Lipoprotein(a) and Aortic Stenosis: From Genetic Risk to Emerging Therapeutic Strategies

Abstract

Aortic stenosis (AS) is the most common valvular heart disease in ageing populations and is associated with substantial morbidity and mortality. Despite advances in surgical and transcatheter valve replacement, no medical therapy has yet been shown to prevent disease onset or slow progression. Calcific AS is now recognised as an active, multifactorial process involving lipid infiltration, inflammation and osteogenic calcification of the aortic valve. Lipoprotein(a) has emerged as a key contributor to these mechanisms and is a genetically determined, lifelong cardiovascular risk factor. Lipoprotein(a) is a major carrier of oxidised phospholipids, which promote valvular inflammation and calcification. Epidemiological and Mendelian randomisation studies consistently demonstrate a strong and likely causal association between elevated lipoprotein(a) and AS. Experimental and translational data suggest that lipoprotein(a) exerts its effects early in the disease course, promoting valve inflammation and calcification before significant stenosis develops. The recent development of lipoprotein(a)-lowering therapies has renewed interest in targeting this pathway, raising the possibility that early lipoprotein(a)-lowering may modify disease progression, a hypothesis now being tested in clinical trials.

Aortic stenosis (AS) is the most common valvular heart disease in developed countries and represents a growing public health burden as populations age. Its prevalence increases markedly with advancing age. Clinically significant AS affects approximately 3–5% of individuals older than 75 years; and with the rapid expansion of the global elderly population, the absolute burden of AS is expected to increase substantially by 2050.1,2

AS is characterised by progressive narrowing of the aortic valve (AV) orifice, leading to left ventricular (LV) outflow obstruction, chronic pressure overload and, ultimately, heart failure and premature death if left untreated.3 Among patients with moderate AS, nearly three-quarters may progress to severe disease within several years. Once AS becomes severe, prognosis is poor in the absence of intervention, with 5-year mortality exceeding 50% in patients with moderate-to-severe or severe disease.4 Currently, AV replacement (AVR), either surgical (SAVR) or transcatheter (TAVR), remains the only effective treatment once severe AS is established. To date, no medical therapy has been shown to prevent disease onset or significantly slow disease progression, highlighting the urgent need for improved strategies for early risk stratification and disease modification.

In recent years, lipoprotein(a) [Lp(a)] has gained attention as a potentially important contributor to calcific AV disease (CAVD).5 Lp(a) is a genetically determined lipoprotein particle that circulates at stable levels throughout life and is largely unaffected by lifestyle or conventional lipid-lowering therapies (LLT).6 Elevated Lp(a) concentration is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD) and has now been consistently linked to both the presence and progression of AS.7 Lp(a) promotes valvular inflammation and calcification through its role as a carrier of oxidised phospholipids (Ox-PLs), providing a plausible biological explanation for its association with AS.6–8 From a clinical perspective, this association is particularly relevant, given that Lp(a) level can identify individuals at increased lifetime risk before overt AV disease develops.6,9 Moreover, the emergence of Lp(a)-targeted therapies has renewed interest in disease-modifying treatment for AS.

This review summarises current evidence on the role of Lp(a) in AS, including mechanistic, genetic, epidemiological and clinical outcome data, and discusses the potential impact of emerging Lp(a)-targeted therapies.

Lp(a): Structure, Genetics and Clinical Relevance

Structurally, Lp(a) consists of an LDL-like particle containing apolipoprotein (apo)B-100, covalently bound to a unique glycoprotein, apo(a), which shares structural homology with plasminogen.7,10

Plasma Lp(a) concentration is mostly determined by genetic variation at the LPA gene locus.11 The most important determinant is the number of kringle IV type 2 (KIV-2) repeats in apo(a), which inversely correlates with circulating Lp(a) level (Figure 1). As a result, Lp(a) concentration varies widely between individuals, often by more than 100-fold, and differs substantially across ethnic groups.12 Importantly, Lp(a) level is established early in life and remains relatively stable over time, with minimal influence from diet, physical activity, or the most commonly used conventional LLT.6,7,11

Figure 1: Mechanisms of Lipoprotein(a)-mediated Aortic Stenosis Progression.

Schematic representation of the proposed mechanisms by which Lp(a) contributes to the development and progression of calcific AS. Elevated Lp(a) promotes endothelial dysfunction and lipid infiltration in the AV, facilitating the accumulation of oxidised phospholipids and activation of inflammatory pathways. This process leads to immune cell recruitment, cytokine expression and osteogenic differentiation of VICs, resulting in microcalcification and progressive calcium deposition. These biological events contribute to fibro-calcific remodelling of the valve and the development of severe AS. Representative CT images illustrate the continuum from a healthy AV to early, intermediate and advanced stages of calcific AS. AS = aortic stenosis; AV = aortic valve; Lp(a) = lipoprotein(a); VEC = valvular endothelial cell; VIC = valvular interstitial cell.

Lp(a) concentration may be reported either as mass concentration (mg/dl) or particle concentration (nmol/l). Because apo(a) isoform size varies considerably between individuals, direct conversion between these units is not uniform. Particle-based measurements expressed in nmol/l more closely reflect the number of circulating Lp(a) particles.

From a clinical perspective, this genetic determination is highly relevant. Elevated Lp(a) represents a lifelong exposure to atherogenic and pro-inflammatory risk, often long before clinical manifestations of ASCVD become apparent. This has important implications for cardiovascular risk stratification, particularly in individuals who develop disease in the absence of traditional risk factors.7

Pathophysiology of Calcific Aortic Stenosis

Calcific AS was long considered a passive degenerative process associated with ageing; however, it is now recognised as an active, multifactorial disease driven by complex biological and cellular processes.1,7,8 These mechanisms develop over many years and share certain similarities with atherosclerosis, while also exhibiting features unique to valvular tissue.13 Figure 1 summarises AV structure and key mechanisms involved in calcific AS progression.

The earliest stage of CAVD is AV sclerosis, characterised by focal leaflet thickening without significant haemodynamic obstruction. Endothelial dysfunction plays a central role at this stage (Figure 1). The aortic surface of the leaflets is exposed to low and oscillatory shear stress, which increases endothelial permeability and facilitates lipid infiltration. Accumulation of circulating lipoproteins within the valve triggers a local inflammatory response, with infiltration of macrophages and T lymphocytes and the release of cytokines and proteolytic enzymes that promote extracellular matrix remodelling. Endothelial injury related to mechanical stress is considered a key trigger for lipid deposition, particularly Lp(a) and LDL particles, resulting in sustained inflammation in the aortic cusps.14,15 Consistent with these mechanisms, observational studies have identified hypertension, elevated LDL cholesterol and increased Lp(a) level as independent risk factors for AS.16–18

As the disease progresses, a propagation phase ensues, characterised by progressive calcium phosphate deposition within the valve, leading to reduced cusp mobility and increasing haemodynamic obstruction. This phase is driven by pro-calcific and pro-osteogenic signalling. Valvular interstitial cells (VICs), which normally maintain valve structure, undergo phenotypic transformation under the influence of inflammation, oxidative stress and mechanical strain, differentiating into activated myofibroblast-like and osteoblast-like cells.19 Calcification initially appears as microcalcifications that progressively coalesce into larger nodules, reducing leaflet flexibility and impairing valve opening.

Mechanistic Links Between Lp(a) and Aortic Stenosis

Experimental, genetic and clinical evidence supports an important role for Lp(a) in the development and progression of calcific AS, although findings across clinical studies are not entirely consistent. Unlike traditional cardiovascular risk factors, Lp(a) appears to exert valve-specific effects that promote inflammation and calcification within the AV, providing a biologically plausible explanation for the strong and consistent associations observed in epidemiological studies.11,14

A defining feature of Lp(a) is its role as a major carrier of Ox-PLs, which accumulate in diseased AV leaflets and act as potent mediators of inflammation and tissue remodelling.14,20 These lipids activate valvular endothelial cells, increase adhesion molecule expression and promote inflammatory cell infiltration, representing an early and critical step in the pathogenesis of CAVD. In the valve, Lp(a) and Ox-PLs modulate VIC behaviour. Under pathological conditions, VICs undergo phenotypic transformation from a quiescent fibroblast-like state into activated myofibroblast-like and osteoblast-like cells. Ox-PLs activate osteogenic signalling pathways, upregulate bone-related transcription factors and increase expression of mineralisation enzymes, directly driving valvular calcification.14,21 These processes are further amplified by local oxidative stress, creating a self-perpetuating cycle of inflammation and mineralisation that operates largely independent of circulating LDL cholesterol and may explain the failure of statins to modify CAVD progression.20,22,23

Supporting a more specific role for Lp(a), Poniedziałek et al. demonstrated a positive correlation between circulating Lp(a) level and the valvular calcium-to-phosphate ratio (Spearman r = 0.49) in patients with severe AS undergoing SAVR, suggesting an association with mineral composition rather than absolute calcium burden.24,25 Human imaging and tissue studies provide further translational support. In the Ring of Fire cohort (n=81), inflammatory activity in the aortic valve of patients aged ≥50 years with mild to severe AS with elevated Lp(a) levels (>50 mg/dL) is increased, as reflected by increased ¹⁸F-FDG uptake in the aortic valve, compared with those with low Lp(a) levels (<50 mg/dL) with a maximal target-to-background ratio [TBR] of 1.60 ± 0.20 versus 1.43 ± 0.16 (p<0.002).26

In contrast, a prospective multimodality imaging study (n=45) found no association between Lp(a) >50 mg/dl and valvular calcium burden in severe AS, with a trend toward higher fibrotic valve volume, particularly among men (p=0.075).8 These findings suggest that the contribution of Lp(a) may vary across different stages of disease and may be more closely related to inflammatory activity and early tissue remodelling than to established calcification in advanced AS. Another hypothesised mechanism involves impaired fibrinolysis, whereby apo(a), through its homology with plasminogen, may reduce local fibrinolytic activity and contribute to a pro-calcific valvular environment.

Genetic and Epidemiological Evidence Linking Lp(a) to Aortic Stenosis

The association between elevated Lp(a) and AS is supported by epidemiological and genetic evidence. Over the past two decades, large population-based studies, complemented by genetic analyses, have consistently demonstrated that Lp(a) is strongly linked not only to the presence of AS but also to its development and progression.6,7,21,27 Importantly, these findings extend beyond traditional cardiovascular risk factors and provide compelling support for a causal relationship.

Observational and Cohort Studies

Initial evidence linking Lp(a) to AS emerged from observational studies conducted in large, well-characterised cohorts.6,7,11,27 These early studies consistently showed that individuals with elevated Lp(a) have a higher prevalence of AV calcification and AS compared with those with lower levels. The earliest report was by Gotoh et al., who described an association between elevated Lp(a) level (>30 mg/dl) and AV sclerosis in 1995.28 In subsequent years, this relationship between Lp(a), AS and AV calcification has been confirmed across multiple cohorts.14,21,27

Longitudinal analyses further demonstrated that elevated Lp(a) is associated with an increased risk of incident AS over time, independent of age, sex, LDL cholesterol and other conventional risk factors. However, the prevalence of elevated Lp(a) among patients with established AS varies. In a cross-sectional study involving 162 unselected patients with AS from a Canadian valve clinic (mean age 75 ± 10 years), elevated Lp(a) (≥100 nmol/l) was present in 24% of patients, with a median Lp(a) of 24 nmol/l. No association was observed between Lp(a) level and age, sex or AS severity.29

Several population-based cohorts have reported a graded, dose– response relationship between Lp(a) concentration and AS risk. Individuals in the highest Lp(a) categories consistently show the greatest risk, supporting a role for cumulative lifetime exposure. In an analysis of two prospective general population studies (the Copenhagen City Heart Study and the Copenhagen General Population Study), individuals with Lp(a) above the 95th percentile had an almost threefold increased risk of AS during a 20-year follow-up.16 Similarly, analysis of UK Biobank data from 127,958 participants demonstrated that Lp(a) ≥50 mg/dl was associated with an increased risk of calcific AS, with an HR of 1.05–1.06 per 10 mg/dl increase.30 While the excess coronary artery disease (CAD) risk associated with Lp(a) was amplified by coexisting dyslipidaemia (relative excess risk due to interaction ≈0.4), no such lipid interactions were observed for calcific AS, suggesting distinct pathogenic pathways.

Additional cohort studies support these findings. In a study of 44,742 individuals with baseline echocardiography and Lp(a) measurements, Lp(a) >100 mg/dl was independently associated with incident severe degenerative AS (adjusted HR 1.96) and subsequent AVR (adjusted HR 2.05) over a median follow-up of 6.8 years.5 These associations were not observed in bicuspid or rheumatic AS. A prospective study of 208 patients with CAD using a study-specific ROC-derived threshold of 26.65 nmol/l showed that high Lp(a) independently predicted new-onset AV calcification over 16 months, with an area under the curve of 0.74.31

Meta-analysis further reinforces the consistency of these associations. In an analysis of 18 observational studies and 153,192 participants, Wambua et al. reported a robust association between elevated Lp(a) and both calcific AS and AV calcification.32 The highest and most reproducible risk was observed at Lp(a) ≥50 mg/dl, although increased risk was also evident at levels ≥30 mg/dl. Racial differences were noted, with Afro-Caribbean populations having higher baseline Lp(a) levels but lower AV calcification prevalence, underscoring the complexity of Lp(a)-mediated valve disease.32,33

Observational studies have also examined disease progression. Higher Lp(a) has been associated with greater valvular calcification burden and faster haemodynamic progression. In a retrospective cohort of 694 individuals with serial Doppler echocardiography, patients with high Lp(a) (≥70 mg/dl) had significantly faster progression of peak aortic jet velocity compared with those with low Lp(a) (<30 mg/dl; 0.03 versus 0.01 m/s/year; adjusted p=0.027), representing an approximately threefold faster progression irrespective of baseline AS status.34 In a meta-analysis combining five longitudinal cohorts (n=710), patients in the highest Lp(a) tertile had 41% faster progression of peak aortic jet velocity and a 57% greater increase in mean transvalvular gradient, with no difference in valve area progression.35

Overall, observational data consistently link elevated Lp(a) with the development of AS; however, the strength of this association varies across studies and appears to be more pronounced in earlier stages of the disease and in younger populations.

Genetic and Mendelian Randomisation Studies

Genome-wide association studies (GWAS) have provided critical insights into the genetic basis of AS and its relationship with Lp(a). Variants in the LPA gene locus have consistently emerged among the strongest genetic determinants of AV calcification and clinically manifest AS across populations.6,36,37 These variants influence circulating Lp(a) concentration and apo(a) isoform size, directly linking genetic regulation of Lp(a) to valvular disease risk. The LPA gene is highly polymorphic, and several variants have been associated with AS.37 The rs10455872 variant is associated with an increased AS risk in all tested ethnicities, while rs3088442 has been linked to CAD severity, highlighting overlapping but distinct lipid-related pathways.6,17 Prospective genetic studies support these observations. Thanassoulis et al. reported that the LPA genotype was associated with incident AS (HR per allele 1.68; 95% CI [1.32–2.15]) and future AVR (HR 1.54; 95% CI [1.05–2.27]).18 Kamstrup et al. showed that carriers of rs10455872 or rs3798220 alleles, as well as individuals with fewer KIV-2 repeats, had significantly higher Lp(a) and increased AS risk.16 Chen et al. demonstrated a gene-dose effect, with AS risk approximately twofold in homozygous rs10455872 carriers, fourfold in homozygous rs3798220 carriers and twofold in heterozygotes.38 The association was strongest in individuals aged 55–64 years for rs10455872, suggesting greater clinical relevance in younger patients. Earlier reports suggested greater risk in male patients, but more recent analyses indicate no consistent sex differences.38,39

Mendelian randomisation studies provide further strong evidence for causality. In the EPIC-Norfolk cohort (n=17,553; mean follow-up 11.7 years), individuals in the highest Lp(a) tertile had a higher risk of incident AS compared with the lowest tertile (HR 1.57; 95% CI [1.02–2.42]).17 Homozygous carriers of rs10455872 had a markedly increased risk, with an HR of 4.83, replicated in independent cohorts.

Meta-analytic data reinforce these findings. Yu et al. reported a 1.44-fold increased risk of CAVD at Lp(a) >30 mg/dl and a 1.95-fold increased risk at >50 mg/dl.40 Mechanistic analyses linked high LPA gene expression to activation of transforming growth factor-β signalling, oxidative phosphorylation and reactive oxygen species pathways, while experimental exposure to Lp(a) induced endothelial-to-mesenchymal transition and osteogenic marker expression in human AV endothelial cells.40

Importantly, associations between LPA variants and AS persist after adjustment for LDL cholesterol, supporting a pathway distinct from traditional lipid mechanisms. Large-scale population analyses further highlight the relative pathogenicity of Lp(a). In the UK Biobank, the OR for valvular heart disease per 1 g/l apoB was substantially higher for Lp(a) (OR 2.71) than for LDL (OR 1.09).41 The study also reported an association with very low-density lipoprotein (VLDL) particles (OR 1.45; 95% CI [1.25–1.69]), indicating that multiple lipoprotein fractions may contribute to valvular disease risk. Genetic mimicry of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition was associated with reduced CAVD risk (OR 0.63; 95% CI [0.56–0.70]), mediated predominantly through apoB (55.9%) and to a lesser extent Lp(a) (4.5%).

Collectively, GWAS and Mendelian randomisation studies support a causal link between lifelong genetically elevated Lp(a) and AS, reinforcing the rationale for early Lp(a)-lowering strategies before advanced AV calcification develops. Consistent with this, a meta-analysis of 44 studies including 163,139 individuals confirmed a robust association between Lp(a) and calcific AS, with the strongest effect observed in younger patients.42 Individuals with AS had mean Lp(a) levels 22.63 nmol/l higher than controls (95% CI 9.98–35.27), while differences were attenuated in older populations.

Lp(a) and Familial Hypercholesterolaemia

Familial hypercholesterolaemia (FH) represents a high-risk clinical setting in which the interplay between lifelong lipid exposure and AV disease is particularly evident.43–46 Individuals with FH are exposed to markedly elevated LDL cholesterol from birth and frequently have concomitantly elevated Lp(a), resulting in a cumulative burden of pro-inflammatory and pro-calcific lipoproteins.47 Observational studies consistently note a higher prevalence of AV sclerosis and stenosis in FH compared with the general population, with disease often manifesting at a younger age and progressing more frequently to AVR, particularly in untreated or late-treated homozygous FH patients.47 In this group, CAVD is a unique complication and may develop even in childhood.

In statin-treated, asymptomatic heterozygous FH patients, Lp(a) >50 mg/dl independently predicts AV calcification, which occurs approximately twice as often as in controls.48 Furthermore, the SAFEHEART registry showed that AVR due to AS is significantly more common in heterozygous FH, particularly among older patients and those with elevated Lp(a), hypertension, or prior ASCVD.47 All these data underscore the importance of screening Lp(a) in all patients with FH, especially those with homozygous disease, and suggest that this population may derive particular benefit from emerging Lp(a)-lowering therapies.

Lp(a) and Bicuspid Aortic Valve Disease

Bicuspid AV (BAV) disease represents a unique model of accelerated valve degeneration. Studies examining the role of Lp(a) in BAV are limited. In a small proof-of-concept case–control study of 69 patients with BAV disease, higher Lp(a) levels were associated with valve calcification and stenosis; all patients without calcification had normal Lp(a) levels, whereas most patients with calcified valves had elevated levels.49 Similarly, an observational cohort study reported that elevated Lp(a) (>50 mg/dl) was more frequent among BAV patients with AS and was associated with an earlier requirement for AVR.50 Although constrained by small sample sizes and heterogeneous designs, these concordant but limited findings suggest that Lp(a) may act as a modifier of disease expression in BAV, contributing to accelerated calcific remodelling and earlier clinical presentation.

Lp(a) and Transcatheter Aortic Valve Replacement

Several observational studies have assessed the association between Lp(a) level and clinical outcome in patients undergoing TAVR. Overall, elevated Lp(a) is common in TAVR populations and may contribute to residual cardiovascular and valve-related risk after intervention, although findings remain heterogeneous. Early retrospective data suggested a high prevalence of elevated Lp(a) among TAVR patients. In a cohort of 131 individuals, Ma et al. reported Lp(a) ≥30 mg/dl in more than one-third of patients, with higher levels associated with greater concomitant CAD burden and increased procedural complications, including paravalvular leak (13% versus 4%), which might be explained by a potential increased aortic cusp and annulus calcification.51 In contrast, larger retrospective cohorts reported weaker associations, with elevated Lp(a) not consistently linked to earlier progression to AVR, particularly in elderly populations with advanced disease. In a study of over 500 patients, Loewenstein et al. found that although Lp(a) was modestly elevated, concentration >50 mg/dl was not associated with younger age at TAVR; the mean age of the study cohort with severe AS was 83.1 ± 6.2 years.52

More recent studies have focused on valve-related outcomes. Elevated baseline Lp(a) has been independently associated with hypo-attenuating leaflet thickening (HALT) within 1 year after TAVR (adjusted OR 1.18 per 10 mg/dl increase).53 Especially in the presence of systemic inflammation (high-sensitivity C-reactive protein ≥3.5 mg/l), patients with Lp(a) ≥40 mg/dl had a 4.74-fold increased risk of HALT, supporting a link between Lp(a), inflammation and post-TAVR leaflet pathology.

Associations with longer-term outcomes also remain inconsistent. While some cohorts have demonstrated an independent relationship between elevated Lp(a) and increased all-cause and cardiovascular mortality, as well as possible structural valve degeneration, other studies have found no association with haemodynamic valve deterioration, valve calcification or mortality, particularly in older, high-risk populations. In a prospective cohort of 601 patients, Hu et al. reported that elevated baseline Lp(a) ≥30 mg/dl was independently associated with higher all-cause (HR 1.81; 95% CI [1.27–2.57]) and cardiovascular mortality (HR 2.02; 95% CI [1.12– 3.66]) and structural valve degeneration (SVD; subdistribution HR 3.40), over a median follow-up of 3.9 years.54 In contrast, Sampath-Kumar et al. found no relationship between Lp(a) level (median 17 mg/dl) and haemodynamic valve deterioration in a cohort of 555 patients.55 Similarly, Bormann et al. reported no association between Lp(a) ≥60 mg/dl and AV calcification or mortality in an elderly (median age 82 years) high-risk TAVR population, again suggesting that the impact of Lp(a) may be attenuated in advanced disease stages or older patients.56

Taken together, available data suggest that Lp(a) may contribute to residual risk after TAVR, particularly in relation to leaflet pathology and long-term outcomes in selected patients, but its prognostic value appears less consistent in older patients with advanced AS.

Lp(a) and Bioprosthetic Aortic Valve Degeneration

Bioprosthetic AVs are increasingly used in the management of AS due to their lower thrombogenicity, lack of mandatory long-term anticoagulation and the expanding TAVR indications. However, SVD remains a major limitation, with reported failure rates reaching 10% at 5 years and 25% at 10 years.23 Degeneration is driven by multifactorial mechanisms, including mechanical stress, fibrocalcific remodelling, inflammation and leaflet tissue disruption, which overlap partly with the pathobiology of native AS.

While Lp(a) is strongly linked to native valve calcification, its role in bioprosthetic valve degeneration remains uncertain. Retrospective studies suggest that metabolic syndrome and dyslipidaemia contribute to SVD, but data addressing Lp(a) are limited and heterogeneous. In the largest retrospective multicentre study to date, Farina et al. analysed 210 patients undergoing bioprosthetic AVR and showed that patients who developed SVD had significantly higher Lp(a) than those without degeneration (median 50.0 versus 15.6 mg/dl; p=0.002).57 Elevated Lp(a) (≥30 mg/dl) was independently associated with a markedly increased risk of SVD (adjusted HR 4.44; 95% CI [1.89–10.42]) over a median follow-up of 4.4 years, suggesting a potential role in long-term valve durability.

Supporting this, a longitudinal cohort (n=174) with extended follow-up (median 7.3 years) demonstrated that Lp(a) >125 nmol/l was associated with a higher cumulative incidence of SVD, particularly for stenotic or mixed degeneration phenotypes (15-year incidence 62% versus 47%; subdistribution HR [SHR] 2.06), with a clear dose–response relationship corresponding to a 13% higher risk per 25 nmol/l increase.58 In contrast, shorter-term studies using multimodality imaging, including ¹⁸F-NaF PET and CT, failed to identify a significant association between Lp(a) and early bioprosthetic degeneration.59 Similarly, prospective TAVR cohorts reported weak or non-significant associations, with stable Lp(a) levels before and after implantation.60 Overall, available data suggest that elevated Lp(a) may contribute to bioprosthetic valve degeneration, particularly in the long term and in stenotic fibrocalcific phenotypes. However, inconsistent findings across studies probably reflect differences in follow-up duration, valve type, imaging strategy and patient age.

Therapeutic Perspectives and Emerging Lp(a)-lowering Therapies

The recognition of Lp(a) as a causal factor in AS has renewed interest in disease-modifying therapies for a condition historically treated only with AVR. LLT has been extensively studied in AS because of the shared risk factors with ASCVD; however, conventional LLT has failed to slow calcific AS progression or delay the need for AVR. Randomised trials have consistently shown no benefit of statins, alone or combined with ezetimibe, on valvular outcomes despite effective LDL cholesterol reduction.61–63 Following TAVR, LLT remains essential for secondary prevention as associated with improved survival, with meta-analyses demonstrating significant reductions in all-cause mortality, particularly with intensive statin therapy.64 Similar survival benefits have been observed after SAVR, although these effects appear unrelated to valve degeneration.65

In the FOURIER trial, evolocumab was associated with a lower risk of AS-related events, an effect that may partly reflect modest reductions in Lp(a) level.22,66 Genetic studies further support this link, showing that lifelong lower PCSK9 activity is associated with reduced AS risk.67 In a large drug-target Mendelian randomisation study by Ciofani et al., genetically proxied PCSK9 inhibition was associated with a substantially lower risk of AS (OR 0.61; 95% CI [0.52–0.72]).68 Mediation analyses showed that this protection was only partially attributable to Lp(a), underscoring the importance of early lipid lowering, while reinforcing the rationale for therapies that directly target Lp(a). Together, these observations support the concept that while conventional LLT improves post-intervention prognosis, targeted Lp(a)-lowering therapies may be required to modify disease biology, particularly when applied at earlier stages.69 However, whether lowering Lp(a) can modify the natural history of AS remains unproven and will need to be demonstrated in randomised clinical trials.

Randomised clinical trials specifically targeting Lp(a) in AS are now under way, marking a critical step towards disease-modifying therapy. The Lp(a) FRONTIERS CAVS trial (NCT05646381) is a Phase II randomised study evaluating whether profound Lp(a) reduction with pelacarsen (antisense oligonucleotide) can slow the progression of mild-to-moderate calcific AS in adults with elevated Lp(a) (≥175 nmol/l) who are optimally treated for other cardiovascular risk factors. In parallel, the EPISODE trial (NCT04968509) is assessing whether PCSK9 inhibition influences AS progression, although Lp(a) lowering is modest and secondary in this setting.

Conclusion

Accumulating epidemiological, genetic, mechanistic and imaging evidence suggests that Lp(a) contributes to the initiation of CAVD, particularly during early disease stages characterised by valve inflammation and initiation of calcification, whereas later stages of established AS appear to be increasingly dominated by progressive fibrocalcific remodelling. Unlike conventional lipid risk factors, Lp(a) exerts valve-specific effects through Ox-PL-mediated inflammation, osteogenic signalling and disordered mineral metabolism, providing a coherent explanation for the failure of traditional LLT to modify disease course once calcification is established. Observational and genetic data consistently support a dose-dependent relationship between Lp(a) and CAVD, with the strongest effects observed in younger individuals and earlier disease stages, reinforcing the importance of lifelong exposure in determining risk.

Looking ahead, the emergence of potent and selective Lp(a)-lowering therapies represents a pivotal opportunity to test disease modification in AS for the first time. Ongoing randomised trials specifically targeting Lp(a) in mild-to-moderate disease will be critical in determining whether early intervention can slow valvular calcification, delay haemodynamic progression and ultimately reduce the need for valve replacement. Until such outcome data become available, increased awareness among cardiologists and cardiac surgeons involved in the management of AS is essential. In this context, measuring Lp(a) in patients with AS may provide valuable prognostic information regarding disease progression, bioprosthetic valve durability and post-procedural complications in individuals undergoing AVR.

Clinical Perspective

• Elevated lipoprotein(a) [Lp(a)] is an independent risk factor for calcific aortic stenosis (AS), with strong genetic evidence supporting a causal contribution to disease initiation and progression.

• Routine measurement of Lp(a) can improve risk stratification, particularly in patients with early AS, rapid progression, bicuspid aortic valves, or a family history of premature cardiovascular disease.

• Lp(a)-driven AS is mediated by pro-inflammatory and pro-calcific pathways, highlighting that AS is an active biological process rather than a purely degenerative condition.

• Emerging Lp(a)-lowering therapies represent a potential therapeutic strategy; however, whether reduction of Lp(a) can slow AS progression or reduce the need for valve intervention remains unknown and requires confirmation in ongoing clinical trials.

• Incorporating Lp(a) into clinical assessment may help identify patients who could benefit from targeted preventive approaches once outcome data are available.