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Threshold effect for lipoprotein(a) in aortic stenosis
  1. Evangelos Tzolos,
  2. Marc Richard Dweck
  1. Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK
  1. Correspondence to Professor Marc Richard Dweck, Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh EH8 9YL, UK; marc.dweck{at}ed.ac.uk

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Calcific aortic stenosis (AS) is the most common form of valvular heart disease in the Western world, and its healthcare burden is expected to double over the next 50 years.1 Currently, no medical therapy has demonstrated an ability to slow or halt progression of this common condition. While surgical or percutaneous aortic valve replacement is the only available treatment, important questions still remain with respect to the optimal timing of intervention, associated procedural risks and long-term durability. The quest to develop novel treatments to prevent or slow down AS, potentially removing the need for surgical intervention altogether, has not been successful up to now. Atherogenic apolipoprotein B-containing lipoproteins, like low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)), have been clearly implicated in the pathophysiology of AS, in particular in the initiation phase of the disease and with incident AS. However, multiple randomised clinical trials Simvastatin and Ezetimibe in Aortic Stenosis (SEAS), Scottish Aortic Stenosis and Lipid Lowering Trial, Impact in Regression (SALTIRE) and Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER)} focusing on lowering LDL cholesterol with statins or ezetimibe failed to modify progression of aortic valve stenosis. Interest has therefore switched more closely to Lp(a), which is largely left unaffected by statin therapy. Encouraging data have demonstrated the association of high Lp(a) levels not only with incident AS but also with increased disease activity and faster disease progression: that is, the propagation phase of the disease which any effective treatment will have to successfully modify.2–4

In this issue of Heart, Kaiser et al 5 further explore the association between high Lp(a) levels and aortic valve calcium (AVC). The authors included 2412 participants from the population-based Rotterdam Study, and 859 apparently healthy individuals from the Amsterdam University Medical Centers outpatient clinic. All participants underwent blood sampling to determine Lp(a) concentration and non-contrast cardiac CT to assess AVC. First, the investigators showed that almost one-third of the patients with aortic valve calcification on the non-enhanced CT scan had high Lp(a) concentrations above the 80th percentile. They then demonstrated that higher Lp(a) concentrations (>80th percentile) were independently associated with AVC presence in both cohorts. Moreover, Lp(a) above the 80th percentile was associated with a marked increase in aortic valve Agatston score compared with participants with Lp(a) values below the 50th percentile. These findings were independent of age, sex, cardiovascular risk factors as well as coronary calcium score. Once again, Lp(a) appears associated with incident AS and the initiation phase of the disease. Interestingly, there appears to be a threshold effect underlying this association around the 80th percentile (47.7 mg/dL). Patients between the 50th and 79th Lp(a) percentiles showed no difference in the presence or absence of AVC. Lp(a) lowering is therefore unlikely to be effective in everyone with AS and should probably only be targeted to those with high levels. Finally, this study importantly demonstrates that the association between AVC prevalence and Lp(a)>80th percentile is observed from a very young age. Indeed, approximately one in six patients aged 45–54 years with Lp(a)>80th percentile had aortic valve calcification, suggesting that high Lp(a) is implicated in the earliest phases of the disease process. The threshold effect observed in this study is consistent with previous data, and also appears related to rates of AS progression. Capoulade et al 6 demonstrated that elevated Lp(a) (>58.5 mg/dL) is associated with 1.5 times faster progression of AS and a twofold increased risk of aortic valve replacement and death, in a secondary analysis of 220 patients from the ASTRONOMER trial followed for an average of 3.5 years. Similarly, Zheng et al,2 in a subsequent study involving 145 patients, showed that patients in the top Lp(a) tertile (>35 mg/dL) showed increased disease activity, faster disease progression and increased risk of aortic valve replacement or death.

Where does the study leave us? In our attempts to develop a disease-modifying medical therapy with the ability to slow AS progression, effect sizes may be small and regulated by complex mechanisms. In order to adequately power future randomised controlled trials, we need to target the patients who might benefit most from an intervention. This study suggests that Lp(a) lowering should target patients above the 80th Lp(a) percentile (≥50 mg/dL) independent of their age. While it may be more effective to target younger patients with the earlier stages of disease, it should be remembered that most patients with aortic sclerosis do not ultimately require aortic valve replacement and therefore cannot benefit from therapy. Ultimately, double-blinded randomised controlled trials are required to assess whether Lp(a) lowering in patients with aortic valve calcification can slow disease progression and improve clinical outcomes.

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Footnotes

  • Twitter @TzolosEvangelos, @MarcDweck

  • Contributors ET and MRD contributed to the drafting and revision of this editorial.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; internally peer reviewed.

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