Abstract
In fitting with the American Heart Association’s 100th anniversary of its founding and Arteriosclerosis, Thrombosis and Vascular Biology organizing a Centennial Collection to celebrate this event, lipoprotein(a) [Lp(a)] celebrates its 61(st) birthday in November 2024. There has been substantial progress in understanding the biology and pathophysiology of Lp(a) in the last 6 decades, including its discovery as a unique β-lipoprotein containing the pathognomonic apolipoprotein(a) moiety covalently bound to apolipoprotein B-100, its independent monogenetic association with cardiovascular disease and calcific aortic valve disease, its increased content of pro-atherogenic and pro-inflammatory of oxidized phospholipids relative to other lipoproteins and the development of RNA therapeutics to lower plasma Lp(a) levels. The validation or refutation of the “Lp(a) hypothesis”, namely that lowering plasma Lp(a) will lead to clinical benefit, is ongoing in 3 clinical outcomes trials. This essay reviews the discovery of Lp(a), summarizes the seminal pathophysiological findings since its discovery, discusses ongoing clinical trials with novel drugs and approaches, and provides a look ahead to unanswered questions.