Role of Lipoprotein(a) in Aortic Valve Calcification: Inflammatory and Oxidative Mechanisms Involved

Figures

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  Figure 1. Structural scheme of Lp(a). Lp(a) consists of an LDL particle containing apolipoprotein B100 (apoB100) covalently linked via a disulfide bond (–S–S–) to apolipoprotein(a) [apo(a)]. Apo(a) is composed of multiple kringle domains—kringle IV (subtypes 1–10) and kringle V—and a catalytically inactive protease domain. The number of kringle IV type 2 (KIV-2) repeats varies widely among individuals and determines apo(a) size and, consequently, plasma Lp(a) concentrations. Abbreviations: LPA: apolipoprotein(a) gene; apoB100: apolipoprotein B100; apo(a): apolipoprotein(a); KIV: kringle IV; KIV-1: kringle IV type 1; KIV-2: kringle IV type 2; KIV-3: kringle IV type 3; KIV-4: kringle IV type 4; KIV-5: kringle IV type 5; KIV-6: kringle IV type 6; KIV-7: kringle IV type 7; KIV-8: kringle IV type 8; KIV-9: kringle IV type 9; KIV-10: kringle IV type 10; KV: kringle V; OxPL: Oxidized phospholipids. Adapted from: [26], Created in BioRender. Osorio, E. (2025) https://BioRender.com/wps73bu (accessed on 25 June 2026).

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  Figure 2. Inflammatory mechanisms linking lipoprotein(a) to aortic valve calcification. This schematic summarizes the main inflammatory pathways by which Lp(a) may contribute to CAVD. After retention within the valvular extracellular matrix, Lp(a) and its OxPL cargo promote endothelial activation, oxidative stress, and inflammatory signaling, favoring monocyte/macrophage recruitment and cytokine amplification. These events drive VICs activation, matrix remodeling, microcalcification, and progressive fibro-calcific remodeling of the aortic valve. Abbreviations: Apo(a): apolipoprotein(a); CAVD: calcific aortic valve disease; ECM: extracellular matrix; ICAM-1: intercellular adhesion molecule-1; IL-1β: interleukin-1 beta; IL-6: interleukin-6; LOX-1: lectin-like oxidized low-density lipoprotein receptor-1; Lp(a): lipoprotein(a); NF-κB: nuclear factor kappa B; NO: nitric oxide; OxPL: oxidized phospholipids; OxPL-R: oxidized phospholipid receptor; ROS: reactive oxygen species; TNF-α: tumor necrosis factor alpha; uPAR: urokinase-type plasminogen activator receptor; VCAM-1: vascular cell adhesion molecule-1; VIC(s): valvular interstitial cell(s). Created in BioRender. Osorio, E. (2026)…

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  Figure 3. Phenotypic transition of valvular interstitial cells in calcific aortic valve disease. This schematic illustrates the transition of quiescent VICs toward either myofibroblastic or osteoblastic phenotypes in CAVD. Biomechanical, inflammatory, lipid, and oxidative cues promote profibrotic and osteogenic signaling, leading to matrix remodeling, apoptosis, osteogenic programming, and calcific nodule formation. Together, these processes converge on fibro-calcific remodeling of the aortic valve. Abbreviations: BMP: bone morphogenetic protein; CAVD: calcific aortic valve disease; ECM: extracellular matrix; EndMT: endothelial-to-mesenchymal transition; Lp(a): lipoprotein(a); MMPs: matrix metalloproteinases; OPN: osteopontin; ox-LDL: oxidized low-density lipoprotein; ROS: reactive oxygen species; RUNX2: runt-related transcription factor 2; TGF-β1: transforming growth factor beta 1; TLR2/4: Toll-like receptor 2/4; VIC(s): valvular interstitial cell(s). Created in BioRender. Osorio, E. (2026) https://BioRender.com/qwdd4ey (accessed on 25 June 2026); figure preparation was completed in June 2026.

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  Figure 4. Early therapeutic window for Lp(a)-targeted prevention in calcific aortic valve disease. Early Lp(a) measurement may identify individuals at increased risk of calcific aortic valve disease before irreversible valvular obstruction develops. Emerging Lp(a)-lowering therapies may attenuate valvular inflammation, osteogenic activation of valvular interstitial cells, and fibrocalcific remodelling, potentially slowing structural and haemodynamic progression. Ongoing trials, including Lp(a)FRONTIERS CAVS, will determine whether Lp(a) reduction modifies disease progression and delays the need for aortic valve replacement. Abbreviations: ASO: antisense oligonucleotide; Lp(a): lipoprotein(a); siRNA: small interfering RNA; VICs: valvular interstitial cells. Created in BioRender. Osorio, E. (2026) https://BioRender.com/2y63zb7 (accessed on 25 June 2026); figure preparation was completed in June 2026.