ceccarelli, G. Di Gianfilippo, C. Donati, H.C. Emsley, S. Forconi, S.J. Hopkins, L. Masotti, K.W. Muir, A. Paciucci, F. Papa, S. Roncacci, D. Sander, K. Sander, C.J. Smith, A. Stefanini, and D. Weber. 2005. Evaluation of C-reactive protein measurement for assessing the risk and prognosis in ischemic stroke: a statement for health care professionals from the CRP Pooling Project members. Stroke 36(6): 1316–1329.PubMedCrossRefGoogle Scholar
  24. 24.
    Ladenvall, C., K. Jood, C. Blomstrand, S. Nilsson, C. Jern, and P. Ladenvall. 2006. Serum C-reactive protein concentration and genotype in relation to ischemic stroke subtype. Stroke 37: 2018–2023.PubMedCrossRefGoogle Scholar
  25. 25.
    Gill, R., J.A. Kemp, C. Sabin, and M.B. Pepys. 2004. Human C-reactive protein increases cerebnan infarcet size after middle cerebnal asteny acclusion in adult rats. Journal of Cerebral Blood Flow and Metabolism 24(11): 1214–1218.PubMedGoogle Scholar
  26. 26.
    Pepys, M.B., G.M. Hirshchfield, G.A. Tennent, J.R. Gallimore, M.C. Kahan, V. Bellotti, P.N. Hawkins, R.M. Myers, M.D. Smith, A. Polara, A.J. Cobb, S.V. Ley, J.A. Aquilina, C.V. Robinson, I. Sharif, G.A. Gray, C.A. Sabin, M.C. Jenvey, S.E. Kolstoe, D. Thompson, and S.P. Wood. 2006. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440(7088): 1217–1221.PubMedCrossRefGoogle Scholar
  27. 27.
    Christensen, H., and G. Boysen. 2004. C-reactive protein and white blood cell court increases in the 24L after acute stroke. Cerebrovascular Diseases 18(3): 214–219.PubMedCrossRefGoogle Scholar
  28. 28.
    Masotti, L., E. Ceccarelli, S. Forconi, and R. Cappelli. 2005. Prognostic role of C-reactive protein is very old patients with acute ischemic stroke. Journal of Internal Medicine 258(2): 145–152.PubMedCrossRefGoogle Scholar
  29. 29.
    Montaner, J., I. Fernandez-cadenas, C.A. Molina, M. Ribó, R. Huertas, A. Rosell, A. Penalba, L. Ortega, P. Chacón, and J. Alvarez-Sabín. 2006. Post stroke C-reactive protein is a powerful prognostic tool among candidates for thrombolysis. Stroke 37(5): 1205–1210.PubMedCrossRefGoogle Scholar
  30. 30.
    Topakion, R., A.M. Strasak, K. Nuss baumer, H.P. Haring, and F.T. Aichner. 2008. Prognostic value of admission C-reactive protein in stroke patients undergoing iv thrombolysis. Journal of Neurology 255(8): 1190–1196.CrossRefGoogle Scholar
  31. 31.
    Libby, P., and M. Aikawa. 2003. Effects of statins in reducing thrombotic risk and modulating plaque vulnerability. Clinical Cardiology 26(1): I11–I14.PubMedCrossRefGoogle Scholar
  32. 32.
    Liu, V.W.T., and L.P. Huang. 2008. Cardiovascular roles of nitric oxide: A review of insights from nitric oxide synthase gene disrupted mice. Cardiovascular Research 77(1): 19–29.PubMedGoogle Scholar
  33. 33.
    Miralles, J.D., E. Martı’nez-Aguilar, A. Florez, C. Varela, S. Bleda, and F. Acin. 2009. Nitric oxide: link between endothelial dysfunction and inflammation in patients with peripheral arterial disease of the lower limbs. Interactive Cardiovascular and Thoracic Surgery 9(1): 107–112.CrossRefGoogle Scholar
  34. 34.
    Clapp, B.R., G.M. Hirchfield, C. Storry, J.R. Galimore, R.P. Stidwilal, and M. Singer. 2005. Inflamation and endothelial function. Direct vascular effects of human C-reactive protein on nitric oxide bio-availability. Circulation 111(12): 1530–1536.PubMedCrossRefGoogle Scholar
  35. 35.
    Ignarro, L.J., G. Cirino, A. Casini, and C. Napoli. 1999. Nitric oxide as a signaling molecule in the vascular system: an overview. Journal of Cardiovascular Pharmacology 34(6): 879–886.PubMedCrossRefGoogle Scholar
  36. 36.
    Rhodes, P., A.M. Leone, P.L. Francis, A.D. Struthers, S. Moncada, and P.M. Rhodes. 1995. The L-arginine:nitric oxide pathway is the major source of plasma nitrite in fasted humans. Biochemical and Biophysical Research Communications 209(2): 590–596.PubMedCrossRefGoogle Scholar
  37. 37.
    Munshi, A., S. Shehnaz, S. Kaul, B. Pulla Reddy, S. Alladi, and A. Jyothy. 2008. Angiotensin converting enzyme insertion/deletion polymorphism and the risk of ischemic stroke in a South Indian population. Journal of Neurological Sciences 272(1–2): 132–135.CrossRefGoogle Scholar
  38. 38.
    Lepoivre, M., B. Chenais, A. Yapo, G. Lemaire, L. Thelander, and J. Tenu. 1990. Alterations of ribonucleotide reductase activity follouring induction of nitrite—gencrating pathway in adeno Carcinoma cells. Journal of Biological Chemistry 265(24): 14143–14149.PubMedGoogle Scholar
  39. 39.
    Smith, C.J., H.C. Emsley, A. Vail, R.F. Georqiou, N.J. Rothwel, P.J. Tyrrell, and S.J. Halpkins. 2006. Varisability of the systemic acute phase response after ischemic stroke. Journal of Neurological Sciences 251(1–2): 77–81.CrossRefGoogle Scholar
  40. 40.
    Chei, C.L., K. Yamagishi, A. Kitamura, M. Kiyama, H. Imano, T. Ohira, R. Cui, T. Tanigawa, T. Sankai, Y. Ishikawa, S. Sato, and H. Iso. 2011. C-reactive protein levels and risk of stroke and its subtype in Japanese: The Circulatory Risk in Communities Study (CIRCS). Atherosclerosis 217(1): 187–193.PubMedCrossRefGoogle Scholar
  41. 41.
    Markus, H.S., B. Hunt, K. Palmer, C. Enzinger, H. Schmidt, and R. Schmidt. 2005. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: Longitudinal results of the austrian Stroke Prevention Study. Stroke 36(7): 1410–1414.PubMedCrossRefGoogle Scholar
  42. 42.
    Castillo, J., R. Rama, and A. Davalos. 2000. Nitric oxide related brain damage in acute ischemic stroke. Stroke 31(4): 852–857.PubMedCrossRefGoogle Scholar
  43. 43.
    Rashid, P.A., A. Whitehurst, N. Lawson, and P.M. Bath. 2003. Plasma nitric oxide (nitrate/nitrite) levels in acute stroke and their relationship with severity and outcome. Journal of Stroke and Cerebrovascular Diseases 12(2): 82–87.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • K. Rajeshwar
    • 1
    • 2
  • Subhash Kaul
    • 3
  • Amal Al-Hazzani
    • 4
  • M. Sai Babu
    • 1
    • 2
  • N. Balakrishna
    • 5
  • Vandana Sharma
    • 1
    • 2
  • A. Jyothy
    • 1
  • Anjana Munshi
    • 1
    • 4
    • 6
  1. 1.Institute of Genetics and Hospital for Genetic DiseasesOsmania UniversityHyderabadIndia
  2. 2.Dr. NTR University of Health SciencesVijayawadaIndia
  3. 3.Nizam’s Institute of Medical SciencesHyderabadIndia
  4. 4.Department of Botany and MicrobiologyKing Saud UniversityRiyadhSaudi Arabia
  5. 5.National Institute of NutritionHyderabadIndia
  6. 6.Department of Molecular BiologyInstitute of Genetics and Hospital for Genetic DiseasesHyderabadIndia

Personalised recommendations