Abstract
The aim of this study was to investigate whether vitamin D deficiency (VDD) is associated with acute ischemic stroke, inflammatory markers, and short-term outcome. 168 acute ischemic stroke patients and 118 controls were included. The modified Rankin Scale (mRS) was applied up to 8 h of admission (baseline) and after three-months follow-up, and blood samples were obtained up to 24 h of admission to evaluate serum levels of 25-hydroxivitamin D [25(OH)D] and inflammatory markers. Vitamin D levels classified the individuals in sufficient (VDS ≥ 30.0 ng/mL), insufficient (VDI 20.0–29.9 ng/mL), and deficient (VDD < 20.0 ng/mL) status. Patients had lower levels of 25(OH)D, higher frequency of VDD (43.45% vs. 5.08%, OR: 16.64, 95% CI: 5.66–42.92, p < 0.001), and higher inflammatory markers than controls (p < 0.05). Patients with VDD showed increased high sensitivity C-reactive protein (hsCRP) levels than those with VDS status (p = 0.043); those with poor outcome presented with lower 25(OH)D levels than those with good outcome (p = 0.008); moreover, 25(OH)D levels were negatively correlated with mRS after three-months follow-up (r = −0.239, p = 0.005). The associations between VDD and higher hsCRP levels and between 25(OH)D levels and poor outcome at short-term in acute ischemic stroke patients suggest the important role of vitamin D in the inflammatory response and pathophysiology of this ischemic event.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adams HP, Bendixen BH, Kappelle LJ et al (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41
American Diabetes Association (2014) Standards of medical care in diabetes--2014. Diabetes Care 37(Suppl 1):S14–80. doi:10.2337/dc14-S014
Arenillas JF, Alvarez-Sabín J, Molina CA et al (2003) C-reactive protein predicts further ischemic events in first-ever transient ischemic attack or stroke patients with intracranial large-artery occlusive disease. Stroke 34:2463–8. doi:10.1161/01.STR.0000089920.93927.A7
Balden R, Selvamani A, Sohrabji F (2012) Vitamin D deficiency exacerbates experimental stroke injury and dysregulates ischemia-induced inflammation in adult rats. Endocrinology 153:2420–2435. doi:10.1210/en.2011-1783
Bolland MJ, Bacon CJ, Horne AM et al (2010) Vitamin D insufficiency and health outcomes over 5 y in older women. Am J Clin Nutr 91:82–9. doi:10.3945/ajcn.2009.28424
Bonita R, Beaglehole R (1988) Recovery of motor function after stroke. Stroke 19:1497–500
Boonstra A, Barrat FJ, Crain C et al (2001) 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 167:4974–80
Brazil (2011) Characteristics of the Population and Households: Results of the Universe. In: Charact. Popul. Households Results Universe. http://www.ibge.gov.br/english/estatistica/populacao/censo2010/caracteristicas_da_populacao/default_caracteristicas_da_populacao.shtm. Accessed 8 Feb 2015
Brøndum-Jacobsen P, Nordestgaard BG, Schnohr P, Benn M (2013) 25-hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Ann Neurol 73:38–47. doi:10.1002/ana.23738
Chaudhuri JR, Mridula KR, Alladi S et al (2014) Serum 25-hydroxyvitamin d deficiency in ischemic stroke and subtypes in Indian patients. J Stroke 16:44–50. doi:10.5853/jos.2014.16.1.44
Chen C, Nan B, Lin P, Yao Q (2008) C-reactive protein increases plasminogen activator inhibitor-1 expression in human endothelial cells. Thromb Res 122:125–33. doi:10.1016/j.thromres.2007.09.006
Cirillo P, Golino P, Calabro P et al (2005) C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc Res 68:47–55. doi:10.1016/j.cardiores.2005.05.010
Cohen-Lahav M, Shany S, Tobvin D et al (2006) Vitamin D decreases NFkappaB activity by increasing IkappaBalpha levels. Nephrol Dial Transplant 21:889–97. doi:10.1093/ndt/gfi254
Daubail B, Jacquin A, Guilland J-C et al (2013) Serum 25-hydroxyvitamin D predicts severity and prognosis in stroke patients. Eur J Neurol 20:57–61. doi:10.1111/j.1468-1331.2012.03758.x
Daubail B, Jacquin A, Guilland J-C et al (2014) Association between serum concentration of vitamin D and 1-year mortality in stroke patients. Cerebrovasc Dis 37:364–7. doi:10.1159/000362534
Di Napoli M, Papa F, Bocola V (2001) Prognostic influence of increased C-reactive protein and fibrinogen levels in ischemic stroke. Stroke 32:133–8
Drechsler C, Pilz S, Obermayer-Pietsch B et al (2010) Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J 31:2253–61. doi:10.1093/eurheartj/ehq246
Durup D, Jørgensen HL, Christensen J et al (2015) A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study. J Clin Endocrinol Metab 100:2339–46. doi:10.1210/jc.2014-4551
Ebeling PR (2014) Vitamin D and bone health: Epidemiologic studies. BoneKEy Rep 3:511. doi:10.1038/bonekey.2014.6
Ford JA, MacLennan GS, Avenell A et al (2014) Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. Am J Clin Nutr 100:746–55. doi:10.3945/ajcn.113.082602
Gupta A, Prabhakar S, Modi M et al (2014) Vitamin D status and risk of ischemic stroke in North Indian patients. Indian J Endocrinol Metab 18:721–5. doi:10.4103/2230-8210.139241
Hattori Y, Matsumura KK, Kasai K (2003) Vascular smooth muscle cell activation by C-reactive protein. Cardiovasc Res 58:186–195. doi:10.1016/S0008-6363(02)00855-6
Holick M (2007) Vitamin D deficiency. N Engl J Med 357:266–81
Huang Y-N, Ho Y-J, Lai C-C et al (2015) 1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures. J Neuroinflammation 12:147. doi:10.1186/s12974-015-0370-0
James PA, Oparil S, Carter BL et al (2014) 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311:507–20. doi:10.1001/jama.2013.284427
Jones G (2008) Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 88:582S–586S
Kendrick J, Targher G, Smits G, Chonchol M (2009) 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 205:255–60. doi:10.1016/j.atherosclerosis.2008.10.033
Kühn T, Kaaks R, Teucher B et al (2013) Plasma 25-Hydroxyvitamin D and Its Genetic Determinants in Relation to Incident Myocardial Infarction and Stroke in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany Study. PLoS One 8:1–12. doi:10.1371/journal.pone.0069080
Ladeby R, Wirenfeldt M, Garcia-Ovejero D et al (2005) Microglial cell population dynamics in the injured adult central nervous system. Brain Res Brain Res Rev 48:196–206. doi:10.1016/j.brainresrev.2004.12.009
Li YC (2003) Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 88:327–31. doi:10.1002/jcb.10343
Liu X, Nelson A, Wang X et al (2014) Vitamin D modulates prostaglandin E2 synthesis and degradation in human lung fibroblasts. Am J Respir Cell Mol Biol 50:40–50. doi:10.1165/rcmb.2013-0211OC
Majumdar V, Prabhakar P, Kulkarni GB, Christopher R (2015) Vitamin D status, hypertension and ischemic stroke: a clinical perspective. J Hum Hypertens. doi:10.1038/jhh.2015.10
Malek HA, Shata A (2014) Effect of a high dose of vitamin D on a rabbit model of atherosclerosis. Int J Immunopathol Pharmacol 27:195–201
Marniemi J, Alanen E, Impivaara O et al (2005) Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects. Nutr Metab Cardiovasc Dis 15:188–97. doi:10.1016/j.numecd.2005.01.001
Martins D, Wolf M, Pan D et al (2007) Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med 167:1159–65. doi:10.1001/archinte.167.11.1159
Michos ED, Reis JP, Post WS et al (2012) 25-Hydroxyvitamin D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files. Nutrition 28:367–71. doi:10.1016/j.nut.2011.10.015
Mitri J, Muraru MD, Pittas AG (2011) Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr 65:1005–15. doi:10.1038/ejcn.2011.118
Mozaffarian D, Benjamin EJ, Go AS et al (2015) Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. doi:10.1161/CIR.0000000000000350
Muir KW, Weir CJ, Alwan W et al (1999) C-reactive protein and outcome after ischemic stroke. Stroke 30:981–5
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and T of HBC in A (Adult TPI) (2002) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–421
Neveu I, Naveilhan P, Jehan F et al (1994) 1,25-dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells. Brain Res Mol Brain Res 24:70–6
Park K-Y, Chung P-W, Kim YB et al (2015) Serum Vitamin D Status as a Predictor of Prognosis in Patients with Acute Ischemic Stroke. Cerebrovasc Dis 40:73–80. doi:10.1159/000434691
Pasceri V, Willerson JT, Yeh ETH (2000) Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells. Circulation 102:2165–2168. doi:10.1161/01.CIR.102.18.2165
Penna G, Roncari A, Amuchastegui S et al (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4 + Foxp3 + regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106:3490–7. doi:10.1182/blood-2005-05-2044
Pilz S, Dobnig H, Fischer JE et al (2008) Low vitamin d levels predict stroke in patients referred to coronary angiography. Stroke 39:2611–3. doi:10.1161/STROKEAHA.107.513655
Rost NS, Wolf PA, Kase CS et al (2001) Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 32:2575–9
Sacco RL, Kasner SE, Broderick JP et al (2013) An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44:2064–89. doi:10.1161/STR.0b013e318296aeca
Shrivastava AK, Singh HV, Raizada A, Singh SK (2014) C-reactive protein, inflammation and coronary heart disease. Egypt Heart J 67:89–97. doi:10.1016/j.ehj.2014.11.005
Sun Q, Pan A, Hu FB et al (2012) 25-Hydroxyvitamin D Levels and the Risk of Stroke: A Prospective Study and Meta-analysis. Stroke 43:1470–1477. doi:10.1161/STROKEAHA.111.636910
Tang J, Zhou R, Luger D et al (2009) Calcitriol Suppresses Antiretinal Autoimmunity through Inhibitory Effects on the Th17 Effector Response. J Immunol 182:4624–4632. doi:10.4049/jimmunol.0801543
Tarcin O, Yavuz DG, Ozben B et al (2009) Effect of Vitamin D Deficiency and Replacement on Endothelial Function in Asymptomatic Subjects. J Clin Endocrinol Metab 94:4023–4030. doi:10.1210/jc.2008-1212
Tu W-J, Zhao S-J, Xu D-J, Chen H (2014) Serum 25-hydroxyvitamin D predicts the short-term outcomes of Chinese patients with acute ischaemic stroke. Clin Sci (Lond) 126:339–46. doi:10.1042/CS20130284
Turetsky A, Goddeau RP, Henninger N (2015) Low Serum Vitamin D Is Independently Associated with Larger Lesion Volumes after Ischemic Stroke. J Stroke Cerebrovasc Dis 24:1555–1563. doi:10.1016/j.jstrokecerebrovasdis.2015.03.051
Venugopal SK, Devaraj S, Yuhanna I et al (2002) Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation 106:1439–41
Vila N, Castillo J, Dávalos A, Chamorro A (2000) Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31:2325–9
Wang Y, Chiang YH, Su TP et al (2000) Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology 39:873–80
Wang Y, Ji H, Tong Y, Zhang Z (2014) Prognostic Value of Serum 25-Hydroxyvitamin D in Patients with Stroke. Neurochem Res 39:1332–1337. doi:10.1007/s11064-014-1316-0
Whiteley W, Jackson C, Lewis S et al (2011) Association of circulating inflammatory markers with recurrent vascular events after stroke: A prospective cohort study. Stroke 42:10–16
Winbeck K, Poppert H, Etgen T et al (2002) Prognostic relevance of early serial C-reactive protein measurements after first ischemic stroke. Stroke 33:2459–64
Worthmann H, Tryc AB, Goldbecker A et al (2010) The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovasc Dis 30:85–92
Zhang Y, Leung DYM, Richers BN et al (2012) Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 188:2127–35. doi:10.4049/jimmunol.1102412
Zittermann A, Gummert JF, Borgermann J (2011) The Role of Vitamin D in Dyslipidemia and Cardiovascular Disease. Curr Pharm Des 17:933–942. doi:10.2174/138161211795428786
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All the authors declare that there is no conflict of interest.
Rights and permissions
About this article
Cite this article
Alfieri, D.F., Lehmann, M.F., Oliveira, S.R. et al. Vitamin D deficiency is associated with acute ischemic stroke, C-reactive protein, and short-term outcome. Metab Brain Dis 32, 493–502 (2017). https://doi.org/10.1007/s11011-016-9939-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-016-9939-2