Lipoprotein (a)

Reference ranges for lipoprotein (a) (Lp[a]), a type of low-density lipoprotein (LDL), vary, being dependent on assay and reporting laboratories. They also differ by population and may vary regionally worldwide. Nonetheless, many US lipidologists generally consider an Lp(a) level of less than 10 mg/dL to indicate a lower cardiovascular risk. Levels higher than 10 mg/dL are associated with an increase in cardiovascular risk (see Interpretation).

The apolipoproteins have a primary responsibility for the transport of lipids and cholesterol. Apolipoprotein B (apoB) is a nonexchangeable lipoprotein that exists in two forms in humans, apoB-100 and apoB-48.

Many US lipidologists consider a Lp(a) level < 10.0 mg/dL to be indicative of lower cardiovascular risk, with higher levels associated with an increase in cardiovascular risk.[1]

As noted by Davidson, the odds ratio for significant coronary heart disease on angiography in patients with a Lp(a) level greater than 30 mg/dL versus a level less than or equal to 5 mg/dL increased from 1.67 to 6.0, as LDL concentrations increased as well.[2]

In addition, a number of prospective trials have demonstrated that Lp(a) predicts risk in a nonlinear fashion; thus, increases in cardiovascular risk are extremely small until Lp(a) levels are within the top 5-10%.[3, 4]

Specimen: Blood

Collection method: Routine venipuncture

Container: Varies widely by reference laboratory and type of assay

Lipoprotein(a) is collected as part of various panels constituting what is known as "advanced lipid testing." These panels are offered by various commercial entities and include those which offer LDL particle testing.

Description

Lipoprotein (a) (Lp[a]) contains the LDL apolipoprotein B-100 (apo B100), which is covalently linked via a disulfide bridge to an apolipoprotein (a) molecule (which is highly homologous to plasminogen).[3, 5] See image below.

Schematic diagram of lipoprotein(a).

As a result of the fact that the apo(a) component of Lp(a) is a complex molecule with great heterogeneity, plasma Lp(a) concentrations are inversely dependent on apo(a) size. Perhaps unsurprisingly, given this level of complexity, more than 25 genetic forms of Lp(a) are known to exist; thus, the importance of the genome in determining plasma levels cannot be overstated. This, in turn, has implications for cardiovascular risk prediction across different populations.[3]

Indications/applications

In the Copenhagen Heart study, Kamstrup et al found that genetic elevations of Lp(a) were associated with an increased risk of myocardial infarction.[6] Furthermore, several prospective epidemiological studies have indicated a causal role for Lp(a) in cardiovascular disease; thus, measurement of Lp(a) may be used as a determinant of cardiovascular risk within the context of a global cardiovascular risk assessment.

A study by Muramatsu et al indicated that in individuals with coronary artery disease, those carrying high levels of Lp(a) have a greater prevalence of the form of vulnerable plaque known as thin-cap fibroatheroma (TCFA). The investigators found that TCFA occurred in 23% of patients with an Lp(a) level of 25 mg/dL or higher, compared with 11% of patients with an Lp(a) level below 25 mg/dL.[7]

A retrospective study by Littmann et al found that among individuals whose Lp(a) levels were assessed during routine clinical care, hazard ratios for those whose levels were above the 90th decile (>90 mg/dL) were 1.25 for major adverse cardiovascular events, 1.37 for atherosclerotic cardiovascular disease, and 1.62 for coronary artery disease, when compared with persons at or below the 50th decile. According to the investigators, this supports the 2019 recommendation by the European Society of Cardiology/European Atherosclerosis Society that Lp(a) be measured at least once during a patient’s lifetime to evaluate cardiovascular risk and suggests that intensive preventive therapy is needed in patients with high Lp(a) concentrations. The study did not find Lp(a) levels to be related to mortality, peripheral artery disease, or ischemic stroke.[8]

In contrast, Langsted et al, using data from the Copenhagen General Population Study and the Copenhagen City Heart Study, found evidence that elevated Lp(a) plasma levels can be linked to increased ischemic stroke risk. The investigators reported that persons with Lp(a) levels above 93 mg/dL had a multivariable-adjusted hazard ratio for ischemic stroke of 1.60, when compared with subjects whose Lp(a) levels were below 10 mg/dL.[9]

Lp(a) is not recommended to be used alone as a sole test for determining cardiovascular risk, but rather as an additional measure to be combined with assessment of traditional cardiovascular risk factors. The measurement of Lp(a) may be most useful in intermediate-risk patients or in those in whom the test result would affect treatment or the aggressiveness of treatment of known cardiovascular risk factors.

As noted by Ridker and Libby, it is uncertain whether the assessment of Lp(a) truly adds prognostic information to overall risk in primary prevention; however, in most studies, Lp(a) has predictive value for those already known to be at high risk because of the presence of other risk factors, in particular elevated LDL-C levels.[3]

Considerations

The standardization of commercial assays for Lp(a) has been problematic owing to dependence on apo(a) size; however, commercial assays that can measure Lp(a) independently and separate from apo(a) size are available now in numerous reference laboratories.[3, 10]

Several prospective studies have shown that Lp(a) predicts cardiovascular risk in a nonlinear fashion, such that the increase in risk is quite small until the highest levels (top 5-10%) of Lp(a) are reached.[3, 4]

Data regarding the use of Lp(a) as a biomarker in certain high-risk groups, such as those with chronic kidney disease or known coronary artery disease, remain controversial.[3]

The observation that extremely high levels of Lp(a) seem to be almost entirely limited to patients with concomitantly high levels of LDL cholesterol brings into question the use of Lp(a) as an independent marker of increased cardiovascular risk and highlights the limitations presented by interactions with LDL cholesterol.[3]

Few interventions have been found to lower Lp(a) levels, with the exception of high-dose niacin. Therapy specifically targeted at modifying Lp(a) also remains controversial.[3, 2, 11, 12]

There are emerging data on the use of apheresis as an effective method to lower Lp(a). No drugs are approved for this, but recent trials have shown that Lp(a) can be substantially lowered with a decrease in other apolioprotein B-100(apoB).[13]