Lp(a)

STRUCTURE: Lp(a) = LDL particle (apoB-100 core) + apolipoprotein(a) attached by a disulfide bond. Apo(a) is encoded by the LPA gene and is structurally homologous to plasminogen (contains kringle IV and kringle V domains plus an inactive protease domain). It is synthesized in the liver.

KEY GENETICS: Levels are mostly inherited (autosomal codominant). Plasma concentration is inversely related to apo(a) isoform size, which depends on the number of kringle IV type 2 (KIV-2) repeats. Fewer repeats give a smaller isoform, faster hepatic secretion, and higher levels. Levels vary by ancestry and are highest in individuals of African descent. About 20% of people have elevated levels.

PATHOPHYSIOLOGY: Lp(a) promotes disease through three mechanisms. 1. Atherogenic: it carries cholesterol and is retained in the intima. It also carries oxidized phospholipids (OxPL), which are pro-inflammatory. 2. Prothrombotic/antifibrinolytic: it resembles plasminogen and competes with it, which impairs fibrinolysis. 3. Pro-calcific: it promotes calcification of the aortic valve.

CLINICAL SIGNIFICANCE: - Elevated Lp(a) is an independent, causal risk factor for premature ASCVD (MI, PAD), calcific aortic valve stenosis, and ischemic stroke. - A common threshold is ≥50 mg/dL (≥125 nmol/L), which is considered a risk-enhancing factor. - Suspect it in premature ASCVD with a family history and normal or modestly elevated LDL, or in recurrent events despite optimal LDL control. - Guidelines (2018 ACC/AHA; ESC/EAS; NLA) recommend measuring it at least once in a lifetime in selected patients: those with a family history of premature ASCVD or elevated Lp(a), or those with unexplained or recurrent ASCVD. Many societies now support universal one-time screening. - LDL-C assays include the cholesterol in Lp(a), so the measured or calculated LDL-C may be falsely elevated.

MANAGEMENT: - Lifestyle changes do not meaningfully lower it. - Statins do not lower it and may slightly raise it. - Niacin lowers it by ~20-30% but is no longer recommended because it does not reduce outcomes. - PCSK9 inhibitors lower it by ~20-30%. - Lipoprotein apheresis is used for refractory, high-risk patients. - Aggressively reduce other risk factors, especially LDL-C, in patients with high Lp(a). - Emerging therapies that target hepatic LPA mRNA are pelacarsen (antisense oligonucleotide) and olpasiran, lepodisiran, and zerlasiran (siRNAs). Outcome trials (e.g., Lp(a)HORIZON for pelacarsen) have been evaluating cardiovascular benefit.

HIGH-YIELD PEARLS: - Lp(a) is the "LDL with a plasminogen-like tail": atherogenic plus thrombogenic. - It is genetically determined and is not modifiable by diet. - It is associated with premature ASCVD and aortic stenosis. - Niacin and PCSK9 inhibitors lower it modestly; statins do not.