Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

Abstract

Calcific aortic stenosis (AS) is the most common form of valve disease in the Western world and affects over 2.5 million individuals in North America. Despite the large burden of disease, there are no medical treatments to slow the development of AS, due at least in part to our incomplete understanding of its causes. The Cohorts for Heart and Aging Research in Genetic Epidemiology extra-coronary calcium consortium reported a genome-wide association study demonstrating that genetic variants in LPA are strongly associated with aortic valve (AV) calcium and clinical AS. Using a Mendelian randomization study design, it was demonstrated that the effect of this genetic variant is mediated by plasma lipoprotein (a) [Lp(a)], directly implicating elevations in Lp(a) as a cause of AV calcium and progression to AS. This discovery has sparked intense interest in Lp(a) as a modifiable cause for AV disease. Herein, we will review the mounting epidemiological and genetic findings in support of Lp(a)-mediated valve disease, discuss potential mechanisms underlying this observation, and outline the steps to translate this discovery to a much needed novel preventive and/or therapeutic strategy for AV disease.

Keywords: calcium; drug therapy/hypolipidemic drugs; lipoproteins; mendelian randomization; oxidized lipids.

Fig. 1.

Genome-wide associations with AVC. Reproduced from (21).

Fig. 2.

Proposed model of Lp(a)-mediated CAVD. A: Lp(a) is a cholesterol-rich lipoprotein in which apoB is covalently linked to apo(a). B: Lp(a) carries OxPLs in plasma (35). C: Lp(a) binds avidly to areas of endothelial injury (29). The AVs (in blue) are particularly susceptible to denudation (denoted by X in the figure) due to hemodynamic stress. D: Deposition of Lp(a) leads to delivery of oxPLs, a known promoter of osteoblastic differentiation (and calcification) (48).