Lipoprotein(a) and Cardiovascular Risk

Lipoprotein(a), written Lp(a), is an LDL-like particle in which an additional protein, apolipoprotein(a), is covalently bound to apolipoprotein B. Its plasma concentration is largely genetically determined and varies widely between individuals, and it is regarded as a distinct, inherited contributor to cardiovascular risk that standard lipid fractions do not capture.

Definition

Lipoprotein(a) is an LDL-like lipoprotein particle in which apolipoprotein(a)—a highly size-polymorphic glycoprotein homologous to plasminogen—is linked to apolipoprotein B-100, present at a plasma concentration that is predominantly genetically determined.

Scope

This topic covers the structure of Lp(a), the genetic determination of its concentration, how it is measured and the challenges of standardising that measurement, and its recognised association with atherosclerotic cardiovascular disease and aortic valve disease. It is a measurement and interpretation topic and does not provide clinical thresholds or treatment guidance.

Core questions

• How does the structure of Lp(a) differ from ordinary LDL?
• Why is the plasma concentration of Lp(a) largely inherited?
• Why is measuring Lp(a) analytically challenging, and how is it standardised?
• What is the recognised relationship between Lp(a) and cardiovascular risk?

Key concepts

• Apolipoprotein(a)
• Covalent linkage to apolipoprotein B-100
• Kringle IV type 2 size polymorphism
• Genetic determination of Lp(a) concentration
• Mass versus molar (particle) measurement
• Homology with plasminogen

Mechanisms

An Lp(a) particle is an LDL-like core to which apolipoprotein(a) is attached by a disulphide bond to apolipoprotein B-100. Apolipoprotein(a) contains a variable number of kringle IV type 2 repeats, producing a size polymorphism that, together with the LPA gene, largely sets an individual's lifelong Lp(a) concentration. Because apolipoprotein(a) is structurally homologous to plasminogen, Lp(a) has been hypothesised to link lipid and thrombotic pathways. The size heterogeneity of apolipoprotein(a) complicates measurement, motivating assays that report particle concentration in molar units and efforts at standardisation.

Clinical relevance

Elevated Lp(a) is recognised as an inherited factor associated with atherosclerotic cardiovascular disease and calcific aortic valve disease, and because it is largely genetically fixed it is generally measured once for risk characterisation. This entry describes what the measurement represents at a conceptual level; it is reference material and does not provide diagnostic thresholds or therapy for individuals.

Epidemiology

Lp(a) concentrations are strongly influenced by ancestry and the LPA genotype and are skewed in the population, with a minority carrying substantially elevated levels. Large collaborative analyses and genetic studies have characterised the association between higher Lp(a) and coronary disease across populations.

Evidence & guidelines

A meta-analysis of long-term studies, Mendelian and genetic association studies, and consensus and review statements have characterised Lp(a) as a cardiovascular risk factor and addressed how it should be measured. These are population-level and laboratory-practice documents rather than individualised recommendations.

History

Lipoprotein(a) was first described in the 1960s as a distinct lipoprotein, and later work established the structure of apolipoprotein(a), its homology with plasminogen, and the kringle IV size polymorphism. Large-scale epidemiological and genetic studies in the 2000s consolidated the association between Lp(a) concentration and coronary disease, and consensus statements then addressed its measurement and place in risk assessment.

Debates

How should Lp(a) be measured and reported?

The size polymorphism of apolipoprotein(a) means mass-based assays can be biased by particle size; whether to report Lp(a) in mass or molar (particle-number) units, and how to standardise assays, remains a methodological discussion in clinical chemistry.

Key figures

• Børge Nordestgaard
• Sotirios Tsimikas
• Robert Clarke
• M. John Chapman

Seminal works

• clarke-2009
• nordestgaard-2010
• tsimikas-2017

Frequently asked questions

How is Lp(a) different from LDL?

Lp(a) has an LDL-like core but carries an extra protein, apolipoprotein(a), covalently bound to apolipoprotein B-100. Its concentration is largely inherited and is not captured by standard LDL cholesterol measurement.

Why is Lp(a) usually measured only once?

Because Lp(a) concentration is predominantly genetically determined and relatively stable over life, a single measurement is generally considered sufficient to characterise an individual's level for risk purposes.