Lp(a) and Aortic Valve Calcification
Lp(a) and Aortic Valve Calcification
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.
Inclusion Criteria:

 -  Men or women with heterozygous FH aged between 18 and 80 years

 -  FH patient carrying a documented mutation in the LDL receptor gene

 -  Subjects must be willing to give written informed consent and able to adhere to visit
 schedule

 Exclusion Criteria:

 -  Men or women < 18 or > 80 years

 -  Non-FH subjects

 -  History of alcohol or drug abuse within the past 2 years

 -  Subjects who are in a situation or have any condition that, in the opinion of the
 investigator, may interfere with optimal participation in the study