Lipoprotein(a) (Lp[a]) can improve the accuracy of assessment of atherosclerotic cardiovascular disease and the risk of aortic valve stenosis. Currently, there is no specific treatment to lower its circulating concentration. Raised Lp(a) is a feature of familial hypercholesterolaemia. Management of high levels encourages rigorous attention to correction of other risk factors, such as blood pressure, smoking and low-density lipoprotein (LDL).
Introduction
Lipoprotein(a) (Lp[a]) was discovered in 1963 as an antigen causing rare blood transfusion reactions.1 The antigen was found to be present in the lipoprotein fraction of plasma, hence the name lipoprotein(antigen). As methods for its measurement improved, researchers realised that Lp(a) had a continuous population frequency distribution, which in people of European descent, was markedly positively skewed.2,3 It was also reported that in those with higher concentrations, the prevalence of coronary heart disease was increased. Furthermore, higher levels were inherited; the concentration of Lp(a) was twice as much in men who had experienced acute myocardial infarction (AMI) before the age of 60 years compared with a control population of factory workers with no previous history of cardiac ischaemia.4 Lp(a) accounted for much of the risk associated with a parental history of early-onset ischaemic heart disease in this and larger later investigations.5,6 It has been repeatedly confirmed in epidemiological and Mendelian randomisation studies that Lp(a) is a risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.2–8
Despite being studied for the past 60 years and being measured in many countries as part of ASCVD risk assessment, Lp(a) has aroused little clinical interest in Britain.9
Lipoprotein(a) structure
A breakthrough in our understanding of Lp(a) occurred in 1987 when a genetics group from San Francisco collaborated with researchers in Chicago who had located Lp(a) in the lipoproteins with a hydrated density at the denser end of the low-density lipoprotein (LDL) spectrum and the least dense part of high-density lipoprotein (HDL).10 Lp(a) was found to have a composition similar to LDL but in addition to containing one molecule of apolipoprotein B (apoB) per particle, there was another large protein termed apolipoprotein (a) (apo[a]). Study of a human hepatic cDNA library allowed the amino acid sequence and predicted structure of apo(a) to be determined11; this and subsequent work2,3 revealed that apo(a) was a member of the plasminogen family of molecules with a protease domain and a long chain of coiled, pretzel-like structures called kringles (figure 1). It is located on the outside of an LDL-like particle, disulphide-linked to its apoB, which winds in and out of the lipid micelle. The hydrolytic site of its protease domain is blocked – the obvious speculation is that it interferes with the activity of plasminogen, promoting thrombogenesis. The length of the kringle chain is highly variable according to the frequency with which kringle IV-2 has been repeated, which can range from 1 to more than 40 times. This gives apo(a) a molecular mass which can range from 200–700 kDa. The lower molecular mass isoforms are synthesised more rapidly by the liver and give rise to higher plasma concentrations of Lp(a). Unlike LDL, Lp(a) has no very low-density lipoprotein (VLDL) precursor. The mass of the whole Lp(a) particle when apo(a) has a molecular mass around 300–400 kDa is roughly 4000 kDa but is variable according to the lipid burden and the apo(a) isoform present. Much of the lipid present is phospholipid and this frequently undergoes peroxidation.12
![Durrington - Figure 1. Structure of the lipoprotein(a) particle. As a member of the plasminogen gene family, apolipoprotein(a) (apo[a]) comprises a protease-like domain (P) and a long chain of kringles (designated KIV and KV) in each of which its amino acid sequence adopts a pretzel-shaped conformation. Apo(a) is a disulphide linked to apolipoprotein B, which is the principal protein moiety of low-density lipoprotein and the ligand which, when fragmented by, for example, oxidation or glycation, permits cholesterol to enter arterial wall macrophages leading to atheroma formation. There is an allelic polymorphism of the number of KIV-2 in apo(a)](https://bjcardio.co.uk/wp-content/uploads/2024/07/Durrington-Figure-1.png)
| Key: ApoB = apolipoprotein B; KIV = kringle IV; KV = kringle V |
Lipoprotein(a) measurement
There has been much controversy regarding assay methods and units of measurement in Lp(a) assessment. Assays measure immunoreactivity, which can only be translated directly into concentration when molecules share a similar immunoreactivity; this is not the case for apo(a). The most antigenic site for polygenic antibodies raised against apo(a), which do not cross-react with other proteins like plasminogen, is the kringle sequence, particularly the kringle IV-2 repeats. This means that low molecular mass isoforms will be less immunoreactive than higher molecular mass ones. Thus, an assay standardised against typical apo(a) with a molecular mass of ~300–400 kDa will tend to underestimate high Lp(a) concentrations and overestimate lower values. One solution is to develop assays which are insensitive to Lp(a) isoforms; so far, this has only been possible in a research laboratory using a kringle 9-specific monoclonal antibody.13 Another potential solution is to calibrate the assay against apo(a) isoforms likely to be present at the concentration of Lp(a) relevant to a clinical decision.14 Thus, if the assay is to be used to screen for increased ASCVD risk, then levels of 30–40 mg/dL have frequently been used (around the 75th percentile). On the other hand, a different standard curve against lower molecular mass apo(a) isoforms would be better for determining particularly high levels, say, 90 mg/dL.
Regarding the units in which Lp(a) should be measured, most reports currently use mg/dL, where mg refers to the mass of the whole Lp(a) particle, not just its apo(a) component. It has been advocated that nmol/L should be the units of choice.13 However, as has been explained, antibody/Lp(a) complex formation will vary not simply with the Lp(a) concentration but also with the apo(a) molecular isoform present. Until an isoform-insensitive assay is generally available, nmol/L is illusory. Furthermore, there can be no universal conversion factor for mg/dL to nmol/L. A conversion factor of 2.4 is commonly used,15 based on an average molecular mass a little over 4,000 kDa. However, if a high level is to be converted, the molecular mass is likely to be lower and the conversion factor thus lower than 2.4. One way to overcome this is to use population percentiles, rather than absolute levels, to inform clinical decisions and determine the overall cost of treatment in the target population.
Atherogenicity of lipoprotein(a)
Table 1. Potential mechanisms by which lipoprotein(a) may promote atherosclerotic cardiovascular disease2,3,12,16
| LDL-like protein rich in cholesterol |
| Not cleared by physiological LDL receptor, prolonging its time in circulation |
| Retention within arterial sub-intima greater than that of LDL due to presence of apo(a) |
| Circulating repository of oxidised phospholipids, which can cause fragmentation of its other protein moiety (apoB) and uptake by arterial wall macrophage receptors |
| Association with inflammatory markers |
| Pro-thrombotic (homology with plasminogen but no proteolytic activity) |
| Key: apoB = apolipoprotein B; LDL = low-density lipoprotein |
Most of the variation in Lp(a) is accounted for by differences in its production rate with higher plasma concentrations occurring in people inheriting the lower molecular mass apo(a) variants. This has made it difficult to decide whether the atherogenicity of Lp(a) is determined by its concentration or by lower molecular mass isoforms. Current thinking trends are that Lp(a) concentration is pre-eminent. Concentration is easier to measure than the size of the apo(a) alleles present. Table 1 summarises the possible reasons why Lp(a) may cause atherothrombosis.
Factors contributing to variation in circulating lipoprotein(a) concentrations
Although the rate of production determined by the molecular mass polymorphism is the main determinant of Lp(a) concentrations in the population as a whole, other factors can play out against this background (table 2).2,3,16–18
Table 2. Factors which influence the circulating lipoprotein(a) concentrations2,3,16–18
| Primary | Secondary |
| 1. Molecular mass polymorphism; plasma concentration inversely proportional to length of KIV2 sequence. Inherited co-dominantly explaining the influence of parental history of ASCVD | 1. Increased in chronic renal disease; reversible in successful renal transplantation and upon resolution of minimal change nephropathy |
| 2. Ethnicity (higher in people of African and Asian descent) | |
| 3. Lower in type 2 diabetes and metabolic syndrome | |
| 4. Increases with bariatric surgery | |
| 5. Slight increase with statins (contentious) | |
| 6. Decreases with PCSK9 inhibitors, nicotinic acid and oestrogen replacement | |
| 7. Decreases in liver disease | |
| 8. Increased in familial hypercholesterolaemia | |
| 9. Influenced by APOE genotype (APOE4>APOE3>APOE4) | |
| Key: APOE = apolipoprotein E; ASCVD = atherosclerotic cardiovascular disease; KIV2 = kringle IV type 2; PCSK9 = proprotein convertase subtilisin/kexin type 9 | |
Lipoprotein(a) in familial hypercholesterolaemia
Familial hypercholesterolaemia (FH) in its heterozygous form affects 1 in 250 to 500 people. Typically in adults, it leads to LDL cholesterol >5 mmol/L and the development of tendon xanthomata on the dorsum of the hands and the Achilles tendons, often preceded by Achilles tenosynovitis.19 If left untreated, ASCVD occurs in the majority of affected men and at least a quarter of women before the age of 60 years, as a result of defective LDL catabolism. This is most frequently due to either a loss of function mutations of the LDL receptor, but occasionally to mutation of apolipoproteinB (apoB), which decreases LDL receptor binding; or to a gain of function mutations of proprotein convertase subtilisin/kexin type 9 (PCSK9), which increase hepatic LDL receptor degradation.
A consortium from Innsbruck and London was the first to report that Lp(a) was increased in heterozygous FH (HeFH),20 which we confirmed, and by studying unaffected first-degree relatives of people with HeFH, found that the inheritance of FH approximately doubled the Lp(a) level.21 We also found that the more common polygenic hypercholesterolaemia did not itself increase Lp(a) concentrations. Lp(a), like LDL cholesterol, is raised in childhood FH.22 Disagreement reverberates to this day about whether the increase in FH was simply because it was more likely to present clinically with ASCVD when Lp(a) was raised due to the coincidental inheritance of lower molecular mass apo(a), or whether it is a consequence of the inherited LDL catabolic defect.23 The former opinion is supported by evidence that Lp(a) catabolism, which is not mediated by LDL receptors, is unimpaired by inheritance of FH and the raised Lp(a) is due to increased production.24 Nonetheless, that FH-causing mutations directly increase Lp(a) was powerfully reinforced when the Innsbruck group collaborated with a group in Johannesburg (FH is frequent in South Africa due to founder gene effects) and showed that the higher Lp(a) in HeFH and homozygous FH was increased independent of the apo(a) molecular polymorphism.25
From a clinical standpoint, raised Lp(a) should be regarded as a component of the FH syndrome.26 A particularly high Lp(a), even in the absence of identification of an FH-causing mutation, can represent a substantially increased ASCVD risk.27 From a research perspective, there appears to be a link between hepatic LDL receptor-mediated catabolism and Lp(a) production.28 This link may involve PCSK9.29 Furthermore in FH, a proportion of LDL is released from the liver, like Lp(a), without a VLDL precursor.30
Many people have written about the perfect storm for ASCVD risk of having both a raised LDL and Lp(a) in FH.28 It appears obvious, but does Lp(a) really increase the already considerably raised likelihood of ASCVD events in FH? Early reports that this was the case may have been due to the admixture of polygenic hypercholesterolaemia with its lower ASCVD risk and lower Lp(a) levels in the population considered by the investigators to have HeFH.30 Using strict clinical criteria for the diagnosis of HeFH, we were not able to find any increase in the prevalence of ASCVD in those whose Lp(a) >30 mg/dL.31 In HeFH defined by DNA analysis, it was, however, reported from Norway that there was an increased prevalence of ASCVD when Lp(a) >90 mg/dL.32
Clinical management of high lipoprotein(a) concentrations
Before discussing the clinical management of elevated Lp(a) concentrations, one must consider how people with high levels are identified. Some authorities recommend that everyone should have Lp(a) measured at least once.9,14,33 At present, few, if any, healthcare providers fund this proposal. It could, for example, be argued that funding might be better provided for detecting and treating metabolic syndrome and type 2 diabetes, which appear to be the major cause for the resurgence of ASCVD in many populations. However, it seems reasonable to argue for Lp(a) measurement in the following scenarios:
- Someone suspected of having HeFH. A high level of both LDL cholesterol and Lp(a) greatly increase the likelihood that the patient has FH and genetic testing and cascade family screening may be appropriate
- When a particularly high Lp(a) is coincidentally inherited with raised LDL cholesterol from any cause. Assiduous management of mutable ASCVD risk factors should be instituted
- In families where precocious ASCVD is evident, but with no obvious risk factors, neglecting Lp(a) might result in a marked underestimation of risk (risk calculator, from the European Atherosclerosis Society, can be found at http://www.lpaclinicalguidance.com). With co-dominant transmission of genetic variants causing high Lp(a) concentration, family screening can help to detect other first-degree relatives at high risk
- In cases of calcific aortic valve stenosis34
- When ASCVD risk is deemed borderline for the introduction of cholesterol-lowering medication.
Of these, the last is the most contentious, particularly if cost is borne not individually, but by a socialised healthcare system. Although logical, it could involve large numbers. This is not to say that testing should not be done in these cases: what is likely more important may be the patient’s attitude to medicalisation and recognition that any decision is not absolute and risk estimation can be repeated with advancing age.
The treatment path will be influenced by the Lp(a) level. For many years, values in excess of 30–40 mg/dL have been considered a definite risk factor. This is around the 75th percentile for populations of European descent. It has been suggested that similar values should be regarded as clinically relevant, regardless of ethnicity. Lp(a) concentrations >90 mg/dL (around the 95th percentile) have been regarded as conferring ASCVD risk broadly equivalent to inheritance of HeFH, even when that diagnosis has not been confirmed by genetic testing.27 Such high levels demand even more assiduous attention to optimising other risk factors. Where else can the clinician turn? Various medications have been explored for Lp(a) reduction, but are either unlicensed for this purpose or not recommended by current NICE guidance. Nicotinic acid lowers Lp(a),35 but is poorly tolerated and lacks clinical trial evidence of efficacy.36 Oestrogen replacement decreases Lp(a) and may be associated with a decrease in ASCVD events in women with higher Lp(a) unselected for high ASCVD risk,37 but then few would advocate oestrogen for those at higher ASCVD risk. Aspirin may lower Lp(a) and decrease its thrombogenicity, but evidence is not yet convincing in primary prevention38 and presumably, aspirin is prescribed in secondary prevention anyway. Renal transplantation will lower Lp(a) and it decreases on resolution of minimal change glomerulopathy.17,18 Conversely, bariatric surgery may raise Lp(a) slightly39 but as it improves insulin resistance, and lipoprotein and inflammatory markers of atherosclerosis, this is likely to be of little importance.16
Statins do not lower Lp(a) and may even raise it slightly.40 However, statins are the most effective medical treatment for prevention of new or recurrent ASCVD events: for every 1 mmol/L decrease in LDL cholesterol, there is a 22% decrease in ASCVD incidence. For example, reducing LDL cholesterol by 3 mmol/L in someone whose ASCVD risk is 30 per 100 over the next 10 years will typically decrease risk to 30 x 0.783 = 14 events.41 Yet, there is still a residual risk; in this case, 16 ASCVD events per 100 over the next 10 years. Adjunctive lipid-lowering drugs intended to reduce this residual risk when given against a background of effective statin therapy fall into two categories: those that have failed or had limited success, like CETP (cholesterylester transfer protein) inhibitors, which raise HDL,42 and fibrates which decrease VLDL and chylomicron remnants43; and those which are successful, like ezetimibe44 and PCSK9 inhibitors.45 PCSK9 inhibitors are not licensed for Lp(a) reduction; however, in the FOURIER trial, a large secondary prevention trial of evolocumab versus placebo in participants receiving statin and statin/ezetimibe combined lasting 2.2 years, there was a median 26.9% decrease in Lp(a) concentration in the treatment group compared to placebo.45 In participants with Lp(a) concentrations above the median value of 37 nmol/L (15 mg/dL), ASCVD events were decreased by 23% (number needed to treat [NNT]=40) whilst in those with lower levels, the decrease was only 7% (NNT=105). Thus, high Lp(a) may support a clinical decision to initiate PCSK9 inhibitors in patients who are considered borderline for their introduction, despite not being licensed specifically for this purpose. The same could also be true for LDL apheresis. Lp(a) is decreased by LDL apheresis and there are apheresis systems specifically designed to lower Lp(a); these are however not yet widely available outside of specialist tertiary centres.46
Results of clinical trials of specific therapies to reduce Lp(a) are in progress. These will report not only on benefit but also on potential ill effects. Low Lp(a) concentrations increase the likelihood of developing type 2 diabetes.9,33,47 There is also the possibility that lowering Lp(a) levels could impede blood clotting. Whilst studies have shown no significant impact of Lp(a) level on outcomes following treatment of acute coronary insufficiency using streptokinase,48 there may be a higher incidence of cerebral haemorrhage when Lp(a) concentrations are low.49
Case study
The referral letter to the lipid clinic reads as follows:
‘Please see this 35-year-old man who has been told by his sister living in Germany that he should have lipoprotein(a) measured. She also assumes he will have had his cholesterol measured, but according to local guidelines, he is not due to have his cholesterol measured until he reaches 40 and we suspended this anyway during COVID. Furthermore, Lp(a) is not listed amongst the NHS tests we can order and our local cardiologist says that, although it can be done privately, he would not know what should be done about a raised level.’
At the clinic, the patient described himself as a healthy, non-smoker who runs 5 miles once a week. He had a BMI of 28.4 kg/m2 and a blood pressure of 134/76 mmHg. He has had difficulty finding running shoes that do not give him painful ankles. His 45-year-old sister has recently undergone coronary angioplasty. His father died suddenly at the age of 43 years.
Examination revealed early corneal arcus (top and bottom, not yet concentric) and some nodularity of the Achilles tendons. Urinalysis revealed no abnormalities and a resting electrocardiogram (ECG) was normal. Laboratory findings (including creatinine, thyroid and liver functions, and HbA1C) were unremarkable, except for his cholesterol levels, which were as follows:
- total cholesterol: 10.7 mmol/L
- triglyceride: 1.6 mmol/L
- HDL cholesterol: 1.4 mmol/L
- LDL cholesterol: 8.6 mmol/L
- non-HDL cholesterol: 9.3 mmol/L.
Lp(a) testing was available in the lipid clinic, and the result was 79 mg/dL (198 nmol/L). The patient was prescribed rosuvastatin 40 mg daily and ezetimibe 10 mg daily. On follow-up two months later, the LDL cholesterol had decreased to 3.6 mmol/L but Lp(a) was 83 mg/dL.
An exercise ECG was requested, along with genotype studies to assess for FH. The results of these are currently awaited. Should the genotype study confirm the presence of FH, cascade screening will be organised for the patient’s family members. Currently, NICE recommends PCSK9 inhibitor treatment in FH without evidence of ASCVD when LDL cholesterol is >5 mmol/L, or if >3.5 mmol/L with evidence of ASCVD.50,51
If FH is not confirmed, we would nonetheless recommend to the patient that his first-degree relatives attend our clinic for measurement of their cholesterol and Lp(a) levels.
Conclusion
Lp(a) is now well established as a risk factor for ASCVD. However, questions remain regarding how identification, measurement and management of elevated Lp(a) can best be conducted in clinical practice.
Key messages
- Lipoprotein(a) (Lp[a]) is a risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis
- Lp(a) is increased by inheritance of familial hypercholesterolaemia
- Currently, there are no drugs specifically indicated for reduction of elevated Lp(a), and thus the finding of a high level demands assiduous attention to other risk factors
Conflicts of interest
None declared.
Funding
PD has received an honorarium for writing this article.
Paul Durrington
Professor of Medicine
University of Manchester
([email protected])
Articles in this supplement
Introduction
Lipoprotein(a) measurement – how, why and in whom?
Clinical utility of lipoprotein(a): an interventionist’s perspective
Raised lipoprotein(a): real-world examples of communication and clinical management
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