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1. Erratum: Differential expression of oxidation-specifi c epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions (J. Lipid Res. (2012) 53 (2773-2790)

Author

Van Dijk, RA, Kolodgie, F, Ravandi, A, Leibundgut, G, Hu, PP, Prasad, A, Mahmud, E, Dennis, E, Curtiss, LK, Witztum, JL, Wasserman, BA, Otsuka, F, Virmani, R, and Tsimikas, S

Subjects
Biochemistry & Molecular Biology, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics
Published
2014

6. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo.

Author

Shaw, PX, Hörkkö, S, Tsimikas, S, Chang, MK, Palinski, W, Silverman, GJ, Chen, PP, and Witztum, JL

Subjects
Macrophages, Animals, Humans, Arteriosclerosis, Malondialdehyde, Lipoproteins, LDL, Antibodies, Monoclonal, Autoantibodies, Epitopes, Immunoglobulin Fab Fragments, atherosclerosis, imaging, antibodies, lipoproteins, Cardiovascular, Atherosclerosis, 2.1 Biological and endogenous factors, Cardiovascular System & Hematology, Cardiorespiratory Medicine and Haematology, Clinical Sciences
Abstract

Autoantibodies to oxidation-specific epitopes of low density lipoprotein (LDL), such as malondialdehyde-modified LDL (MDA-LDL), occur in plasma and atherosclerotic lesions of humans and animals. Plasma titers of such antibodies are correlated with atherosclerosis in murine models, and several such autoantibodies have been cloned. However, human-derived monoclonal antibodies to epitopes of oxidized LDL (OxLDL) have not yet been reported. We constructed a phage display antibody library from a patient with high plasma anti-MDA-LDL titers and isolated 3 monoclonal IgG Fab antibodies, which specifically bound to MDA-LDL. One of these, IK17, also bound to intact OxLDL as well as to its lipid and protein moieties but not to those of native LDL. IK17 inhibited the uptake of OxLDL by macrophages and also bound to apoptotic cells and inhibited their phagocytosis by macrophages. IK17 strongly immunostained necrotic cores of human and rabbit atherosclerotic lesions. When (125)I-IK17 was injected intravenously into LDL receptor-deficient mice, its specific uptake was greatly enriched in atherosclerotic plaques versus normal aortic tissue. Human autoantibodies to OxLDL have important biological properties that could influence the natural course of atherogenesis.

Published
2001

7. Circulating autoantibodies to oxidized LDL correlate with arterial accumulation and depletion of oxidized LDL in LDL receptor-deficient mice.

Author

Tsimikas, S, Palinski, W, and Witztum, JL

Subjects
Aorta, Animals, Mice, Knockout, Mice, Arteriosclerosis, Disease Models, Animal, Lipoproteins, LDL, Receptors, LDL, Autoantibodies, Oxidation-Reduction, Male, regression, progression, atherosclerosis, lipoproteins, autoantibodies, Cardiovascular System & Hematology, Cardiorespiratory Medicine and Haematology, Clinical Sciences
Abstract

Autoantibodies to oxidized low density lipoprotein (OxLDL) are elevated in some human populations with increased risk of atherosclerosis. To determine whether autoantibody levels to epitopes of OxLDL reflect the extent of aortic atherosclerosis and the content of OxLDL, we measured IgG and IgM autoantibody titers to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL) in 43 LDL receptor-deficient mice consuming atherogenic and regression diets. Antibody titers were correlated to percent atherosclerotic surface area, aortic weight, and aortic OxLDL content, measured as the in vivo uptake of (125)I-MDA2, a monoclonal antibody to MDA-LDL. All mice were fed an atherogenic diet for 6 months, and 1 group was euthanized. The other 3 groups were fed an atherogenic diet (fat/CHOL group), normal mouse chow (chow group), or mouse chow supplemented with vitamins E and C (chow+VIT group) for an additional 6 months. After dietary intervention, compared with their own baseline, autoantibody titers to MDA-LDL and Cu-OxLDL increased significantly in the fat/CHOL group, whereas they did not change or decreased significantly in the chow and chow+VIT groups. Aortic weight and surface area showed significant progression in the fat/CHOL group, mild progression in the chow group, and no progression in the chow+VIT group (P

Published
2001

8. In vivo uptake of radiolabeled MDA2, an oxidation-specific monoclonal antibody, provides an accurate measure of atherosclerotic lesions rich in oxidized LDL and is highly sensitive to their regression.

Author

Tsimikas, S, Shortal, BP, Witztum, JL, and Palinski, W

Subjects
Aorta, Thoracic, Animals, Mice, Knockout, Rabbits, Mice, Arteriosclerosis, Iodine Radioisotopes, Malondialdehyde, Vitamin E, Cholesterol, Triglycerides, Lipoproteins, LDL, Receptors, LDL, Antibodies, Monoclonal, Epitopes, Organ Size, Staining and Labeling, Diet, Atherogenic, Antibody Specificity, Oxidation-Reduction, Hyperlipidemias, atherosclerosis, lipoproteins, oxidation, radioisotopes, imaging, Aging, Atherosclerosis, Cardiovascular, Heart Disease, Nutrition, 2.1 Biological and endogenous factors, Cardiovascular System & Hematology, Cardiorespiratory Medicine and Haematology, Clinical Sciences
Abstract

To determine whether labeled antibodies against oxidized LDL (OxLDL) offer advantages for quantifying atherosclerosis, we compared in vivo aortic uptake of (125)I-labeled MDA2, a monoclonal antibody against malondialdehyde-lysine epitopes), atherosclerotic surface area, and aortic weight in Watanabe heritable hyperlipidemic and New Zealand White rabbits and in low density lipoprotein receptor-deficient (LDLR(-/-)) and apolipoprotein E-deficient (apoE(-/-)) mice. Absolute and specific uptakes of (125)I-MDA2 were significantly greater in plaque than in normal aortas. Uptake of (125)I-MDA2 significantly correlated with aortic weight and percent atherosclerotic surface area in rabbits and mice. To assess whether (125)I-MDA2 uptake reflects changes in lesion content of OxLDL, in a separate study, extensive atherosclerosis was induced in 4 groups of LDLR(-/-) mice by feeding them a high fat/cholesterol diet for 6 months. A baseline group was euthanized at this time. The remaining groups were fed "regression" diets (chow or chow+1% vitamin E+0.05% vitamin C) or the high fat/cholesterol diet for 6 more months. When atherosclerosis was measured as percent surface area or aortic weight, there was strong progression in the high fat/cholesterol group, moderate progression in the chow group, and no progression in the chow+vitamin E+vitamin C group compared with the baseline group. The (125)I-MDA2 method also yielded a significant increase in atherosclerosis in the high fat/cholesterol group but significant decreases in the chow and chow+vitamin E+vitamin C groups. Immunocytochemistry showed fewer oxidation-specific epitopes in lesions from the chow and chow+vitamin E+vitamin C groups. Thus, the uptake of (125)I-MDA2 correlates well with traditional measures of atherosclerosis but also reflects reduced plaque OxLDL content after hypocholesterolemic intervention.

Published
2000

10. Inhibition of novel lipoprotein(a) receptor major facilitator superfamily domain containing 5 (MFSD5) reduces development of aortic valve calcification

Author

Bartoli-Leonard, F, primary, Rogers, M, additional, Zheng, K, additional, Small, A, additional, Asano, T, additional, Kuraoka, S, additional, Blaser, M, additional, Natarajan, P, additional, Yeang, C, additional, Tsimikas, S, additional, O'donnell, C, additional, Aikawa, M, additional, Singh, S, additional, Stroes, E, additional, and Aikawa, E, additional

Published
2022
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11. Generation of cardio-protective antibodies after pneumococcal polysaccharide vaccine: Early results from a randomised controlled trial.

Author

Ren, S, Hansbro, PM, Srikusalanukul, W, Horvat, JC, Hunter, T, Brown, AC, Peel, R, Faulkner, J, Evans, T-J, Li, SC, Newby, D, Hure, A, Abhayaratna, WP, Tsimikas, S, Gonen, A, Witztum, JL, Attia, J, AUSPICE investigators, Ren, S, Hansbro, PM, Srikusalanukul, W, Horvat, JC, Hunter, T, Brown, AC, Peel, R, Faulkner, J, Evans, T-J, Li, SC, Newby, D, Hure, A, Abhayaratna, WP, Tsimikas, S, Gonen, A, Witztum, JL, Attia, J, and AUSPICE investigators

Abstract

BACKGROUND AND AIMS: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. METHODS: A subgroup of participants at one centre (Canberra; n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). RESULTS: Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years; there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. CONCLUSIONS: PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-yea

Published
2022

12. EVALUATION OF THE EFFICACY AND SAFETY OF IONIS-TTR-LRX IN PATIENTS WITH TRANSTHYRETIN-MEDIATED AMYLOID CARDIOMYOPATHY: THE CARDIO-TTRANSFORM STUDY

Author

Maurer, M, primary, Kristen, A, additional, Benson, M, additional, Falk, R, additional, Buchele, G, additional, Brambatti, M, additional, Tsimikas, S, additional, Viney, N, additional, Tai, L, additional, Monteiro, C, additional, Yang, Q, additional, O'Dea, L, additional, Schneider, E, additional, Geary, R, additional, and Monia, B, additional

Published
2021
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14. HDL compartmentalisation regulates PCSK9 activity

Author

Burnap, S.A., primary, Sattler, K., additional, Pechlaner, R., additional, Theofilatos, K., additional, Takov, K., additional, Heusch, G., additional, Tsimikas, S., additional, Fernández-Hernando, C., additional, Berry, S.E., additional, Hall, W., additional, Notdurfter, M., additional, Rungger, G., additional, Willeit, J., additional, Kiechl, S., additional, Levkau, B., additional, and Mayr, M., additional

Published
2021
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15. Residual inflammatory risk increases endothelial metabolism, thereby facilitating sustained vascular inflammation and leukocyte extravasation

Author

Hanford, K.M.L., primary, Schnitzler, J.G., additional, Hoogeveen, R.M., additional, Ali, K., additional, Prange, K.H.M., additional, Weeghel, M.V., additional, Versloot, M., additional, Waissi, F., additional, Houtkooper, R., additional, De Kleijn, D.P.V., additional, De Winther, M., additional, Koschinsky, M.L., additional, Tsimikas, S., additional, Witztum, J.L., additional, Stroes, E.S.G., additional, and Kroon, J., additional

Published
2021
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18. Familial hypercholesterolemia and elevated lipoprotein(a) : double heritable risk and new therapeutic opportunities

Author

Vuorio, A., Watts, G. F., Schneider, W. J., Tsimikas, S., Kovanen, P. T., Department of Forensic Medicine, and University of Helsinki

Subjects
therapy, familial hypercholesterolemia, 3121 General medicine, internal medicine and other clinical medicine, lipoprotein (a), lipids (amino acids, peptides, and proteins), atherosclerotic cardiovascular disease, burden
Abstract

Vuorio A, Watts GF, Schneider WJ, Tsimikas S, Kovanen PT (Mehilainen Airport Health Centre, Vantaa; University of Helsinki, Helsinki, Finland; University of Western Australia, Perth, Australia; Royal Perth Hospital, Perth, Australia; Medical University of Vienna, Vienna, Austria; University of California San Diego, La Jolla, CA, USA; Wihuri Research Institute, Helsinki, Finland). Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities (Review). J Intern Med 2020; 287: 2-18. There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.

Published
2020

19. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome

Author

Bittner, V. A. (Vera A.), Szarek, M. (Michael), Aylward, P. E. (Philip E.), Bhatt, D. L. (Deepak L.), Diaz, R. (Rafael), Edelberg, J. M. (Jay M.), Fras, Z. (Zlatko), Goodman, S. G. (Shaun G.), Halvorsen, S. (Sigrun), Hanotin, C. (Corinne), Harrington, R. A. (Robert A.), Jukema, W. (Wouter), Loizeau, V. (Virginie), Moriarty, P. M. (Patrick M.), Moryusef, A. (Angèle), Pordy, R. (Robert), Roe, M. T. (Matthew T.), Sinnaeve, P. (Peter), Tsimikas, S. (Sotirios), Vogel, R. (Robert), White, H. D. (Harvey D.), Zahger, D. (Doron), Zeiher, A. M. (Andreas M.), Steg, G. (Gabriel), Schwartz, G. G. (Gregory G.), and Huikuri, H. (Heikki)

Subjects
low-density lipoprotein cholesterol, proprotein convertase subtilisin/kexin type 9 inhibition, lipids (amino acids, peptides, and proteins), acute coronary syndromes, alirocumab, cardiovascular diseases, major adverse cardiovascular events
Abstract

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C). Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE). Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina. Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081). Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)

Published
2020

21. Atherogenic lipoprotein(A) increases vascular glycolysis, thereby facilitating inflammation and leukocyte extravasation

Author

Schnitzler, J.G., primary, Hoogeveen, R.M., additional, Ali, L., additional, Prange, K., additional, Weeghel, M.V., additional, Versloot, M., additional, Waissi, F., additional, Houtkooper, R., additional, De Kleijn, D.P.V., additional, De Winther, M., additional, Koschinsky, M., additional, Tsimikas, S., additional, Witztum, J.L., additional, Stroes, E., additional, and Kroon, J., additional

Published
2020
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23. Elevated Lipoprotein(a) in Perinatally HIV-Infected Children Compared With Healthy Ethnicity-Matched Controls

Author

Hof, M. van den, Haneveld, M.J.K., Blokhuis, C., Scherpbier, H.J., Jansen, H.P.G., Kootstra, N.A., Dallinga-Thie, G.M., Deventer, S.J.H. van, Tsimikas, S., Pajkre, D., Cohen, S., Kuijpers, T.W., Plas, A. van der, Weijsenfeld, A., Stege, J.S. ter, Caan, M.W.A., Mutsaerts, H.J.M.M., Majoie, C.B.L.M., Deinirkaya, N., Verbraak, F.D., Schmand, B., Geurtsen, G., Mathot, R.A.A., Wit, F.W.N.M., Reiss, P., Teunissen, C.F., Kuhle, J., Meijer, J.C.M., and NOVICE Study Grp

Subjects
lipids, lipoprotein(a), lipids (amino acids, peptides, and proteins), perinatal HIV infection, cardiovascular disease risk, MRI
Abstract

Background. HIV-associated cardiovascular disease (CVD) risk in combination antiretroviral therapy (cART)-treated perinatally HIV-infected patients (PHIV+) remains unknown due to the young age of this population. Lipoprotein(a) (Lp(a)) has been established as an independent causal risk factor for CVD in the general population but has not been well established in the population of PHIV+.Methods. We cross-sectionally compared lipid profiles, including nonfasting Lp(a), together with total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides between 35 cART-treated PHIV+ children aged 8-18 years and 37 controls who were matched for age, sex, ethnicity, and socioeconomic status. We explored associations between Lp(a) and disease- and treatment-related factors (inflammation, monocyte activation, and vascular), biomarkers, and neuroimaging outcomes using linear regression models.Results. PHIV+ children had significantly higher levels of Lp(a) compared with controls (median, 43.6 [21.6-82.4] vs 21.8 [16.8-46.6] mg/dL; P = .033). Other lipid levels were comparable between groups. Additional assessment of apolipoprotein B, apolipoprotein CIII, apolipoprotein E, and APOE genotype revealed no significant differences. Higher Lp(a) levels were associated with higher plasma apoB levels and with lower monocyte chemoattractant protein-1 and TG levels in PHIV+ children. Lp(a) was not associated with HIV- or cART-related variables or with neuroimaging outcomes.Conclusions. cART-treated PHIV+ children appear to have higher levels of Lp(a) compared with ethnicity-matched controls, which may implicate higher CVD risk in this population. Future research should focus on the association between Lp(a) and (sub) clinical CVD measurements in cART-treated PHIV+ patients.

Published
2019

27. Lipoprotein(A) Predicts Cardiovascular Events In Statin Outcome Trials: Pooled Analysis Of Seven Randomised Controlled Trials

Author

Willeit, P., primary, Ridker, P., additional, Nestel, P.J., additional, Simes, J., additional, Tonkin, A.M., additional, Pedersen, T.R., additional, Schwartz, G.G., additional, Olsson, A.G., additional, Colhoun, H.M., additional, Kronenberg, F., additional, Drechsler, C., additional, Wanner, C., additional, Mora, S., additional, Lesogor, A., additional, and Tsimikas, S., additional

Published
2019
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28. Targeting Lipoprotein(A)-Induced Endothelial Cell Metabolic Reprogramming Reverses Inflammation And Leukocyte Migration

Author

Schnitzler, J., primary, Hoogeveen, R., additional, Ali, L., additional, Prange, K., additional, Van Weeghel, M., additional, Bachmann, J., additional, Versloot, M., additional, Houtkooper, R., additional, Tsimikas, S., additional, Koschinksky, M., additional, De Winther, M., additional, Groen, A., additional, Stroes, E., additional, and Kroon, J., additional

Published
2019
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29. Lipoprotein(A), Oxidized Phospholipids, And Aortic Valve Microcalcification Assessed By 18f-Naf Pet/Ct

Author

Després, A.A., primary, Perrot, N., additional, Tastet, L., additional, Pouliot, A., additional, Shen, M., additional, Chen, H.Y., additional, Bourgeois, R., additional, Trottier, M., additional, Guimond, J., additional, Tessier, M., additional, Nadeau, M., additional, Sebastien, T., additional, Couture, P., additional, Dweck, M., additional, Tsimikas, S., additional, Thanassoulis, G., additional, Pibarot, P., additional, Marie-Annick Clavel, M.A.C., additional, and Arsenault, B., additional

Published
2019
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34. P1761Diabetic status influences the effect of pro-inflammatory interleukin-1 genotypes on lipoprotein(a) mediated risk of coronary artery disease and cardiovascular events

Author

Naka, K.K., primary, Bechlioulis, A., additional, Douchette-Stamm, L., additional, Wilkins, L., additional, Marini, A., additional, Bougiakli, M., additional, Giannitsi, S., additional, Rogus, J., additional, Kornman, K., additional, Witztum, J.L., additional, Tsimikas, S., additional, and Michalis, L.K., additional

Published
2017
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35. The APPROACH Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Volanesorsen Administered Subcutaneously to Patients with Familial Chylomicronemia Syndrome (FCS)

Author

Gaudet, D., primary, Digenio, A., additional, Alexander, V.J., additional, Arca, M., additional, Jones, A.F., additional, Stroes, E., additional, Bergeron, J., additional, Civeira, F., additional, Hemphill, L., additional, Blom, D.J., additional, Flaim, J., additional, Hughes, S., additional, Geary, R., additional, Tsimikas, S., additional, Witztum, J.L., additional, and Bruckert, E., additional

Published
2017
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36. Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans

Author

Valk, F.M. van der, Bekkering, S., Kroon, J., Yeang, C., Bossche, J. Van den, Buul, J.D. van, Ravandi, A., Nederveen, A.J., Verberne, H.J., Scipione, C., Nieuwdorp, M., Joosten, L.A.B., Netea, M.G., Koschinsky, M.L., Witztum, J.L., Tsimikas, S., Riksen, N.P., Stroes, E.S., Valk, F.M. van der, Bekkering, S., Kroon, J., Yeang, C., Bossche, J. Van den, Buul, J.D. van, Ravandi, A., Nederveen, A.J., Verberne, H.J., Scipione, C., Nieuwdorp, M., Joosten, L.A.B., Netea, M.G., Koschinsky, M.L., Witztum, J.L., Tsimikas, S., Riksen, N.P., and Stroes, E.S.

Abstract

Contains fulltext : 165726.pdf (publisher's version ) (Closed access), BACKGROUND: Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway. METHODS: In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity. RESULTS: We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a). CONCLUSIONS: These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease. CLINICAL TRIAL

Published
2016

37. PREVALENCE OF LPA SINGLE NUCLEOTIDE POLYMORPHISMS AND ISOFORMS IN PATIENTS ENROLLED IN A PHASE 2 IONIS-APO(A)(RX) CLINICAL TRIAL

Author

Stroes, E. S., van der Valk, F. M., Gaudet, D., Gouni-Berthold, I., Riksen, N. P., Steinhagen-Thiessen, E., Isermann, B., Nordestgaard, B., Viney, N. J., Marcovina, S., Hughes, S. G., Tami, J., Xia, S., Witztum, J. L., Tsimikas, S., Stroes, E. S., van der Valk, F. M., Gaudet, D., Gouni-Berthold, I., Riksen, N. P., Steinhagen-Thiessen, E., Isermann, B., Nordestgaard, B., Viney, N. J., Marcovina, S., Hughes, S. G., Tami, J., Xia, S., Witztum, J. L., and Tsimikas, S.

Published
2016

43. Prevalence of LPA single nucleotide polymorphisms and isoforms in patients enrolled in a phase 2 IONIS-APO(a) Rx clinical trial

Author

Stroes, E.S., primary, van der Valk, F.M., additional, Gaudet, D., additional, Gouni-Berthold, I., additional, Riksen, N.P., additional, Steinhagen-Thiessen, E., additional, Isermann, B., additional, Nordestgaard, B., additional, Viney, N.J., additional, Marcovina, S., additional, Hughes, S.G., additional, Tami, J., additional, Xia, S., additional, Witztum, J.L., additional, and Tsimikas, S., additional

Published
2016
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46. Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease

Author

Nsaibia, M. J., primary, Mahmut, A., additional, Boulanger, M.-C., additional, Arsenault, B. J., additional, Bouchareb, R., additional, Simard, S., additional, Witztum, J. L., additional, Clavel, M.-A., additional, Pibarot, P., additional, Bossé, Y., additional, Tsimikas, S., additional, and Mathieu, P., additional

Published
2016
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47. Apolipoprotein C-III: From Pathophysiology to Pharmacology

Author

Norata, Giuseppe, Tsimikas, S., Pirillo, A., Catapano, A., Norata, Giuseppe, Tsimikas, S., Pirillo, A., and Catapano, A.

Abstract

© 2015 Elsevier Ltd. All rights reserved. Apolipoprotein C-III (apoC-III) has a critical role in the metabolism of triglyceride (TG)-rich lipoproteins (TRLs). Animal models lacking the APOC3 gene exhibit reduced plasma TG levels, whereas the overexpression of APOC3 leads to increased TG levels. In humans, loss-of-function mutations in APOC3 are associated with reduced plasma TG levels and reduced risk for ischemic vascular disease and coronary heart disease. Several hypolipidemic agents have been shown to reduce apoC-III, including fibrates and statins, and antisense technology aimed at inhibiting APOC3 mRNA to decrease the production of apoC-III is currently in Phase III of clinical development. Here, we review the pathophysiological role of apoC-III in TG metabolism and the evidence supporting this apolipoprotein as an emerging target for hypertriglyceridemia (HTG) and associated cardiovascular disorders.

Published
2015

48. Secretory phospholipase A2-IIA and cardiovascular disease: a mendelian randomization study

Author

Holmes, M.V., Simon, T., Exeter, H.J, Folkersen, L., Asselbergs, F.W., Guardiola, M., Cooper, J.A., Palmen, J., Hubacek, J.A., Carruthers, K.F., Horne, B.D., Brunisholz, K.D., Mega, J.L., Van Iperen, E.P., Li, M., Leusink, M., Trompet, S., Verschuren, J.J., Hovingh, G.K., Dehghan, A., Nelson, C.P., Kotti, S., Danchin, N., Scholz, M., Haase, C.L., Rothenbacher, D., Swerdlow, D.I., Kuchenbaecker, K.B., Staines-Urias, E., Goel, A., Van 't Hooft, F., Gertow, K., De Faire, U., Panayiotou, A.G., Tremoli, E., Baldassarre, D., Veglia, F., Holdt, L.M., Beutner, F., Gansevoort. R.T., Navis, G.J., Mateo, L.I., Breitling, L.P., Brenner, H., Thiery, J., Dallmeier, D., Franco-Cereceda, A., Boer, J.M., Stephens, J.W., Hofker, M.H., Tedgui, A., Hofman, A., Uitterlinden, A.G., Adamkova, V., Pitha, J., Onland-Moret, N.C., Cramer, M.J., Nathoe, H.M., Spiering, W., Klungel, O.H., Kumari, M., Whincup, P.H., Morrow, D.A., Braund, P.S., Hall, A.S., Olsson, A.G., Doevendans, P.A., Trip, M.D., Tobin, M.D., Hamsten, A., Watkins, H., Koenig, W., Nicolaides, A.N., Teupser, D., Day, I.N., Carlquist, J.F., Gaunt, T.R., Ford, I., Sattar, N., Tsimikas, S., Schwartz, G.G., Lawlor, D.A., Morris, R.W., Sandhu, M.S., Poledne, R., Maitland-van der Zee, A.H., Khaw, K.T., Keating, B.J., Van der Harst, P., Price, J.F., Mehta, S.R., Yusuf, S., Witteman, J.C., Franco, O.H., Jukema, J.W., De Knijff, P., Tybjaerg-Hansen, A., Rader, D.J., Farrall, M., Samani, N.J., Kivimaki, M., Fox, K.A., Humphries, S.E., Anderson, J.L., Boekholdt, S.M., Palmer, T.M., Eriksson, P., Paré, G., Hingorani, A.D., Sabatine, M.S., Mallat, Z., Casas, J.P., Talmud, P.J., Medicina i Cirurgia, and Universitat Rovira i Virgili.

Subjects
0735-1097, Cardiovascular diseases, Drug development, Epidemiology, Genetics, Mendelian randomization, Sistema cardiovascular--Malalties, Clinical Medicine, Medical and Health Sciences
Abstract

Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2-IIA mass or sPLA 2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA 2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Published
2013

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