Lipoprotein(a) and Aortic Valve Stenosis: From Pathophysiology to Emerging Pharmacological Agents

Sep 30, 2026

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Aortic valve stenosis (AVS) is the most common valvular disease in developed countries, and no pharmacological therapy is currently available. Accumulating evidence identifies lipoprotein(a) [Lp(a)] as a causal link between lipid metabolism, inflammation, and valve calcification. Because Lp(a) levels are largely genetically determined and stable across life, they represent an actionable therapeutic target. This review synthesizes evidence on Lp(a)–AVS pathophysiology, diagnostic and prognostic value, and Lp(a)-lowering treatments, highlighting antisense oligonucleotides and siRNA agents.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Aortic valve stenosis and current therapies

Lp(a) as a novel causal risk factor

Biochemical Structure and Metabolism of Lp(a)

Review Lipoprotein(a) and Aortic Valve Stenosis: From Pathophysiology to Emerging Pharmacological Agents Federica Agnello 1,2, Giulia Laterra 1,2, Lorenzo Scalia 2, Maria Sara Mauro 3, Orazio Strazzieri 2, Claudia Reddavid 2, Salvatore Ingala 2, Simona Guarino 2, Chiara Barbera 2, Maria Daniela Russo 2 and Marco Barbanti 1,2, * Academic Editor: Antonios Halapas Received: 30 September 2025 Revised: 6 December 2025 Accepted: 8 December 2025 Published: 30 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Faculty of Medicine and Surgery, Università degli Studi di Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy 2 Division of Cardiology, Ospedale Umberto I, ASP 4 di Enna, 94100 Enna, Italy 3 Division of Cardiology, A.O.U. Policlinico “G. Rodolico San Marco”, 95123 Catania, Italy * [Correspondence: mbarbanti83@gmail.com](Correspondence: mbarbanti83@gmail.com); Tel.: +39-095-378-1170 Abstract Aortic valve stenosis (AVS) is the most common valvular disease in developed countries, and no pharmacological therapy is currently available. Increasing evidence identifies lipoprotein(a) [Lp(a)] as a causal factor linking lipid metabolism, inflammation, and valve calcification. Lp(a) levels are largely genetically determined and remain stable throughout life, making them a potential therapeutic target. This review summarizes the current evidence on Lp(a) and AVS pathophysiology, the diagnostic and prognostic role of Lp(a), and the therapeutic potential of Lp(a)-lowering agents. Emerging Lp(a)-targeted therapies, including antisense oligonucleotides and siRNA-based agents, could reshape AVS management by providing the first pharmacological option to slow disease progression in selected high-risk patients. Keywords: Lp(a); aortic valve stenosis; atherosclerosis; PCSK9i; statin 1. Introduction Aortic valve stenosis (AVS) is the most common valvular heart disease in developed countries (with a prevalence of approximately 40% in those over 75 years) and its prevalence is expected to increase, due to longer life expectancy [1] . Symptomatic AVS has poor prognosis, and the only available treatment options are surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI), both recommended as class I, level A indications in latest guidelines for the management of valvular heart disease of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery (ESC/EACTS) [2] . Degenerative calcific AVS is the most common cause of AVS, sharing common pathophysiology with atherosclerosis [3–5] . Conversely, no modifiable risk factor has been identified as a potentially therapeutic target to slow AVS progression. Therefore, patients with mild or moderate aortic stenosis undergo periodic follow-up visits, since effective pharmacological options are currently lacking [6,7] . In this context, lipoprotein(a) [Lp(a)] has emerged as a novel risk factor, playing a determinant role in the development of cardiovascular disease, including coronary artery disease (CAD), aortic valve calcification, and stenosis [8,9] . In fact, recent research has shown that Lp(a) promotes atherosclerosis, inflammation, and thrombosis [10] . Regarding the link between Lp(a) and AVS, many observational studies supported its association with aortic valve calcification and AVS progression; next, large Mendelian randomization studies revealed the causal role of elevated Lp(a) levels in higher incidence of aortic valve calcifications and AVS [11–17] . This evidence has paved the way to a new field of research, investigating pharmacological strategies to reduce Lp(a) concentration and address different cardiovascular unmet clinical needs, such as the management of residual cardiovascular risk and the progression of AVS [18]

FAQs

Why is lipoprotein(a) considered a causal factor in aortic valve stenosis?

Evidence links Lp(a) to lipid metabolism, inflammation, and valve calcification, and higher Lp(a) levels show causal associations with aortic valve calcification and AVS progression.

What makes Lp(a) a promising therapeutic target?

Lp(a) concentrations are largely genetically determined and remain stable throughout life, supporting its potential as a durable target for treatment strategies.

Which emerging therapies targeting Lp(a) are discussed?

The review highlights Lp(a)-lowering approaches including antisense oligonucleotides and siRNA-based agents, with pelacarsen and lepodisiran evaluated in ongoing phase III trials.

Sep 30, 2026

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