Lipoprotein(a) [Lp(a)] is a cholesterol particle that has emerged as a significant marker for cardiovascular health. Unlike low-density lipoprotein (LDL) cholesterol, Lp(a) levels are largely determined by genetics, making it a highly inherited risk factor. Elevated concentrations act as an independent factor for developing heart disease, even in individuals who manage other traditional risk factors well.
Understanding Lipoprotein a Structure and Function
Lipoprotein(a) is structurally similar to an LDL particle, but it possesses an additional protein component called apolipoprotein(a), or Apo(a). This unique protein is covalently linked to the ApoB-100 protein. Apo(a) is distinctive because it contains structures called kringle domains, which closely resemble plasminogen, a protein involved in dissolving blood clots.
Lp(a) is synthesized primarily in the liver, and its concentration is overwhelmingly determined by the LPA gene. Genetic variation in this gene dictates the size of the Apo(a) protein, which strongly correlates with the circulating level of Lp(a). Levels are established early in childhood and remain relatively stable throughout life, with little influence from diet, exercise, or most common cholesterol medications.
Lp(a) as a Cardiovascular Risk Factor
The danger of high Lp(a) stems from its dual mechanism of harm: promoting plaque buildup and increasing the risk of blood clotting. Like LDL, the Lp(a) particle can penetrate the artery wall, initiating atherosclerosis. It also carries pro-inflammatory oxidized phospholipids, which contribute to the progression and instability of arterial plaques.
The structural similarity of Apo(a) to plasminogen introduces a pro-thrombotic risk. By competing with plasminogen for binding sites, Lp(a) can inhibit the body’s natural ability to break down fibrin clots. This interference with fibrinolysis increases the likelihood of a thrombotic event, such as a heart attack or stroke, once a vulnerable plaque ruptures.
Elevated Lp(a) is an independent causal risk factor for several cardiovascular conditions, including premature coronary artery disease and calcific aortic valve stenosis. The risk of cardiovascular events increases continuously as Lp(a) concentrations rise. Individuals with very high levels, such as those above 100 mg/dL, may face a two-to-four-fold increase in cardiovascular event risk compared to those with low levels.
Testing and Monitoring Lp(a) Levels
Measuring Lp(a) is typically a one-time measurement for most adults because levels are genetically determined and stable. Testing is particularly recommended for individuals with a family history of premature heart disease or stroke, or those with high LDL cholesterol levels that do not respond to typical treatment.
Results are commonly reported in two units: mass concentration (mg/dL) and molar concentration (nmol/L). Because the size of the Apo(a) protein varies greatly, the conversion factor between these units is not fixed. Most international consensus statements consider a level above 50 mg/dL or 125 nmol/L to be a high-risk threshold. The nmol/L unit, which measures the number of Lp(a) particles, is generally preferred by experts for a more accurate reflection of risk.
Current Approaches to Lowering High Lp(a)
The management of elevated Lp(a) is challenging because traditional lipid-lowering therapies have a minimal effect on its concentration. The primary approach currently involves aggressively reducing all other cardiovascular risk factors, particularly LDL cholesterol, to mitigate the overall risk burden.
A few existing medications show some ability to reduce Lp(a) levels, though they are not specifically approved for this purpose. PCSK9 inhibitors can lower Lp(a) by approximately 20 to 30 percent. High-dose niacin can also reduce Lp(a), but its use is limited by potential side effects and the lack of clear evidence that this reduction leads to better cardiovascular outcomes. For patients with extremely high levels and progressive heart disease, a procedure called LDL apheresis is an option.
The most significant progress is occurring in the development of targeted therapies that specifically inhibit the production of Apo(a) in the liver. These emerging treatments, which include antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have demonstrated the ability to reduce Lp(a) concentrations by as much as 80 to 97 percent in clinical trials. These novel therapies are currently being studied in large-scale Phase 3 trials to determine if lowering Lp(a) directly translates into a reduction in major cardiovascular events.