lipoprotein(a)

**Structure** - LDL-like particle (cholesterol-rich core, apoB-100) plus apolipoprotein(a) attached by a disulfide bond. - Apo(a) is structurally homologous to plasminogen. It has multiple kringle IV repeats (especially KIV-2) and an inactive protease domain. - Synthesized in the liver. The LPA gene is on chromosome 6q26-27. - Size of apo(a), determined by the number of KIV-2 repeats, is inversely related to plasma level. Fewer repeats give a smaller isoform and higher Lp(a).

**Pathophysiology (why it is atherogenic and thrombogenic)** 1. LDL-like: it deposits cholesterol in the intima and promotes foam cell formation. 2. Carries oxidized phospholipids (OxPL), which are proinflammatory and promote endothelial dysfunction, plaque inflammation, and valve calcification. 3. Plasminogen mimicry: it competes with plasminogen, which impairs fibrinolysis (prothrombotic). The effect on venous thromboembolism is weaker and less consistent than on arterial disease.

**Clinical significance** - Mendelian randomization and genetic studies support a causal role in: - Premature ASCVD (MI, PAD) - Ischemic stroke - Calcific aortic valve stenosis - Possibly heart failure - Elevated Lp(a) is common (~20% of people). The usual threshold is ≥50 mg/dL (≥125 nmol/L). This is a "risk-enhancing factor" in the 2018 AHA/ACC cholesterol guideline. Black individuals tend to have higher levels. - Consider measuring it once in a lifetime in these patients: - Premature ASCVD - Family history of premature ASCVD or high Lp(a) - Familial hypercholesterolemia - Recurrent ASCVD despite optimal statin therapy - Calcific aortic stenosis - Levels are stable through life and largely not modifiable by lifestyle. - Interpretation caveat: LDL-C measured or calculated includes cholesterol carried on Lp(a), so LDL-C can be overestimated and "statin-resistant LDL" may reflect high Lp(a).

**Management** - No approved Lp(a)-specific therapy yet. Management is aggressive reduction of all other risk factors, especially LDL-C (high-intensity statin, ezetimibe, PCSK9 inhibitor). - Statins do not lower Lp(a) and may modestly raise it. - Drugs that lower Lp(a): - PCSK9 inhibitors (~20-30%) - Niacin (~20-30%), but no clinical benefit shown and no longer recommended for this purpose - Lipoprotein apheresis (used in select high-risk patients) - Mipomersen and lomitapide (used in HoFH) lower it modestly. - Investigational agents: - Pelacarsen (antisense oligonucleotide) - Olpasiran and lepodisiran (siRNA) - Muvalaplin (oral small molecule) - These lower Lp(a) by ~80-95%. Cardiovascular outcomes trials (e.g., Lp(a)HORIZON for pelacarsen, OCEAN(a)-Outcomes for olpasiran) are ongoing or recently reported, so check current status.

**High-yield board points** - "Plasminogen-like" apo(a) means atherogenic plus prothrombotic. - Genetically determined and not responsive to diet or exercise. - Think of it in a young patient with premature CAD and normal or only mildly elevated LDL, or a family history of early MI. - Measure it once. Elevated Lp(a) is a risk enhancer that favors more aggressive LDL lowering.