Academy of Diagnostics & Laboratory Medicine - Scientific Short

Lipoprotein (a) - Do moles even matter?

Alexander Fohl, PharmD

Despite advances in technology, diagnostics and treatment, atherosclerotic cardiovascular disease (ASCVD) continues to be the leading cause of morbidity and mortality worldwide and in the United States.1 Although improvements in age‐adjusted mortality from cardiovascular disease have been observed from 2000 to 2019, the rate of improvement declined from 3.7% per year between 2000 to 2011 to 0.7% during 2011 to 2019.2 This trend signals the need to identify and address the underlying causes related to the slowed improvement. Lipoprotein (a) (Lp(a)) is emerging as an important, yet under-utilized, potential risk factor for cardiovascular disease and may be one underlying risk factor which can help identify people before an event occurs.

Globally, as many as one in five people has elevated Lp(a).3 Lp(a) has been shown to promote plaque development within artery walls, clot formation and aortic valve calcification, which have all been associated with an increased risk of cardiovascular (CV) events.4 Unfortunately, lifestyle interventions such as diet and exercise appear to have no significant impact on Lp(a) concentrations and more than 90% of the Lp(a) concentration is influenced by variations in the genes controlling the Lp(a) particle production.4 Despite the influence genetics have on Lp(a) concentrations, Lp(a) levels can be influenced by non-genetic factors causing the concentration to decrease in conditions including kidney and liver diseases, and hyperthyroidism and conversely causing the concentration to increase in women following menopause.5 The prevalence of elevated Lp(a) concentrations is particularly prevalent among people of African American decent; while people of east asian decent tend to have lower Lp(a) concentrations.6

Since its discovery in 1963 by a Norwegian geneticist named Kare Berg, Lp(a) has been known to vary widely between people and has been linked to coronary heart disease dating back to 1974.7 Additionally, the National Lipid Association (NLA) favors Lp(a) measurements in molar units rather than mass units to reduce isoform sensitivity given the difference in the sizes of Lp(a) particles found in the population.

Due to genetic variability and post-translational modifications, Lp(a) can vary in size and has no single, defined molecular weight. For this reason, there is a consensus in the scientific community that Lp(a) levels should be measured in terms of the number of particles per liter of blood (nmol/L), rather than mass units (mg/dL), and that any conversion between mass and molar units is generally imprecise and unreliable. By using molar units, laboratory professionals and clinicians know the Lp(a) measurements reflect the number of particles, and the reported value is less sensitive to any difference in the size of the particles. The measurement of Lp(a) is useful in evaluating lipid metabolism disorders and assessing atherosclerotic cardiovascular disease (ASCVD) risk when used in conjunction with clinical evaluation and other lipoprotein tests.1,8,9

Although the current treatment options for individuals with elevated Lp(a) values are limited to reducing traditional ASCVD risk factors including managing hypertension, weight, sleep quality, tobacco use, dietary choices, hypercholesterolemia, diabetes and physical fitness, there are therapeutic options in development specifically targeting Lp(a) particles in the body. Standardizing Lp(a) testing to molar measurements will help to reduce confounders in these upcoming pharmacotherapeutic studies and ASCVD risk assessments. Lp(a) testing is therefore expected to become a part of regular diagnostic testing in the coming years, enabling clinicians to make a more accurate assessment of ASCVD risk and further reduce potential underlying causes of atherosclerotic cardiovascular disease.

References

  1. Arnett DK et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Sep 10;140(11):e563-e595. doi: 10.1161/CIR.0000000000000677.
  2. Sawyer A and Flagg LA. State declines in heart disease mortality in the United States, 2000–2019. NCHS Data Briefs. 2021; December. https://stacks.cdc.gov/view/cdc/112339 [accessed 2/21/2025].
  3. Tsimikas S and Marcovina S, Ancestry, Lipoprotein(a), and Cardiovascular Risk Thresholds: JACC Review Topic of the Week, J Am Coll Cardiol. 2022 Aug, 80 (9) 934–946
  4. Kronenberg F. et al, Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement, European Heart Journal, Volume 43, Issue 39, 14 October 2022, Pages 3925–3946
  5. Simony SB, Mortensen MB, Langsted A, Afzal S, Kamstrup PR, Nordestgaard BG. Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: The Copenhagen General Population Study. Atherosclerosis. 2022 Aug;355:76-82. doi: 10.1016/j.atherosclerosis.2022.06.1023. Epub 2022 Jun 27. PMID: 35803767.
  6. Mehta A, Jain V, Saeed A, Saseen JJ, Gulati M, Ballantyne CM, Virani SS. Lipoprotein(a) and ethnicities. Atherosclerosis. 2022 May;349:42-52. doi: 10.1016/j.atherosclerosis.2022.04.005. PMID: 35606075. 
  7. Kostner KM, Kostner GM. Lipoprotein (a): a historical appraisal. J Lipid Res. 2017 Jan;58(1):1-14. doi: 10.1194/jlr.R071571. Epub 2016 Nov 7. PMID: 27821413; PMCID: PMC5234731.
  8. Koschinsky ML et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol. 2024 May-Jun;18(3):e308-e319. doi: 10.1016/j.jacl.2024.03.001.
  9. Cao J, Donato L, El-Khoury JM, Goldberg A, Meeusen JW, Remaley AT. ADLM guidance document on the measurement and reporting of lipids and lipoproteins. J Appl Lab Med 2024;9:1040-56 

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