What is lipoprotein(a), why is it important, and how can it be modulated?
Recent scientific evidence shows that the blood concentration of lipoprotein(a) (Lp(a)) is an important marker for the risk of developing heart disease. Nonetheless, Lp(a) measurements are not widely available and are seldom used in routine clinical practice.
A traditional lipid panel measures total cholesterol, triglycerides,and high-density lipoprotein cholesterol (HDL-C) The numbers are then used to calculate low-density lipoprotein cholesterol (LDL-C), which is strongly correlated with the risk of coronary heart disease and stroke.
Lately, measuring the concentration or number of lipoprotein particles has been found to be useful to assess risk. Examples of such measurements are measurements of LDL particle number (LDL-P), apolipoprotein B and Lp(a).
It has been known for some time that Lp(a) is a decisive risk factor for developing coronary heart disease and calcific narrowing of the aortic valve (aortic valve stenosis). However, the lack of clinical trial data has caused it to be largely ignored by the medical community. This is mainly due to the absence of lifestyle measures or therapies that may lower blood levels of Lp(a).
Blood levels of Lp(a) are genetically determined, meaning that environmental factors have a limited influence on the blood levels of the substance.
What Is Lipoprotein(a)?
Lipoproteins are particles that transport cholesterol and triglycerides in the bloodstream. They are composed of proteins (apolipoproteins), phospholipids, triglycerides, and cholesterol.
The lipoproteins vary in the major lipoprotein present and the relative contents of the different lipid components.
There are six major types of lipoproteins; chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and Lp(a)
Lp(a) was first described by Kåre Berg, a Norwegian professor, in 1963 (1). It is a type of low-density lipoprotein and is rich in cholesterol.
Lp(a)consists of an LDL-like core lipoprotein molecule but differs from other lipoproteins as it contains a unique apolipoprotein(a) or apo(a)(2).
Similar to LDL, an Lp(a) particle also contains one molecule of apolipoprotein B (apoB).
Lipoproteins that promote atherosclerosis (the leading underlying cause of heart disease) are termed atherogenic. ApoB is an essential component of all atherogenic lipoproteins.
How Does an Excess of Lipoprotein(a) Cause Heart Disease?
There are several mechanisms by which Lp(a) may cause heart disease.
Firstly, like all other Apo B containing lipoproteins, Lp(a) may enter the arterial wall and promote inflammatory reactions, subsequently leading to atherosclerosis (3).
Secondly, Lp(a) is an important carrier of oxidized phospholipids (OxPLs) (4).
Blood levels of OxPLs have been previously demonstrated to be strongly associated with atherosclerotic cardiovascular disease (5). Furthermore, OxPLs seem to be associated with an increased risk of developing calcified aortic valve stenosis (6).
Thirdly, the apolioprotein (a) component of Lp(a) resembles plasminogen, an important enzyme participating in the dissolution of blood clots. Therefore, it has been suggested that high levels of Lp(a) may inhibit the natural role of plasminogen and thereby increase the risk of blood clots (7).
Lipoprotein(a) and Coronary Heart Disease
Several studies have shown that Lp(a) is a significant risk factor for developing coronary heart disease.
In a summary of 36 cohort studies, Lp(a) levels were found to be associated with increased risk of coronary heart disease and stroke (8).
In the Copenhagen City Heart Study, elevated Lp(a) levels were associated with a 1.9- and 2.6-fold increased risk of myocardial infarction (heart attack) over a 16-year follow-up period (9).
A recently published case-control study predicted that pharmacologic reduction of Lp(a) in individuals with the highest concentration would substantially decrease the risk of cardiovascular disease (13).
Lipoprotein(a) and Aortic Valve Stenosis
Aortic valve abnormalities are pretty frequent in older people. A thickening or calcification of the aortic valve or calcification, without significant obstruction, is found in 26 percent of people older than 65 years (14).
In some people, the aortic valve’s leaflets may become stiff, leading to a narrowing of the aortic valve opening. If severe, this may obstruct blood flow from the left ventricle; a condition called aortic valve stenosis.
Clinical studies demonstrate a significant association between Lp(a) levels and aortic valve stenosis.
Furthermore, genome-wide and Mendelian randomization studies suggest that high Lp(a) levels play a causative role in developing the disorder (4).
What Is the Normal Range For Blood Levels of Lipoprotein(a)?
Here’s how Lp(a) levels are looked at in terms of risk:
- Desirable: < 14 mg/dL (< 35 nmol/l)
- Borderline risk: 14 – 30 mg/dL (35 – 75 nmol/l)
- High risk: 31 – 50 mg/dL (75 – 125 nmol/l)
- Very high risk: > 50 mg/dL (> 125 nmol/l)
How Can Lipoprotein(a) Be Modulated?
Lp(a) levels are primarily genetically determined. Nonetheless, lifestyle factors may also play a role.
Interestingly, a low-fat, high-carbohydrate diet may increase Lp(a) levels compared to a high-fat, low-carbohydrate diet (16).
The data on the effect of statin drugs on Lp(a)levels are conflicting.
For example, one study showed that statins significantly increase plasma Lp(a) levels (17). However, the same study suggested that statins lowered non-HDL cholesterol substantially and reduced overall cardiovascular risk.
Niacin decreases Lp(a) levels by approximately 20%-30% (18).
Recently, Lp(a)-specific lowering medications have become available. Major ongoing clinical trials are investigating the clinical efficacy of these agents in patients with elevated Lp(a) levels.
The HORIZON phase III trial is investigating the benefit of Lp(a)-lowering with an antisense oligonucleotide (ASO), TQJ230, compared to placebo, on major cardiovascular events, in patients with established cardiovascular disease (19).
The Take-Home Message
Lipoprotein(a) is a strong risk factor for developing coronary heart disease and calcific narrowing of the aortic valve (aortic valve stenosis).
Mendelian randomization studies have provided strong evidence for a direct causative role of Lipoprotein(a) in developing these disorders.
Lipoprotein(a) levels are primarily genetically determined. Nonetheless, lifestyle factors may also play a role.
High-fat, low-carbohydrate diets lower lipoprotein(a) more effectively than low-fat diets.
Major ongoing clinical trials are currently investigating the clinical efficacy of specific lipoprotein(a)-lowering agents in patients with elevated lipoprotein(a) levels.