Aortic valvular stenosis: Novel therapeutic strategies

Abstract

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.

The mechanistic pathways of oxidative stress in aortic stenosis and clinical implications

“…As the pathways of oxidative stress in degenerative AS are complex, perhaps targeting a single component may not lead to clinically significant results. There is some evidence that targets outside the oxidative stress pathway, such as inhibition of cadherin 11, matrix metalloproteinases and even the use of direct oral anticoagulants (dabigatran, apixaban and rivaroxaban) may slow the progression of AS 138 - 139 . Although oxidative stress in itself forms a major part of the pathophysiology of AS, it is not the full picture.…”

Niveles elevados de lipoproteína (a) y riesgo de eventos clínicos relacionados con la estenosis valvular aórtica: una revisión sistemática

“…Se ha demostrado que estos fosfolípidos modificados promueven la mineralización y la calcificación valvular a través de la regulación positiva de las especies reactivas de oxígeno y de las citocinas inflamatorias liberadas por los macrófagos. (6,22). Además, dentro de la válvula, la fosfolipasa A2 asociada a las lipoproteínas utiliza fosfolípidos oxidados para generar lisofosfatidilcolina, enzima que ha demostrado "in vitro" un efecto sobre la mineralización.…”

“…La estenosis valvular aórtica es la valvulopatía más frecuente y la más prevalente en la población de más edad, y la degeneración cálcica es la causa adquirida más común. (6) Curiosamente, se ha observado dentro de las válvulas aórticas estenóticas una acumulación de lipoproteínas o precursores lipídicos. Estas incluyen partículas de LDL convencionales, LDL oxidadas y fosfolípidos oxidados.…”

Models and Techniques to Study Aortic Valve Calcification in Vitro, ex Vivo and in Vivo. An Overview

“…Handling of cells and cell cultures are presented in more details than other techniques here because it is probably the most widely spread and concise method to study the basic cellular and molecular events of aortic valve calcification. Additionally, cell culture models are also used for initial screening of potential inhibitory drugs ( Dutta et al, 2021 ; Natorska et al, 2021 ; Parra-Izquierdo et al, 2021 ; Wang et al, 2021 ).…”