Autoantibody titers against OxLDL are correlated with Achilles tendon thickness in patients with familial hypercholesterolemia

Achilles tendon xanthomas are associated with increased cardiovascular risk in patients with familial hypercholesterolemia (FH). Oxidized low density lipoprotein (OxLDL), the antibodies against OxLDL, and the LDL-associated phospholipase A2 (Lp-PLA2) may play important roles in atherogenesis. We investigated the possible association between plasma levels of OxLDL, Lp-PLA2 activity, and autoantibody titers against various types of mildly OxLDL with Achilles tendon thickness (ATT). ATT was determined by sonography in 80 unrelated heterozygous FH patients. Three different types of mildly OxLDL were prepared: OxLDLL, OxLDLP, and OxLDLD, at the end of the lag, propagation, and decomposition phases of oxidation, respectively. Similar types of OxLDL were also prepared after inactivation of the LDL-associated Lp-PLA2. These types were denoted OxLDL(−)L, OxLDL(−)P, and OxLDL(−)D. FH patients exhibited significantly higher plasma OxLDL levels and serum IgG titers against OxLDLP and OxLDLD compared with 40 normolipidemic apparently healthy controls. ATT values were positively correlated with autoantibody titers against OxLDLP and OxLDLD; however, in multiple regression analysis, ATT was independently associated only with the autoantibody titers against OxLDLD. We conclude that the IgG autoantibody titers against OxLDLD but not OxLDL or Lp-PLA2 may play an important role in the pathogenesis of Achilles tendon xanthomas in FH patients. Achilles tendon xanthomas are associated with increased cardiovascular risk in patients with familial hypercholesterolemia (FH). Oxidized low density lipoprotein (OxLDL), the antibodies against OxLDL, and the LDL-associated phospholipase A2 (Lp-PLA2) may play important roles in atherogenesis. We investigated the possible association between plasma levels of OxLDL, Lp-PLA2 activity, and autoantibody titers against various types of mildly OxLDL with Achilles tendon thickness (ATT). ATT was determined by sonography in 80 unrelated heterozygous FH patients. Three different types of mildly OxLDL were prepared: OxLDLL, OxLDLP, and OxLDLD, at the end of the lag, propagation, and decomposition phases of oxidation, respectively. Similar types of OxLDL were also prepared after inactivation of the LDL-associated Lp-PLA2. These types were denoted OxLDL(−)L, OxLDL(−)P, and OxLDL(−)D. FH patients exhibited significantly higher plasma OxLDL levels and serum IgG titers against OxLDLP and OxLDLD compared with 40 normolipidemic apparently healthy controls. ATT values were positively correlated with autoantibody titers against OxLDLP and OxLDLD; however, in multiple regression analysis, ATT was independently associated only with the autoantibody titers against OxLDLD. We conclude that the IgG autoantibody titers against OxLDLD but not OxLDL or Lp-PLA2 may play an important role in the pathogenesis of Achilles tendon xanthomas in FH patients. Oxidative modification of LDL is an important event in the development of atherosclerosis. Oxidized low density lipoprotein (OxLDL) is present in atherosclerotic lesions and promotes atherosclerosis by several different mechanisms (1Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity..N. Engl. J. Med. 1989; 320: 915-924PubMed Google Scholar, 2Bhakdi S. Lackner K.J. Han S.R. Torzewski M. Husmann M. Beyond cholesterol: the enigma of atherosclerosis revisited..Thromb. Haemost. 2004; 91: 639-645Crossref PubMed Google Scholar, 3Holvoet P. Collen D. Oxidation of low density lipoproteins in the pathogenesis of atherosclerosis..Atherosclerosis. 1998; 137 (Suppl.):: 33-38Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). During LDL oxidation, the lipids and apolipoprotein B-100 (apoB-100) undergo a variety of chemical changes via radical-mediated reactions as well as modifications by chemically active products formed on OxLDL particles (4Esterbauer H. Gebicki J. Puhl H. Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL..Free Radic. Biol. Med. 1992; 13: 341-390Crossref PubMed Scopus (2136) Google Scholar). Oxidation of LDL in vitro occurs in three phases: i) the lag phase, during which consumption of the endogenous antioxidants occurs; ii) the propagation phase, in which the sn-2 unsaturated fatty acids of phosphatidylcholine molecules are rapidly oxidized to their hydroperoxides; and iii) the decomposition phase, when these hydroperoxides are cleaved, generating reactive aldehydes, such as malondialdehyde and 4-hydroxynonenal, as well as oxidized phospholipids (OxPL) containing short acyl groups at the sn-2 position (4Esterbauer H. Gebicki J. Puhl H. Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL..Free Radic. Biol. Med. 1992; 13: 341-390Crossref PubMed Scopus (2136) Google Scholar). OxPL can be hydrolyzed into lysophosphatidylcholine (lyso-PC) by the LDL-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor (PAF) acetylhydrolase (5Tselepis A.D. Chapman M.J. Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase..Atheroscler. Suppl. 2002; 3: 57-68Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). Lp-PLA2 exhibits a Ca2+-independent phospholipase A2 activity and preferentially hydrolyzes phospholipids containing short acyl groups at the sn-2 position, such as PAF and OxPL (5Tselepis A.D. Chapman M.J. Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase..Atheroscler. Suppl. 2002; 3: 57-68Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). OxLDL is immunogenic, and its constituents OxPL, aldehydes, and lyso-PC play important roles in OxLDL antigenicity, participating in the formation of several epitopes (6Wu R. Huang Y.H. Elinder L.S. Frostegard J. Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL..Arterioscler. Thromb. Vasc. Biol. 1998; 18: 626-630Crossref PubMed Scopus (66) Google Scholar, 7Palinski W. Witztum J.L. Immune responses to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis..J. Intern. Med. 2000; 247: 371-380Crossref PubMed Scopus (194) Google Scholar). These epitopes are recognized by specific autoantibodies, which are present in serum of healthy individuals as well as in various disease states, including atherosclerotic diseases (reviewed in 8Shoenfeld Y. Wu R. Dearing L.D. Matsuura E. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective?.Circulation. 2004; 110: 2552-2558Crossref PubMed Scopus (137) Google Scholar). Because the extent of LDL oxidation and the LDL-associated Lp-PLA2 activity significantly influence the levels of OxPL, lyso-PC, and aldehydes during LDL oxidation (9Karabina S-A. P. Elisaf M. Bairaktari E. Tzallas C. Siamopoulos K.C. Tselepis A.D. Increased activity of PAF-acetylhydrolase in low density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolemia..Eur. J. Clin. Invest. 1997; 27: 595-602Crossref PubMed Scopus (66) Google Scholar), these factors could also influence the types of epitopes formed on OxLDL and consequently the specificity and the plasma levels of autoantibodies against OxLDL. Indeed, we recently showed that the extent of LDL oxidation and the activity of LDL-associated Lp-PLA2 significantly affect the antibody titers against OxLDL (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). Tendon xanthomas are deposits of lipid and connective tissue in tendons and are commonly found in patients with severe hyperlipidemia, such as familial hypercholesterolemia (FH) (11Bertolini S. Cantafora A. Averna M. Cortese C. Motti C. Martini S. Pes G. Postiglione A. Stefanutti C. Blotta I. et al.Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype..Arterioscler. Thromb. Vasc. Biol. 2000; 20: 41-52Crossref PubMed Google Scholar, 12Mabuchi H. Tatami R. Haba T. Ueda K. Ueda R. Ito S. Karnetani T. Koizurni J. Miyamoto S. Ohta M. et al.Achilles tendon thickness and ischemic heart disease in familial hypercholesterolemia..Metabolism. 1978; 27: 1672-1679Abstract Full Text PDF PubMed Scopus (30) Google Scholar, 13Tsouli S.G. Kiortsis D.N. Argyropoulou M.I. Mikhailidis D.P. Elisaf M.S. Pathogenesis, detection and treatment of Achilles tendon xanthomas..Eur. J. Clin. Invest. 2005; 35: 236-244Crossref PubMed Scopus (88) Google Scholar). Importantly, it has been shown that the presence of tendon xanthomas in patients with FH is associated with increased cardiovascular risk independently of the underlying LDL receptor gene mutation (14Civeira F. Castillo S. R. E. A. M. P. E. M. P. Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene Thromb. Vasc. Biol. 2005; PubMed Scopus Google Scholar). The of tendon xanthomas exhibits to that of atherosclerotic S.G. Kiortsis D.N. Argyropoulou M.I. Mikhailidis D.P. Elisaf M.S. Pathogenesis, detection and treatment of Achilles tendon xanthomas..Eur. J. Clin. Invest. 2005; 35: 236-244Crossref PubMed Scopus (88) Google Scholar). Indeed, tendon xanthomas are by the of and as well as connective tissue and by the of in tendon J. Google Scholar, of with the lipids of tendon Clin. Invest. 1978; PubMed Scopus (30) Google Scholar). The underlying mechanisms by which FH patients tendon xanthomas and not to be it was that FH patients with tendon xanthomas are to the of OxLDL compared with FH patients tendon xanthomas M. A. C. P. M.J. M. F. Tendon xanthomas in familial hypercholesterolemia are associated with a of to oxidized 2005; PubMed Scopus Google Scholar). against OxLDL may play important roles in atherosclerosis Y. Wu R. Dearing L.D. Matsuura E. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective?.Circulation. 2004; 110: 2552-2558Crossref PubMed Scopus (137) Google Scholar, K. M. and R. Oxidative modification of low-density lipoprotein and of atherosclerosis. Scholar). the of is a of the autoantibody titers in FH patients with to the presence of tendon the of was to the autoantibody titers against various types of mildly OxLDL as well as the plasma levels of OxLDL and Lp-PLA2 activity in to Achilles tendon thickness determined by sonography in heterozygous FH patients. unrelated patients with heterozygous FH in the The of FH was to recently heterozygous familial hypercholesterolemia by J. Full Text PDF PubMed Scopus Google and was by the G. Elisaf M. Bairaktari H. P. and of the low density lipoprotein receptor gene mutations in Scopus Google Scholar). normolipidemic apparently healthy with of hypercholesterolemia or coronary artery disease were also in the or of cardiovascular or of the of plasma or of or of and levels of the was including or known to affect lipid including during the During the patients were on an and in at into the was were after a was and the was by the of the of were a and a on the as the The were in the position with the the end of the were on The ATT was the to was to the to the an was on to the presence of xanthomas the of The the of the The of Achilles tendon was into three of the tendon and xanthomas S.G. Kiortsis D.N. Argyropoulou M.I. Mikhailidis D.P. Elisaf M.S. Pathogenesis, detection and treatment of Achilles tendon xanthomas..Eur. J. Clin. Invest. 2005; 35: 236-244Crossref PubMed Scopus (88) Google Scholar). were after patients levels of and were determined on the was the that levels were S. C. R. J. E. J. Witztum J.L. in plasma of oxidized low-density lipoprotein the presence of coronary PubMed Scopus Google Scholar). levels were with a Bairaktari E. G. Chapman M.J. Tselepis A.D. Elisaf M. of platelet-activating activity between LDL and as a of the of 2002; Full Text Full Text PDF PubMed Google Scholar). LDL was by plasma S. Tselepis A.D. factor formation during oxidative modification of low-density lipoprotein when PAF-acetylhydrolase has been PubMed Scopus Google Scholar). oxidation, a of LDL was with at to the it was against to the of (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). LDL with active Lp-PLA2 or LDL Lp-PLA2 and denoted at a of was oxidized in the presence of at The of oxidation were determined by the increase in the at (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). Oxidation of LDL or was by the of at the end of the lag or OxLDL(−)L, at the end of the propagation or OxLDL(−)P, or at of oxidation during the decomposition or The between the lag and propagation phases was determined as recently (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). types of OxLDL were at to The serum autoantibody titers of IgG against of OxLDL were determined by an as we recently (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). were with of of of OxLDL or LDL and at the were with an of the serum was to well and at the of were also in were and of an IgG antibody was to the and at the of the was and as and the density was at (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). The serum autoantibody titers of against of OxLDL were also determined by the of the serum and antibody The were as the of antibody to various types of OxLDL or LDL or respectively. be that of serum to was at and IgG and respectively. levels of OxLDL were by a a specific antibody to the by the The specificity of was by the in different plasma in which or of of LDL or OxLDLD was and of of the were and respectively. Lp-PLA2 activity in plasma and in plasma was by the as a as we Bairaktari E. G. Chapman M.J. Tselepis A.D. Elisaf M. of platelet-activating activity between LDL and as a of the of 2002; Full Text Full Text PDF PubMed Google Scholar). The was at and Lp-PLA2 activity was as PAF are as were of by the between was by the with the was the between the various and were antibody titers between the different phases of oxidation, we also multiple regression was to factors independently associated with ATT in FH patients. in we ATT as a and that were significantly correlated with ATT in the as were with was The and of the are shown in FH patients significantly higher levels of serum and compared with normolipidemic Lp-PLA2 activity in plasma was also significantly higher in FH patients compared with activity was between the a in with Bairaktari E. G. Chapman M.J. Tselepis A.D. Elisaf M. of platelet-activating activity between LDL and as a of the of 2002; Full Text Full Text PDF PubMed Google Scholar). Achilles tendon xanthomas were by in only FH patients patients exhibited xanthomas in and and of the 40 compared with compared with compared with compared with compared with compared with plasma Lp-PLA2 activity, compared with activity, tendon tendon xanthomas were by of Achilles apolipoprotein familial LDL-associated phospholipase LDL-associated phospholipase OxLDL, oxidized low-density are compared with compared with Achilles tendon xanthomas were by in a apolipoprotein familial LDL-associated phospholipase LDL-associated phospholipase OxLDL, oxidized low-density are FH patients exhibited significantly higher plasma OxLDL levels controls. The of OxLDL to the of oxidized to was also significantly higher in FH patients compared with OxLDL was positively correlated with and OxLDL and the of OxLDL to were positively correlated with plasma Lp-PLA2 activity and a was between these and activity and an to the specificity of the to OxLDL in we different of LDL or OxLDL into different plasma containing OxLDL. We found that in plasma with or of the OxLDL levels determined with were increased to or respectively. of the plasma with or of OxLDLD in an increase of OxLDL levels to or respectively. We determined the autoantibody titers of IgG and against three different types of OxLDL OxLDLP, and and three types of OxLDL(−)P, and prepared as in IgG and antibody titers against types of OxLDL and were in FH patients as well as in controls. The IgG titers in FH patients were significantly higher when the OxLDLP and OxLDLD types were as compared with OxLDLL, the titers against OxLDLD higher against OxLDLP FH patients exhibited higher titers against compared with OxLDLP and OxLDLD the titers against OxLDLD against The was when the types were as the IgG titers against of were higher compared with the of OxLDL, the was the titers Similar were the IgG or titers in the not FH patients exhibited significantly higher IgG autoantibody titers against OxLDLP and OxLDLD compared with in the titers against of OxLDL or was between the groups not be that was found between the IgG or titers against of OxLDL and the plasma levels of titers of IgG against various types of OxLDL in FH patients and compared with compared with and OxLDL in the lag, propagation, and decomposition OxLDL(−)L, and OxLDL in which the endogenous Lp-PLA2 was oxidation, at the end of the lag, propagation, and decomposition compared with compared with controls. in a OxLDLL, and OxLDL in the lag, propagation, and decomposition OxLDL(−)L, and OxLDL in which the endogenous Lp-PLA2 was oxidation, at the end of the lag, propagation, and decomposition respectively. of Achilles in which the of the tendon was was in in the of Achilles tendon was also in FH patients exhibited the patients with exhibited xanthomas with lesions in Achilles tendon were in patients shown in in ATT values were and in FH patients. Importantly, FH patients with tendon and exhibited significantly higher ATT values compared with analysis, ATT values in the of FH patients were positively correlated with and serum an was between ATT values and serum levels the antibody titers against several types of OxLDL, ATT was positively correlated only with the IgG titers against OxLDLP and OxLDLD, was between ATT and the plasma levels of OxLDL multiple regression was to factors independently associated with ATT in the FH patients. we ATT as the and that were significantly correlated with ATT in the as shown in the independently associated with ATT were and antibody titers against of factors ATT in FH Achilles tendon in a of factors ATT in FH in a Achilles tendon the that autoantibodies against mildly OxLDL are increased in patients with heterozygous FH that autoantibodies against OxLDLD are independently associated with the plasma levels of OxLDL or Lp-PLA2 activity, increased significantly in FH patients compared with are not correlated with OxLDL is present in and several been to OxLDL by antibodies that a specific of OxLDL or a specific on OxLDL S. 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T. et levels of oxidized low density lipoprotein a with the of coronary PubMed Scopus Google Scholar). we that the present not a specificity OxLDL and that it also LDL in the of OxLDL to in FH patients is higher compared with that in a not the of to that not a specificity OxLDL, it may the OxLDL levels in plasma when are as a to is important that be a is the specificity of the to OxLDL in the that OxLDL is positively correlated with plasma Lp-PLA2 could be to the that plasma Lp-PLA2 is associated with which is positively correlated with OxLDL. activity was also positively correlated with the of OxLDL to we may not the that the increased Lp-PLA2 activity in FH patients to the of increased of aldehydes the of These with of S. M.I. S. against oxidized low-density lipoprotein and in patients with coronary heart Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar), generating increased of epitopes on OxLDL recognized by to plasma activity is correlated with plasma OxLDL could be to the of LDL oxidation, in which an important role (5Tselepis A.D. Chapman M.J. Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase..Atheroscler. Suppl. 2002; 3: 57-68Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). the increased plasma levels of OxLDL in FH is not correlated with OxLDL is important lipid and the formation of in Achilles tendons in tendon J. Google Scholar), its plasma levels may not be a factor the formation of tendon Indeed, FH patients with tendon xanthomas higher to formation in the presence of OxLDL and are to the of OxLDL compared with FH patients tendon that the important their formation is the determined higher of to OxLDL M. A. C. P. M.J. M. F. Tendon xanthomas in familial hypercholesterolemia are associated with a of to oxidized 2005; PubMed Scopus Google Scholar). showed that the autoantibody titers of IgG against OxLDLP and OxLDLD are increased in FH patients compared with between these groups was in the titers against types of OxLDL or been the IgG antibodies against OxLDL role in atherosclerotic diseases Y. Wu R. Dearing L.D. Matsuura E. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective?.Circulation. 2004; 110: 2552-2558Crossref PubMed Scopus (137) Google Scholar, S. C. R. J. E. J. Witztum J.L. in plasma of oxidized low-density lipoprotein the presence of coronary PubMed Scopus Google Scholar, J. E. G. to oxidized LDL in to and phospholipase Thromb. Vasc. Biol. PubMed Scopus (88) Google Scholar, J. J. A. I. titers against oxidized LDL are not in patients with familial Thromb. Vasc. Biol. 1998; 18: PubMed Scopus Google Scholar, R. Huang Y.H. Elinder L.S. Frostegard J. Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL..Arterioscler. Thromb. Vasc. Biol. 1998; 18: 626-630Crossref PubMed Google Scholar), of the that OxLDL antibodies may play an role (reviewed in K. M. and R. Oxidative modification of low-density lipoprotein and of atherosclerosis. Scholar). plasma OxLDL autoantibodies been in patients with S. C. R. J. E. J. Witztum J.L. in plasma of oxidized low-density lipoprotein the presence of coronary PubMed Scopus Google Scholar, S. M.I. S. against oxidized low-density lipoprotein and in patients with coronary heart Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar), coronary artery disease S. M.I. S. against oxidized low-density lipoprotein and in patients with coronary heart Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar, J. to LDL in to in and in healthy Thromb. Vasc. Biol. PubMed Scopus Google Scholar), and R. Huang Y.H. Elinder L.S. Frostegard J. Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL..Arterioscler. Thromb. Vasc. Biol. 1998; 18: 626-630Crossref PubMed Google and been associated with increased thickness J. to LDL in to in and in healthy Thromb. Vasc. Biol. PubMed Scopus Google Scholar). Because only the IgG titers against OxLDLP and OxLDLD are increased in FH we that IgG antibodies against mildly oxidized of LDL to of may be involved in the atherosclerosis in a not in the autoantibody titers between heterozygous FH patients and normolipidemic however, OxLDL of or were as in that J. J. A. I. titers against oxidized LDL are not in patients with familial Thromb. Vasc. Biol. 1998; 18: PubMed Scopus Google Scholar). we that the extent of LDL oxidation significantly the plasma autoantibody levels in FH patients. is by recently in patients with coronary artery disease (10Lourida, E. S., A. I. Papathanasiou, J. A. Goudevenos, and A. D. Tselepis. The low-density lipoprotein (LDL)-associated PAF-acetylhydrolase activity and the extent of LDL oxidation are important determinants of the autoantibody titers against oxidized LDL in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. Epub ahead of print. May 30, 2006; doi:10.1016/j.plefa.2006.03.012.Google Scholar). to these the OxLDLP and OxLDLD types are in lyso-PC and aldehydes but significantly OxPL compared with the as a of the of we that epitopes formed in the presence of lyso-PC and aldehydes may be the increased IgG titers in FH patients. these epitopes to be in Importantly, only the IgG titers against OxLDLD are independently associated with that these antibodies are involved in the pathogenesis of Achilles tendon The pathogenesis of tendon xanthomas that of atherosclerotic S.G. Kiortsis D.N. Argyropoulou M.I. Mikhailidis D.P. Elisaf M.S. Pathogenesis, detection and treatment of Achilles tendon xanthomas..Eur. J. Clin. Invest. 2005; 35: 236-244Crossref PubMed Scopus (88) Google Scholar). The role of mechanisms in atherosclerosis is and are autoantibodies against OxLDL or OxLDL may or atherosclerosis Y. Wu R. Dearing L.D. Matsuura E. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective?.Circulation. 2004; 110: 2552-2558Crossref PubMed Scopus (137) Google Scholar, K. M. and R. Oxidative modification of low-density lipoprotein and of atherosclerosis. Scholar). it to be the IgG antibodies against OxLDLD or the development of Achilles tendon are to the IgG titers against OxLDLD in FH patients may the development of Achilles tendon which are associated with cardiovascular risk factors and a higher of coronary artery disease in (14Civeira F. Castillo S. R. E. A. M. P. E. M. P. Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene Thromb. Vasc. Biol. 2005; PubMed Scopus Google Scholar). the that IgG titers against OxLDLD are independently associated with that may play a role in the pathogenesis of in heterozygous FH patients.