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Association of OPG–RANKL ratio with left ventricular hypertrophy and geometric remodeling in male overweight/obese youths

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Abstract

Purpose

Receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) axis has been hypothesized as a potential mediator of left ventricular hypertrophy (LVH). The aim of the study was to assess whether circulating concentrations of RANKL, RANK, and OPG were associated with early signs of morphological cardiac changes in overweight/obese youths.

Methods

We determined serum levels of RANKL, RANK and OPG by enzyme-linked immunosorbent assays in 188 overweight/obese children and adolescents. LV mass index (LVMI) and relative wall thickness (RWT) were estimated using M-mode echocardiography.

Results

OPG and RANKL levels were higher among girls than among boys [1.73 (1.64–1.86) and 3.28 (1.90–6.37) pmol/L, respectively, vs. 1.69 (1.59–1.82) and 2.12 (1.52–3.80) pmol/L; p = 0.02 and p = 0.0001, respectively], but the OPG/RANKL ratio was lower [0.52 (0.26–0.88) vs 0.77 (0.44–1.11); p = 0.001]. In gender-specific multivariate linear regression, OPG/RANKL ratio was associated with LVMI and RWT in boys but not in girls. In multiple logistic regression, after adjustment for clinical variables, OPG/RANKL ratio was associated with concentric remodeling, eccentric and concentric LVH in boys but not in girls.

Conclusion

OPG/RANKL ratio is independently associated with LVH and patterns of LV structural remodeling in male overweight/obese children and adolescents.

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References

  1. Brady TM (2016) The role of obesity in the development of left ventricular hypertrophy among children and adolescents. Curr Hypertens Rep 18:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lavie CJ, Patel DA, Milani RV, Ventura HO, Shah S, Gilliland Y (2014) Impact of echocardiographic left ventricular geometry on clinical prognosis. Prog Cardiovasc Dis 57:3–9

    Article  PubMed  Google Scholar 

  3. Lai CC, Sun D, Cen R, Wang J, Li S, Fernandez-Alonso C, Chen W, Srinivasan SR, Berenson GS (2014) Impact of long-term burden of excessive adiposity and elevated blood pressure from childhood on adulthood left ventricular remodeling patterns: the Bogalusa heart study. J Am Coll Cardiol 64:1580–1587

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yang H, Huynh QL, Venn AJ, Dwyer T, Marwick TH (2017) Associations of childhood and adult obesity with left ventricular structure and function. Int J Obes 41:560–568

    Article  CAS  Google Scholar 

  5. Yan Y, Liu J, Wang L, Hou D, Zhao X, Cheng H, Mi J (2017) Independent influences of excessive body weight and elevated blood pressure from childhood on left ventricular geometric remodeling in adulthood. Int J Cardiol 243:492–496

    Article  PubMed  Google Scholar 

  6. Omland T, Drazner MH, Ueland T, Abedin M, Murphy SA, Aukrust P, de Lemos JA (2007) Plasma osteoprotegerin levels in the general population: relation to indices of left ventricular structure and function. Hypertension 49:1392–1398

    Article  CAS  PubMed  Google Scholar 

  7. Noheria A, Mosley TH Jr, Kullo IJ (2010) Association of serum osteoprotegerin with left ventricular mass in African American adults with hypertension. Am J Hypertens 23:767–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lu J, Liu F, Liu D, Du H, Hao J, Yang X, Cui W (2016) Amlodipine and atorvastatin improved hypertensive cardiac hypertrophy through regulation of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin system in spontaneous hypertension rats. Exp Biol Med (Maywood) 241:1237–1249

    Article  CAS  Google Scholar 

  9. Hao Y, Tsuruda T, Sekita-Hatakeyama Y, Kurogi S, Kubo K, Sakamoto S, Hatakeyama K, Chosa E, Asada Y, Kitamura K (2016) Cardiac hypertrophy is exacerbated in aged mice lacking the osteoprotegerin gene. Cardiovasc Res 110:62–72

    Article  CAS  PubMed  Google Scholar 

  10. Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, Quinn JM, Niforas P, Ng KW, Martin TJ, Gillespie MT (1999) Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extra skeletal tissues. Bone 25:525–534

    Article  CAS  PubMed  Google Scholar 

  11. Baud’huin M, Lamoureux F, Duplomb L, Rédini F, Heymann D (2007) RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cell Mol Life Sci 64:2334–2350

    Article  CAS  PubMed  Google Scholar 

  12. Montagnana M, Lippi G, Danese E, Guidi GC (2013) The role of osteoprotegerin in cardiovascular disease. Ann Med 45:254–264

    Article  CAS  PubMed  Google Scholar 

  13. Omland T, Ueland T, Jansson AM, Persson A, Karlsson T, Smith C, Herlitz J, Aukrust P, Hartford M, Caidahl K (2008) Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol 51:627–633

    Article  CAS  PubMed  Google Scholar 

  14. Suliburska J, Bogdanski P, Gajewska E, Kalmus G, Sobieska M, Samborski W (2013) The association of insulin resistance with serum osteoprotegerin in obese adolescents. J Physiol Biochem 69:847–853

    Article  CAS  PubMed  Google Scholar 

  15. Vik A, Mathiesen EB, Brox J, Wilsgaard T, Njølstad I, Jørgensen L, Hansen JB (2010) Relation between serum osteoprotegerin and carotid intima media thickness in a general population—the Tromsø Study. J Thromb Haemost 8:2133–2139

    Article  CAS  PubMed  Google Scholar 

  16. Pepene CE, Ilie IR, Marian I, Duncea I (2011) Circulating osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in polycystic ovary syndrome: relationships to insulin resistance and endothelial dysfunction. Eur J Endocrinol 164:61–68

    Article  CAS  PubMed  Google Scholar 

  17. Tschiderer L, Willeit J, Schett G, Kiechl S, Willeit P (2017) Osteoprotegerin concentration and risk of cardiovascular outcomes in nine general population studies: Literature-based meta-analysis involving 26,442 participants. PLoS ONE 12:e0183910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pacifico L, Cantisani V, Ricci P, Osborn JF, Schiavo E, Anania C, Chiesa C (2008) Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Pediatr Res 63:423–427

    Article  CAS  PubMed  Google Scholar 

  19. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH (2000) Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320:1240–1243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pacifico L, Di Martino M, De Merulis A, Bezzi M, Osborn JF, Catalano C, Chiesa C (2014) Left ventricular dysfunction in obese children and adolescents with nonalcoholic fatty liver disease. Hepatology 59:461–470

    Article  CAS  PubMed  Google Scholar 

  21. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA et al (2006) Recommendations for chamber quantification. Eur J Echocardiogr 7:79–108

    Article  PubMed  Google Scholar 

  22. Khoury PR, Mitsnefes M, Daniels SR, Kimball TR (2009) Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr 22:709–714

    Article  PubMed  Google Scholar 

  23. Di Bonito P, Moio N, Sibilio G, Cavuto L, Sanguigno E, Forziato C, de Simone G, Capaldo B (2014) Cardiometabolic phenotype in children with obesity. J Pediatr 165:1184–1189

    Article  PubMed  Google Scholar 

  24. Song DH, Zhou PZ, Xiu XL, Zhou GH, Sun YX, Song C (2016) Relationships of OPG genetic polymorphisms with susceptibility to cardiovascular disease: a meta-analysis. Med Sci Monit 22:1223–1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kiechl S, Schett G, Schwaiger J, Seppi K, Eder P, Egger G, Santer P, Mayr A, Xu Q, Willeit J (2007) Soluble receptor activator of nuclear factor-kappa B ligand and risk for cardiovascular disease. Circulation 116:385–391

    Article  CAS  PubMed  Google Scholar 

  26. Semb AG, Ueland T, Aukrust P, Wareham NJ, Luben R, Gullestad L, Kastelein JJ, Khaw KT, Boekholdt SM (2009) Osteoprotegerin and soluble receptor activator of nuclear factor-kappa B ligand and risk for coronary events: a nested case–control approach in the prospective EPIC-Norfolk population study 1993–2003. Arterioscler Thromb Vasc Biol 29:975–980

    Article  CAS  PubMed  Google Scholar 

  27. Schoppet M, Schaefer JR, Hofbauer LC (2003) Low serum levels of soluble RANK ligand are associated with the presence of coronary artery disease in men. Circulation 107:e76

    Article  CAS  PubMed  Google Scholar 

  28. Lieb W, Gona P, Larson MG, Massaro JM, Lipinska I, Keaney JF Jr, Rong J, Corey D, Hoffmann U, Fox CS, Vasan RS, Benjamin EJ, O’Donnell CJ, Kathiresan S (2010) Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality. Arterioscler Thromb Vasc Biol 30:1849–1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sandberg WJ, Yndestad A, Øie E, Smith C, Ueland T, Ovchinnikova O, Robertson AK, Müller F, Semb AG, Scholz H, Andreassen AK, Gullestad L, Damås JK, Frøland SS, Hansson GK, Halvorsen B, Aukrust P (2006) Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol 226:857–863

    Article  CAS  Google Scholar 

  30. Ueland T, Yndestad A, Dahl CP, Gullestad L, Aukrust P (2012) TNF revisited: osteoprotegerin and TNF-related molecules in heart failure. Curr Heart Fail Rep 9:92–100

    Article  CAS  PubMed  Google Scholar 

  31. Stern A, Laughlin GA, Bergstrom J, Barrett-Connor E (2007) The sex-specific association of serum osteoprotegerin and receptor activator of nuclear factor kappaB legend with bone mineral density in older adults: the Rancho Bernardo study. Eur J Endocrinol 156:555–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Litwin SE (2014) Childhood obesity and adult cardiovascular disease. J AM Coll Cardiol 64:1588–1590

    Article  PubMed  Google Scholar 

  33. Caprio S, Perry R, Kursawe R (2017) Adolescent obesity and insulin resistance: roles of ectopic fat accumulation and adipose inflammation. Gastroenterology 152:1638–1646

    Article  CAS  PubMed  Google Scholar 

  34. Skinner AC, Perrin EM, Moss LA, Skelton JA (2015) Cardiometabolic risks and severity of obesity in children and young adults. N Engl J Med 373:1307–1317

    Article  PubMed  Google Scholar 

  35. Srinivasan SR, Bao W, Wattigney WA, Berenson GS (1996) Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism 45:235–240

    Article  CAS  PubMed  Google Scholar 

  36. Freedman DS, Mei Z, Dietz WH, Srinivasan SR, Berenson GS (2001) Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study. Pediatrics 108:712–718

    Article  CAS  PubMed  Google Scholar 

  37. Urbina EM, Gidding SS, Bao W, Pickoff AS, Berdusis K, Berenson GS (1995) Effect of body size, ponderosity, and blood pressure on left ventricular growth in children and young adults in the Bogalusa Heart Study. Circulation 91:2400–2406

    Article  CAS  PubMed  Google Scholar 

  38. Li X, Li S, Ulusoy E, Chen W, Srinivasan SR, Berenson GS (2004) Childhood adiposity as a predictor of cardiac mass in adulthood: the Bogalusa Heart Study. Circulation 110:3488–3492

    Article  PubMed  Google Scholar 

  39. Toprak A, Wang H, Chen W, Paul T, Srinivasan S, Berenson G (2008) Relation of childhood risk factors to left ventricular hypertrophy (eccentric or concentric) in relatively young adulthood (from the Bogalusa Heart Study). Am J Cardiol 101:1621–1625

    Article  PubMed  Google Scholar 

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Correspondence to R. Buzzetti.

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No disclosure for any prior publication or submission. No conflict of interest or role of any sponsor is present in this work. The authors alone are responsible for the content and the writing of the paper.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individuals, parents/guardians of participants included in the study.

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Zampetti, S., Lucantoni, F., Pacifico, L. et al. Association of OPG–RANKL ratio with left ventricular hypertrophy and geometric remodeling in male overweight/obese youths. J Endocrinol Invest 42, 427–434 (2019). https://doi.org/10.1007/s40618-018-0932-y

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  • DOI: https://doi.org/10.1007/s40618-018-0932-y

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