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Lipoprotein(a) and aortic stenosis
  1. Kwan-Leung Chan
  1. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
  1. Correspondence to Dr Kwan-Leung Chan, University of Ottawa, Ottawa, ON K1N 6N5, Canada; kchan{at}ottawaheart.ca

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Aortic valve stenosis (AS) is the most common valvular heart disease in the Western world, affecting about 3% of the population over 75 years of age and after onset of symptoms is associated with adverse events including death.1 With the ageing of the population, AS likely will become an increasingly important health issue. Despite this grim prospect, a therapeutic strategy to slow the progression of AS has not been developed and the only effective treatment is aortic valve replacement. Furthermore, AS is a progressive condition, but the rate of progression is quite variable from individual to individual. The predilection of AS in the older individuals has led to the belief that AS was an inevitable result of a degenerative process, but research has shown that it is an active process involving multiple metabolic pathways, raising the possibility that the process can potentially be modified or interrupted.2

Epidemiological studies have shown that AS is associated with traditional atherosclerotic risk factors such as hypertension, smoking, diabetes and increased cholesterol. At the molecular level, AS also shares common features with atherosclerosis including lipid infiltration, inflammation, fibrosis and calcification in the subendothelial space and lamina fibrosa. Since lipoproteins are involved in several putative pathways in the development of AS, lipid-lowering agents such as statins would be expected to have a beneficial impact on AS progression due to their effect on inflammation and atherosclerosis, and yet randomised trials have shown no benefit of statin on AS progression despite a marked reduction in cholesterol levels in individuals with mild to moderate AS.3

High levels of lipoprotein(a) (Lp(a)), a lipoprotein structurally similar to low-density lipoprotein, have been associated with an increased risk of atherosclerosis and more recently AS. Genetic variation mediated by Lp(a) levels has been shown to be associated with aortic valve calcification (AVC) and incident AS in multiple ethnic groups. In the Copenhagen General Population study, Lp(a) levels were correlated with progressively increased risk of AS after adjustment for risk factors including age and cholesterol. People with above 90th percentile levels had a twofold to threefold increased risk of AS.4 In a follow-up study in the same cohort, an increased risk of AS was associated with higher levels of Lp(a) and oxidised phospholipids but not with low-density lipoprotein cholesterol. The association between the risk of AS and genetic variation affecting plasma levels of Lp(a) and the dose-dependent relationship between Lp(a) level and the incident risk of AS suggested that the association may be causal.

Transthoracic echocardiography is the imaging modality of choice to provide a comprehensive haemodynamic assessment of AS severity. AVC has emerged as a reliable marker of AS severity and a robust predictor of a more rapid progression. Echocardiography yields only a qualitative assessment of AVC. CT is the preferred modality for AVC by providing a quantitative and accurate measure of AVC, and recommendations of its use are included in current guidelines on the management of AS. Recent enthusiasm in hybrid imaging particularly with 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/CT is based on the notion that it can provide both anatomic and molecular data. 18F-NaF uptake in calcified aortic valves has been shown to extend beyond areas of macrocalcification and to predict new area of calcium deposition and subsequent increase in AVC. Thus, 18F-NaF uptake not only correlates with AS severity, but it appears to be a measure of the pathological process of ongoing calcifying activity. Zheng et al showed that in patients with AS, elevated Lp(a) levels (>35 mg/dL) were associated with increased AVC activity measured by 18F-NaF uptake on PET/CT, increased progression of AVC, more rapid AS progression and increased risks of aortic valve replacement and death.5 These findings suggest that Lp(a) lowering may be a good approach and 18F-NaF uptake a surrogate marker of progression in trials on prevention of AS progression.

Kaiser et al investigated the relationship between Lp(a) and 18F-NaF uptake in 52 individuals with mild to moderate AS by matching individuals with high Lp(a) values (>50 mg/dL) with those who had lower values.6 They showed that 18F-NaF uptake was not different between high and low Lp(a) groups, and AVC but not Lp(a) was the key determinant of 18F-NaF uptake. The authors acknowledged that the sample size was small and there were no data on the progression of AVC which is a better endpoint for 18F-NaF uptake. Nonetheless, the findings did not support the concept that Lp(a) lowering would be an effective strategy to prevent AS progression. On the other hand, increased 18F-NaF uptake has been reported to be associated with increased age and elevated Lp(a) levels in healthy individuals with no observable AVC, but whether this predicts a higher risk of subsequent development of AVC and incident AS is not known .7 8 I believe these contradictory findings can be reconciled in light of the pathophysiology of AS which consists of three phases (the initiation, propagation and end-stage calcification phases) during which different specific metabolic pathways may be dominant.2 At the initiation stage, there is mild leaflet thickening with no significant AVC. At the late stage when severe AS ensues, there is invariably dense AVC. When macrocalcification is evident as in the individuals in the study of Kaiser et al, extracellular bone matrix proteins rather than lipids play a dominant role in the calcifying process, whereas in the initiation stage, lipid infiltration, inflammation and microcalcification may be more important. I agree with Kaiser et al that ‘established valvular calcific burden is the most important disease driver of AS’, but the presence of AVC represents a late stage of the disease which is likely the reason why trials on lipid lowering to prevent AS progression so far have been unsuccessful. Prevention approaches targeting lipids including Lp(a) may be more effective in individual at risk for AS such as individuals with bicuspid aortic valve before the development of significant AVC. When AVC is present, strategies targeting specific mediators of the calcification process appear more appropriate and we await the results of the ongoing trials based on this approach.

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  • Funding The author has 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; externally peer reviewed.

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