Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia

Vuorio, Alpo; Watts, Gerald F.; Kovanen, Petri T.

doi:10.1016/j.atherosclerosis.2018.11.040

Cited by 29 publications

(15 citation statements)

References 73 publications

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“…Compelling evidence from traditional epidemiological, genome-wide association, and Mendelian randomization studies has revealed that elevated plasma Lp(a) level increases the risk of acute myocardial infarction (AMI), ischemic stroke, calcific aortic valve disease, and peripheral arterial disease in non-FH patients [ 38 ]. Elevated lipoprotein (a) was found to be a significant CVD risk factor in HeFH [ 39 ], and Lp(a) level above 50 mg/dL is recently found to be an independent risk factor for calcific aortic valvulopathy among HeFH patients [ 40 ]. Safety analysis demonstrated that PCSK9-mAbs showed good safety, and the incidence of common and serious adverse reactions was basically the same as that of the placebo group in addition to abnormal liver function risk.…”

Section: Discussionmentioning

confidence: 99%

[Retracted] A Systematic Review and Meta‐Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia

Zhu

Zeng

et al. 2021

BioMed Research International

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Objectives. The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). Methods. A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: “AMG 145”, “evolocumab”, “SAR236553/REGN727”, “alirocumab”, “RG7652”, “LY3015014”, “RN316/bococizumab”, “PCSK9”, and “familial hypercholesterolemia” up to November 2020. Study quality was assessed with the Cochrane Collaboration’s tool, and publication bias was evaluated by a contour-enhanced funnel plot and the Harbord modification of the Egger test. After obtaining the data, a meta-analysis was performed using R software, version 4.0.3. Results. A meta-analysis was performed on 7 clinical trials (926 total patients). The results showed that PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD −49.14%, 95% CI: −55.81 to −42.47%, on FH versus control groups. PCSK9-mAbs also significantly reduced lipoprotein (a) (Lp (a)), total cholesterol (TC), triglycerides (TG), apolipoprotein-B (Apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and increased HDL-C and apolipoprotein-A1 (Apo-A1) levels of beneficial lipoproteins. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. Conclusion. PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment.

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Section: Discussionmentioning

confidence: 99%

[Retracted] A Systematic Review and Meta‐Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia

Zhu

Zeng

et al. 2021

BioMed Research International

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“…Hypercholesterolemic LDLr −/− ApoB 100/100 mice are not only a model of CAVD but also a relevant model for human FH. Most (90%) FH patients have a mutation in the LDLr gene, whereas only a minority of patients have mutations in the apolipoprotein-B or PCSK9 genes that are associated with high cholesterol levels already in utero 38 . Since FH patients have a higher risk of developing CAVD, our study suggests that FH patients might be more vulnerable to the hyperlipidemic side effects of vitamin K. In our study, we used MK4, which is an active metabolite of vitamin K1 and is present in meat, cheese and eggs 26 .…”

Section: Discussionmentioning

confidence: 99%

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Weisell

Ruotsalainen

Näpänkangas

et al. 2021

Sci Rep

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In calcific aortic valve disease (CAVD) progressive valvular calcification causes aortic valve dysfunction. CAVD has several risk factors such as age and dyslipidemia. Vitamin K was shown to inhibit vascular calcification in mice and valvular calcification in patients with CAVD. We studied the effect of menaquinone 4 (MK4/vitamin K2) on valvular calcification in the hypercholesterolemic mouse model of CAVD. LDLr−/−ApoB100/100 male mice were fed with a Western diet for 5 months, with (n = 10) or without (n = 10) added 0.2 mg/g MK4. Body weight gain was followed weekly. Morphology of aortic valves and liver was assessed with immunohistochemistry. Plasma cholesterol levels and cytokines from hepatic tissue were assessed in the end of the study. Hepatic gene expression of lipid metabolism regulating genes were assessed after 18 h diet. MK4 exacerbated the lipoprotein lipid profile without affecting aortic valve morphology in hypercholesterolemic LDLr−/− ApoB100/100 mice. The MK4-containing WD diet increased plasma levels of LDL and triglycerides, hepatic steatosis, and mRNA expression of genes required for triglyceride and cholesterol synthesis. MK4 diminished levels of several cytokines and chemokines in liver, including IL-6, TNFα and MCP1, as measured by hepatic cytokine array. Consequently, MK4 may exert non-beneficial effects on circulating lipid levels, especially in hypercholesterolemic individuals.

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“…Red blood cells express a variety of apolipoprotein receptors, in primis the receptor for ApoA1 and B as demonstrated by the hypocholesterolemia and reduced levels of circulating ApoA1 and B expressed by patients with the acquired erythrocytosis Polycythemia Vera (Fujita et al, 2012). Given the great number of RBCs present in the circulation, these receptors are efficient lipid scavengers contributing to maintain the lipid content of the plasma within physiologic levels preventing atherosclerosis and kidney malfunctions (Wahl et al, 2016; Saraf et al, 2017; Vuorio et al, 2018). The effects on erythroblast expansion sustained by VLDL and LDL described in this study suggests that, in addition to exerting scavenger functions, the lipoprotein receptors expressed by erythroid cells tune lipid availability to prevent possible membrane abnormalities due to impairment of lipid metabolism induced by Dex in RBCs produced under conditions of erythroid stress.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone Predisposes Human Erythroblasts Toward Impaired Lipid Metabolism and Renders Their ex vivo Expansion Highly Dependent on Plasma Lipoproteins

et al. 2019

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Cultures of stem cells from discarded sources supplemented with dexamethasone, a synthetic glucocorticoid receptor agonist, generate cultured red blood cells (cRBCs) in numbers sufficient for transfusion. According to the literature, however, erythroblasts generated with dexamethasone exhibit low enucleation rates giving rise to cRBCs that survive poorly in vivo . The knowledge that the glucocorticoid receptor regulates lipid metabolism and that lipid composition dictates the fragility of the plasma membrane suggests that insufficient lipid bioavailability restrains generation of cRBCs. To test this hypothesis, we first compared the expression profiling of erythroblasts generated with or without dexamethasone. This analysis revealed differences in expression of 55 genes, 6 of which encoding proteins involved in lipid metabolism. These were represented by genes encoding the mitochondrial proteins 3-Hydroxymethyl-3-Methylglutaryl-CoA lyase, upregulated, and 3-Oxoacid CoA-Transferase1 and glycerol-3-phosphate acyltransferase1, both downregulated, and the proteins ATP-binding cassette transporter1 and Hydroxysteroid-17-Beta-Dehydrogenase7, upregulated, and cAMP-dependent protein kinase catalytic subunit beta, downregulated. This profiling predicts that dexamethasone, possibly by interfering with mitochondrial functions, impairs the intrinsic lipid metabolism making the synthesis of the plasma membrane of erythroid cells depend on lipid-uptake from external sources. Optical and electron microscopy analyses confirmed that the mitochondria of erythroblasts generated with dexamethasone are abnormal and that their plasma membranes present pebbles associated with membrane ruptures releasing exosomes and micro-vesicles. These results indicate that the lipid supplements of media currently available are not adequate for cRBCs. To identify better lipid supplements, we determined the number of erythroblasts generated in synthetic media supplemented with either currently used liposomes or with lipoproteins purified from human plasma [the total lipoprotein fraction (TL) or its high (HDL), low (LDL) and very low (VLDL) density lipoprotein components]. Both LDL and VLDL generated numbers of erythroid cells 3-2-fold greater than that observed in controls. These greater numbers were associated with 2–3-fold greater amplification of erythroid cells due both to increased proliferation and to resistance to stress-induced death. In conclusion, dexamethasone impairs lipid metabolism making ex vivo expansion of erythroid cells highly dependent on lipid absorbed from external sources and the use of LDL and VLDL as lipid supplements improves the generation of cRBCs.

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Lipoprotein(a) as a risk factor for calcific aortic valvulopathy in heterozygous familial hypercholesterolemia

Cited by 29 publications

References 73 publications

[Retracted] A Systematic Review and Meta‐Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia

[Retracted] A Systematic Review and Meta‐Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Dexamethasone Predisposes Human Erythroblasts Toward Impaired Lipid Metabolism and Renders Their ex vivo Expansion Highly Dependent on Plasma Lipoproteins

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