NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis

Abstract

Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.

Keywords: aortic stenosis; cardiovascular disease; lipoprotein(a); metabolism; pathophysiology; therapy.

Central Illustration. Global Prevalence of Elevated Lp(A) Levels, Metabolism of Lp(A) Ad Phenotypic Expression of Disease, and Unmet Needs In Lp(A) Pathophysiology

The top of the figure depicts the migration of the LPA gene, and its multiple apo(a) isoforms, out of Africa to the rest of the world. Due to differences in migration of different isoforms, as well as subsequent LPA gene remodeling of single nucleotide polymorphisms, the prevalence of Lp(a) plasma levels is variable. The estimates of prevalence of elevated Lp(a) (> 50 mg/dL or >125 nmol/L is given, based on current estimates of threshold prevalence. The middle panels depict the synthesis of both alleles of apo(a) and the subsequent assembly into Lp(a) with an LDL-like particle. Lp(a) is secreted into circulation and accumulates in vascular tissues and aortic valve leaflets over a lifetime. The clearance of Lp(a) is less well understood but a large portion is cleared via hepatic receptors, and a smaller portion by renal mechanisms and other unidentified pathways. On the bottom is a very brief summary of unmet needs in the understanding of Lp(a) pathophysiology.