Lipoprotein(a): a new cardiovascular risk marker

The classic lipid panel measures total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol. Then low-density lipoprotein (LDL) cholesterol is calculated, which is strongly linked to the risk of coronary heart disease and stroke, and does not include measurement of lipoprotein(a) (pronounced "lipo-protein petit a" or "L P petit a").
1- What is lipoprotein(a)?
Lipoproteins are particles that transport cholesterol and triglycerides in the blood. They are composed of proteins (apolipoproteins), phospholipids, triglycerides and cholesterol.
Lp(a) is an LDL-type molecule, but it also contains an apolipoprotein (a) or apo(a) and, like LDL, an apolipoprotein B (apo B) molecule. It has the same density and size characteristics as LDL, which makes it so dangerous.
Lp(a) has actually been known for 60 years, but the lack of clinical trial data has meant that it has been largely ignored by the medical community. This is mainly due to the absence of lifestyle measures or therapies to reduce Lp(a) blood levels. Lp(a) blood levels are genetically determined, which means that environmental factors have very little influence on blood levels. Levels are rarely determined in routine practice, and the test (which costs 19 euros) is not covered by the health insurance system.
LP(a) is manufactured in the liver and circulates in the blood like other lipoproteins. To oversimplify, it's an LDL molecule with a sort of side chain: apolipoprotein a (hence its name), with deleterious effects, notably on blood coagulation (increased risk of blood clots).
2- Excess lipoprotein (a) accelerates cardiovascular disease
Like all other lipoproteins containing Apoprotein B, Lp(a) can penetrate the arterial wall and promote inflammatory reactions, subsequently leading to atherosclerosis, as it binds to the arterial mucosa via its "sticky" apolipoprotein (a). Lp(a) is an important transporter of oxidized phospholipids, which are strongly associated with atherosclerotic cardiovascular disease.
- Lipoprotein (a) and coronary heart disease
In 36 cohort studies, Lp(a) levels were associated with a 2-3 fold increased risk of coronary heart disease.
The role of Lp(a) in the risk of plaque rupture and coronary thrombosis, and in the risk of recurrence of coronary artery disease, has also been observed. Some experts believe that there is a greater effect on the coagulation system than on the promotion of atherosclerosis.
Genetics provides strong evidence of a direct role for Lp(a) in the development of coronary heart disease. This has led doctors to establish that high Lp(a) is a risk factor for cardiovascular disease.

- Lipoprotein(a) and aortic valve stenosis
Aortic valve abnormalities are quite common in the elderly. Thickening or calcification of the aortic valve, without significant obstruction, is found in 25% of people over 65.
In some people, the leaflets of the aortic valve may become rigid, resulting in a narrowing of the aortic valve opening. If severe, this can obstruct the outflow of blood from the left ventricle. Excessive Lp(a) accelerates aortic valve ageing.
3- When should Lp(a) be measured, and for which patients?
Lp(a) testing was initially proposed as a once-in-a-lifetime measure to establish a possible excess cardiovascular risk, leading to enhanced management of other modifiable factors (in practice, aiming for a lower LDL target).
Currently, this assay is considered useful in patients with familial hypercholesterolemia, when there is unexplained or early cardiovascular disease, or in patients at intermediate risk.
Lp(a) measurement is useful for stratifying cardiovascular risk in primary prevention (in patients who have never had a cardiovascular event) and for identifying patients at high risk of recurrence of a cardiovascular event.
Lp(a) should be measured once in the following situations: subjects at high cardiovascular risk or with a family history of premature coronary disease, in cases of familial hypercholesterolemia, type 1 or type 2 diabetes and chronic renal failure.
4- What are the blood lipoprotein (a) values?
- Desirable: < 0.14 g/L
- Borderline risk: 0.14 to 0.3 g/L
- High risk: 0.31 to 0.5 g/L
- Very high risk: > 0.5 g/L



5- How to treat excess lipoprotein (a) levels
Specific anti-Lp(a) drugs are currently being studied in patients with very high Lp(a) levels, with very wide expected variations. These are so-called gene therapies (biotherapy).
As in the case of major familial hypercholesterolemia, the only treatment currently available is plasmapheresis, i.e. regular filtration of the patient's blood.

Key messages to remember
- Lipoprotein(a) is made up of an atherogenic LDL particle and a potentially thrombogenic apolipoprotein(a).
- Lipoprotein(a) is a major risk factor for coronary heart disease and aortic valve narrowing.
- Its plasma concentration is genetically determined.
- Its measurement is recommended in subjects at cardiovascular risk.
- Specific therapies (notably gene therapies) are currently being developed.

Bibliographic reference
Lipoprotein a: European consensus on its prognostic role and management. Kronenberg F & al. Eur Heart J 14 Oct. 2022

Key words: lipoprotein(a)- cardiovascular risk - coronary artery disease-aortic narrowing - treatment - gene therapy - cholesterol plaque- atheromatous disease