NCT02976818: FHLPA

Lp(a) and Aortic Valve Calcification

Completed Last updated 21 February 2020

What this trial tests

trial in Heterozygous Familial Hypercholesterolemia in 173 participants. Completed in 19 February 2020.

Timeline

30 April 2017

Primary endpoint
31 October 2019

19 February 2020

Quick facts

Lead sponsor	Laval University
Status	Completed
Study type	OBSERVATIONAL
Enrollment	173
Start date	30 April 2017
Primary completion	31 October 2019
Estimated completion	19 February 2020
Sites	1 location across Canada

Conditions studied

• Heterozygous Familial Hypercholesterolemia — all drugs for Heterozygous Familial Hypercholesterolemia →

Sponsor

Laval University

Who can join

Adults 18 to 80, any sex, with Heterozygous Familial Hypercholesterolemia. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

No peer-reviewed publications indexed yet for this trial. Completed trials usually publish results within 12-18 months.