Serum levels of retinol-binding protein-4 are associated with the presence and severity of coronary artery disease

Vaia Lambadiari, Nikolaos P E Kadoglou, Vassilios Stasinos, Eirini Maratou, Aias Antoniadis, Fotios Kolokathis, John Parissis, Erifili Hatziagelaki, Efstathios K Iliodromitis, George Dimitriadis, Vaia Lambadiari, Nikolaos P E Kadoglou, Vassilios Stasinos, Eirini Maratou, Aias Antoniadis, Fotios Kolokathis, John Parissis, Erifili Hatziagelaki, Efstathios K Iliodromitis, George Dimitriadis

Abstract

Background: The interplay between the novel adipokine retinol-binding protein-4 (RBP4) and coronary artery disease (CAD) is still obscure. We investigated the relationship between RBP4 levels and the presence and severity of angiographically proven CAD and determined its possible role in acute myocardial infarction (AMI).

Methods: 305 individuals with angiographically proven CAD (CAD-patients), were classified into 2 subgroups: 1) acute myocardial infarction (AMI, n = 141), and 2) stable angina (SA, n = 164). Ninety-one age- and sex-matched individuals without CAD, but with at least 2 classical cardiovascular risk factors, served as controls (non-CAD group). RBP4 serum levels were measured at hospital admission and were analyzed in relation to the coronary severity stenosis, assessed by the Gensini-score and the number of coronary narrowed vessels. Other clinical parameters, including insulin levels, HOMA-IR, hsCRP, glycaemic and lipid profile, and left-ventricular ejection fraction were also assessed.

Results: Serum RBP4 levels were significantly elevated in patients with CAD compared to non-CAD patients (39.29 ± 11.72 mg/L vs. 24.83 ± 11.27 mg/L, p < 0.001). We did not observe a significant difference in RBP4 levels between AMI and SA subgroups (p = 0.734). Logistic regression analysis revealed an independent association of CAD presence with serum RBP4 (β = 0.163, p = 0.006), and hsCRP (β = 0.122, p = 0.022) levels, in the whole study group. Among variables, hsCRP (β = 0.220), HDL (β = -0.150), and RBP4 (β = 0.297), correlated in both univariate and multivariate analysis with CAD severity (R2 = 0.422, p < 0.001). Similarly, RBP4 concentrations increased with the number of coronary narrowed vessels (p < 0.05).

Conclusion: Patients with CAD, both SA and AMI, showed elevated RBP4 serum levels. Notably, increased RBP4 concentration seemed to independently correlate with CAD severity, but no with AMI.

Trial registration: The ClinicalTrials.gov Identifier is: NCT00636766.

Figures

Figure 1
Figure 1
Receiver operating characteristic curve analysis of Retinol-Binding Protein-4 (RBP4) (blue line) and hsCRP (green line) as markers for the diagnosis of coronary artery disease (CAD).

References

    1. van Holten TC, Waanders LF, de Groot PG, Vissers J, Hoefer IE, Pasterkamp G, Prins MW, Roest M. Circulating biomarkers for predicting cardiovascular disease risk; a systematic review and comprehensive overview of meta-analyses. PLoS One. 2013;22:e62080. doi: 10.1371/journal.pone.0062080.
    1. Hemingway H, Philipson P, Chen R, Fitzpatrick NK, Damant J, Shipley M, Abrams KR, Moreno S, McAllister KS, Palmer S, Kaski JC, Timmis AD, Hingorani AD. Evaluating the quality of research into a single prognostic biomarker: a systematic review and meta-analysis of 83 studies of C-reactive protein in stable coronary artery disease. PLoS Med. 2010;7:e1000286. doi: 10.1371/journal.pmed.1000286.
    1. Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MS, Go AS, Harrell FE, Jr, Hong Y, Howard BV, Howard VJ, Hsue PY, Kramer CM, McConnell JP, Normand SL, O'Donnell CJ, Smith SC, Jr, Wilson PW. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119:2408–2416. doi: 10.1161/CIRCULATIONAHA.109.192278.
    1. Kadoglou NP, Lampropoulos S, Kapelouzou A, Gkontopoulos A, Theofilogiannakos EK, Fotiadis G, Kottas G. Serum levels of apelin and ghrelin in patients with acute coronary syndromes and established coronary artery disease–KOZANI STUDY. Transl Res. 2010;155:238–246. doi: 10.1016/j.trsl.2010.01.004.
    1. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356–362. doi: 10.1038/nature03711.
    1. Broch M, Vendrell J, Ricart W, Richart C, Fernández-Real JM. Circulating retinol-binding protein-4, insulin sensitivity, insulin secretion, and insulin disposition index in obese and nonobese subjects. Diabetes Care. 2007;30:1802–1806. doi: 10.2337/dc06-2034.
    1. Promintzer M, Krebs M, Todoric J, Luger A, Bischof MG, Nowotny P, Wagner O, Esterbauer H, Anderwald C. Insulin resistance is unrelated to circulating retinol binding protein and protein C inhibitor. J Clin Endocrinol Metab. 2007;92:4306–4312. doi: 10.1210/jc.2006-2522.
    1. Graham TE, Yang Q, Blüher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;15:2552–2563. doi: 10.1056/NEJMoa054862.
    1. Lee JW, Im JA, Lee HR, Shim JY, Youn BS, Lee DC. Visceral adiposity is associated with serum retinol binding protein-4 levels in healthy women. Obesity (Silver Spring) 2007;15:2225–2232. doi: 10.1038/oby.2007.264.
    1. Friebe D, Neef M, Erbs S, Dittrich K, Kratzsch J, Kovacs P, Blüher M, Kiess W, Körner A. Retinol binding protein 4 (RBP4) is primarily associated with adipose tissue mass in children. Int J Pediatr Obes. 2011;6:345–352. doi: 10.3109/17477166.2010.491228.
    1. Conroy R, Espinal Y, Fennoy I, Accacha S, Boucher-Berry C, Carey DE, Close S, DeSantis D, Gupta R, Hassoun AA, Iazzetti L, Jacques FJ, Jean AM, Michel L, Pavlovich K, Rapaports R, Rosenfeld W, Shamoon E, Shelov S, Speiser PW, Ten S, Rosenbaum M. Retinol binding protein 4 is associated with adiposity-related co-morbidity risk factors in children. J Pediatr Endocrinol Metab. 2011;24:913–919. doi: 10.1515/JPEM.2011.297.
    1. Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T. Retinol binding protein-4 levels and clinical features of type 2 diabetes patients. J Clin Endocrinol Metab. 2007;92:2712–2719. doi: 10.1210/jc.2006-1249.
    1. Klöting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer M, Schön MR, Stumvoll M, Blüher M, Kahn BB. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 2007;6:79–87. doi: 10.1016/j.cmet.2007.06.002.
    1. Christou GA, Tellis CC, Elisaf MS, Tselepis AD, Kiortsis DN. The changes in plasma retinol-binding protein 4 levels are associated with those of the apolipoprotein B-containing lipoproteins during dietary and drug treatment. Angiology. 2012;63:67–75. doi: 10.1177/0003319711407628.
    1. Huang G, Wang D, Khan UI, Zeb I, Manson JE, Miller V, Hodis HN, Budoff MJ, Merriam GR, Harman SM, Brinton EA, Cedars MI, Lobo RA, Naftolin F, Santoro N, Taylor HS, Wildman RP, Su Y. Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: Cross-sectional analyses from the KEEPS Study. Cardiovasc Diabetol. 2012;11:52. doi: 10.1186/1475-2840-11-52.
    1. Aust G, Uptaite-Patapoviene M, Scholz M, Richter O, Rohm S, Bluher M. Circulating Nampt and RBP4 levels in patients with carotid stenosis undergoing carotid endarterectomy (CEA) Clin Chim Acta. 2011;412:1195–1200. doi: 10.1016/j.cca.2011.03.008.
    1. Mallat Z, Simon T, Benessiano J, Clément K, Taleb S, Wareham NJ, Luben R, Khaw KT, Tedgui A, Boekholdt SM. Retinol-binding protein 4 and prediction of incident coronary events in healthy men and women. J Clin Endocrinol Metab. 2009;94:255–260. doi: 10.1210/jc.2008-0253.
    1. Martinez-Hervas S, Real JT, Priego MA, Carratalá A, Sniderman AD, Carmena R, Ascaso JF. Establishing cut-off values for apolipoprotein B and non-HDL-C according to LDL-C values in a South European population. Int J Clin Pract. 2013;67:81–88. doi: 10.1111/j.1742-1241.2012.02998.x.
    1. Ingelsson E, Lind L. Circulating retinol-binding protein 4 and subclinical cardiovascular disease in the elderly. Diabetes Care. 2009;32:733–735. doi: 10.2337/dc08-1656.
    1. Xiao Y, Xu A, Hui X, Zhou P, Li X, Zhong H, Tang W, Huang G, Zhou Z. Circulating lipocalin-2 and retinol-binding protein 4 are associated with intima-media thickness and subclinical atherosclerosis in patients with type 2 diabetes. PLoS One. 2013;8:e66607. doi: 10.1371/journal.pone.0066607.
    1. Bobbert T, Raila J, Schwarz F, Mai K, Henze A, Pfeiffer AF, Schweigert FJ, Spranger J. Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness. Atherosclerosis. 2010;213:549–551. doi: 10.1016/j.atherosclerosis.2010.07.063.
    1. Ingelsson E, Sundström J, Melhus H, Michaëlsson K, Berne C, Vasan RS, Risérus U, Blomhoff R, Lind L, Arnlöv J. Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly. Atherosclerosis. 2009;206:239–244. doi: 10.1016/j.atherosclerosis.2009.02.029.
    1. Kim HJ, Yoo HS, Kim PK, Kim MR, Lee HW, Kim CW. Comparative analysis of serum proteomes of patients with cardiovascular disease. Clin Biochem. 2011;44:178–184. doi: 10.1016/j.clinbiochem.2010.09.027.
    1. Sun Q, Kiernan UA, Shi L, Phillips DA, Kahn BB, Hu FB, Manson JE, Albert CM, Rexrode KM. Plasma retinol-binding protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses’ health study. Circulation. 2013;127:1938–1947. doi: 10.1161/CIRCULATIONAHA.113.002073.
    1. Calò LA1, Maiolino G, Pagnin E, Vertolli U, Davis PA. Increased RBP4 in a human model of activated anti-atherosclerotic and antiremodelling defences. Eur J Clin Invest. 2014;44:567–572. doi: 10.1111/eci.12270.
    1. Takebayashi K1, Sohma R, Aso Y, Inukai T. Effects of retinol binding protein-4 on vascular endothelial cells. Biochem Biophys Res Commun. 2011;29(408):58–64. doi: 10.1016/j.bbrc.2011.03.116.
    1. Cubedo J1, Padró T, Cinca J, Mata P, Alonso R, Badimon L. Retinol-binding protein 4 levels and susceptibility to ischaemic events in men. Eur J Clin Invest. 2014;44:266–275. doi: 10.1111/eci.12229.
    1. Kadoglou NP, Gkontopoulos A, Kapelouzou A, Fotiadis G, Theofilogiannakos EK, Kottas G, Lampropoulos S. Serum levels of vaspin and visfatin in patients with coronary artery disease-Kozani study. Clin Chim Acta. 2011;412:48–52. doi: 10.1016/j.cca.2010.09.012.
    1. Salgado-Somoza A, Teijeira-Fernández E, Rubio J, Couso E, González-Juanatey JR, Eiras S. Coronary artery disease is associated with higher epicardial retinol-binding protein 4 (RBP4) and lower glucose transporter (GLUT) 4 levels in epicardial and subcutaneous adipose tissue. Clin Endocrinol (Oxf) 2012;76:51–58. doi: 10.1111/j.1365-2265.2011.04140.x.
    1. Solini A, Stea F, Santini E, Bruno RM, Duranti E, Taddei S, Ghiadoni L. Adipocytokine levels mark endothelial function in normotensive individuals. Cardiovasc Diabetol. 2012;11:103. doi: 10.1186/1475-2840-11-103.
    1. Farjo KM, Farjo RA, Halsey S, Moiseyev G, Ma JX. Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase- and nuclear factor kappa B-dependent and retinol-independent mechanism. Mol Cell Biol. 2012;32:5103–5115. doi: 10.1128/MCB.00820-12.
    1. Al-Daghri NM, Al-Attas OS, Alokail M, Draz HM, Bamakhramah A, Sabico S. Retinol binding protein-4 is associated with TNF-alpha and not insulin resistance in subjects with type 2 diabetes mellitus and coronary heart disease. Dis Markers. 2009;26:135–140. doi: 10.1155/2009/725948.
    1. Staels B. Regulation of lipid and lipoprotein metabolism by retinoids. J Am Acad Dermatol. 2001;45:158–167. doi: 10.1067/mjd.2001.113718.
    1. von Eynatten M, Lepper PM, Liu D, Lang K, Baumann M, Nawroth PP, Bierhaus A, Dugi KA, Heemann U, Allolio B, Humpert PM. Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease. Diabetologia. 2007;50:1930–1937. doi: 10.1007/s00125-007-0743-8.
    1. Vergès B, Guiu B, Cercueil JP, Duvillard L, Robin I, Buffier P, Bouillet B, Aho S, Brindisi MC, Petit JM. Retinol-binding protein 4 is an independent factor associated with triglycerides and a determinant of very low-density lipoprotein-apolipoprotein B100 catabolism in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2012;32:3050–3057. doi: 10.1161/ATVBAHA.112.255190.
    1. Alwaili K1, Bailey D, Awan Z, Bailey SD, Ruel I, Hafiane A, Krimbou L, Laboissiere S, Genest J. The HDL proteome in acute coronary syndromes shifts to an inflammatory profile. Biochim Biophys Acta. 2012;1821(3):405–415. doi: 10.1016/j.bbalip.2011.07.013.
    1. Kaess BM, Enserro DM, McManus DD, Xanthakis V, Chen MH, Sullivan LM, Ingram C, O'Donnell CJ, Keaney JF, Vasan RS, Glazer NL. Cardiometabolic correlates and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study. J Clin Endocrinol Metab. 2012;97:1943–1947. doi: 10.1210/jc.2012-1458.
    1. Frey SK1, Spranger J, Henze A, Pfeiffer AF, Schweigert FJ, Raila J. Factors that influence retinol-binding protein 4-transthyretin interaction are not altered in overweight subjects and overweight subjects with type 2 diabetes mellitus. Metabolism. 2009;58(10):1386–1392. doi: 10.1016/j.metabol.2009.05.003.

Source: PubMed

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