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Review
. 2023 Feb 23;10(3):96.
doi: 10.3390/jcdd10030096.

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in "Treating" Aortic Valve Calcification

Donatos Tsamoulis  1   2 , Iliana Siountri  3 , Loukianos S Rallidis  4
Affiliations
Review

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in "Treating" Aortic Valve Calcification

Donatos Tsamoulis et al. J Cardiovasc Dev Dis. .

Abstract

The treatment of patients with aortic valve calcification (AVC) and calcific aortic valve stenosis (CAVS) remains challenging as, until today, all non-invasive interventions have proven fruitless in preventing the disease's onset and progression. Despite the similarities in the pathogenesis of AVC and atherosclerosis, statins failed to show a favorable effect in preventing AVC progression. The recognition of lipoprotein(a) [Lp(a)] as a strong and potentially modifiable risk factor for the development and, perhaps, the progression of AVC and CAVS and the evolution of novel agents leading in a robust Lp(a) reduction, have rekindled hope for a promising future in the treatment of those patients. Lp(a) seems to promote AVC via a 'three hit' mechanism including lipid deposition, inflammation and autotaxin transportation. All of these lead to valve interstitial cells transition into osteoblast-like cells and, thus, to parenchymal calcification. Currently available lipid-lowering therapies have shown a neutral or mild effect on Lp(a), which was proven insufficient to contribute to clinical benefits. The short-term safety and the efficacy of the emerging agents in reducing Lp(a) have been proven; nevertheless, their effect on cardiovascular risk is currently under investigation in phase 3 clinical trials. A positive result of these trials will probably be the spark to test the hypothesis of the modification of AVC's natural history with the novel Lp(a)-lowering agents.

Keywords: PCSK9 inhibitors; RNA-related treatments; aortic valve calcification; aortic valve stenosis; familial hypercholesterolemia; lipoprotein apheresis; lipoprotein(a); olpasiran; pelacarsen; statins.

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Conflict of interest statement

D.T. and I.S. declare that they have no conflict of interest. L.S.R. has received research grants and honoraria from Amgen, ELPEN, Sanofi-Aventis, Viatris, Integris Pharma, Novartis, and Servier.

Figures

Figure 1
Figure 1
Lipoprotein(a) [Lp(a)] is an atherogenic, pro-inflammatory and, potentially, thrombogenic lipoprotein. These properties are mostly determined by its composition: a newly synthesized low-density lipoprotein (LDL) particle, linked to a unique apolipoprotein, known as apolipoprotein(a) [apo(a)] [7]. What makes apo(a) specific is its structural similarity to plasminogen and its binding to oxidized phospholipids (OxPL). The Lp(a) gene is believed to be derived from the plasminogen gene (PLG). PLG encodes five kringle domains (KI-KV), of which only KIV and KV are maintained in Lp(a). Additionally, KIV is converted, resulting in ten different KIV subtypes from which KIV-2 is found in multiple intragenic copies (1–40). Its similarity to plasminogen could theoretically lead to thrombogenicity [8,9,10]. The LDL particle contributes, partly, to Lp(a) atherogenic potential [11], while OxPL may play a major proinflammatory role [12,13,14].
Figure 2
Figure 2
The mechanisms whereby Lp(a) contributes to valve interstitial cell transition into osteoblast-like cells. A ‘three hit’ hypothesis: Lp(a) penetrates into aortic valve tissue through microfractures in the valve endothelium. Autotaxin transportation and inflammation as well as lipid deposition contribute to the transition of VICs into osteoblast-like cells. BMP-2 and RUNX2 are the key signaling factors of the transition process.
Figure 3
Figure 3
Current and emerging lipid lowering treatments and their effect on Lp(a).
See this image and copyright information in PMC

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