Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

Thanassoulis, George

doi:10.1194/jlr.r051870

Cited by 81 publications

(54 citation statements)

References 57 publications

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“…A role for Lp(a) in atherogenesis has now been established by both meta-analyses of epidemiological studies, as well as by genome-wide association and Mendelian randomization studies showing a strong, independent and likely causal relationship between Lp(a) and myocardial infarction, stroke, peripheral artery disease and calcific aortic valve stenosis. 1,2 …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Background Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor but the underlying mechanisms responsible for its pathogenicity are poorly defined. Since Lp(a) is the prominent carrier of pro-inflammatory oxidized phospholipids (OxPL), part of its atherothrombosis might be mediated through this pathway. Methods In vivo imaging techniques MR imaging, 18F-FDG-PET/CT and SPECT/CT were used to measure subsequently atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed using FACS analysis, inflammatory stimulation assays and transendothelial migration assays. In vitro studies to the pathophysiology of Lp(a) on monocytes were performed using an in vitro model for trained immunity. Results We show that subjects with elevated Lp(a) (108 [50–195] mg/dL; n=30) have increased arterial inflammation and enhanced PBMCs trafficking to the arterial wall, compared with subjects with normal Lp(a) (7 [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 pro-inflammatory cytokines upon stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the pro-inflammatory response in monocytes derived from healthy controls (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apo(a). Conclusions These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease. Clinical Trial Registration URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5006 Unique Identifier: NTR5006 (VIPER study)

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Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Повышен-ный уровень Лп(а) является независимым, генетиче-ским фактором риска возникновения и развития ате-росклероза различных локализаций, ИБС, ССО и стеноза аортального клапана [21,22]. Уровень Лп(а) контролируется на генетическом уровне и устойчив к существующим гиполипидемическим препаратам [21].…”

Section: препараты на основе антисмысловых олигонуклеотидов (асо)unclassified

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

2018

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Development of innovational biotechnological medications based on humanized or completely human monoclonal antibodies or antisense oligonucleotides has opened a novel epoque in lipid disorders treatment. High efficacy of such biological drugs influencing the main chains of lipid metabolism (apoprotein B100, apoprotein (a), apoprotein CIII, proprotein-convertase subtilisin-kexin type 9, antipoetin like protein 3) does open a perspective for correction of severe and statin-resistant forms of dyslipidemias, with a possibility to achieve almost complete remission of the disease. However, the evidence of safety of antisense oligonucleotides drugs demands for broader investigation. Such drugs might be used in patients with orphan diseases or serious lipid disorders, not having alternative treatment. Vice versa, the drugs based on the human monoclonal antibodies thank to evidence are started to be in clinical use at the moment.

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“…9,11,28 The only limitation of the study is defining the degree of stenosis with the amount of OxPL and other traditional risk factors important in the progression of CAVD. 1 The patient population with CAVD in this study did have aortic valve jet velocity >2.5 m/s and aortic valve area of <2.0 cm 2 .…”

Section: Arterioscler Thromb Vasc Biol August 2017mentioning

confidence: 99%

“…The authors concluded that OxPL-apoB and OxPL-apo(a) are novel genetic and potentially causal risk factors for CAVD and mechanistically helps us to understand the association of lipoprotein(a) with CAVD. Thanassoulis 11 and Smith et al 12 have further proposed that targeted therapy of Lp(a) may be a novel target for treating CAVD, after confirming the genetics of Lp(a) in patients with CAVD. MESA also confirmed the discovery of Lp(a) as a significant risk factor for CAVD.…”

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confidence: 96%

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Rajamannan

2017

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Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

Cited by 81 publications

References 57 publications

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

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

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

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