Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

Perrot, Nicolas; Valerio, Vincenza; Moschetta, Donato; Boekholdt, S. Matthijs; Dina, Christian; Chen, Hao Yu; Abner, Erik; Martinsson, Andreas; Manikpurage, Hasanga D.; Rigade, Sidwell; Capoulade, Romain; Mass, Elvira; Clavel, Marie‐Annick; Tourneau, Thierry Le; Messika–Zeitoun, David; Wareham, Nicholas J.; Engert, James C.; Polvani, Gianluca; Pîbarot, Philippe; Esko, Tõnu; Smith, J. G.; Mathieu, Patrick; Thanassoulis, George; Schott, Jean Jacques; Bossé, Yohan; Camera, Marina; Thériault, Sébastien; Poggio, Paolo; Arsenault, Benoît J.

doi:10.1016/j.jacbts.2020.05.004

Cited by 55 publications

(55 citation statements)

References 29 publications

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“…In this issue of JACC: Basic to Translational Science , Perrot et al. ( 4 ) provided compelling data to advance our understanding of the role of PCSK9 in the pathogenesis of CAVS. They provided a meta-analysis of 10 genetic association studies that included 12,059 patients with CAVS and 541,081 control subjects to reveal that the odds of CAVS were lower in carriers of the PCSK9 R46L loss-of-function variant.…”

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confidence: 99%

“…Thus, although the relationship among PCSK9, lipid levels, and atherosclerosis has been studied extensively, far less is known about PCSK9 and CAVS. The study by Perrot et al ( 4 ) moves the field forward by directly implicating PCSK9 in VIC calcification and by providing convincing evidence that decreased PCSK9 activity is protective from CAVS. Collectively, these findings open the door to future studies that will define the mechanism(s) by which PCSK9, beyond its effects on lipid levels, promotes CAVS.…”

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confidence: 99%

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PCSK9 and Calcific Aortic Valve Stenosis

Leopold

2020

JACC: Basic to Translational Science

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confidence: 99%

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confidence: 99%

PCSK9 and Calcific Aortic Valve Stenosis

Leopold

2020

JACC: Basic to Translational Science

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“…While valvular expression of PCSK9 is evident in both calcified and non‐calcified valve leaflets, calcified leaflets are characterized by significantly higher PCSK9 levels 50 . Moreover, stimulation of VICs with an osteogenic medium resulted in PCSK9 overexpression and the inhibition of PCSK9 was associated with reduced calcium deposition 50 . Langsted et al 51 showed in humans that the PCSK9 R46L loss‐of‐function mutation was associated with lower LDL and Lp(a) levels, as well as with reduced risk of AS.…”

Section: Resultsmentioning

confidence: 99%

“…Wang et al 49 have demonstrated that plasma PCSK9 levels are associated with the presence of AS, but not with the severity of the disease. While valvular expression of PCSK9 is evident in both calcified and non‐calcified valve leaflets, calcified leaflets are characterized by significantly higher PCSK9 levels 50 . Moreover, stimulation of VICs with an osteogenic medium resulted in PCSK9 overexpression and the inhibition of PCSK9 was associated with reduced calcium deposition 50 .…”

Section: Resultsmentioning

confidence: 99%

Aortic valvular stenosis: Novel therapeutic strategies

Natorska

Kopytek

Undas

2021

Eur J Clin Investigation

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Background Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non‐surgical AS treatment, at least in patients with mild‐to‐moderate AS. Materials and Methods The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021. Results Growing evidence indicates that therapies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, simvastatin/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro‐inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non‐vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs. Conclusion Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin/ezetimibe combination, lipoprotein(a)‐lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.

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“…33 This was suggested after finding that CVAS is less prevalent in carriers of the PCSK9 R46 L variant compared with non-carriers. 34…”

Section: Resultsmentioning

confidence: 99%

Umbrella Review on Non-Statin Lipid-Lowering Therapy

Beshir

Hussain

Elnor

et al. 2021

J Cardiovasc Pharmacol Ther

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Dyslipidemia, particularly increased low-density lipoprotein cholesterol (LDL-C) levels, are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. There is an unmet need for ASCVD risk reduction even with the optimal use of statin therapy, which has led to an ongoing search for novel targets for cholesterol reduction to decrease ASCVD events. Objectives: The main aim of this review was to summarize current evidence on approved and emerging non-statin lipid-lowering therapies. Methods and Materials: Recent literature on U.S. FDA approved non-statin lipid-lowering therapies and evolving lipid-lowering drugs currently under development was reviewed. Results and Discussion: In the past 20 years, the emergence of non-statin cholesterol-lowering drugs has changed the landscape of dyslipidemia management. Food and Drug Administration approval of non-statin lipid-lowering therapies such as ezetimibe, proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab), bempedoic acid and combination of bempedoic acid and ezetimibe, evinacumab and other triglyceride-lowering agents (eg, icosapent ethyl) has emerged. The European Commission has also recently approved inclisiran for treatment of hypercholesterolemia and mixed hypercholesterolemia even though FDA has put the approval of this drug on hold. Recent guidelines have incorporated PCSK9 inhibitors to treat patients with primary hyperlipidemia and patients with very high-risk ASCVD, who could not achieve adequate lipid-lowering with combination therapy of maximally tolerated statin and ezetimibe. Icosapent ethyl use as an adjunct therapy to statins is also recommended to reduce the risk of ASCVD in patients with hypertriglyceridemia. Conclusion: Despite cost limitations, the uptake of PCSK9 inhibitors is increasing. Approval of bempedoic acid alone or in combination with ezetimibe has provided additional oral lipid-lowering drug alternatives to ezetimibe. Various lipid-lowering drug targets are under investigation.

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Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

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Cited by 55 publications

References 29 publications

PCSK9 and Calcific Aortic Valve Stenosis

PCSK9 and Calcific Aortic Valve Stenosis

Aortic valvular stenosis: Novel therapeutic strategies

Umbrella Review on Non-Statin Lipid-Lowering Therapy

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