Lipoprotein(a) and oxidized phospholipids in calcific aortic valve stenosis

Abstract

Purpose of review: As the incidence of calcific aortic valve stenosis increases with the aging of the population, improved understanding and novel therapies to reduce its progression and need for aortic valve replacement are urgently needed.

Recent findings: Lipoprotein(a) is the only monogenetic risk factor for calcific aortic stenosis. Elevated levels are a strong, causal, independent risk factor, as demonstrated in epidemiological, genome-wide association studies and Mendelian randomization studies. Lipoprotein(a) is the major lipoprotein carrier of oxidized phospholipids, which are proinflammatory and promote calcification of vascular cells, two key pathophysiological drivers of aortic stenosis. Elevated plasma lipoprotein(a) and oxidized phospholipids predict progression of pre-existing aortic stenosis and need for aortic valve replacement. The failure of statin trials in pre-existing aortic stenosis may be partially due to an increase in lipoprotein(a) and oxidized phospholipid levels caused by statins. Antisense oligonucleotides targeted to apo(a) are in Phase 2 clinical development and shown to lower both lipoprotein(a) and oxidized phospholipids.

Summary: Lipoprotein(a) and oxidized phospholipids are key therapeutic targets in calcific aortic stenosis. Strategies aimed at potent lipoprotein(a) lowering to normalize levels and/or to suppress the proinflammatory effects of oxidized phospholipids may prevent progression of this disease.

Figure 1. Effects of therapeutic interventions on OxPL-apoB and Lp(a) levels

Systematic review of trials with OxPL-apoB and Lp(a) levels following intervention with statins (brown), beneficial diets (blue), and Lp(a) lowering therapies (black). Each filled symbol represents the mean percent change, or the delta mean percent change between the intervention and placebo group where available, from each respective trial. Diamond symbols represent the mean change within each respective interventional category and span the 95% confidence interval. Data from trials with larger of subjects are represented with larger symbol. Reprinted with permission from J Clinical Lipidology [28].

Figure 2. Potential mechanisms for the causal role of Lp(a) and OxPL in AS

(A) Molecular changes involved in progression of AS. Fibrin is exposed at sites of aorta endothelial injury (depicted by lightning bolt) and can bind to Lp(a), leading to its retention in the valve. Pro-inflammatory lipids on Lp(a), such as OxPL, can promote calcification and bone formation via VIC directly or via up-regulation of ROS and pro-inflammatory cytokines in macrophages. (B) Anatomic changes with progression of a normal valve (left) to a severely stenotic valve (right). Abbreviations: ATX = autotaxin; Lp-PLA₂ = Lipoprotein-associated phospholipase A₂; LPC = lysophosphatidylcholine; LPA = lysophosphatidic acid; OxPL = oxidized phospholipids; Lp(a) = lipoprotein(a); ROS = reactive oxygen species; VIC = vascular interstitial cell; ALP = alkaline phosphatase

Figure 3. Rates of AS progression in stain trials

Annual rates of progression in those with mild-moderate (mod) AS (composite estimate using data from ASTRONOMER [6], SEAS [5], and TASS [20]), those with mild-mod AS and low Lp(a) and high Lp(a) [orange bars] (data from Capoulade et al. [16]), and those with severe AS (estimated using data from SALTIRE [4]).