The Current Landscape Of Lipoprotein(A) In Calcific Aortic Valvular Disease

Purpose of review Calcific aortic stenosis (CAVS) is the most common form of valvular heart disease in developed countries, increasing in prevalence with the aging population. Surgical or transcatheter aortic valve replacement is the only treatment available for CAVS. However, these interventions are typically reserved for severe symptomatic aortic stenosis (AS). The purpose of this review is to summarize the recent literature in uncovering the underlying pathophysiology of CAVS in the setting of lipoprotein (a) [Lp(a)] and emerging therapies targeting Lp(a) which may help halt disease progression in CAVS. Recent findings Pathophysiologic, epidemiological, and genetic studies over the past two decades have provided strong evidence that Lp(a) is an important mediator of calcific aortic valvular disease (CAVD). Studies suggest that Lp(a) is a key carrier of pro-calcifying oxidized phospholipids (OxPL). The metabolism of OxPL results in a pro-inflammatory state and subsequent valvular thickening and mineralization through pro-osteogenic signaling. The identification of Lp(a) as a causal mediator of CAVD has allowed for opportunities for emerging therapeutic agents which may slow the progression of CAVD (Fig. 1 FIGURE 1 Lipoprotein (a) mediates the progression of calcific aortic valvular disease. Upon endothelial damage, lipoprotein(a) and oxidized phospholipids (OxPL) accumulate within the valvular tissue, driving a feed-forward cycle of inflammation, calcification, and fibrosis. This ultimately results in calcified aortic valve stenosis. Currently, there are no approved medical therapies for aortic stenosis. However, emerging therapies to target Lp(a), including PCSK9 inhibitors and RNA-based therapeutics, may halt disease progression in aortic stenosis. ). This review summarizes the current knowledge on the association of Lp(a) with CAVD and ongoing studies of potential Lp(a)-lowering therapies. Based on the rate-limiting and causal role of Lp(a) in progression of CAVS, these therapies may represent novel pharmacotherapies in AS and inform the developing role of Lp(a) in the clinical management of CAVD.