Lipoprotein(a) (Lp(a)) is a lipid particle in the blood that is a significant factor in cardiovascular health. It is a distinct component of the overall cholesterol profile, independent of the commonly measured low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Elevated concentrations of Lp(a) are strongly and causally linked to an increased lifetime risk of developing heart disease.
Understanding the Structure and Function of Lipoprotein(a)
Lp(a) is essentially an LDL-like particle, containing a core of lipids and a single molecule of apolipoprotein B-100 (apoB-100) on its surface. The unique feature is an additional protein, apolipoprotein(a) or apo(a), which is covalently attached to the apoB-100 component by a disulfide bond.
Apo(a) is a large glycoprotein that shares structural similarity with plasminogen, a protein involved in dissolving blood clots. The physiological role of Lp(a) is not fully understood, but it is theorized to play a part in processes like wound healing and tissue repair. Lp(a) is not considered a necessary molecule, as individuals with undetectable levels show no apparent deficiency.
The Primary Role of Genetics in Determining Lp(a) Levels
The concentration of Lp(a) in a person’s bloodstream is overwhelmingly determined by genetics, with heritability estimated to be as high as 70 to 90%. The primary cause of high levels is the size of the apo(a) protein, which is governed by the \(LPA\) gene located on chromosome 6. This gene contains a highly polymorphic region with a variable number of Kringle IV type 2 (KIV-2) repeats.
A key inverse relationship exists: a smaller number of KIV-2 repeats results in a smaller apo(a) protein isoform. These smaller isoforms are synthesized and secreted more efficiently by the liver, leading directly to higher concentrations of Lp(a) in the blood. Conversely, individuals with larger isoforms tend to have lower plasma levels. Because of this strong genetic control, an individual’s Lp(a) level is largely stable throughout their lifetime and is minimally affected by diet, exercise, or most cholesterol-lowering medications.
How Elevated Lipoprotein(a) Contributes to Cardiovascular Disease
Elevated Lp(a) is considered a causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) through a dual mechanism combining cholesterol deposition and impaired clot breakdown. Lp(a) acts as a pro-atherogenic particle because its LDL-like structure allows it to carry cholesterol into the artery walls. Once retained, it contributes to plaque formation and is a preferential carrier of pro-inflammatory oxidized phospholipids that accelerate the disease process.
The unique apo(a) component also confers a pro-thrombotic, or clot-promoting, effect. Due to the structural mimicry of plasminogen, Lp(a) can compete with plasminogen for binding sites on cells and clots. This interference inhibits fibrinolysis, the body’s mechanism for dissolving blood clots, making existing plaques more prone to dangerous blockages. This combination significantly increases the risk for premature coronary artery disease, ischemic stroke, and aortic valve calcification.
Strategies for Assessment and Management
Given the genetic nature of Lp(a), it is recommended that all adults have their level measured at least once in their lifetime. Testing is especially important for those with:
- A strong family history of premature heart disease.
- Established atherosclerotic cardiovascular disease.
- Recurrent events despite optimal lipid-lowering therapy.
The measurement of Lp(a) should ideally be reported in molar concentration (nanomoles per liter, nmol/L), rather than mass concentration (mg/dL). Molar concentration is the preferred unit because it reflects the actual number of Lp(a) particles, which is more relevant to risk. Since the size of the apo(a) protein is variable, the mass of the particle is also variable, making the conversion between mass and molar units inaccurate and unreliable. A level above 125 nmol/L (or 50 mg/dL) is considered elevated and is associated with a significantly increased cardiovascular risk.
Since lifestyle changes and standard treatments like statins have a negligible effect on Lp(a) levels, current management focuses on aggressively lowering all other modifiable cardiovascular risk factors. This includes achieving very low targets for LDL cholesterol and controlling blood pressure and diabetes. A new generation of targeted therapies directly addresses the cause of high levels.
Emerging Targeted Therapies
These emerging treatments are based on RNA technology, specifically antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). Drugs like pelacarsen (ASO) and olpasiran (siRNA) work by targeting and degrading the messenger RNA transcript of the \(LPA\) gene in the liver. This molecular action prevents the liver from synthesizing the apo(a) protein, which drastically reduces the plasma concentration of Lp(a) by up to 80% to 97%. These therapies are currently being evaluated in large-scale clinical trials to prove that lowering Lp(a) directly translates into a reduction in cardiovascular events.