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

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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://www.randox.com/lipoprotein-a or email: reagents@randox.com  


Lipoprotein(a) Foundation commend celebrity personal trainer, Bob Harper, as he speaks out about the risk of Lp(a)

The Lipoprotein(a) Foundation have commended health and fitness expert Bob Harper for speaking out after recently suffering a heart attack. The celebrity personal trainer and host of the US television series ‘The Biggest Loser’, has revealed that high levels of Lp(a) were responsible for the heart attack he suffered at the age of 51 at the beginning of this year.1

Harper had been completing a normal workout at his gym when he suffered full cardiac arrest. Luckily, two doctors were in the vicinity who saved his life by performing CPR and using an Automated External Defibrillator (AED). In an interview following his heart attack, Harper has said,

“I’ve learned a lot about the fact genetics does play a part in this, it is so important to know your health… I’m a guy that lives a very healthy lifestyle, very regimented, I work out all the time, but there were things going on inside of my body that I needed to be more aware of and I strongly encourage anyone that’s listening right now to go to their doctor, get their cholesterol checked, see what’s going on on the inside”.

Scroll down to watch the interview in full.

What is Lp(a)?

Lp(a) is a particle which is produced in the liver and found in the blood which carries cholesterol, fats and proteins. Levels of Lp(a) in individuals are genetically determined, and are not affected by diet, exercise or lifestyle changes.2

So how does a seemingly fit and healthy person have a heart attack at the age of 51?

Lp(a) is currently the strongest inherited risk factor for heart attack and stroke, with one in five people globally inheriting high Lp(a).1 Levels of Lp(a) are not routinely tested in standard cardiovascular assessments, and despite the particle itself being an altered form of LDL cholesterol, standard cholesterol tests do not reveal inherited Lp(a) levels as it is independent from total cholesterol and LDL levels.3

High Lp(a) can also be unrelated to other common risks factors of cardiovascular diseases for example, smoking, diet, diabetes, high blood pressure and lack of exercise. This is why seemingly healthy individuals can have high Lp(a) in their genes and still be at high risk of cardiovascular diseases.

Why is Lp(a) not routinely measured if high levels pose such a risk?

The widespread use of Lp(a) as an independent risk factor for cardiovascular disease risk has, until recently, been hindered by the lack of internationally accepted standardisation and the fact that many commercial Lp(a) methods suffer from apo(a) size related bias, potentially leading to patient misclassification.

The size of the apo(a) protein is genetically determined and varies widely hence, levels of Lp(a) can vary up to 1000-fold between individuals.4 To find out more about the clinical significance of Lp(a), please refer to the section below entitled ‘For Health Professionals’.

What can you do if you have high Lp(a)?

Research has shown that lowering Lp(a) could significantly reduce the impact of cardiovascular diseases. A recent study published in the American Heart Association journal, Arteriosclerosis, Thrombosis and Vascular Biology, found that reducing high Lp(a) could potentially prevent up to 1 in 14 cases of myocardial infarction (heart attack) and 1 in 7 cases of aortic valve stenosis.5 Of those studied, nearly one third of heart attacks and half of all cases of aortic stenosis were attributed to high Lp(a).6 This study demonstrates the clinical significance of measuring Lp(a), making it a major independent genetic risk factor for cardiovascular diseases.

Why test Lp(a)?

Lp(a) will be tested as part of a lipid profile if: there is a strong family history of CVD, a patient has existing heart or vascular diseases, a patient has an inherited predisposition for high cholesterol or if a person has had a stroke or heart attack but has normal lipid levels.7

Dr Christie Ballantyne, Chief of Cardiology at Baylor College of Medicine, has said “the most important part of knowing your Lp(a) level is understanding your overall risk and finding the right lifestyle modifications or medications to target all the other traditional risk factors. Those risk factors become even more important to monitor when your Lp(a) levels are high”.8

For patients

If you are concerned that you may be at risk of having elevated levels of Lp(a) due to your family history, ask your doctor or medical provider to test lipoprotein (a), along with other lipid tests, to clinically evaluate your risk of developing cardiovascular diseases.

For health professionals

Click below for information regarding the challenges associated with the measurement of Lp(a) and the clinical significance it holds.

The widespread use of Lp(a) as an independent risk factor for cardiovascular disease risk has, until recently, been impeded by the lack of internationally accepted standardisation and the fact that many commercial Lp(a) methods suffer from apo(a) size related bias, potentially leading to patient misclassification. The size of the apo(a) protein is genetically determined and varies widely hence, levels of Lp(a) can vary up to 1000-fold between individuals.4 

As a result, international criteria has been set to overcome these challenges. The International Federation of Clinical Chemistry (IFCC) Working Group on Lp(a) recommends that laboratories use assays which do not suffer from apo(a) size-related bias, in order to minimise the potential risk of misclassification of patients for coronary heart disease. The Lipoprotein(a) Foundation has referenced Marcovina and Albers (2016) as their recommendation for the best Lp(a) test.9 This recommendation is a result of the following conclusions:

  • Robust assays based on the Denka method are available, which are reported in nanomoles per litre (nmol/L) and are traceable to WHO/IFCC reference material
  • Five point calibrators with accuracy assigned target values will minimise the sensitivity to apo(a) size

A number of guidelines are in place for the testing of Lp(a) in patients.

-The European Guidelines for Management of Dyslipidaemia state that Lp(a) should be measured in individuals considered at high risk of CVD or with a strong family history of premature CVD.

-The European Atherosclerotic Society suggest that Lp(a) should be measured once in all subjects at intermediate or high risk of CVD/CHD who present with10 :

1. Premature CVD
2. Family hypercholesterolaemia
3. A family history of premature CVD and/or elevated Lp(a)
4. Recurrent CVD despite statin treatment
5.
≥3% 10-year risk of fatal CVD according to the European guidelines
6.  ≥10% 10-year risk of fatal and/or non-fatal CHD according to the US guidelines

-EAS Consensus Panel states the evidence clearly supports Lp(a) as a priority for reducing cardiovascular risk, beyond that associated with LDL cholesterol.  Clinicians should consider screening statin-treated patients with recurrent heart disease, in addition to those considered at moderate to high risk of heart disease.

  • 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 therefore suffers minimal size related bias – providing more accurate and consistent results. The Randox Lp(a) kit is standardised to the WHO/ IFCC reference material SRM 2B and is closest in terms of agreement to the ELISA reference method.
  • Five calibrators with accuracy-based assigned target values are provided – which accurately reflect the heterogeneity of isoforms present in the general population
  • Measuring units available in nmol/L upon request
  • Highly sensitive and specific – method for Lp(a) detection in serum and plasma
  • Applications are available for a wide range of biochemistry analysers – which detail instrument-specific settings for the convenient use of Randox Lp(a) on a variety of systems
  • Liquid ready-to-use reagents – for convenience and ease-of-use

For further information on Lp(a), click here or email: reagents@randox.com

Watch the interview with Bob Harper here:

1. Lipoprotein(a) Foundation, Lipoprotein(a) Foundation Thanks Bob Harper for Revealing High Lp(a) Levels Led to His Recent Heart Attack on The Dr Oz Show, 2017 Available from: http://www.businesswire.com/news/home/20170425006724/en/ [Accessed: 16 March 2017]

2. Lipoprotein Foundation, Understand Inherited Lipoprotein (a), Available from: https://goo.gl/bH5A8R [Accessed: 16 March 2017]

3. Kumar, V., Abbas, A. K. and Aster, J. C., Robbins and Cotran Pathologic Basic of Disease, (Philadelphia: Elsevier Saunders, 2015), p. 494 in Google books, https://goo.gl/VEnVX9 [Accessed 27th April 2017]

4. Kamstrup P.R., Tybjaerg-Hansen A., Steffensen R., Nordestgaard B.G. Genetically elevated lipoprotein (a) and increased risk of myocardial infarction. JAMA. Vol. 301, p. 2331-2339 (2009).

5. Afshar, M. Kamstrup, P.R., Williams, K., Snidermann, A. D., Nordestgaard, B.G., Thanassoulis, G., Estimating the Population Impact of Lp(a) Lowering on the Incidence of Myocardial Infarction and Aortic Stenosis – Brief Report., Ateriosclerosis, Thrombosis, and Vascular Biology, 2016;36:2421-2423, Available from: http://doi.org/10.1161/ATVBAHA.116.308271

6. The Lipoprotein(a) Foundation, Lipoprotein(a) Foundation Supports National Heart Valve Disease Month, Highlights Genetic Link between Lp(a) and Aortic Valve Disease, Business Wire. (2017), Available from: https://goo.gl/LhQFGj [Accessed: 16 March 2017]

7. Lab Tests Online, Lp(a), 2014, Available from: https://goo.gl/W2PWSN [Accessed: 16 March 2017]

8.Gutierrez, G., The heart attack risk factor you haven’t heard of, Baylor College of Medicine, 2017, Available from: https://goo.gl/9X4Xko [Accessed: 16 March 2017]

9. Marcovina, S.M. and Albers, J.J. Lipoprotein (a) measurements for clinical application. Lipid Res. Vol. 57, p. 526-37 (2016).

10. Nordestgaard, B. G., Chapman, M. J., Ray, K., Bore´n, J., Andreotti, F., Watts, G. F., Ginsberg, H., Amarenco, P., Catapano, A., Descamps, O. S., Fisher, E., Kovanen, P. T., Kuivenhoven, J. A., Lesnik, P., Masana, L., Reiner, Z., Taskinen, M. R., Tokgozoglu, L., and Tybjærg-Hansen, A., for the European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. European Heart Journal. Vol. 23, p. 2844-2853 (2010).

lipoprotein(a)


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