Lp(a): For the Accurate Detection of CVD Risk

Lp(a) is an independent risk factor for cardiovascular disease (CVD), even when classical risk factors such as hypertension, elevated cholesterol, and diabetes have been taken into consideration.  High levels of Lp(a) is a heredity condition, associated with complex mechanisms involving the proatherogenic and prothrombotic pathways (1).

 

Traditional CVD testing panel

According to the World Health Organisation (WHO), CVD is the leading cause of death globally, accounting for 31 percent of deaths, totalling 17.7 million deaths per year.  80 percent of all CVD deaths are attributed to heart attacks and strokes, equivalent to 1 in 4.  Identifying those who are at a high risk of developing CVD and ensuring that they are receiving the appropriate treatment can prevent premature deaths (2).

The lipid profile is frequently used to assess an individual’s risk of CVD developing later in life.  Routine tests to assess CVD risk include: triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).  LDL-C has been found to strongly correlate with CVD risk (3).  NICE recommend measuring total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides as the full lipid profile and then review other risk factors, including: age, diet, smoking, QRISK, co-morbidities to view risk and the management of risk (4).  However, the current lipid panel needs to be adjusted to ensure that its utilisation is effective in meeting clinician and patient needs.

 

Lipoprotein(a)

Lipoprotein (a) or Lp(a) consists of two protein molecules, apolipoprotein (a) or apo(a) is covalently linked by a disulphide bond to the apolipoprotein B-100 or apoB-100 of a cholesterol-rich low-density lipoprotein or LDL like particle.  Lp(a) is synthesised in the liver and is detectable in the bloodstream (5).

The structure of Lp(a) resembles that of the proteins involved in the breakdown of blood clots, plasminogen and tissue plasminogen activator (TPA).  As a result, the biggest concern with Lp(a) is that it prohibits the ability of these proteins to break down blood clots by competing for the ‘binding to fibrin’, boosting the blood’s clotting ability within arteries, thus heightening the risk of heart attacks and strokes.  Consequently, high levels of Lp(a) is characterised by atherosclerosis including coronary heart disease, peripheral vascular disease, aortic stenosis, thrombosis and stroke (6).

The Journal of the American Medical Association reviewed 36 studies in 2009 which assessed ‘the role of Lp(a) and vascular disease’ in 126,634 individuals.  The study found that a 3.5-fold increase in Lp(a) levels was accompanied with a 13 percent higher risk of coronary heart events and a 10 percent higher risk of stroke (7).

Later, an Italian population study carried out on 826 individuals in 2014 found that elevated levels of Lp(a) is due to two different variations of the apo(a) gene which is determined by the kringle sequence differences at the apo(a) locus.  The study found that individuals with one variation had a 50 percent greater risk of CVD, while individuals with both variations had 2.5 times greater risk (7).

According to the Lipoprotein Foundation (2015), based on genetic factors, from birth, one in five or 20% of individuals have high Lp(a) levels greater than 50mg/dL, with most blissfully unaware they have it.  Overtime, high levels of Lp(a) gradually narrow the arteries, limiting blood supply to the brain, heart, kidneys and legs, increasing the risk of heart attacks and strokes (5).

 

Testing for high Lp(a) levels

The Lipoprotein (a) Foundation (2015) recommends that Lp(a) levels should be tested if:

  • There is a family history of cardiovascular disease including stroke, heart attack, circulation problems in the legs and/or narrowing of the aorta, at a young age
  • Stroke or heart attack if classical risk factors including high LDL-cholesterol, obesity, diabetes and smoking have been eliminated
  • High levels of LDL-cholesterol following treatment with statins or other LDL lowering medications(5)

When selecting a Lp(a) assay, the Internal Federation of Clinical Chemistry (IFCC) (2004) Working Group on Lp(a) recommends that laboratories use assays that do not suffer from apo(a) size-related bias to minimise the potential risk of misclassification of patients for coronary heart disease (8).

The Lp(a) Foundation reference Marcovina and Albers (2016) in their recommendations for the best Lp(a) test.  The study came to the following conclusions:

  • Robust assays based on the Denka method, reportable in nanomoles per litre (nmol/L) are traceable to WHO/IFCC reference material
  • Five-point calibrators with accuracy-based assigned target values will minimise the sensitivity of to the size of apo(a)
  • Upon request, manufacturers should provide the certificate of evaluation of the calibrator and reagent lots with the relative expiration dates (9)

 

Benefits of the Randox Lp(a) assay

The Randox Lp(a) assay is one of the only methodologies on the market that detects the non-variable part of the Lp(a) molecule and so suffers minimal size related bias providing more accurate and consistent results.  This methodology allows for the detection of Lp(a) in serum and plasma.  The Randox Lp(a) kit is standardized to the WHO/IFCC reference material, SRM 2B, and is the closest in terms of agreement to the ELISA reference method.

A five-point calibrator is provided with accuracy-based assigned target values which accurately reflects the heterogeneity of isoforms present in the general population.

Liquid ready-to-use reagents are more convenient as the reagent does not need to be reconstituted, reducing the risk of errors.

Applications are available for a wide range of biochemistry analysers which details instrument-specific settings for the convenient use of the Randox Lp(a) assay on a variety of systems.  Measuring units in nmol/L are available upon request.

 

References

  1. Li, Yonghong, et al. Genetic Variants in the Apolipoprotein(a) Gene and Coronary Heart Disease. Circulation: Genomic and Precision Medicine. [Online] October 2011. [Cited: April 24, 2018.] http://circgenetics.ahajournals.org/content/4/5/565.
  2. World Health Organisation. Cardiovascular Disease. [Online] 2017. [Cited: April 30, 2018.] http://www.who.int/cardiovascular_diseases/en/.
  3. Doc’s Opinion. Lipoprotein (a). [Online] 2013. [Cited: April 30, 2018.] https://www.docsopinion.com/health-and-nutrition/lipids/lipoprotein-a/.
  4. National Institutional for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. [Online] July 2014. [Cited: April 30, 2018.] https://www.nice.org.uk/guidance/cg181/chapter/1-recommendations#lipid-modification-therapy-for-the-primary-and-secondary-prevention-of-cvd-2.
  5. Lipoprotein(a) Foundation. Understand Inherited Lipoprotein(a). [Online] 2015. [Cited: April 24, 2018.] http://www.lipoproteinafoundation.org/?page=UnderstandLpa.
  6. Heart UK. Lipoprotein (a). [Online] June 23, 2014. [Cited: April 24, 2018.] https://heartuk.org.uk/files/uploads/huk_fs_mfss_lipoprotein_02.pdf.
  7. Ashley, Robert. High lipoprotein(a) levels may indicate heart disease in some. The Brunswick News. [Online] March 05, 2018. [Cited: April 24, 2018.] https://thebrunswicknews.com/opinion/advice_columns/high-lipoprotein-a-levels-may-indicate-heart-disease-in-some/article_16ab1049-7a6f-5da0-8966-59e94ae31b6d.html.
  8. Dati, F; Tate, J R; Marcovina, S M; Steinmetz, A; International Federation of Clinical Chemistry and Laboratory Medicine; IFCC Working Group for Lipoprotein(a) Assay Standardization. First WHO/IFCC International Reference Reagent for Lipoprotein(a) for Immunoassay–Lp(a) SRM 2B. NCBI. [Online] 2004. [Cited: April 30, 2018.] https://www.ncbi.nlm.nih.gov/pubmed/15259385.
  9. Tsimikas, Sotirios. A Test in Context: Lipoprotein(a) – Diagnosis, Prognosis, Controversies, and Emergining Therapies. 6, s.l. : Elsevier, 2017, Vol. 69. 0735-1097.

If you are a cardiologist or a laboratory who are interested in running cardiology and lipid assays, Randox offer a wide range of high-quality, routine and niche assays including: adiponectin, H-FABP, sLDL, TxBCardio, HDL2/3-C, Homocysteine, Apo C-II, Apo C-III and Apo E.  These can be run on most automated biochemistry analysers.

Instrument Specific Applications (ISA’s) are available for a wide range of biochemistry analysers.

For more information, visit: https://dev.randox.com/lipoprotein-a or email: reagents@randox.com  


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