Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA

Abstract

To date, no medical therapy can slow the progression of aortic stenosis. Fibrocalcific stenosis is the most frequent form in the general population and affects about 6% of the elderly population. Over the years, diagnosis has evolved thanks to echocardiography and computed tomography assessments. The application of artificial intelligence to electrocardiography could further implement early diagnosis. Patients with severe aortic stenosis, especially symptomatic patients, have valve repair as their only therapeutic option by surgical or percutaneous technique (TAVI). The discovery that the pathogenetic mechanism of aortic stenosis is similar to the atherosclerosis process has made it possible to evaluate the hypothesis of medical therapy for aortic stenosis. Several drugs have been tested to reduce low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) levels, inflammation, and calcification. The Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i) could decrease the progression of aortic stenosis and the requirement for valve implantation. Great interest is related to circulating Lp(a) levels as causally linked to degenerative aortic stenosis. New therapies with ASO (antisense oligonucleotides) and siRNA (small interfering RNA) are currently being tested. Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85–90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population.

Estimating the Prevalence and Characteristics of Patients Potentially Eligible for Lipoprotein(a)-Lowering Therapies in a Real-World Setting

“…Emerging lipid-lowering drugsnamely small interfering ribonucleic acid (siRNA) agents olpasiran (LY3819469, SLN360, formerly known as AMG-890, ARO-LPA) and the second-generation antisense oligopeptide pelacarsen (also known as AKCEA-APO[a]-LRx)-are being developed to specifically interfere with Lp(a) synthesis by preventing the protein translation of apo(a) messenger RNA (mRNA) into apo(a) [8]. The ultimate objective of this therapy is to genetically silence LPA, reduce apo(a) production and lower the circulating Lp(a) levels, of consequence [9]. The available evidence shows that the monthly subcutaneous administration of these agents yields reductions in Lp(a) up to 95% that persist over time and are expected to be enough to optimize the risk of ASCVD, as far as reductions in Lp(a) plasma levels by 80-90% are expected to exert a clinically significant effect [10].…”