Lp(a) and Aortic Valve Calcification
Condition: Heterozygous Familial Hypercholesterolemia
MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia
Study type: Observational

Summary: 
      Aortic valve stenosis (AVS), the most common form of valve disease in the western world,
      afflicts more than 1 million individuals in North America [1] and the burden of AVS is high
      and is expected to double within the next 50 years [2]. Medical therapy to prevent
      development or reduce progression of AVS is currently not available and the only effective
      treatment for AVS is aortic valve replacement, for which costs have been estimated up to
      120,000$ [3,4]. Recently, we and others have identified rs10455872 at the LPA locus as a
      susceptibility single nucleotide polymorphism (SNP) for aortic valve calcification (AVC) and
      AVS [5,6] and rs10455872 is associated with elevated plasma lipoprotein (Lp)(a) levels [7].
      Lp(a) is a LDL-like particle consisting of hepatically synthesized apolipoprotein B-100 that
      is noncovalently bound to the plasminogen-like glycoprotein apolipoprotein(a) [8]. Lp(a)
      promotes atherosclerotic stenosis, and possibly thrombosis, and has been hypothesized to
      contribute to wound healing, each of which could explain an association with AVS [9,10].
      Lp(a) is relatively refractory to both lifestyle and drug intervention, with only nicotinic
      acid and monoclonal antibody inhibition of the proprotein convertase subtilisin/kexin type 9
      that have showed reductions in Lp(a) levels [11,12]. However, the evidence that patients with
      AVS could be characterized by high Lp(a) levels is scarce. Glader et al. [13] showed that
      plasma levels of Lp(a) were almost 1.5-fold higher in 101 patients with AVS compared to
      matched controls, although this relationship did not reach statistical significance.
      Subsequent studies have also reported an association between elevated plasma Lp(a) levels and
      higher prevalence of AVS. More specifically, Kamstrup and colleagues [14] reported that
      elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS
      in the general population with levels >90 mg/dL predicting a threefold increased risk. We
      have measured Lp(a) and oxidized phospholipids plasma levels in 220 patients with
      mild-to-moderate calcific AVS enrolled in the Aortic Stenosis Progression Observation:
      Measuring Effects of Rosuvastatin (ASTRONOMER) trial [15]. Results of this study suggest that
      high Lp(a) and oxidized phospholipids both predict calcific AVS progression, especially in
      younger patients with calcific AVS. We also found that statin therapy considerably increased
      both Lp(a) and oxidized phospholipids levels. Whether the fact that statins increase these
      risk factors for calcific AVS might explain at least to a certain extent why statins failed
      to promote calcific AVS regression or stabilization in at least four trials, including
      ASTRONOMER.

      Familial hypercholesterolemia (FH) is an autosomal codominant single-gene disorder caused by
      mutations in the LDL receptor gene that disrupt normal clearance of LDL. Phenotypic features
      characteristic of the disease's heterozygous form are 2- to 3-fold raise in plasma
      LDL-cholesterol concentrations, tendinous xanthomatosis and premature atherosclerotic
      coronary artery disease. High Lp(a) levels have been shown to explain residual cardiovascular
      disease risk in FH [16,17]. Recent studies have demonstrated that FH heterozygotes have
      elevated AVC compared with non-FH subjects [18] and that Lp(a) levels were positively
      correlated with AVC in asymptomatic FH heterozygotes [19]. Vongpromek et al. [19]
      demonstrated that plasma Lp(a) concentration is a independent risk factor for AVC in a cohort
      of 129 asymptomatic heterozygous FH patients aged between 40 and 69 years. In this study, AVC
      was significantly associated with plasma Lp(a) level, age, body mass index, blood pressure,
      duration of statin use, cholesterol-year score and coronary artery calcification (CAC) score.
    


Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        primary care clinic