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.

Keywords: AVR; Lp(a); TAVI; aortic valve stenosis; artificial intelligence; calcification; dyslipidemia; inflammation; olpasiran; pelacarsen.

Figure 1

Prognosis of symptomatic patients with severe aortic stenosis in the absence of specific treatment (modified from Ross and Braunwald [4]). y, years.

Figure 2

The pathogenetic mechanism of aortic valve stenosis: dyslipidemia, inflammation, and calcification. The figure summarizes the main pathways involved in the aortic valve calcification process. Lp(a), lipoprotein(a); LDL, low-density lipoprotein; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; OxPL, oxidized phospholipids; OxLDL, oxidized LDL; LpPLA2, lipoprotein-associated phospholipase A2; LysoPC, lysophosphatidylcholine; ATX, autotaxin; LysoPA, lysophosphatidic acid; AA, arachidonic acid; COX2, cyclooxygenase-2; 5LO, 5-lipoxygenase; MMP, matrix metalloproteinases; TIMP, tissue inhibitor of metalloprotease; TNF, tumor necrosis factor; IL1, interleukin-1; IL6, interleukin-6; VEGF, vascular endothelial growth factor; ACE, angiotensin converting enzyme; BMP2, bone morphogenetic protein 2; RUNX2, runt-related transcription factor 2; MSX2, Msh Homeobox 2; RANKL, receptor activator of nuclear factor κB Ligand; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase I; NT5E, ecto-5′-nucleotidase; ALP, alkaline phosphatase.

Figure 3

Flow chart for severe aortic stenosis treatment, according to VHD ESC guidelines 2021. In the figure, the green boxes indicate class I of recommendation, and the yellow boxes indicate class IIa of recommendation. The red box groups all conditions that need to be assessed by the heart team. V, aortic valve peak velocity; G, aortic valve mean gradient; AVA, aortic valve area; LVEF, left ventricular ejection fraction; Svi, systolic volume index; ETT, exercise tolerance test; BP, blood pressure; CCT, Cardiac Computed Tomography; BNP, brain natriuretic peptide; AVR, aortic valve implantation; TAVI, transcatheter aortic valve replacement.