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Identification of mildly oxidized low-density lipoprotein (electronegative LDL) and its auto-antibodies IgG in children and adolescents hypercholesterolemic offsprings

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Identification of mildly oxidized low-density lipoprotein (electronegative LDL) and its auto-antibodies IgG in children and adolescents hypercholesterolemic offsprings
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  Atherosclerosis 184 (2006) 103–107 Identification of mildly oxidized low-density lipoprotein (electronegativeLDL) and its auto-antibodies IgG in children and adolescentshypercholesterolemic offsprings Marcos Roberto Andrade Costa Barros a , Marcelo Chiara Bertolami a , ∗ ,Dulcin´eia Saes Parra Abdalla b , Waldinai Pereira Ferreira a a  Dyslipidemias Section of Instituto Dante Pazzanese de Cardiologia, Av. Sabi´ a 667, Ap. 141, Moema, S˜ ao Paulo, SP 04515-000, Brazil b University of S˜ ao Paulo, School of Pharmaceutical Sciences, Brazil Received 7 September 2004; received in revised form 6 November 2004; accepted 15 November 2004Available online 17 May 2005 Abstract  Background:  Oxidative modification of low-density lipoproteins (LDL) is an essential step in atherogenesis, generating minimally oxidizedLDL, also called electronegative LDL [LDL( − )], which has chemotactic, cytotoxic and immunogenic properties.  Methods and results:  Serum LDL( − ) and anti-LDL( − ) auto-antibodies (IgG) were evaluated in 28 children and adolescents with familialhypercholesterolemia (FH) antecedents, with or without early coronary artery disease in first-degree relatives (eCAD), hypercholesterolemic(hc) or normocholesterolemic (nc) versus a control group of normocholesterolemic children without pathologic antecedents (C). ELISAmethod was used for detection of LDL( − ) and anti-LDL( − ) IgG. LDL( − ) serum levels did not differ among the four groups (FH-eCAD-hc 41.4 ± 24.9  g/dl; FH-hc 38.3 ± 11.2  g/dl; FH-nc 47.3 ± 17.0  g/dl and C 44.2 ± 28.8  g/dl,  p =0.659). However, IgG anti-LDL( − )auto-antibodies were significantly higher in the control group in comparison to the FH groups with or without eCAD, independent of hyper-cholesterolemia or normocholesterolemia (FH-eCAD-hc 0.825 ± 0.289  g/dl; FH-hc 0.667 ± 0.307  g/dl; FH-nc 0.763 ± 0.204  g/dl and C1.105 ± 0.233  g/dl,  p =0.006).Whentheauto-antibodiesofgroupswithFH,withorwithouteCADandwithorwithouthypercholesterolemiawere compared, no differences were found (  p =0.509). Conclusion:  These results showed that FH and/or eCAD children and adolescents have lower titers of auto-antibodies anti-LDL( − ) thanchildren from normal families, independent of serum LDL-cholesterol or serum LDL( − ).© 2005 Elsevier Ireland Ltd. All rights reserved. Keywords:  Familial hypercholesterolemia; Oxidized LDL; LDL-cholesterol; Auto-antibodies; Coronary artery disease; Electronegative LDL 1. Introduction Although clinical manifestations of atherosclerosisusually begin in the fifth decade of life, several post mortemstudies have confirmed that atherosclerotic lesions in aortaand coronary artery may already exist in adolescence andeven throughout childhood [1–4]. These lesions so early in life have been associated with obesity, high blood pressureand hypercholesterolemia [5–7]. Other risk factors for the ∗ Corresponding author. Tel.: +55 11 50518048; fax: +55 11 55494205.  E-mail address:  bertolami@uol.com.br (M.C. Bertolami). development of atherosclerosis during childhood are familyhistoryofearlycoronaryarterydisease(eCAD)[8]andfamil-ialhypercholesterolemia(FH)[9,10],mainlyduetoelevationof cholesterol carried by low-density lipoprotein (LDL-c).The pathogenesis of atherosclerosis involves LDL oxi-dation, generating the minimally oxidized LDL (moxLDL).This LDL subfraction is thrombogenic, acts as a chemotaxicagenttomonocytesandsmoothvascularmusclecells[11]by activation of vascular and intercellular adhesion molecules,along with inhibition of endothelial cell migration and of the effect of vasodilators such as nitric oxide [12,13]. LDL modification by agents such as malondialdehyde, copper, 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.atherosclerosis.2004.11.027  104  M.R.A.C. Barros et al. / Atherosclerosis 184 (2006) 103–107  lipooxygenase and peroxidase increase the negative chargeof the moxLDL particle and may contribute to the in vivogeneration of the electronegative LDL subfraction, LDL( − ).These moxLDL particles have low affinity for the LDLreceptor being recognized by the scavenger receptors andcorrelates with coronary artery disease [14].Inflammatory and immune reactions are widely recog-nized as being an integral part of the pathogenesis of theatherosclerotic lesion [15]. The moxLDL plays an immuno- genicroleinthisprocess:IgMandIgGantibodiesspecificallydirected against oxidized LDL are found in such lesions andin the blood of patients with atherosclerosis, independent of the involved arterial territory [16].Several lines of investigation have shown a correlationbetween serum oxidized LDL and its auto-antibodies withthe development of atherosclerosis [17], the severity of CAD(particularly regarding the degree of coronary stenosis)[18], the development of atherosclerosis in transplantedhearts [19,20], peripheral arterial disease [21] and carotid atherosclerosis [22], as well as with the acute phase and pos-sible instability of the coronary plaque [23,24]. In oppositionto these findings, some authors have found an association of anti-LDLantibodieswithlowriskforCADinadults[25–27].However, data on the association between oxidized LDL andatherosclerosisinchildrenandadolescentsarescanty[28,29].Our purpose is therefore to study the serum concentrationof moxLDL, determined as the LDL( − ) subfraction, and itsIgG auto-antibodies in children and adolescents belongingto two families with history of hypercholesterolemia, one of which also having a history of eCAD, compared to a healthycontrol group belonging to families with no known risk fac-tors for atherosclerosis. 2. Methods Patientpopulation—individualswithagesbetween2and19 years old, belonging to two families with history of FHwith eCAD and FH without eCAD. At the ambulatory of dyslipidemias of the Instituto Dante Pazzanese de Cardiolo-gia, from November 1998 to April 2001, all patients with theclinical diagnosis of FH [30] and documented high serumtotal cholesterol (>290mg/dl) or diagnosis of eCAD — menyounger than 55 years old or women younger than 65 yearsoldwithoneormoreofthefollowing:myocardialinfarction,coronary artery bypass surgery or percutaneous transluminalcoronary angioplasty; obstruction of 50% or more at least inone coronary artery shown by coronary angiography [31] —were invited to bring their offspring below 20 years old toscreen for FH [32]. The control group comprised individu- als with “innocent” heart murmurs referred for an outpatientcardiac check up and echocardiography, matching for age.The exclusion criteria included: (1) individuals youngerthan 2 and older than 19 years of age; (2) individuals whosefamily history was unknown or uncertain; (3) individualswith family history of isolated familial hypertriglyceridemiaor familial combined hyperlipidemia; (4) individualswhose parents had secondary hypercholesterolemia; (5)individuals harboring conditions capable of influencinglipids metabolism, such as obesity, diabetes mellitus,hypothyroidism, nephrotic syndrome or renal dysfunction;(6) individuals with history of smoking, use of alcoholicbeverages and use of illicit drugs; (7) individuals in activetreatment for chronic medical conditions (including use of non-steroidal anti-inflammatory drugs for 5 days or more).Finally four groups of children and adolescents wereformed as follows: •  FH-eCAD-HC  :Childrenandadolescentswhowerehyper-cholesterolemic and whose parents had FH and eCAD. •  FH-HC  : Children and adolescents who were hypercholes-terolemic and whose parents had FH without eCAD. •  HF-NC  :Childrenandadolescentswhowerenormocholes-terolemic and whose parents had FH without eCAD. •  Control :Childrenandadolescentswhowerenormocholes-terolemic from families without FH or eCAD.ThestudywasapprovedbytheInstitutionalReviewBoardof the Instituto Dante Pazzanese de Cardiologia. All studyparticipants (or their guardians) were informed about thestudy and signed a written informed consent. 2.1. Determination of lipids, electronegative LDL[LDL( − )] and anti-LDL( − ) IgG auto-antibodies Totalcholesterol,HDL-cholesterolandtriglyceridesweremeasured by enzymatic colorimetric methods (Hitachi 912).VLDL-cholesterol and LDL-cholesterol were calculated us-ingtheFriedewald’sformula[33].Thereferencerangeswere those published in the NCEP ATP III Guidelines for individ-uals with ages from 2 to 20 years old.The tests for LDL( − ) and its IgG auto-antibodies wereperformed at the Clinical Biochemistry Laboratory of theFaculty of Pharmacy, University of S˜ao Paulo, as publishedelsewhere [34]. 2.2. Statistical analysis The results were presented as means and standard devi-ations. Kruskal–Wallis test was used to compare the fourgroups. Mann–Whitney test was used for 2 × 2 comparisons.All tests were two-tailed and a  p -value less than 0.05 wasconsidered as statistically significant. 3. Results Forty individuals with age between 2 and 20 years old(mean 10.8 ± 4.59) were evaluated (Table 1). They were al- located into the four groups previously specified as follows:HF-eCAD-HC 8 individuals; HF-HC 6 individuals; HF-NC14 individuals; control group 12 individuals.The groups did not differ regarding mean age or bodymass index (  p =0.651 and 0.243, respectively), as well as the   M.R.A.C. Barros et al. / Atherosclerosis 184 (2006) 103–107   105Table 1Characteristics of the groupsFH-eCAD-HC FH-HC FH-NC C  N   08 06 14 12Age a 9.8 ± 4.9 10.8 ± 5.85 10.3 ± 5.1 12 ± 3.3Female 6 (75%) 3 (50%) 9 (64.3%) 4 (33.3%)BMI a 17.5 ± 2.8 21.3 ± 4.0 18.9 ± 3.9 19.6 ± 3.9NSAI 2 (25%) – – 1 (8.3%)Tabagism – – – –Etilism – – – –FH ANT 8 (100%) 6 (100%) 14 (100%) –ECAD ANT 8 (100%) – – –TIR ANT 1 (12.5%) – 1 (8.3%)DM ANT – 1 (16.7%) 1 (7.1%) –Ht ANT 4 (50%) – 3 (21.4%) 2 (16.7%)Obesity ANT 1 (12.5%) – – –BMI: body mass index; NSAI: non-steroidal anti-inflammatory; ANT: familial antecedent; HF: familial hypercholesterolemia; ECAD: early coronary arterydisease; TIR: hypothyroidism; DM: diabetes mellitus; Ht: hypertension. a Median ± standard deviation (md ± S.D.). family history of other conditions that could be related toabnormalities of the lipid metabolism. Two children in thegroup HF-eCAD-HC and one child in the control group hadusednon-steroidalanti-inflammatorydrugs,atlowdosesandfor a short period of time (<3 doses and <5 days), during theseven days preceding their blood drawing. 4. Lipid profile All individuals had the lipid profile determined. To-tal serum cholesterol varied from 112 to 340mg/dl (mean190 ± 50.9mg/dl), serum HDL-cholesterol varied from 30to91mg/dl(54.7 ± 12.8mg/dl);serumLDL-cholesterolvar-ied from 42 to 263.4mg/dl (mean 121.6 ± 49.1mg/dl) andserum triglycerides varied from 35 to 148mg/dl (mean71.3 ± 28.9mg/dl).Serum HDL-cholesterol and serum triglycerides weresimilar in all groups (  p =0.527 and 0.184, respectively).As expected, total serum cholesterol and LDL-cholesteroldiffered significantly between the groups characterized byhypercholesterolemia or normocholesterolemia as can beseen in Table 2. 4.1. LDL( − ) Serum LDL( − ) varied from 10 to 95.1  g/ml (mean43.9 ± 21.7  g/ml). The values according to the four groupsare depicted in Table 3. The difference between groups was not statistically significant (  p =0.659). 4.2. Anti-LDL( − ) IgG auto-antibodies SerumIgGauto-antibodiesvariedfrom0.341to1.404IgGequivalents (mean 0.864 ± 0.290). The combined analysis of all groups showed that the control group had higher serumanti-LDL( − ) IgG auto-antibodies when compared to theother groups (  p =0.006). This difference remained when thecontrolgroupwascomparedtoHF-eCAD-HC(  p =0.037),toHF-HC (  p =0.009) and to HF-NC (  p =0.003) groups. How-ever, no differences were found between HF-eCAD-HC and Table 2Serum lipid profile of the groupsFH-eCAD-HC FH-HC FH-NC C  p Total cholesterol 242.2  ±  53.3 243.6  ±  36.0 160.1  ±  24.9 165.3  ±  26.8 <0 . 001HDL-cholesterol 50.4  ±  13.6 54.5  ±  9.9 59.6  ±  14.8 51.9  ±  10.3 0 . 527LDL-cholesterol 175.9  ±  48.6 170.2  ±  33.5 88.8  ±  23.3 99.6  ±  23.9 <0 . 001Triglycerides 80.1  ±  37.1 94.8  ±  41.4 58.4  ±  11.3 68.8  ±  24.0 0 . 184Table 3Serum LDL( − ) (  g/ml) and anti-LDL( − ) IgG auto-antibodies concentrations of the groupsFH-CAD-HC FH-HC FH-NC C  N   8 6 14 12LDL( − ) ∗ 41.4 ± 24.9 38.3 ± 11.2 47.3 ± 17.0 44.2 ± 28.8Anti-LDL( − ) † 0.825 ± 0.289 0.667 ± 0.307 0.763 ± 0.204 1.105 ± 0.233 *  p =0.659. †  p =0.006.  106  M.R.A.C. Barros et al. / Atherosclerosis 184 (2006) 103–107  HF-HC(  p =0.302),HF-CAD-HCandHF-NC(  p =0.306),orHF-HC and HF-NC (  p =0.509). 5. Discussion In the present study it was shown that serum LDL( − ) lev-els of children and adolescents with a positive family historyof FH, with or without eCAD, did not differ from those of normal controls. However, higher levels of anti-LDL( − ) IgGauto-antibodies in the control group compared to the othergroups were found.Theseresultssuggestthatamongindividualsbelongingtofamilies with FH, hypercholesterolemia or family history of eCAD were not associated to differences in the serum levelsof free anti-LDL( − ) IgG auto-antibodies, but a history of FH was associated to lower levels of free anti-LDL( − ) IgGauto-antibodies even in individuals with normal cholesterollevels.The relationship between anti-oxidized LDL antibodiesand atherosclerosis is still the focus of intense clinicalresearch, even in the adult population. Available data arerather conflicting with some results indicating a protectiveeffect [26,35,36], whereas others suggesting a deleteriouseffect [20,37–39] of these antibodies in atherosclerosisdevelopment. However, these studies have used differentmethodologies for measuring IgA, IgM and IgG antibodiesagainst modified LDL by malondialdehyde, copper, andperoxidase. So, it is not defined yet which class of antibodies(IgG, IgM), as well as, if their binding to the differentepitopes on moxLDL particles, facilitates or prevents theprocess of atherosclerosis in adults.It has been reported that children have higher titers of antibodies against oxidized LDL than adults [40]. On the other hand, even in children, anti-oxidized LDL antibodieshave been found either in chronic diseases as rheumatic dis-eases [41] or hemoglobinopathies [42] or in acute diseases, as in upper airways infections [43]. This presence of im-munoglobulins reactive to oxidized LDL in individuals with-out atherosclerosis risk factors agree with the recent studiesrelating atherosclerosis with inflammation [44–46].Orchard et al. [36] found a negative correlation betweenfree anti-oxidized LDL antibodies and coronary arterydisease in diabetic adults. Nevertheless, immunocomplexescontaining modified Apo B were higher in diabetic adultswith CAD than in those without CAD. Furthermore, Islamet al. [29] described the presence of immunocomplexescontaining oxidized LDL in children with familial hyper-cholesterolemia. This same study showed that the familyhistory of early CAD, small Apo A I phenotypes and highLDL-cholesterol levels were responsible for 54% of thevariation of the immunocomplexes after multiple regressionanalysis[29].Thefindingofanegativecorrelationofthefree anti-oxidized LDL antibodies with the immunocomplexessuggests that the excessive formation of oxidized LDL couldsaturate the binding sites of the antibodies reactive againstoxLDL consuming the circulating antibodies what wouldprevent the detection of free antibodies in serum.Then, the discrepancy of data about anti-LDL( − ) auto-antibodiesandatherosclerosiscouldbeenattributedtoseveralfactors,includingthepoorstandardizationofthemethodsfordetection of the serum levels of antibodies against differentgroups of oxidized LDL; the incomplete determination of the class of antibodies (IgG or IgM) reactive to oxLDL, andto the possible existence of circulating immunocomplexes,which could contribute for decreasing the serum levels of free anti-oxLDL antibodies.Data of the present study are in contrast with thosereported by Kelishadi et al. [28] showing that childrenbelonging to families with FH had higher levels of oxidizedLDL than their healthy neighbors. In the latter study,hypercholesterolemia was associated with elevated serummalondialdehyde-modified LDL in individuals with FHhistory. A possible explanation for the difference betweenthe two studies may be related to the fact that the lowerserum anti-LDL auto-antibodies found in the groups withhigher risk for atherosclerosis could reflect the formationof immunocomplexes with serum LDL( − ), undetectableby the ELISA method used here. Thus, serum LDL( − )could be higher in FH groups than in the control one, whatwould result in sequestering circulating anti-LDL( − ) auto-antibodies to form LDL( − ) IgG complexes, contributing todecrease the levels of free IgG anti-LDL( − ) antibodies inFH groups in comparison to the control group. Alternatively,aslipoproteinoxidationispartoftheatheroscleroticprocess,oxidized LDL could play a role as a marker of activedisease instead of a marker for genetic predisposition. Inconclusion, it was shown here that FH and/or eCAD childrenand adolescents have lower titers of auto-antibodies anti-LDL( − ) than children from normal families. This findingwarrants additional studies to elucidate the role of LDL( − ),anti-LDL( − ) auto-antibodies, and LDL( − ) IgG complexesin subclinical atherosclerosis in children and adolescents todefineiftheycanbemarkersofdiseaseactivityinchildhood. References [1] M¨onckeberg JG. Zentralblatt f ¨ur Herz und Gef ¨asskrankheiten1915;7(7–10):336–43;Strong JP. Coronary atherosclerosis in soldiers. A clue to the naturalhistory of atherosclerosis in the young. JAMA 1986;256:2863–6.[2] Enos WF, Holmes RH, Beyer J. Coronary disease among UnitedStates soldiers killed in action in Korea. JAMA 1953;152:1090–3.[3] McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary arterydisease in combat casualties in Vietnam. JAMA 1971;216:1185–7.[4] Tanaka K, Masuda J, Iamamura T, et al. 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