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

Area of Science:

• Cardiology
• Medical Therapy
• Atherosclerosis Research

Background:

• Aortic stenosis (AS) is a prevalent condition in the elderly, with fibrocalcific AS being the most common form.
• Current treatment for severe AS primarily involves valve repair (surgical or TAVI), as no medical therapy can halt its progression.
• The pathogenetic overlap between AS and atherosclerosis has opened avenues for medical interventions.

Purpose of the Study:

• To explore the potential of novel medical therapies in slowing the progression of aortic stenosis.
• To investigate the role of lipoprotein(a) (Lp(a)) in AS pathogenesis and its therapeutic targeting.
• To assess the efficacy of emerging treatments in reducing cardiovascular events in patients with elevated Lp(a).

Main Methods:

• Review of current therapeutic strategies and diagnostic advancements in aortic stenosis.
• Evaluation of drugs targeting low-density lipoprotein (LDL), lipoprotein(a) (Lp(a)), inflammation, and calcification.
• Focus on Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i), antisense oligonucleotides (ASO), and small interfering RNA (siRNA) therapies.
• Analysis of ongoing Phase 3 clinical trials for olpasiran and pelacarsen in patients with elevated Lp(a) and cardiovascular diseases (CVD).

Main Results:

• PCSK9 inhibitors may reduce AS progression and the need for valve implantation.
• Circulating Lp(a) levels are causally linked to degenerative AS.
• Olpasiran and pelacarsen demonstrate significant Lp(a) reduction (85-90%).

Conclusions:

• Emerging therapies targeting Lp(a) hold significant potential for managing aortic stenosis.
• Further prospective trials are crucial to confirm the association between Lp(a) reduction and AS prevention/slower progression.
• These advancements offer hope for a new medical treatment paradigm for aortic stenosis.