Neutrophil-to-lymphocyte ratio: an inflammation marker related to cardiovascular risk in children

Summary

Low-grade chronic inflammation plays a pathogenic role in cardiovascular disease. An increase in the ratio of circulating neutrophils to lymphocytes (N/L ratio) may serve as a marker of cardiovascular risk in adults. It was the study objective to study whether N/L ratio associates with vascular parameters in children. Subjects were 501 prepubertal and early pubertal Caucasian children (mean age 8.0 years; mean body mass index (BMI) Z-score 0.2 ± 0.9; 266 boys and 235 girls) recruited within an ongoing population-based study. The subjects were stratified into three groups according to age. Neutrophil, lymphocyte, BMI, waist circumference, systolic blood pressure (SBP) and carotid intima-media thickness (cIMT), assessed in all children. The N/L ratio, derived from the absolute neutrophil and lymphocyte counts. In children aged < 7 years (n=190, all prepubertal), no associations were observed between N/L ratio and either anthropometric or cardiovascular parameters. In children aged 7–9 years (n=171, 1.7 % early pubertal), higher N/L ratio associated with higher BMI Z-score and waist circumference (p=0.008 to p< 0.0001). In children aged > 9 years (n=140, 29.2 % early pubertal), N/L ratio associated again with BMI Z-score and waist circumference and also positively with SBP and cIMT (all p=0.008 to p< 0.0001). These associations remained significant in linear regression models following adjustment for possible confounding variables such as age, gender, fasting triglycerides, C-reactive protein and puberty (and for SBP and cIMT, adjustment also for BMI). In conclusion, our results provide the first evidence that a higher N/L ratio is associated with a less favourable cardiovascular profile in children and delineate the development of these associations from late childhood onwards.

Keywords

Body mass index - cardiovascular risk - children - intima-media thickness - neutrophils to lymphocytes ratio

• References

• 1 Vanderlaan PA, Reardon CA. Thematic review series: the immune system and atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis. J Lipid Res 2005; 46: 829-838.
• 2 Ionita MG, van den Borne P, Catanzariti LM. et al. High neutrophil numbers in human carotid atherosclerotic plaques are associated with characteristics of rupture-prone lesions. Arterioscler Thromb Vasc Biol 2010; 30: 1842-1848.
• 3 Dale DC, Boxer L, Liles WC. The phagocytes: neutrophils and monocytes. Blood 2008; 112: 935-945.
• 4 Hosokawa T, Kumon Y, Kobayashi T. et al. Neutrophil infiltration and oxidant-production in human atherosclerotic carotid plaques. Histol Histopathol 2011; 26: 1-11.
• 5 Naruko T, Ueda M, Haze K. et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 2002; 106: 2894-2900.
• 6 Kostis JB, Turkevich D, Sharp J. Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary arteriography. Am J Cardiol 1984; 53: 997-999.
• 7 Friedman GD, Klatsky AL, Siegelaub AB. The leukocyte count as a predictor of myocardial infarction. N Engl J Med 1974; 290: 1275-1278.
• 8 Núñez J, Miñana G, Bodí V. et al. Low lymphocyte count and cardiovascular diseases. Curr Med Chem 2011; 18: 3226-3233.
• 9 Solak Y, Yilmaz MI, Sonmez A. et al. Neutrophil to lymphocyte ratio independently predicts cardiovascular events in patients with chronic kidney disease. Clin Exp Nephrol 2013; 17: 532-540.
• 10 Papa A, Emdin M, Passino C. et al. Predictive value of elevated neutrophillymphocyte ratio on cardiac mortality in patients with stable coronary artery disease. Clin Chim Acta 2008; 395: 27-31.
• 11 Shah N, Parikh V, Patel N. et al. Neutrophil lymphocyte ratio significantly improves the Framingham risk score in prediction of coronary heart disease mortality: insights from the National Health and Nutrition Examination Survey-III. Int J Cardiol 2014; 171: 390-397.
• 12 Melo-Valls M, Murciano-Carrillo T. Interpretación del hemograma [Interpretation of blood count and differential]. Pediatr Integr 2012; 413: e1-e6.
• 13 García-Martín M, Zurita-Molina A. Transaminasas: Valoración y significación clínica [Transaminases: Assessment and clinical significance]. Gastroenterol Hepatol y Nutr Pediátrica 2012; 2: 267-275.
• 14 Argüelles B, Barja J, Hernández-Sáez MR. et al. Valores de referencia de urea, creatinina y aclaramiento de creatinina en niños adolescentes [Reference values for urea, creatinine and creatinine clearance in children]. Nefrología 1994; 14: 175-180.
• 15 Treuth MS, Butte NF, Wong WW. et al. Body composition in prepubertal girls: comparison of six methods. Int J Obes Relat Metab Disord 2001; 25: 1352-1359.
• 16 Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969; 44: 291-303.
• 17 Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970; 45: 13-23.
• 18 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111: 1805-1812.
• 19 Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999; 340: 115-126.
• 20 Van der Wal AC, Becker AE, van der Loos CM. et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 36-44.
• 21 Stary HC, Chandler AB, Dinsmore RE. et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995; 92: 1355-1374.
• 22 Peter K, Nawroth P, Conradt C. et al. Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. Arterioscler Thromb Vasc Biol 1997; 17: 505-512.
• 23 Cook DG, Mendall MA, Whincup PH. et al. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factors. Atherosclerosis 2000; 149: 139-150.
• 24 Fritsch P, Kleber M, Rosenkranz A. et al. Haemostatic alterations in overweight children: associations between metabolic syndrome, thrombin generation, and fibrinogen levels. Atherosclerosis 2010; 212: 650-655.
• 25 Ridker PM, Rifai N, Pfeffer MA. et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998; 98: 839-844.
• 26 Ridker PM, Rifai N, Pfeffer MA. et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100: 230-235.
• 27 Albert MA, Danielson E, Rifai N. et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. J Am Med Assoc 2001; 286: 64-70.
• 28 Järvisalo MJ, Harmoinen A, Hakanen M. et al. Elevated serum C-reactive protein levels and early arterial changes in healthy children. Arterioscler Thromb Vasc Biol 2002; 22: 1323-1328.
• 29 Pearson TA, Mensah GA, Alexander RW. et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107: 499-511.
• 30 Keizman D, Ish-Shalom M, Huang P. et al. The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma. Eur J Cancer 2012; 48: 202-208.
• 31 Ibáñez L, Fucci A, Valls C. et al. Neutrophil count in small-for-gestational age children: contrasting effects of metformin and growth hormone therapy. J Clin Endocrinol Metab 2005; 90: 3435-3439.
• 32 Girn HRS, Orsi NM, Homer-Vanniasinkam S. An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease. Vasc Med 2007; 12: 299-309.
• 33 Kleemann R, Zadelaar S, Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360-376.
• 34 Zheng L, Nukuna B, Brennan M-L. et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest 2004; 114: 529-541.
• 35 Oliver SR, Rosa JS, Milne GL. et al. Increased oxidative stress and altered substrate metabolism in obese children. Int J Pediatr Obes 2010; 5: 436-444.
• 36 Nilsson J, Wigren M, Shah PK. Regulatory T cells and the control of modified lipoprotein autoimmunity-driven atherosclerosis. Trends Cardiovasc Med 2009; 19: 272-276.
• 37 Williams IL, Wheatcroft SB, Shah AM. et al. Obesity, atherosclerosis and the vascular endothelium: mechanisms of reduced nitric oxide bioavailability in obese humans. International Journal of Obesity 2002; 26: 754-764.
• 38 Bergt C, Pennathur S, Fu X. et al. The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc Natl Acad Sci USA 2004; 101: 13032-13037.
• 39 Major AS, Fazio S, Linton MF. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler Thromb Vasc Biol 2002; 22: 1892-1898.
• 40 Park B-J, Shim J-Y, Lee H-R et al.. Relationship of neutrophil-lymphocyte ratio with arterial stiffness and coronary calcium score. Clin Chim Acta 2011; 412: 925-929.
• 41 Açar G, Fidan S, Uslu ZA. et al. Relationship of neutrophil-lymphocyte ratio with the presence, severity, and extent of coronary atherosclerosis detected by coronary computed tomography angiography. Angiology 2015; 66: 174-179.
• 42 Berenson GS, Srinivasan SR, Bao W. et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338: 1650-1656.
• 43 Mangge H, Schauenstein K, Stroedter L. et al. Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis. Exp Clin Endocrinol Diabetes 2004; 112: 378-382.
• 44 Tounian P, Aggoun Y, Dubern B. et al. Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study. Lancet 2001; 358: 1400-1404.
• 45 Visser M, Bouter LM, McQuillan GM. et al. Low-grade systemic inflammation in overweight children. Pediatrics 2001; 107: E13.
• 46 Bural GG, Torigian DA, Chamroonrat W. et al. FDG-PET is an effective imaging modality to detect and quantify age-related atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 2008; 35: 562-569.
• 47 Kortelainen ML. Adiposity, cardiac size and precursors of coronary atherosclerosis in 5 to 15-year-old children: a retrospective study of 210 violent deaths. Int J Obes Relat Metab Disord 1997; 21: 691-697.
• 48 Daniels SR. Cardiovascular disease risk factors and atherosclerosis in children and adolescents. Curr Atheroscler Rep 2001; 3: 479-485.
• 49 Lauer RM, Anderson AR, Beaglehole R. et al. Factors related to tracking of blood pressure in children. U.S. National Center for Health Statistics Health Examination Surveys Cycles II and III. Hypertension 1984; 6: 307-314.
• 50 Vinet A, Nottin S, Beck L. et al. Effect of maturational status and training on upper limb pulse wave velocity. Eur J Pediatr 2005; 164: 197-201.