Lp(a) Test: The Overlooked Cardiovascular Risk Factor
Lipoprotein(a), commonly abbreviated as Lp(a), represents one of the most significant yet under-tested independent risk factors for atherosclerotic cardiovascular disease.
For individuals seeking a comprehensive longevity risk assessment, an Lp(a) test in New Zealand provides critical information that standard lipid panels do not capture — a single, largely genetically determined measurement that may fundamentally alter how cardiovascular risk is understood and managed.
What is Lp(a)?
Lipoprotein(a) is a lipoprotein particle structurally similar to low-density lipoprotein (LDL) but distinguished by the covalent attachment of apolipoprotein(a), or apo(a), to apolipoprotein B-100 via a disulphide bond. The apo(a) protein is encoded by the LPA gene on chromosome 6q25-26 and exhibits remarkable size heterogeneity due to a variable number of kringle IV type 2 (KIV-2) repeats — a copy number variation that is the primary genetic determinant of circulating Lp(a) concentrations (Kronenberg & Utermann, 2013).
Plasma Lp(a) concentrations are approximately 70–90% genetically determined, with an inverse relationship between apo(a) isoform size and Lp(a) concentration: smaller isoforms are associated with higher plasma levels. Unlike most other lipoproteins, Lp(a) levels are minimally influenced by diet, exercise, or conventional lipid-lowering therapies. Concentrations are established early in life, remain relatively stable throughout adulthood, and vary substantially across populations. Individuals of African ancestry tend to have higher median Lp(a) concentrations compared to those of European or East Asian ancestry, though the clinical significance of this variation across ethnic groups remains an area of active investigation (Tsimikas et al., 2018).
In the New Zealand context, Lp(a) is not routinely included in standard lipid panels, meaning many individuals with significantly elevated levels remain unidentified despite carrying a substantially increased cardiovascular risk burden.
How it works
The pathogenicity of Lp(a) operates through at least three distinct but interrelated mechanisms, which collectively explain its association with both atherosclerotic disease and calcific aortic valve stenosis.
Atherogenic mechanism:
Like LDL, Lp(a) contains a single apolipoprotein B-100 molecule and carries cholesterol into the arterial wall. However, Lp(a) demonstrates preferential retention in the subendothelial space due to its additional binding interactions. The apo(a) component binds to extracellular matrix proteins, including fibronectin and laminin, enhancing arterial wall retention beyond that of native LDL particles (Boffa & Koschinsky, 2019). Once retained, Lp(a) delivers its cholesterol payload and contributes to foam cell formation and plaque development.
Pro-inflammatory mechanism:
Lp(a) is the primary carrier of oxidised phospholipids (OxPL) in human plasma. These oxidised phospholipids activate inflammatory pathways, including monocyte chemotaxis and endothelial cell activation, amplifying the inflammatory cascade within the arterial wall. The OxPL-Lp(a) axis has been identified as a key mediator linking elevated Lp(a) to accelerated atherogenesis (Tsimikas et al., 2005).
Anti-fibrinolytic and prothrombotic mechanism:
The apo(a) protein shares striking structural homology with plasminogen, the zymogen precursor to plasmin — the enzyme responsible for fibrinolysis. Apo(a) competes with plasminogen for binding sites on fibrin and cellular receptors but lacks enzymatic activity, effectively inhibiting endogenous fibrinolysis. This prothrombotic property distinguishes Lp(a) fundamentally from LDL and may contribute to acute thrombotic events superimposed on existing atherosclerotic lesions (Nordestgaard et al., 2010).
Aortic valve calcification:
Lp(a) and its associated OxPL promote the osteogenic differentiation of valvular interstitial cells through autotaxin-mediated lysophosphatidic acid production, contributing to progressive calcific aortic valve disease — a mechanism distinct from its arterial effects (Thanassoulis et al., 2013).
These layered mechanisms — atherogenic, inflammatory, prothrombotic, and pro-calcific — explain why Lp(a) is classified as an independent cardiovascular risk factor, operating through pathways that overlap with but extend substantially beyond those of conventional LDL cholesterol.
The evidence
The association between elevated Lp(a) and cardiovascular disease is supported by a convergence of epidemiological, genetic, and Mendelian randomisation data that has strengthened considerably over the past two decades.
Epidemiological evidence:
The Copenhagen City Heart Study, following over 9,000 individuals, demonstrated that Lp(a) concentrations above the 95th percentile (approximately >150 nmol/L or >60 mg/dL) were associated with a 2.6-fold increased risk of myocardial infarction and a 2.2-fold increased risk of ischaemic stroke compared with levels below the 22nd percentile (Kamstrup et al., 2009). A subsequent meta-analysis of 36 prospective studies involving over 126,000 participants confirmed a continuous, log-linear association between Lp(a) concentration and coronary heart disease risk (Erqou et al., 2009).
Mendelian randomisation evidence:
Because Lp(a) levels are predominantly genetically determined,LPAgene variants serve as natural instruments for Mendelian randomisation analyses. These studies have consistently demonstrated a causal relationship between genetically elevated Lp(a) and coronary artery disease, peripheral arterial disease, ischaemic stroke, heart failure, and calcific aortic valve stenosis (Burgess et al., 2018; Arsenault et al., 2020). This genetic evidence is particularly compelling because it is less susceptible to confounding and reverse causation than observational data.
Aortic valve disease:
A genome-wide association study identifiedLPAvariants as the strongest common genetic risk factor for aortic valve calcification and clinical aortic stenosis, with elevated Lp(a) conferring a 1.5- to 2-fold increased risk (Thanassoulis et al., 2013). This finding has been replicated across multiple cohorts and represents a unique pathological role not shared by LDL cholesterol.
Interaction with other risk factors:
Elevated Lp(a) appears to act synergistically with other established cardiovascular risk factors. Individuals with both elevated Lp(a) and elevated LDL-C carry disproportionately higher risk than would be predicted by either factor alone (Tsimikas et al., 2018). This multiplicative risk interaction underscores the importance of comprehensive lipid assessment.
Importantly, the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines now recommend that Lp(a) be measured at least once in every adult's lifetime to identify those with very high inherited levels (Mach et al., 2020). The 2022 Canadian Cardiovascular Society guidelines echo this recommendation. In New Zealand, BPAC NZ has acknowledged the role of Lp(a) in cardiovascular risk assessment, though routine population-based screening has not yet been formally incorporated into standard clinical practice guidelines.
Who may benefit
Testing for Lp(a) may be appropriate for a broad range of individuals, given that approximately 20% of the global population has Lp(a) levels above the threshold associated with meaningfully increased cardiovascular risk.
Individuals who may particularly benefit from Lp(a) measurement include those with a personal history of premature atherosclerotic cardiovascular disease (defined as events occurring before age 55 in males or 65 in females), a family history of premature cardiovascular disease or sudden cardiac death, familial hypercholesterolaemia, recurrent cardiovascular events despite optimal statin therapy, progressive calcific aortic valve stenosis without traditional risk factors, or a family history of elevated Lp(a).
Because Lp(a) levels are genetically determined and remain stable over a lifetime, a single measurement is generally sufficient for risk stratification — making it an efficient and cost-effective addition to a comprehensive cardiovascular risk profile. The stability of Lp(a) also means that cascade testing of first-degree relatives of affected individuals may identify additional at-risk family members.
For individuals pursuing a proactive approach to longevity medicine, Lp(a) testing fills a critical gap in standard cardiovascular risk assessment tools. Standard New Zealand cardiovascular risk calculators, including those based on the Framingham and PREDICT equations, do not incorporate Lp(a), meaning individuals with significantly elevated levels may be misclassified into lower risk categories than their true risk warrants.
What to expect
An Lp(a) test requires a blood sample collection. No fasting is required, as Lp(a) concentrations are not significantly affected by recent food intake.
Results are reported in either nmol/L (the preferred unit, as it measures particle number independent of isoform size) or mg/dL. The two units are not directly interconvertible due to the variable molecular weight of apo(a) isoforms, though an approximate conversion factor of 2.4 (nmol/L ≈ mg/dL × 2.4) is sometimes applied. International consensus increasingly favours nmol/L reporting to avoid the inaccuracy inherent in mass-based assays across different isoform sizes.
General thresholds used in clinical practice and guidelines are:
Desirable: below 75 nmol/L (approximately <30 mg/dL)
Elevated: 75–125 nmol/L (approximately 30–50 mg/dL)
High: above 125 nmol/L (approximately >50 mg/dL)
Very high: above 180 nmol/L (approximately >75 mg/dL)
In New Zealand, Lp(a) testing is available through community laboratories, though it is not typically included in routine lipid panels and may not always be funded. Lp(a) is included as part of the comprehensive blood panel in Longevity Club. Turnaround time is generally within several working days, depending on the laboratory.
Because a single measurement provides a lifetime risk indicator, repeat testing is usually unnecessary unless there is clinical suspicion of a secondary cause affecting Lp(a) levels, such as renal disease or significant hepatic dysfunction.
Considerations and safety
There are no contraindications to Lp(a) testing itself, as it involves only a standard blood draw. However, the clinical interpretation and management implications of elevated Lp(a) require careful consideration.
Current therapeutic limitations:
No pharmacological therapy is currently approved specifically for lowering Lp(a). Statins do not reduce Lp(a) — some evidence suggests they may modestly increase levels, though this does not negate their overall cardiovascular benefit. Niacin reduces Lp(a) by approximately 20–30%, but the AIM-HIGH and HPS2-THRIVE trials failed to demonstrate cardiovascular outcome benefit from niacin added to statin therapy (AIM-HIGH Investigators, 2011; HPS2-THRIVE Collaborative Group, 2014). PCSK9 inhibitors (evolocumab and alirocumab) reduce Lp(a) by approximately 20–30%, with post-hoc analyses of the FOURIER trial suggesting that the Lp(a) reduction may contribute independently to cardiovascular risk reduction (O'Donoghue et al., 2019). Medsafe NZ has approved PCSK9 inhibitors for specific lipid-lowering indications, though not specifically for Lp(a) reduction.
Emerging therapies:
The most promising therapeutic development is antisense oligonucleotide (ASO) therapy targeting hepaticLPAmRNA. Pelacarsen, an antisense oligonucleotide directed against apo(a), has demonstrated Lp(a) reductions exceeding 80% in phase II trials (Tsimikas et al., 2020). The phase III HORIZON trial (NCT04023552) is currently evaluating whether this reduction translates into cardiovascular outcome benefit, with results anticipated in the coming years. Small interfering RNA (siRNA) approaches, including olpasiran and lepodisiran, have shown similarly dramatic Lp(a) reductions in early-phase trials (O'Donoghue et al., 2022).
Risk management in the interim:
Until specific Lp(a)-lowering therapies with proven outcome benefit become available, the clinical response to elevated Lp(a) centres on aggressive management of all modifiable cardiovascular risk factors — particularly LDL-C reduction to lower thresholds than might otherwise be targeted, blood pressure optimisation, glycaemic control, smoking cessation, and consideration of antiplatelet or anticoagulant therapy where clinically indicated. Knowledge of elevated Lp(a) may reclassify an individual's risk category upward, justifying more intensive preventive strategies.
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REFERENCES
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O'Donoghue ML, Rosenson RS, Ganda OP, et al. Zerlasiran (olpasiran) for lowering lipoprotein(a). N Engl J Med. 2022;387(3):235-245. [citation needed — verify exact PMID and author list].
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This article is intended for educational purposes only and does not constitute medical advice. Individual health needs vary. All Drips services are delivered by registered health professionals and are preceded by a clinical assessment to determine suitability. Our services are not intended to replace emergency, acute or ongoing primary medical care.
Learn more about blood testing at drips.nz/blood-test or Longevity Club membership offerings.
